ATM kinase inhibitors and compositions and methods of their use

Abstract

Certain ATM kinase inhibitors are provided according to formula (I). Also provided herein are compositions of such compounds and methods of their use. TIFF2023505485000275.tif31160

Description

[Technical Field]

[0001] Cross-reference to related patent applications This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 943,694, filed December 4, 2019, which is incorporated herein by reference in its entirety.

[0002] Provided herein are certain inhibitors of ataxia telangiectasia mutated ("ATM") kinase, their compositions, and methods of their use. [Background technology]

[0003] ATM is a serine / threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins, which triggers activation of DNA damage checkpoints, leading to cell cycle arrest, DNA repair, or apoptosis. The protein was named for the disorder ataxia-telangiectasia, which is caused by mutations in ATM.

[0004] ATM plays a central role in maintaining genome integrity by regulating the detection and repair of DNA double-strand breaks. Genetic and pharmacological reduction of ATM signaling can ameliorate mutant huntingtin ("mHTT") toxicity in cell and animal models of Huntington's disease ("HD"). Furthermore, ATM kinase signaling has been shown to be altered in postmortem brains of HD patients. Therefore, selective inhibition of ATM may be a novel clinical intervention strategy for the treatment of HD. Therefore, inhibitors of ATM kinase are needed. Summary of the Invention

[0005] The present disclosure relates to compounds useful for inhibiting ATM kinase. Some embodiments include compounds of Formula I:

[0006] [ka] [In formula: Ring B is a heterocycloalkyl ring optionally having 1 to 3 additional heteroatoms selected from O, N, and S; X is CH or N; (i) Z is N and Y is -CH(R 1 )- or -CH2-; or (ii) ZY is -C=C(R 1 )- or -C=C(H)-; L is C optionally substituted with C alkoxy. 1~3 is alkylene; Each R 1 are independently C1-4 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy or C 3~6 is cycloalkyl; or two R's 1 together with the carbon atoms to which they are attached, combine to form a cycloalkyl ring; Each R 2 is selected from the group consisting of hydroxy, halo, C1-4 alkyl optionally substituted with C1-4 alkoxy, halo-C1-4 alkyl optionally substituted with C1-4 alkoxy, C1-4 alkoxy optionally substituted with cycloalkyl, halo-C1-4 alkoxy, C 3~6 Cycloalkyl, and C 3~6 independently selected from cycloalkoxy; or two R's 2 When present on the same carbon atom, they combine to form oxo; or two R's 2 together with the carbon atoms to which they are attached, join to form a ring optionally substituted with 1 to 3 halo; R 3 is H or -N(R 8 )(R 9 ), C1-4 alkoxy or C 3~6 C1-6 alkyl optionally substituted with cycloalkyl; R 4 is H or halo; R 5 is an aryl ring or a heteroaryl ring, each of which is 6 optionally substituted with; Each R 6 are independently halo, C1-6 alkyl, halo-C1-6 alkyl, or -OR 7 and; Each R 7 is independently selected from heterocycloalkyl and C1-6 alkyl optionally substituted with C1-4 alkoxy or halo; R 8 and R 9 are each independently selected from H and C alkyl; p is 0, 1, 2 or 3; m is 0, 1, 2 or 3. or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0007] Additionally, pharmaceutical compositions comprising a compound described herein or a deuterated analogue thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers, and a pharmaceutically acceptable carrier are also provided.

[0008] Also provided is a process for preparing a pharmaceutical composition, comprising admixing a compound described herein or a deuterated analogue thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers, and a pharmaceutically acceptable carrier.

[0009] Also provided is a method of treating a condition or disorder mediated by ATM kinase in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.

[0010] Detailed Description of the Invention definition The following description describes exemplary embodiments of the present technology, but it should be recognized that such description is not intended as a limitation on the scope of the present invention, but rather is provided as a description of exemplary embodiments.

[0011] As used herein, the following words, phrases, and symbols are generally intended to have the meanings set forth below, except to the extent that the context in which they are used herein indicates otherwise.

[0012] A dash ("-") that is not between two letters or two symbols is used to indicate a point of attachment for a substituent, for example, -C(O)NH2 is attached through a carbon atom.

[0013] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples where the event or circumstance occurs and examples where it does not occur. An "optionally substituted" group is one that may be unsubstituted with the group shown or defined. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl," as defined below. Those skilled in the art will understand that with respect to any group containing one or more substituents, it is not intended to introduce any substitution or substitution pattern that would make such group sterically impractical, synthetically infeasible, and / or inherently unstable.

[0014] "Alkyl" includes straight- and branched-chain hydrocarbon groups having the designated number of carbon atoms, usually 1 to 20 carbon atoms, e.g., 1 to 8 carbon atoms, e.g., 1 to 6 carbon atoms. For example, C1-C6 alkyl includes both straight- and branched-chain alkyls of 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and the like. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be included, so, for example, "butyl" includes n-butyl, sec-butyl, isobutyl, and t-butyl, and "propyl" is meant to include n-propyl and isopropyl.

[0015] The term "alkylene" encompasses straight- and branched-chain diradical hydrocarbon groups having the indicated number of carbon atoms, typically 1 to 20 carbon atoms, such as 1 to 8 carbon atoms, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms. For example, a C1 alkylene is a methylene group. Additional examples of C1-C4 alkylene include 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,1-butylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, 2-methyl-1,2-propylene, and 2-methyl-1,3-propylene.

[0016] "Alkoxy" means an alkyl group of the indicated number of carbon atoms attached through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. Alkoxy groups will typically have from 1 to 6 carbon atoms.

[0017] "Aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon atoms, e.g., 6 to 12 or 6 to 10 carbon atoms. Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, a polycyclic aryl group may contain a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to an aromatic ring, provided that the polycyclic aryl group is attached to the parent structure through an atom in the aromatic carbocyclic ring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (where the moiety is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, while a 1,2,3,4-tetrahydronaphthalen-1-yl group (where the moiety is attached to the parent structure through a non-aromatic carbon atom) is not considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (where the moiety is attached to the parent structure via an aromatic carbon atom) is considered an aryl group, while a 1,2,3,4-tetrahydroquinolin-1-yl group (where the moiety is attached to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl," as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some examples, aryl is phenyl or naphthyl. In certain examples, aryl is phenyl.

[0018] Divalent radicals formed from substituted benzene derivatives and having a free valence at a ring atom are named substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals by removing one hydrogen atom from the carbon atom having the free valence, whose names end in "-yl", are named by adding "-ydene" to the name of the corresponding monovalent radical; for example, a naphthyl group with two points of attachment is called a naphthylidene.

[0019] "Cycloalkyl" refers to a non-aromatic, fully saturated or partially unsaturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10, 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl, as well as bridged spirocyclic and caged ring groups (e.g., norbornane, bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkyl group can be aromatic, provided the polycyclic cycloalkyl group is attached to the parent structure through a non-aromatic carbon. For example, a 1,2,3,4-tetrahydronaphthalen-1-yl group (the moiety is attached to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, while a 1,2,3,4-tetrahydronaphthalen-5-yl group (the moiety is attached to the parent structure through an aromatic carbon atom) is not considered a cycloalkyl group; it is considered an aryl group.

[0020] "Cycloalkoxy" means a cycloalkyl group of the indicated number of carbon atoms attached through an oxygen atom. Examples include cyclopropoxy, cyclopentoxy, cyclohexoxy, and the like.

[0021] The term "halo" includes fluoro, chloro, bromo, and iodo, and the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0022] The term "haloalkyl" refers to a C alkyl group substituted with one halogen up to full substitution ("perhaloalkyl") groups. 1~6 Indicates an alkyl group. Fully substituted C 1~6 Haloalkyl is a group of formula C n L 2n+1where L is a halogen and "n" is 1, 2, 3, 4, 5, or 6; when more than one halogen is present, each halogen may be the same or different and is selected from the group consisting of F, Cl, Br, and I, e.g., F. 1~6 Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, perfluoropentyl, and the like.

[0023] The term "haloalkoxy" refers to a haloalkyl attached to the parent structure via an oxygen atom. Examples include, but are not limited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like.

[0024] "Heteroaryl" refers to an aromatic ring (e.g., a 5- to 12-membered or 5- to 10-membered heteroaryl) containing the indicated number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon. A heteroaryl group does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in a heteroaryl group is 1 or less. Unless otherwise indicated, a heteroaryl group may be attached to the parent structure by a carbon or nitrogen atom, valence permitting. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl groups, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl groups. When nitrogen is present in a heteroaryl ring, it may be in any oxidized state (i.e., N), if the nature of the adjacent atoms and groups permits. + -O - Additionally, when sulfur is present in a heteroaryl ring, it may be present in an oxidized state (i.e., S + -O -or SO2). Heteroaryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).

[0025] In some cases, the heteroaryl group is monocyclic. Examples include, but are not limited to, pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine), and tetrazine.

[0026] In some cases, both rings of the polycyclic heteroaryl group are aromatic. Examples include, but are not limited to, indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[3,4 ... H-Pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5 -c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,[4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole.

[0027] In other examples, a polycyclic heteroaryl group can include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided that the polycyclic heteroaryl group is attached to the parent structure through an atom in an aromatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (where the moiety is attached to the parent structure through an aromatic carbon atom) is considered a heteroaryl group, while a 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl group (where the moiety is attached to the parent structure through a non-aromatic carbon atom) is not considered a heteroaryl group.

[0028] "Heterocycloalkyl" refers to a non-aromatic saturated or partially unsaturated ring having the indicated number of atoms (e.g., 3- to 10-membered, or 3- to 7-membered heterocycloalkyl) containing one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon. The term "heterocycloalkyl" includes heterocycloalkenyl groups (i.e., heterocycloalkyl groups having at least one double bond) and includes one or more oxo (=O) or N-oxide (-O) groups. -) moieties. Heterocycloalkyl groups can be monocyclic (i.e., heteromonocyclic) or polycyclic (e.g., bicyclic (i.e., heterobicyclic), including spirocyclic and bridged ring systems). The definition of heterocycloalkyl encompasses ring systems in which the ring is 1,2- or 1,3-fused to another cycloalkyl or heterocycloalkyl ring (where a carbon or nitrogen atom can form the ring junction (where the structure is chemically feasible)), as well as ring systems in which the ring has a C1-C2 alkyl bridge, and ring systems in which the ring is 1,2-fused to an aromatic or heteroaromatic ring, provided that the moiety is attached to the parent structure through a non-aromatic carbon or nitrogen atom.

[0029] Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, 3-azabicyclo[3.1.0]hexan-3-yl, indolin-1-yl, isoindolin-2-yl, 1,2,3,4-tetrahydroquinolin-2-yl, 3,4-dihydroquinolin-1(2H)-yl, and 7,8-dihydro-1,6-naphthyridin-6(5H)-yl, 1-oxa-5-azaspiro[3.3]heptane- 5-yl, 1-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 1,5-diazaspiro[3.3]heptan-1-yl, 1,6-diazaspiro[3.3]heptan-6-yl, 1,6-diazaspiro[3.3]heptan-1-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 1-oxa-5-azaspiro[3.4]octan-5-yl, 1-oxa-6-azaspiro[3.4]octan-6-yl, 2-oxa -5-Azaspiro[3.4]octan-5-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 1,5-diazaspiro[3.4]octan-5-yl, 1,6-diazaspiro[3.4]octan-6-yl, 2,5-diazaspiro[3.4]octan-5-yl, 2,6-diazaspiro[3.4]octan-6-yl, 1-oxa-5-azaspiro[3.5]nonan-5-yl, 1-oxa-6-azaspiro[3.5]nonan-6-yl, 1-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-5-azaspiro[3.5] nonan-5-yl, 2-oxa-6-azaspiro[3.5]nonan-6-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 1,5-diazaspiro[3.5]nonan-5-yl, 1,6-diazaspiro[3.5]nonan-6-yl, 1,7-diazaspiro[3.5]nonan-7-yl, 2,5-diazaspiro[3.5]nonan-5-yl, 2,6-diazaspiro[3.5]nonan-6-yl, 2,7-diazaspiro[3.5]nonan-7-yl, 1-oxa-5-azaspiro[3.6]decan-5-yl, 1-oxa-6-azaspiro[3.6]decan-6-yl, 1-oxa-7-azaspiro[3.6]decan-7-yl, 2-oxa-5-azaspiro[3.6]decan-5-yl, 2-oxa-6-azaspiro[3.6]decan-6-yl, 2-oxa-7-azaspiro[3.6]decan-7-yl, 1,5-diazaspiro[3.6]decan-5-yl, 1,6-diazaspiro[3.6]decan-6-yl, 1,7-diazaspiro[3.6]decan-7-yl Examples include 2,5-diazaspiro[3.6]decan-5-yl, 2,6-diazaspiro[3.6]decan-6-yl, 2,7-diazaspiro[3.6]decan-7-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 2-azabicyclo[3.2.1]octan-2-yl, 3-azabicyclo[3.2.1]octan-3-yl, and 6-azabicyclo[3.2.1]octan-6-yl.

[0030] When nitrogen is present in a heterocycloalkyl ring, it may be present in any oxidation state (i.e., N + -O - ) Examples include pyridinyl N-oxide, piperidinyl N-oxide, and morpholinyl-N-oxide. Additionally, when sulfur is present in a heterocycloalkyl ring, it may be present in any oxidized state (i.e., S + -O - or -SO2-). Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide.

[0031] "Solvate" refers to an association or complex of one or more solvent molecules and a compound described herein. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0032] "Prodrug" refers to any compound that releases an active parent drug in vivo according to the structures described herein when such prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds described herein in such a way that the modification can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in the compounds described herein in such a way that the modification can be cleaved, either by routine manipulation or in vivo, to release the parent compound. Prodrugs include compounds described herein in which a hydroxy, amino, carboxyl, or sulfhydryl group in the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives at hydroxy groups), amides (e.g., at amino groups), guanidines (e.g., at amino groups), carbamates (e.g., N,N-dimethylaminocarbonyl at hydroxy groups), and the like, derived from functional groups in the compounds described herein. The preparation, selection and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14; "Design of Prodrugs," edited by H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0033] The term "substituted," as used herein, means that any one or more hydrogens on the designated atom or group are replaced with a moiety from the indicated group, provided that the valence of the atom is not exceeded. When the substituent is oxo (i.e., =0), two hydrogen atoms on the atom are replaced. A substitution is acceptable only if it results in a stable compound or a useful synthetic intermediate. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture and subsequent formulation as a pharmaceutical agent having at least practical utility. When (cycloalkyl)alkyl is listed as a possible substituent, it is to be understood that the point of attachment of this substituent to the core structure is within the alkyl portion.

[0034] The terms "substituted" alkyl (including, without limitation, C1-C4 alkyl), cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, unless expressly defined otherwise, refer to a group in which one or more (e.g., up to five, e.g., up to three) hydrogen atoms have been replaced with -R a , -OR b , —O(C1-C2 alkyl)O— (e.g., methylenedioxy-), —SR b , guanidine (-NHC(=NH)NH2), guanidine in which one or more of the guanidine hydrogens are replaced with a C1-C4 alkyl group, -NR b R c , halo, cyano, oxo (as a substituent for heterocycloalkyl), nitro, -COR b , -CO2R b , -CONR b R c , -OCOR b , -OCO2R a , -OCONR b R c , -NR c COR b , -NR c CO2R a , -NR c CONR b R c , -SOR a , -SO2Ra , -SO2NR b R c and -NR c SO2R a and R are each substituted by a substituent independently selected from alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, a is selected from C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; R b is selected from H, C1-C6 alkyl, aryl, and heteroaryl; R c is selected from hydrogen and C1-C4 alkyl; or R b and R cand the nitrogen to which they are attached form a heterocycloalkyl group; wherein each of C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl is C1-C4 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl-, —O-C4 alkyl, —O-C4 alkylphenyl, —C1-C4 alkyl-OH, —C1-C4 alkyl-O—C1-C4 alkyl, —O-C4 haloalkyl, halo, —OH, —NH, —C1-C4 alkyl-NH, —N(C1-C4 alkyl)(C1-C4 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkylphenyl), —NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for heteroaryl), —CO2H , -C(O)OC1~C4 alkyl, -CON(C1~C4 alkyl)(C1~C4 alkyl), -CONH(C1~C4 alkyl), -CONH2, -NHC(O)(C1~C4 alkyl), -NHC(O)(phenyl), -N(C1~C4 alkyl)C(O)(C1~C4 alkyl), -N(C1~C4 alkyl)C(O)(phenyl), -C(O)C1~C4 alkyl, -C(O)C1~C4 phenyl, -C(O)C1~C4 haloalkyl , -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SON2NH2, -SON2NH(C1-C4 alkyl), -SON2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl).

[0035] "Stereoisomer" refers to one of a series of compounds composed of the same atoms connected by the same bonds but having different, non-interchangeable three-dimensional structures. The term "enantiomer" refers to one of a pair of stereoisomers that are non-superimposable mirror images of each other. A compound depicted as a single stereoisomer is intended to encompass a mixture of stereoisomers. In particular, asymmetric ("chiral") carbon centers may be enriched or racemic mixtures with respect to each such center in the compound.

[0036] The compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures. In such situations, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high-pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) column. Additionally, such compounds include Z and E forms (or cis and trans forms) of compounds with carbon-carbon double bonds. If the compounds described herein exist in various tautomeric forms, the term "compound" is intended to include all tautomeric forms of the compound. Such compounds also include crystalline forms, including polymorphs and clathrates. Similarly, the term "salt" of a compound is intended to include all tautomeric and crystalline forms of the salt of the compound.

[0037] "Pharmaceutically acceptable salts" include, but are not limited to, salts with inorganic acids, such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and the like; and salts with organic acids, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoates, such as acetate, HOOC-(CH2) q-COOH, where q is 0 to 4, and similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0038] In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0039] As used herein, the terms "group," "radical," or "fragment" are intended to be synonymous and denote moieties or fragments that can be attached by a bond.

[0040] The present disclosure includes all isotopes of atoms occurring in the compounds described herein and their pharmaceutically acceptable salts. Isotopes include those atoms having the same atomic number but different mass numbers. The present disclosure also includes any combination of one or more atoms in the compounds described herein and their pharmaceutically acceptable salts, which are replaced with an atom having the same atomic number but different mass number. One such example is the most naturally abundant isotope found in one of the compounds described herein and their pharmaceutically acceptable salts, e.g., 1 H or 12 Replacement of an atom that is C with a different atom that is not the most naturally abundant isotope, e.g., 1 Replaced by H 2 H (i.e., deuterium) or 3 H, or 12 Replaced by C 11 C. 13 C or 14C. Compounds with such replacements are commonly referred to as isotopically labeled. The isotopically labeled compounds described herein and their pharmaceutically acceptable salts can generally be prepared by following procedures similar to those disclosed in the Examples below, by substituting a non-isotopically labeled reagent for the isotopically labeled reagent. Compounds in which one or more hydrogen atoms are replaced by deuterium atoms are termed "deuterated analogs" of the compounds.

[0041] Thus, the compounds described herein are intended to encompass deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers thereof.

[0042] The term "therapeutically effective amount" means an amount that, when administered to a human or non-human patient, is effective to provide a therapeutic benefit, e.g., amelioration of symptoms, slowing of disease progression, or prevention of disease; for example, a therapeutically effective amount can be an amount sufficient to reduce the symptoms of a disease responsive to inhibition of ATM activity.

[0043] As used herein, the terms "ATM," "ATM kinase," or "ATM serine / threonine kinase" and "ataxia telangiectasia mutated protein" refer to a 350 kDa protein consisting of 3056 amino acids belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family. ATM and its isoforms have sequences according to NP_000042, NP_000042.3, NP_001338763, NP_001338764, NP_001338765, and NP_031525. ATM kinase plays a role in cell cycle delay after DNA damage, especially after double-strand breaks (DSBs).

[0044] The terms "ATM inhibitor" and "inhibitor of ATM" are intended to mean a compound described herein or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof that is capable of interacting with ATM kinase and inhibiting its enzymatic activity.

[0045] The term "condition or disorder mediated by ATM," as used herein, refers to a condition or disorder in which ATM and / or the actions of ATM are important or necessary, for example, for the initiation, progression, development, etc. of the condition, or a condition known to be treated by an ATM inhibitor.

[0046] The term "inhibiting ATM enzymatic activity" is intended to mean reducing the enzymatic activity of ATM. Enzymatic activity can include phosphorylation of a target protein. The concentration of an inhibitor that reduces the activity of the ATM protein to 50% of the activity of the uninhibited enzyme is called the IC 50 In some embodiments, such reduction in ATM protein activity is at least 50%, e.g., at least about 75%, e.g., at least about 90%. In some embodiments, ATM protein activity is reduced by at least 95%, e.g., at least 99%. In some embodiments, the compounds described herein and pharmaceutically acceptable salts thereof have an IC50 of less than 100 nanomolar. 50 In some embodiments, the compounds described herein and pharmaceutically acceptable salts thereof have an IC value of 100 nanomolar to 1 micromolar. 50 In some embodiments, the compounds described herein and pharmaceutically acceptable salts thereof have an IC value of 1 micromolar to 25 micromolar. 50 It has a value.

[0047] "Treatment" or "treating" means a) To prevent the disease, i.e., to prevent the clinical symptoms of the disease from developing; b) inhibiting the disease; c) slowing or halting the onset of clinical symptoms; and / or d) To alleviate the disease, i.e., to cause regression of clinical symptoms By "treatment" is meant any treatment of a disease state in a patient, including

[0048] "Subject" or "patient" refers to an animal, e.g., a mammal, who is or will be the object of treatment, observation, or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0049] A compound described herein refers to any compound of Formula I, Formula II, Formula II(a), Formula II(b), Formula II(a)(i), Formula II(a)(ii), Formula II(b)(i), Formula II(b)(ii), Formula III, Formula III(a), Formula III(b), Formula III(a)(i), Formula III(a)(ii), Formula III(b)(i), Formula III(b)(ii) or Formula IV or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof, or a compound of the Examples, or a compound of Table 1.

[0050] It should be understood that certain features described herein, for clarity, in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features described herein, for brevity, that are described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. All combinations of embodiments relating to chemical groups represented by variables contained within Formula I, to the extent that such combinations include compounds that result in stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), are specifically embraced by this specification as if each and every combination were individually and expressly recited. In addition, all subcombinations of chemical groups listed in embodiments describing such variables, and all subcombinations of uses and medical applications described herein, e.g., conditions or disorders mediated by ATM kinase, are also specifically embraced by this specification as if each and every subcombination of chemical groups and subcombinations of uses and medical applications were individually and expressly recited herein. In addition, some embodiments include any and all combinations of one or more additional agents disclosed herein, as if each and every combination were individually and expressly listed.

[0051] [Table 1] TIFF0007727627000003.tif125162

[0052] compound Provided herein are compounds of formula I:

[0053] [ka] [In formula: Ring B is a heterocycloalkyl ring optionally having 1 to 3 additional heteroatoms selected from O, N, and S; X is CH or N; (i) Z is N and Y is -CH(R 1 )- or -CH2-; or (ii) ZY is -C=C(R 1 )- or -C=C(H)-; L is C optionally substituted with C alkoxy. 1~3 is alkylene; Each R 1 are independently C1-4 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy or C 3~6 is cycloalkyl; or two R's 1 together with the carbon atoms to which they are attached, combine to form a cycloalkyl ring; Each R 2 is selected from the group consisting of hydroxy, halo, C1-4 alkyl optionally substituted with C1-4 alkoxy, halo-C1-4 alkyl optionally substituted with C1-4 alkoxy, C1-4 alkoxy optionally substituted with cycloalkyl, halo-C1-4 alkoxy, C 3~6 Cycloalkyl, and C 3~6 independently selected from cycloalkoxy; or two R's 2 When present on the same carbon atom, they combine to form oxo; or two R's 2 together with the carbon atoms to which they are attached, join to form a ring optionally substituted with 1 to 3 halo; R 3 is H, or -N(R 8 )(R 9 ), C1-4 alkoxy or C 3~6 C1-6 alkyl optionally substituted with cycloalkyl; R 4 is H or halo; R 5 is an aryl ring or a heteroaryl ring, each of which is 6 optionally substituted with; Each R 6are independently halo, C1-6 alkyl, halo-C1-6 alkyl, or -OR 7 and; Each R 7 is independently selected from heterocycloalkyl and C1-6 alkyl optionally substituted with C1-4 alkoxy or halo; R 8 and R 9 are each independently selected from H and C alkyl; p is 0, 1, 2 or 3; m is 0, 1, 2 or 3. or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0054] In some embodiments, provided is a compound of formula II:

[0055] [ka] [In formula: X is CH or N; (i) Z is N and Y is -CH(R 1 )- or -CH2-; or (ii) ZY is -C=C(R 1 )- or -C=C(H)-; L is C optionally substituted with C alkoxy. 1~3 is alkylene; Each R 1 are independently C1-4 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy or C 3~6 is cycloalkyl; or two R's 1 together with the carbon atoms to which they are attached, combine to form a cycloalkyl ring; Each R 2is selected from the group consisting of hydroxy, halo, C1-4 alkyl optionally substituted with C1-4 alkoxy, halo-C1-4 alkyl optionally substituted with C1-4 alkoxy, C1-4 alkoxy optionally substituted with cycloalkyl, halo-C1-4 alkoxy, C 3~6 Cycloalkyl, and C 3~6 independently selected from cycloalkoxy; or two R's 2 When present on the same carbon atom, they combine to form oxo; or two R's 2 together with the carbon atoms to which they are attached, join to form a ring optionally substituted with 1 to 3 halo; R 3 is H, or -N(R 8 )(R 9 ), C1-4 alkoxy or C 3~6 C1-6 alkyl optionally substituted with cycloalkyl; R 4 is H or halo; R 5 is an aryl ring or a heteroaryl ring, each of which is 6 optionally substituted with; Each R 6 are independently halo, C1-6 alkyl, halo-C1-6 alkyl, or -OR 7 and; Each R 7 is independently selected from heterocycloalkyl and C1-6 alkyl optionally substituted with C1-4 alkoxy or halo; R 8 and R 9 are each independently selected from H and C alkyl; p is 0, 1, 2 or 3; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4. or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0056] In some embodiments, the compound of Formula II has the formula II(a):

[0057] [ka] or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0058] In some embodiments, the compound of Formula II has Formula II(b):

[0059] [ka] or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0060] In some embodiments, the compound of Formula II has the formula II(a)(i):

[0061] [ka] TIFF0007727627000009.tif8161 or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0062] In some embodiments, the compound of Formula II has the formula II(a)(ii):

[0063] [ka] or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0064] In some embodiments, the compound of Formula II has the formula II(b)(i):

[0065] [ka] or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0066] In some embodiments, the compound of Formula II has the formula II(b)(ii):

[0067] [ka] or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0068] Also provided is a compound of formula III:

[0069] [ka] [In formula: X is CH or N; (i) Z is N and Y is -CH(R 1 )- or -CH2-; or (ii) ZY is -C=C(R 1 )-and; R 1 is H, C1-4 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy or C 3~6 is cycloalkyl; or two R's 1 together with the carbon atoms to which they are attached, combine to form a cycloalkyl ring; Each R 2 is selected from the group consisting of hydroxy, halo, C1-4 alkyl optionally substituted with C1-4 alkoxy, halo-C1-4 alkyl optionally substituted with C1-4 alkoxy, C1-4 alkoxy optionally substituted with cycloalkyl, halo-C1-4 alkoxy, C 3~6 Cycloalkyl, and C 3~6independently selected from cycloalkoxy; or two R's 2 When present on the same carbon atom, they combine to form oxo; or two R's 2 together with the carbon atoms to which they are attached, join to form a ring optionally substituted with 1 to 3 halo; R 3 is H, or -N(R 8 )(R 9 ), C1-4 alkoxy or C 3~6 C1-3 alkyl optionally substituted with cycloalkyl; R 4 is H or halo; R 5 is an aryl ring or a heteroaryl ring, each of which is 6 optionally substituted with; Each R 6 are independently halo, C1-6 alkyl, halo-C1-6 alkyl, or -OR 7 and; Each R 7 is independently selected from heterocycloalkyl and C1-6 alkyl optionally substituted with C1-4 alkoxy or halo; R 8 and R 9 are each independently selected from H and C alkyl; R 10 and R 11 are each independently selected from H or C alkyl; p is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4. or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0070] In some embodiments, the compound of Formula III has the formula III(a):

[0071] [ka] or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0072] In some embodiments, the compound of Formula III has Formula III(b):

[0073] [ka] or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0074] In some embodiments, the compound of Formula III has the formula III(a)(i):

[0075] [ka] or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0076] In some embodiments, the compound of Formula III has the formula III(a)(ii):

[0077] [ka] or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0078] In some embodiments, the compound of Formula III has the formula III(b)(i):

[0079] [ka] or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0080] In some embodiments, the compound of Formula III has the formula III(b)(ii):

[0081] [ka] or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0082] Also provided is a compound of formula IV:

[0083] [ka] [In formula: X is CH or N; R 1 is H or C1-3 alkyl; Each R 2 is selected from the group consisting of hydroxy, halo, C1-4 alkyl optionally substituted with C1-4 alkoxy, halo-C1-4 alkyl optionally substituted with C1-4 alkoxy, C1-4 alkoxy optionally substituted with cycloalkyl, halo-C1-4 alkoxy, C 3~6 Cycloalkyl, and C 3~6 independently selected from cycloalkoxy; or two R's 2 When present on the same carbon atom, they combine to form oxo; or two R's 2 together with the carbon atoms to which they are attached, join to form a ring optionally substituted with 1 to 3 halo; R 3 is H or C1-3 alkyl; R 4 is H or halo; R 5 is an aryl ring or a heteroaryl ring, each of which is 6 optionally substituted with; Each R 6are independently halo, C1-6 alkyl, halo-C1-6 alkyl, or -OR 7 and; Each R 7 is independently selected from heterocycloalkyl and C1-6 alkyl optionally substituted with C1-4 alkoxy or halo; R 10 and R 11 are each independently selected from H or methyl; p is 0, 1, 2 or 3; n is 2, 3 or 4. or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0084] In some embodiments, m is 1 and R 1 is methyl.

[0085] In some embodiments, m is 0.

[0086] In some embodiments, R 1 is H or methyl. In some embodiments, R 1 is methyl.

[0087] In some embodiments, R 1 is H.

[0088] In some embodiments, R 3 is H or methyl.

[0089] In some embodiments, R 3 is H.

[0090] In some embodiments, R 4 is H or fluoro.

[0091] In some embodiments, R 5 is 1 to 3 R 6 is aryl optionally substituted with

[0092] In some embodiments, R 5 is aryl.

[0093] In some embodiments, R 5 is phenyl.

[0094] In some embodiments, R 5 is 1 to 3 R 6 is phenyl optionally substituted with

[0095] In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0096] In some embodiments, two R 2 taken together with the carbon atoms to which they are attached, join to form a ring that is optionally substituted with 1 to 3 halo. In some embodiments, the ring is a saturated ring. In some embodiments, the ring is a saturated 3- to 7-membered fused, bridged, or spiro ring that optionally contains 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, the ring is a saturated 3- to 7-membered fused, bridged, or spiro cycloalkyl ring.

[0097] In some embodiments, two R 2 together with the carbon atoms to which they are attached, join to form a 3- to 7-membered cycloalkyl ring optionally substituted with 1 to 3 halo. 2 taken together with the carbon atoms to which they are attached, join to form a 3- to 7-membered heterocycloalkyl ring optionally substituted with 1 to 3 halo, wherein the heterocycloalkyl ring contains 1 to 3 heteroatoms selected from N, O, and S.

[0098] In some embodiments, two R 2are joined together with the carbon atoms to which they are attached to form a bridged ring that is optionally substituted with 1 to 3 halo. In some embodiments, the bridged ring is a 3- to 7-membered cycloalkyl ring. In some embodiments, two R 2 together with the carbon atom to which they are attached, join to form a cyclopropyl ring optionally substituted with 1 to 3 halo.

[0099] In some embodiments, provided is a pharmaceutical composition comprising a compound described herein or a deuterated analog thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers, and a pharmaceutically acceptable carrier.

[0100] In some embodiments, provided is a method of treating a condition or disorder mediated by ATM kinase in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.

[0101] In some embodiments, the condition or disorder is Huntington's disease, Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NIID), dentatorubral-pallidoluysian atrophy (DRPLA), Friedreich's ataxia, Rubenstein-Taubi syndrome, polyglutamine diseases, e.g., Huntington's disease; spinocerebellar ataxia 1 (SCA 1), spinocerebellar ataxia 7 (SCA 2), 7), Seizures, Striatonigral Degeneration, Progressive Supranuclear Palsy, Torsion Dystonia, Spasmodic Torticollis, Dyskinesia, Familial Tremor, Gilles de la Tourette Syndrome, Diffuse Lewy Body Disease, Progressive Supranuclear Palsy, Pick's Disease, Primary Lateral Sclerosis, Progressive Neuromuscular Atrophy, Spinal Muscular Atrophy, Hypertrophic Interstitial Polyneuropathy, Retinitis Pigmentosa, Hereditary Optic Atrophy, Hereditary Spastic Paraplegia, Shy-Drager Syndrome, Kennedy Disease, Protein Aggregation-Associated Neurodegeneration, Machado-Joseph Disease, Spongiotic Encephalopathy, prion-related disease, multiple sclerosis (MS), progressive supranuclear palsy (Steele-Richardson-Olszewski disease), Hallervorden-Spatz disease, progressive familial myoclonic epilepsy, cerebellar degeneration, motor neuron disease, Werdnig-Hoffmann disease, Wohlfahrt-Kugelberg-Welander disease, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, retinitis pigmentosa, Leber's disease, progressive systemic sclerosis, dermatomyositis, or mixed connective tissue disease.

[0102] In some embodiments, the condition or disorder is Huntington's disease.

[0103] In some embodiments, the condition or disorder is cancer.

[0104] In some embodiments, the compound or deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof can be selected from compounds as described in one or more of the Examples. In certain embodiments, provided is a compound as described in one or more of the Examples for use in the methods described herein.

[0105] Also provided is a compound selected from the compounds in Table 1, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof:

[0106] [Table 2] TIFF0007727627000022.tif220169TIFF0007727627000023.tif223169TIFF0007727627000024.tif223169TIFF0007727627000025.tif211167TIFF0007727627000026.tif224167TIFF0007727627000027.tif224167TIFF0007727627000028.tif224167TIFF0007727627000029.tif224167TIFF0007727627000030.tif224167TIFF0007727627000031.tif224169TIFF0007727627000032.tif224167TIFF0007727627000033.tif224167TIFF0007727627000034.tif224167TIFF0007727627000035.tif224167TIFF0007727627000036.tif224167TIFF0007727627000037.tif224167TIFF0007727627000038.tif224167TIFF0007727627000039.tif224167TIFF0007727627000040.tif224167TIFF0007727627000041.tif224167TIFF0007727627000042.tif224167TIFF0007727627000043.tif224167TIFF0007727627000044.tif224167TIFF0007727627000045.tif224167TIFF0007727627000046.tif224167TIFF0007727627000047.tif224167TIFF0007727627000048.tif224167TIFF0007727627000049.tif224167TIFF0007727627000050.tif226168TIFF0007727627000051.tif226168TIFF0007727627000052.tif224167TIFF0007727627000053.tif226169TIFF0007727627000054.tif93167

[0107] In some embodiments, the formula

[0108] [ka] The compound of, for example, Example 100 or Example 101,

[0109] [ka] The compound has a structure selected from:

[0110] In some embodiments, the formula

[0111] [ka] Compounds of, for example, Example 165,

[0112] [ka] The compound has a structure selected from:

[0113] In some embodiments, the formula

[0114] [ka] Compounds of, for example, Example 166,

[0115] [ka] The compound has a structure selected from:

[0116] In some embodiments, the formula

[0117] [ka] Compounds of the formula, for example, Example 246 or 247,

[0118] [ka] The compound has a structure selected from:

[0119] In some embodiments, the formula

[0120] [ka] Compounds of the formula, for example Example 252,

[0121] [ka] The compound has a structure selected from:

[0122] In some embodiments, the formula

[0123] [ka] Compounds of the formula, for example, Example 320 or 321,

[0124] [ka] The compound has a structure selected from:

[0125] In some embodiments, the formula

[0126] [ka] Compounds of the formula, for example Examples 326, 327 or 328,

[0127] [ka] The compound has a structure selected from:

[0128] In some embodiments, the formula

[0129] [ka] Compounds of the formula, for example, Example 329 or 330,

[0130] [ka] The compound has a structure selected from:

[0131] In some embodiments, the formula

[0132] [ka] Compounds of the formula, for example Examples 333, 334, 335 or 336,

[0133] [ka] The compound has a structure selected from:

[0134] In some embodiments, the formula

[0135] [ka] Compounds of the formula, for example, Examples 337 or 338,

[0136] [ka] The compound has a structure selected from:

[0137] In some embodiments, the formula

[0138] [ka] Compounds of the formula, for example Examples 339, 340, 341 or 342,

[0139] [ka] The compound has a structure selected from:

[0140] In some embodiments, the formula

[0141] [ka] Compounds of the formula, for example Examples 352, 353, 354 or 355,

[0142] [ka] The compound has a structure selected from:

[0143] Treatment Methods and Uses Methods for obtaining the compounds described herein or pharmaceutically acceptable salts thereof will be apparent to those skilled in the art, and suitable procedures are described, for example, in the Examples below and in the references cited therein.

[0144] Also provided are methods of inhibiting ATM kinase. Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting ATM kinase. Also provided is at least one compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting ATM kinase. In some embodiments, the inhibition is in a cell.

[0145] Also provided is a method of treating a condition or disorder mediated by ATM in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition or disorder mediated by ATM.

[0146] Also provided is a method of treating a condition or disorder responsive to inhibition of ATM kinase in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the condition or disorder involves a neurodegenerative pathology. In some embodiments, the condition or disorder is Huntington's disease.

[0147] In some embodiments, the condition or disorder mediated by ATM comprises a neurodegenerative disease. Accordingly, also provided is a method of treating a neurodegenerative disease mediated by ATM in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the neurodegenerative disease is Huntington's disease, Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NIID), dentatorubral-pallidoluysian atrophy (DRPLA), Friedreich's ataxia, Rubenstein-Taubi syndrome, polyglutamine diseases, e.g., Huntington's disease; spinocerebellar ataxia 1 (SCA 1), spinocerebellar ataxia 7 (SCA 7), 7), Seizures, Striatonigral Degeneration, Progressive Supranuclear Palsy, Torsion Dystonia, Spasmodic Torticollis, Dyskinesia, Familial Tremor, Gilles de la Tourette Syndrome, Diffuse Lewy Body Disease, Progressive Supranuclear Palsy, Pick's Disease, Primary Lateral Sclerosis, Progressive Neuromuscular Atrophy, Spinal Muscular Atrophy, Hypertrophic Interstitial Polyneuropathy, Retinitis Pigmentosa, Hereditary Optic Atrophy, Hereditary Spastic Paraplegia, Shy-Drager Syndrome, Kennedy Disease, Protein Aggregation-Associated Neurodegeneration, Machado-Joseph Disease, Spongiotic The neurodegenerative disease is selected from the group consisting of encephalopathy, prion-related disease, multiple sclerosis (MS), progressive supranuclear palsy (Steele-Richardson-Olszewski disease), Hallervorden-Spatz disease, progressive familial myoclonic epilepsy, cerebellar degeneration, motor neuron disease, Werdnig-Hoffmann disease, Wohlfart-Kugelberg-Welander disease, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, retinitis pigmentosa, Leber's disease, progressive systemic sclerosis, dermatomyositis, and mixed connective tissue disease. In some embodiments, the neurodegenerative disease is Huntington's disease. In some embodiments, the neurodegenerative disease is Alzheimer's disease.

[0149] In some embodiments, the ATM-mediated condition or disorder includes cancer. Accordingly, also provided is a method of treating ATM-mediated cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is lymphoma, pancreatic cancer, colorectal cancer, hepatocellular carcinoma, Waldenstrom's macroglobulinemia, hormone-refractory cancer of the prostate, leukemia, acute myeloid leukemia, breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, renal cancer, gastric cancer, brain cancer, head and neck squamous cell carcinoma, B-cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma. In some further embodiments, the cancer is of the following types: cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic lung carcinoma (squamous cell, small undifferentiated cell, non-small cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, Tubular adenoma, villous adenoma, hamartoma, leiomyoma; genitourinary system: kidney (adenocarcinoma, Wilms' tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: hepatocellular carcinoma, bile duct adenocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor;Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pinealoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial carcinoma), cervix (cervical carcinoma, preneoplastic cervical dysplasia), ovary (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant tumor teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (renal clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematologic system: blood (myelocytic leukemia [acute and chronic], acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, molar dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma;

[0150] Also provided is a method of sensitizing a tumor to radiation therapy by administering a compound according to the present disclosure before, during, or after irradiation of the tumor to treat cancer.

[0151] Generally, the compounds described herein or their pharmaceutically acceptable salts are administered in a therapeutically effective amount by any of the accepted modes of administration for drugs serving similar purposes. The actual amount of the compound, i.e., the active ingredient, depends on many factors, such as the severity of the disease being treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors well known to skilled artisans. The drug can be administered at least once a day, for example, once or twice a day.

[0152] Pharmaceutical Compositions and Modes of Administration In some embodiments, a compound described herein, or a deuterated analog thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or a mixture of stereoisomers thereof, is administered as a pharmaceutical composition. Accordingly, provided is a pharmaceutical composition comprising a compound described herein, or a deuterated analog thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or a mixture of stereoisomers thereof, together with a pharmaceutically acceptable vehicle selected from a carrier, an adjuvant, and an excipient. The compounds of the present disclosure can be formulated into pharmaceutical compositions using techniques well known to those skilled in the art.

[0153] Pharmaceutically acceptable vehicles must be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the animal being treated. Vehicles can be inert or can have pharmaceutical benefits. The amount of vehicle used in conjunction with the compound or its deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers is sufficient to provide the practical quantity of material for administration per unit dose of the compound or its deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers.

[0154] Exemplary pharmaceutically acceptable carriers or components thereof are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; synthetic oils; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; phosphate buffer solutions; emulsifiers such as TWEEN®; wetting agents such as sodium lauryl sulfate; colorants; flavorings; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0155] Any active agent can be included in the pharmaceutical composition that does not substantially interfere with the activity of the compounds described herein or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers.

[0156] An effective concentration of a compound described herein, or its deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers, is mixed with a suitable pharmaceutically acceptable vehicle. In instances where the compound, or its deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers, exhibits insufficient solubility, methods for solubilizing the compound can be used. Such methods are known to those skilled in the art and include, but are not limited to, using a cosolvent, such as dimethyl sulfoxide (DMSO), using a surfactant, such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

[0157] Upon mixing or addition of a compound described herein or a deuterated analog thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or a mixture of stereoisomers, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture will depend on a number of factors, including the intended mode of administration and the solubility of the compound or deuterated analog thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or a mixture of stereoisomers in the selected vehicle. The effective concentration sufficient to ameliorate the symptoms of the treated disease will be empirically determined.

[0158] The compounds described herein or deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers or mixtures of stereoisomers thereof can be administered orally, topically, parenterally, intravenously, by intramuscular injection, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means in dosage unit formulations.

[0159] Pharmaceutical compositions can be formulated for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, or syrups or elixirs. Pharmaceutical compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically elegant and palatable preparation. In some embodiments, oral pharmaceutical compositions contain 0.1% to 99% of a compound described herein, its deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers. In some embodiments, oral pharmaceutical compositions contain at least 5% (by weight) of a compound described herein, its deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers. Some embodiments contain 25% to 50%, or 5% to 75% of a compound described herein or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.

[0160] Orally administered pharmaceutical compositions further include solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Oral pharmaceutical compositions may contain preservatives, flavoring agents, sweetening agents, such as sucrose or saccharin, flavoring agents, and coloring agents.

[0161] Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose.These pharmaceutical compositions can also contain demulcents.

[0162] The compounds described herein or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers can be incorporated into, for example, oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. Additionally, pharmaceutical compositions containing the compounds described herein or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as non-aqueous vehicles which may include suspending agents (e.g., sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats), emulsifiers (e.g., lecithin, sorbitan monooleate, or acacia), edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol, and ethyl alcohol), and preservatives (e.g., methyl or propyl p-hydroxybenzoates and sorbic acid).

[0163] For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, Avicel® RC-591, tragacanth, and sodium alginate, typical wetting agents include lecithin and polysorbate 80, and typical preservatives include methylparaben and sodium benzoate.

[0164] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum acacia; dispersing or wetting agents, such as naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with fatty acids and hexitols, such as polyoxyethylene sorbitol substitutes, or condensation products of ethylene oxide with fatty acids and hexitol anhydrides, such as polyethylene sorbitan substitutes. Aqueous suspensions can also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate.

[0165] Oily suspensions can be prepared by suspending the active ingredient in vegetable oils, such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oils, such as liquid paraffin.Oily suspensions can contain thickening agents, such as beeswax, hard paraffin or cetyl alcohol.Sweetening agents, such as those described above, and flavoring agents can be added to provide a palatable oral preparation.These pharmaceutical compositions can be preserved by adding antioxidants, such as ascorbic acid.

[0166] The pharmaceutical composition may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as acacia gum or tragacanth gum, naturally occurring phosphatides, such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0167] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.

[0168] Tablets typically contain conventional pharmaceutically acceptable adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders, such as starch, gelatin, and sucrose; disintegrants, such as starch, alginic acid, and croscarmellose; and lubricants, such as magnesium stearate, stearic acid, and talc. Glidants, such as silicon dioxide, can be used to improve the flow characteristics of powder mixtures. Coloring agents, such as FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, can be useful adjuvants for chewable tablets. Capsules (including time-release and sustained-release formulations) typically contain one or more solid diluents as disclosed above. The selection of carrier components often depends on secondary considerations such as taste, cost, and storage stability.

[0169] Such pharmaceutical compositions may also be coated by conventional methods, typically with a pH or time-dependent coating, so that the compound or its deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers is released in the gastrointestinal tract in the vicinity of the desired local application or at various times to extend the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, Eudragit® coating, wax, and shellac.

[0170] Pharmaceutical compositions for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0171] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable vehicle, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, can be useful in the preparation of injectables.

[0172] The compounds described herein, or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers, can be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous injection, intravenous, intramuscular, intrathecal injection, or infusion techniques. The compounds described herein, or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers, can be either suspended or dissolved in the vehicle, depending on the vehicle and concentration used. Advantageously, adjuvants, such as local anesthetics, preservatives, and buffering agents, can be dissolved in the vehicle. In many pharmaceutical compositions for parenteral administration, the carrier comprises at least 90% by weight of the total composition. In some embodiments, the carrier for parenteral administration is selected from propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.

[0173] The compounds described herein, or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers, can also be administered in the form of suppositories for rectal administration of the drug. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby dissolving in the rectum and releasing the drug. Such materials include cocoa butter and polyethylene glycol.

[0174] The compounds described herein or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers or mixtures of stereoisomers can be formulated for topical or local application, e.g., to the skin and mucous membranes, e.g., in the eye, in the form of gels, creams and lotions, and for application to the eye. Topical pharmaceutical compositions can be in any form, including, for example, solutions, creams, ointments, gels, lotions, milks, cleansers, moisturizers, sprays, skin patches, etc.

[0175] Such solutions can be formulated with appropriate salts as 0.01% to 10% isotonic solutions, pH 5 to 7. The compounds described herein or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers can also be formulated for transdermal administration as a transdermal patch.

[0176] Topical pharmaceutical compositions containing the compounds described herein or deuterated analogs thereof, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers can be admixed with a variety of carrier materials well known in the art, such as water, alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oil, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.

[0177] Other materials suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners, and powders. Examples of each of these types of materials, which can be used singly or as a mixture of one or more materials, are as follows:

[0178] Representative emollients include stearyl alcohol, glyceryl monolaurate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di- n-Butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum oil, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, and myristyl myristate; propellants, such as propane, butane, isopropyl alcohol, -butane, dimethyl ether, carbon dioxide and nitrous oxide; solvents such as ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran; humectants such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate and gelatin; and powders such as chalk, talc, fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose and ethylene glycol monostearate.

[0179] The compounds described herein or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers can also be administered topically in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0180] Other pharmaceutical compositions useful for achieving systemic delivery of the compound or its deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or stereoisomer mixture include sublingual, buccal, and nasal dosage forms.These pharmaceutical compositions typically contain soluble filler materials, such as sucrose, sorbitol, and mannitol, and binders, such as one or more of acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose.The glidants, lubricants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above may also be included.

[0181] Pharmaceutical compositions for inhalation can typically be provided in the form of a solution, suspension or emulsion which can be administered as a dry powder, or in the form of an aerosol using a conventional propellant (e.g., dichlorodifluoromethane or trichlorofluoromethane).

[0182] The pharmaceutical compositions may also optionally include an excipient. The excipient may be selected from a wide variety of molecules that function in different ways or independently to enhance the therapeutic effect of the compounds described herein or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers. Particular classes of excipients include skin penetration enhancers and absorption enhancers.

[0183] The pharmaceutical compositions may also contain additional active agents, which may be selected from a wide variety of molecules that can function in different ways to enhance the therapeutic effect of the compounds described herein or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers. These optional other active agents, if present, are typically used in pharmaceutical compositions at levels ranging from 0.01% to 15%. Some embodiments contain 0.1% to 10% by weight of the composition. Other embodiments contain 0.5% to 5% by weight of the composition. The additional active agents may be, for example, agents described herein for combination therapy or as known in the art.

[0184] packaging Also provided are packaged pharmaceutical compositions. Such packaged compositions include pharmaceutical compositions comprising a compound described herein or a deuterated analog thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers, and instructions for using the composition to treat a subject (typically a human patient). In some embodiments, the instructions are for using the pharmaceutical composition to treat a subject suffering from a condition or disorder mediated by ATM. The packaged pharmaceutical composition can include providing prescribing information, for example, to the patient or healthcare provider or as labeling in the packaged pharmaceutical composition. The prescribing information can include, for example, efficacy, dosage and administration, contraindications, and adverse reaction information related to the pharmaceutical composition.

[0185] In all of the foregoing, the compound or its deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers may be administered alone, as a mixture, or in combination with other active agents.

[0186] Combination Therapy The methods described herein include methods of treating Huntington's disease, including treating memory and / or cognitive deficits associated with Huntington's disease, comprising administering to a subject simultaneously or sequentially a compound described herein or a deuterated analog thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers, and one or more additional agents used in the treatment of Huntington's disease, such as, but not limited to, amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, tetrabenazine, haloperidol, chlorpromazine, thioridazine, sulpride, quetiapine, clozapine, and risperidone. In methods using simultaneous administration, the agents can be present in a combined composition or can be administered separately. As a result, also provided are pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof, and one or more additional pharmaceutical agents used in the treatment of Huntington's disease, such as, but not limited to, amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, tetrabenazine, haloperidol, chlorpromazine, thioridazine, sulpride, quetiapine, clozapine, and risperidone. Also provided are pharmaceutical compositions comprising a compound described herein or a deuterated analogue thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers, as well as other compositions comprising one or more additional pharmaceutical agents used in the treatment of Huntington's disease, such as, but not limited to, packaged pharmaceutical compositions containing amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, tetrabenazine, haloperidol, chlorpromazine, thioridazine, sulpride, quetiapine, clozapine, and risperidone.

[0187] Also provided are methods for treating Alzheimer's disease, including treating memory and / or cognitive deficits associated with Alzheimer's disease, comprising administering to a subject, simultaneously or sequentially, a compound described herein or a deuterated analog thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers, and one or more additional agents used in the treatment of Alzheimer's disease, such as, but not limited to, Reminyl®, Cognex®, Aricept®, Exelon®, Akatinol®, Neotropin™, Eldepryl®, estrogen, and clioquinol. In methods using simultaneous administration, the agents can be present in a combined composition or can be administered separately. Additionally provided are pharmaceutical compositions comprising a compound described herein or a deuterated analogue thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers, and one or more additional pharmaceutical agents used in the treatment of Alzheimer's disease, such as, but not limited to, Reminyl®, Cognex®, Aricept®, Exelon®, Akatinol®, Neotropin™, Eldepryl®, estrogen, and clioquinol. Also provided are pharmaceutical compositions comprising a compound described herein or a deuterated analogue thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers, as well as other compositions comprising one or more additional pharmaceutical agents used in the treatment of Alzheimer's disease, such as, but not limited to, Reminyl®, Cognex®, Aricept®, Exelon®, Akatinol®, Neotropin™, Eldepryl®, estrogen, and clioquinol.

[0188] Also provided are compounds described herein or deuterated analogs thereof, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers or mixtures of stereoisomers, and one or more additional active agents for use in the treatment of cancer, including, but not limited to, antitumor agents in the following categories: (i) other cell cycle inhibitory agents that act by the same or different mechanisms as those defined above, such as cyclin-dependent kinase (CDK) inhibitors, in particular CDK2 inhibitors; (ii) Cytostatic agents, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, exemestane), antiprogestogens, antiandrogens (e.g., flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (e.g., goserelin acetate, leuprolide), testosterone inhibitors of thrombin 5α-dihydroreductase (e.g., finasteride), anti-inflammatory agents (e.g., metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function) and inhibitors of growth factor function (such growth factors include, for example, vascular endothelial growth factor, epidermal growth factor, platelet-derived growth factor, and hepatocyte growth factor, and such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors, and serine / threonine kinase inhibitors); (iii) Antiproliferative / antineoplastic drugs and combinations thereof as used in medical oncology, for example, antimetabolites (e.g., antifolates such as methotrexate, fluoropyrimidines such as 5-fluorouracil, purine and adenosine analogs, cytosine arabinoside); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin); platinum derivatives anti-inflammatory drugs (e.g., cisplatin, carboplatin); alkylating agents (e.g., nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); anti-mitotic agents (e.g., vinca alkaloids such as vincristine, and taxoids such as taxol and taxotere); topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan); (iv) Antiangiogenic agents that act by mechanisms different from those defined above (e.g., receptor tyrosine kinases such as Tie-2, integrin α V Inhibitors of β3 function, including angiostatin, razoxin, thalidomide), and vascular targeting agents; and (v) differentiation agents (e.g., retinoic acid and vitamin D) and (iii) administering to a subject, simultaneously or sequentially,

[0189] In methods using simultaneous administration, the agents can be present in a combined composition or can be administered separately. Also provided are pharmaceutical compositions comprising a compound described herein or a deuterated analog thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers, and one or more anti-tumor agents as described herein. Also provided are packaged pharmaceutical compositions containing a pharmaceutical composition comprising a compound described herein or a deuterated analog thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers, and another composition comprising one or more anti-tumor agents as described herein. When used in combination with one or more additional pharmaceutical agents or drugs, the compounds described herein can be administered prior to, concurrently with, or subsequent to the administration of the additional pharmaceutical agent(s).

[0190] In some embodiments, a compound described herein, or a deuterated analogue thereof, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, is administered in conjunction with surgery or radiation therapy, optionally in combination with one or more additional agents used in the treatment of cancer.

[0191] dosage The dosage of the compounds described herein will depend on a variety of factors, including the particular syndrome being treated, the severity of the symptoms, the route of administration, the frequency of administration intervals, the particular compound utilized, the efficacy, toxicology profile, pharmacokinetic profile of the compound, and the presence of any adverse side effects, among other considerations.

[0192] The compounds described herein, or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers, are typically administered at dosage levels and in a manner customary for ATM inhibitors. For example, the compounds, or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers, can generally be administered by oral administration at dosage levels of 0.001 to 100 mg / kg / day, e.g., 0.01 to 100 mg / kg / day, e.g., 0.1 to 70 mg / kg / day, e.g., 0.5 to 10 mg / kg / day, in single or multiple doses. A unit dosage form can generally contain 0.01 to 1000 mg of a compound described herein or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, e.g., 0.1 to 50 mg of a compound described herein or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof. For intravenous administration, the compound or a deuterated analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof can be administered in single or multiple doses, e.g., at dosage levels of 0.001 to 50 mg / kg / day, e.g., 0.001 to 10 mg / kg / day, e.g., 0.01 to 1 mg / kg / day. A unit dosage form can contain, for example, 0.1 to 10 mg of a compound described herein or a deuterated analogue thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or a mixture of stereoisomers.

[0193] Compound synthesis The compounds can be prepared using the methods disclosed herein, as well as routine modifications that are apparent from the disclosures herein and methods well known in the art. Conventional and well-known synthetic methods can be used in addition to the teachings herein. The synthesis of typical compounds described herein can be achieved as described in the following examples. Where available, reagents can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0194] The compounds of this disclosure can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it is understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0195] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, numerous protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006), Greene's protective groups in organic synthesis, Hoboken, NJ, Wiley-Interscience, and the references cited therein.

[0196] Furthermore, compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, supercritical fluid chromatography, chiral resolving agents, and the like.

[0197] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial sources, such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chem or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference texts, such as Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 5th ed., 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0198] The terms "solvent," "inert organic solvent," or "inert solvent" refer to a solvent that is inert under the conditions of the reaction being described therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, and the like). Unless otherwise specified, the solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.

[0199] The term "quantity" means adding a quantity sufficient to accomplish a stated function, for example, to bring a solution to the desired volume (ie, 100%).

[0200] It will also be understood that in each of the schemes, the addition of any substituents may result in the production of multiple isomeric products (including, but not limited to, enantiomers or one or more diastereomers), any or all of which may be isolated and purified using conventional techniques. Where enantiomerically pure or enriched compounds are desired, chiral chromatography and / or enantiomerically pure or enriched starting materials may be employed as conventionally used in the art or as described in the examples.

[0201] [Example] Compounds were named using Cambridgesoft Chemistry Cartridge (v.16.0.0.82) software.

[0202] The term "qs" means adding a quantity sufficient to achieve a stated function, for example, to bring a solution to the desired volume (ie, 100%).

[0203] It is also understood that the addition of any substituent in each of the above schemes may result in the production of multiple isomeric products (including, but not limited to, enantiomers or one or more diastereomers), any or all of which can be isolated and purified using conventional techniques. Where an enantiomerically pure or enriched compound is desired, chiral chromatography and / or enantiomerically pure or enriched starting materials may be utilized as conventionally used in the art or as described in the Examples.

[0204] general synthesis The compounds of the present disclosure can be synthesized according to the general reaction schemes and / or examples described below. The general schemes can be varied by substituting starting materials with other materials of similar structure to yield the corresponding products. The structure of the desired product will generally reveal the necessary starting materials to one skilled in the art.

[0205] Scheme 1 shows an exemplary synthetic route for synthesizing compounds provided herein, such as compounds of Formula I. Compounds of Formula I or other formulas, or compounds disclosed herein, are typically prepared by first obtaining a core formula X(a) and then attaching (e.g., coupling) the desired substituents using suitable conditions.

[0206] In some embodiments, the synthesis of compounds of Formula I proceeds according to Scheme 1.

[0207] [ka]

[0208] In Scheme 1, a compound of formula X(a) is converted to a compound of formula X(b) or formula X(c). Compounds of formula X(b) or formula X(c), respectively, can then be converted to a compound of formula X(d) and subsequently to a compound of formula I. Compound X(a) can be obtained by known methods or by methods described herein and specifically described for the synthesis of any of Scaffold 1, Scaffold 2, Scaffold 3, Scaffold 4, Scaffold 5, Scaffold 6, or Scaffold 7. In Scheme 1, X, Y, Z, m, and p are as defined in Formula I.

[0209] In Scheme 1, LG 1 and L.G. 2 Each of LG is independently a suitable leaving group, for example, a halide (e.g., chloro, bromo, iodo) or a sulfur derivative (e.g., SCH, S(O)CH). 1 or LG 2When LG is a sulfur derivative, the group can be activated to a sulfone by oxidation (e.g., with mCPBA). 1 or LG 2 can be displaced under nucleophilic aryl coupling conditions, for example, using a metal catalyst (e.g., Pd2(dba)3, RuPhos palladacycle G1 methyl tert-butyl ether adduct, RuPhos, Pd(OAc)2), optionally in the presence of a base (e.g., Cs2CO3, NaOtBu, NaH, Na2CO3), in an inert solvent (e.g., 1,4-dioxane, DMF, THF) upon contact with a ligand (e.g., BINAP, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl). When the reaction is substantially complete, the product is isolated by conventional means. LG 1 or LG 2 Examples of substitutions of include, but are not limited to, Method C and Method D. Alternatively, LG 1 or LG 2 can be substituted under nucleophilic substitution conditions, for example, in the presence of a base (e.g., DIPEA, triethylamine) in an inert solvent (e.g., DMSO, DMF), optionally in the presence of a fluoride source (e.g., TBAF) at a temperature between rt and 100°C for 1 to 72 hours. When the reaction is substantially complete, the product is isolated by conventional means. LG 1 or LG 2 Examples of nucleophilic substitution of include, but are not limited to, Method F and Method G.

[0210] PG is a hydroxyl protecting group, such as para-methoxybenzyl or tert-butyl. PG can be removed under suitable hydroxyl deprotection conditions, including hydrogenation in the presence of a reducing agent, such as hydrogen or 1-methylcyclohexa-1,4-diene, in contact with a catalyst, such as palladium on carbon. The reaction can be carried out in an inert solvent, such as an alcohol, e.g., ethanol, or an ether, e.g., tetrahydrofuran, at a temperature of rt to 150°C for 5 minutes to 24 hours. When the reaction is substantially complete, the product is isolated by conventional means. Alternatively, PG can be removed under suitable acidic conditions, for example, containing an acid, e.g., TiCl4, in an inert solvent, e.g., DCM, at a temperature of -78°C to rt. When the reaction is substantially complete, the product is isolated by conventional means. Examples of PG deprotection include, but are not limited to, Method E.

[0211] R 41 is hydrogen or R 4 R 41 is hydrogen, R 4 can be added by standard synthetic transformations, e.g., nucleophilic substitution. 31 is hydrogen or R 3 or R 31 does not exist. R 31 is hydrogen, R 3 can be added by standard synthetic transformations, such as nucleophilic substitution. 11 are independently 1 or R 1 It is a derivative of R 11 If is a derivative, R 1 can be obtained by standard synthetic transformations. 21 is independently R 2 or R 2 It is a derivative of R 21 If is a derivative, R 2 is obtained by standard synthetic transformations. 51 is R 5 or R 5 It is a derivative of R 51 If is a derivative, R 5is obtainable by standard synthetic transformations. L' is L or a derivative of L. When L' is a derivative, L is obtainable by standard synthetic transformations.

[0212] Those of skill in the art will appreciate that any of the compounds of formula X(a), X(b), X(c), or X(d) may, in certain embodiments, be available from commercial suppliers. Alternative syntheses of compounds of formula X(a), X(b), X(c), or X(d) may be as described herein or known to those of skill in the art.

[0213] Synthesis Example 1.Analysis method Purification method: Preparative HPLC purification was performed by reverse-phase HPLC using a Waters Fractionlynx™ preparative HPLC system (2525 pump, 2996 / 2998 UV / VIS detector, 2767 liquid handler) or an equivalent HPLC system, such as a Gilson Trilution® UV-directed system. The Waters® 2767 liquid handler acted as both the autosampler and fraction collector.

[0214] The columns used for the preparative purification of the compounds were Waters Sunfire® OBD Phenomenex Luna® Phenyl Hexyl, or Waters Xbridge® Phenyl, 10 μm 19×150 mm, or Waters CSH™ Phenyl Hexyl, 19×150, 5 μm columns.

[0215] Appropriate focusing gradients were selected based on acetonitrile and methanol solvent systems under either acidic or basic conditions, with the modifiers used under acidic / basic conditions being formic acid or trifluoroacetic acid (0.1% V / V), and ammonium bicarbonate (10 mM), respectively.

[0216] The purification was controlled by Waters Fractionlynx™ software through monitoring from 210 to 400 nm, and a threshold collection value of 260 nm was initiated. Using Fractionlynx™, the presence of the target molecular ion was observed under APi conditions. Collected fractions were analyzed by LCMS (Waters Acquity™ system with a Waters SQD).

[0217] Analysis method A: Analytical UPLC-MS was performed on a Waters Acquity I-Class UPLC with a Waters diode array detector (210–400 nm) coupled to a Waters SQD2 single-quadrupole UPLC mass spectrometer using an HSS C18 column (1.8 μm 100 × 2.1 mm plus guard). Method details are: 1) Mobile phase: A: 0.1% formic acid (v / v) in water; B: 0.1% formic acid (v / v) in acetonitrile; 2) Gradient: 0–1.2 min 95% A to 5% B, 1.2–3.5 min linear gradient to 0% A to 100% B, 3.5–4.9 min 0% A to 100% B, 4.9–5.0 min gradient to 95% A to 5% B, 5.0–6.0 min 95% A to 5% B; 3) Flow rate: 0.5 mL / min.

[0218] Analysis method B: Analytical UPLC-MS was performed on a Waters Acquity I-Class UPLC with a Waters diode array detector (210–400 nm) coupled to a Waters SQD2 single quadrupole UPLC mass spectrometer using a BEH Shield RP18 column (1.7 μm, 100 × 2.1 mm, PlusGuard cartridge). Method details are: 1) Mobile phase: A: 10 mM ammonium bicarbonate in water; B: acetonitrile; 2) Gradient: 0–1.2 min 95% A to 5% B, 1.2–3.5 min linear gradient to 0% A to 100% B, 3.5–4.9 min 0% A to 100% B, 4.9–5.0 min 95% A to 5% B, 5.0–6.0 min 95% A to 5% B; 3) Flow rate: 0.5 mL / min.

[0219] SFC method: All compounds purified using supercritical fluid chromatography (SFC) used either a Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler with stacked injection module) or a Waters Thar Investigator semi-preparative system (Waters fluid delivery module, 2998 UV / VIS detector, Waters fraction collection module). When a Waters 2767 liquid handler was used, it acted as both the autosampler and fraction collector.

[0220] Compounds were purified using appropriate columns from YMC Amylose-C, YMC Cellulose-C, Phenomenex LUX Cellulose-3, and Phenomenex LUX Cellulose-4. Appropriate isocratic methods were selected based on methanol, ethanol, or isopropanol solvent systems under unmodified or basic conditions. The standard method used was modifier / CO2, 100 ml / min (or as needed), 120 Bar back pressure, and 40°C column temperature, where the specific modifier composition was as stated by the method development.

[0221] The modifier used under basic conditions was diethylamine (0.1% V / V). Purification was controlled by either Waters Fractionlynx or Waters Chromscope software via monitoring at 210-400 nm, and threshold collection at the appropriate wavelength was initiated. Collected fractions were analyzed by SFC (Waters / Thar SFC system with Waters SQD or Waters UPCC with Waters QDa). Fractions containing the desired product were concentrated by vacuum centrifugation.

[0222] [Table 3]

[0223] [Table 4]

[0224] Analysis method HPLC: All compounds were purified using a Gilson AutoPrep system (Gilson 322 pump, Gilson 155 UV / VIS detector, GX-281 liquid handler), which acted as both the autosampler and fraction collector.

[0225] Compounds were purified using the columns described in the specific examples.

[0226] An appropriate isocratic method was selected based on an ethanol or isopropanol solvent system under acidic or basic conditions. The standard method used was modifier / heptane, 20 ml / min, room temperature, when the specific modifier composition was as stated by the method development.

[0227] The modifier used under basic conditions was diethylamine (0.1% V / V), and the modifier used under acidic conditions was formic acid (0.1% V / V).

[0228] Purification was controlled by Gilson Trilution V2.1 through monitoring at designated wavelengths determined by method development, and threshold collection values ​​at the appropriate wavelengths were initiated. Collected fractions were analyzed by an Agilent 1200 Series HPLC system with a DAD detector. Fractions containing the desired product were concentrated by vacuum centrifugation.

[0229] 2. Scaffold The following scaffolds were used in the synthesis of the final compounds:

[0230] [Table 5]

[0231] General method for preparing scaffolds 1-4 Method A: To a mixture of (4-methoxyphenyl)methanol (1.1 eq.) in THF (0.4 M) was added NaH (2 eq., 60% mineral oil) portionwise at 0 °C. The reaction was stirred for 15 min. 4-(2,6-dichloropyridin-4-yl)morpholine derivative (1 eq.) was added dropwise as a solution in THF (0.7 M). After the addition was complete, the reaction was warmed to rt and heated to reflux for 19 h. The reaction mixture was cooled to 0 °C and carefully quenched with water. THF was removed under reduced pressure. The residue was dissolved in EtOAc and washed successively with water and brine. The organic extract was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by trituration or silica gel column chromatography.

[0232] Method B: A mixture of amine (1.0 eq.), 2,6-dichloro-4-iodopyridine (1.0 eq.), NaOtBu (2 eq.), and PdCl(tBuPferrocene) (0.025 eq.) in toluene (0.3 M) was placed in a sealed reaction tube under nitrogen and heated at 50 °C for 20 h. The reaction mixture was cooled to rt and filtered through Celite. The mixture was concentrated under reduced pressure and purified by silica gel chromatography.

[0233] Scaffold 1: 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine

[0234] [ka]

[0235] Step 1: 4-(2,6-dichloropyridin-4-yl)morpholine 2,6-Dichloropyridin-4-amine (10 g, 61.3 mmol) was dissolved in DMF (200 mL) and cooled to 0 °C. Sodium hydride (6.13 g, 153 mmol) was added portionwise over 20 minutes. After 15 minutes, 1-chloro-2-(2-ethoxy)ethane (8.63 mL, 73.62 mmol) was added dropwise. The reaction mixture was warmed to rt and stirred for 21.5 hours. After this time, the reaction was cooled to 0 °C and carefully quenched with water. DMF was removed under reduced pressure. The resulting residue was dissolved in DCM and washed with water. The organic layer was dried (MgSO), filtered, and concentrated under reduced pressure. The crude product was triturated with EtOAc and iso-hexane to provide the title compound.

[0236] Step 2: 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following method A using 4-(2,6-dichloropyridin-4-yl)morpholine (9.27 g, 39.8 mmol). The crude product was triturated with EtOAc and iso-hexane to give the title compound. 1 H NMR (400 MHz, CDCl3): δ 7.39 - 7.35 (2H, m), 6.91 - 6.88 (2H, m), 6.40 (1H, d, J=2.0 Hz), 5.99 (1H, d, J=2.0 Hz), 5.25 (2H, s), 3.81 - 3.77 (7H, m), 3.25 - 3.21 (4H, m).

[0237] Scaffold 2: (R)-4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-methylmorpholine

[0238] [ka]

[0239] Step 1: (R)-4-(2,6-dichloropyridin-4-yl)-2-methylmorpholine Following Method B using 2-R-methylmorpholine (0.5 g, 5 mmol). Purification by silica gel column chromatography (gradient elution, 10-50% EtOAc / iso-hexane) gave the title compound.

[0240] Step 2: (R)-4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-methylmorpholine Following Method A using (R)-4-(2,6-dichloropyridin-4-yl)-2-methylmorpholine (1.6 g, 6.4 mmol), purified by silica gel column chromatography (gradient elution, 5-40% EtOAc / iso-hexane) to give the title compound. 1 H NMR (400 MHz, CDCl3): δ 7.39 - 7.36 (2H, m), 6.91 - 6.88 (2H, m), 6.40 (1H, d, J=2.0 Hz), 5.98 (1H, d, J=2.0 Hz), 5.24 (2H, s), 4.00 - 3.95 (1H, m), 3.81 (3H, s), 3.71 - 3.61 (2H, m), 3.52 - 3.42 (2H, m), 2.96 - 2.88 (1H, m), 2.58 (1H, dd, J=10.4, 12.4 Hz), 1.24 - 1.21 (3H, m).

[0241] Scaffold 3: 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyrimidin-4-yl)morpholine Scaffold 3 was prepared according to the route described in Bioorganic & Medicinal Chemistry Letters, 2012, 22(21), pp. 6665-6670.

[0242] Scaffold 4: 4-(6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidin-4-yl)morpholine

[0243] [ka]

[0244] Step 1: 4-(6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidin-4-yl)morpholine NaH (3.43 g, 85.8 mmol, 60% dispersion in mineral oil) was suspended in DMF (70 mL) and cooled to 0 °C. 4-Methoxybenzyl alcohol (6.52 g, 47.2 mmol) in DMF (30 mL) was added dropwise to the suspension over 15 min. After stirring at 0 °C for 15 min, 4-(6-chloro-2-(methylthio)pyrimidin-4-yl)morpholine (10.54 g, 42.9 mmol, prepared according to WO 2008 / 125839) in DMF (90 mL) was added. The reaction was warmed to rt and stirred for 4.5 h. The reaction was cooled to 0 °C and carefully quenched with water. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with brine and water. The organic extract was dried (MgSO), filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (gradient elution, 10-50% EtOAc / iso-hexane) afforded the title compound.

[0245] Step 2: 4-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)morpholine mCPBA (759 mg, 4.4 mmol, 50-55% wt in HO) was added portionwise to a solution of 4-(6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidin-4-yl)morpholine (695 mg, 2.0 mmol) in DCM (20 mL) at rt. After 2 h, the reaction was filtered and the precipitate was washed with DCM. The filtrate was washed successively with saturated NaHCO (aq), brine, dried (phase separator), and concentrated under reduced pressure to give the product, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.38 - 7.35 (2H, m), 6.91 - 6.88 (2H, m), 5.88 (1H, s), 5.36 (2H, s), 3.81 (3H, s), 3.78 - 3.74 (4H, m), 3.63 - 3.57 (4H, m), 3.26 (3H, s).

[0246] Scaffold 5: (R)-4-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2-methylmorpholine

[0247] [ka]

[0248] Step 1: 4-chloro-6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidine A solution of 4,6-dichloro-2-(methylthio)pyrimidine (15.0 g, 77.0 mmol) in dry DMF (205 mL) was treated with para-methoxybenzyl alcohol (11.7 g, 84.6 mmol) and K2CO3 (42.6 g, 308 mmol) at rt. The reaction was stirred at 60 °C for 64 h. After cooling to rt, the mixture was diluted with water (700 mL) and stirred vigorously at rt for 2 h. The formed solid was collected by filtration and washed with water to give the title compound. 1 H NMR (400 MHz, CDCl3): δ 7.35 (2H, d, J=8.8 Hz), 6.92 - 6.89 (2H, m), 6.42 (1H, s), 5.35 (2H, s), 3.81 (3H, s), 2.56 (3H, s).

[0249] Step 2: (R)-4-(6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidin-4-yl)-2-methylmorpholine A solution of 4-chloro-6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidine (11.3 g, 38.0 mmol) in dry THF (95 mL) was treated with DIPEA (20.0 mL, 114 mmol) and (2R)-methylmorpholine hydrochloride (5.75 g, 41.8 mmol). The mixture was stirred at 65 °C for 16 h. After cooling to rt, the reaction mixture was poured into water. DCM was added and the layers were separated by passage through a hydrophobic frit. The DCM layer was concentrated and purified by silica gel column chromatography (gradient elution, 0-25% EtOAc / iso-hexane) to give the title compound. 1 H NMR (400 MHz, CDCl3): δ 7.36 - 7.33 (2H, m), 6.90 - 6.87 (2H, m), 5.53 (1H, s), 5.30 (2H, s), 4.09 - 3.91 (3H, m), 3.81 (3H, s), 3.64 - 3.54 (2H, m), 2.96 (1H, ddd, J=3.6, 11.9, 13.0 Hz), 2.61 (1H, dd, J=10.5, 13.0 Hz), 2.51 (3H, s), 1.22 (3H, d, J=6.5 Hz).

[0250] Step 3: (R)-4-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2-methylmorpholine

[0251] A solution of (R)-4-(6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidin-4-yl)-2-methylmorpholine (9.37 g, 25.9 mmol) in DCM (172 mL) at rt was treated with mCPBA (19.7 g, 57.0 mmol, 50-55 wt % in HO) and the mixture was stirred at rt for 4 h. Solid impurities were then filtered off and the organic filtrate was shaken with saturated NaHCO solution (2x). The organic phase was dried (phase separator) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, 0-65% EtOAc / iso-hexane) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 7.36 (2H, d, J=8.7 Hz), 6.90 (2H, d, J=8.7 Hz), 5.88 (1H, s), 5.35 (2H, s), 4.14 - 4.02 (2H, m), 3.98 (1H, ddd, J=1.4, 3.7, 11.8 Hz), 3.81 (3H, s), 3.69 - 3.55 (2H, m), 3.26 (3H, s), 3.07 (1H, ddd, J=3.7, 11.9, 12.9 Hz), 2.71 (1H, dd, J=10.5, 13.1 Hz), 1.24 (3H, d, J=6.4 Hz).

[0252] Scaffold 6: 2-(2-benzylpyrrolidin-1-yl)-4-chloro-6-((4-methoxybenzyl)oxy)pyrimidine

[0253] [ka]

[0254] Step 1: 4-chloro-6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidine A solution of 4-chloro-6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidine (1.11 g, 3.75 mmol, scaffold 5, step 1) in DCM (35 mL) was cooled at 0 °C and treated with mCPBA (2.75 g, 7.97 mmol, 50 wt % in water). The reaction mixture was warmed to rt and stirred for 21 h. The reaction mixture was washed with 2 M NaOH (20 mL) and the organic layer was dried (phase separator). After concentration, the title compound was obtained containing 9 wt % DCM. 1 H NMR (400 MHz, CDCl3): δ 7.41 (2H, d, J=8.6 Hz), 6.94 - 6.90 (3H, m), 5.48 (2H, s), 3.82 (3H, s), 3.34 (3H, s).

[0255] Step 2: 2-(2-benzylpyrrolidin-1-yl)-4-chloro-6-((4-methoxybenzyl)oxy)pyrimidine Following Method G from 4-chloro-6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidine (1.14 g, 3.49 mmol) and 2-benzylpyrrolidine (602 mg, 3.73 mmol). The reaction was stirred at 80° C. for 17 h. Purification by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) gave the title compound. 1 H NMR (400 MHz, CDCl3): δ 7.41 - 7.17 (7H, m), 6.89 (2H, d, J=6.8 Hz), 6.04 (1H, s), 5.49 - 5.27 (2H, m), 4.39 (1H, br s), 3.80 (3H, s), 3.62 - 3.49 (2H, m), 3.27 (1H, d, J=13.6 Hz), 2.62 (1H, br s), 1.90 - 1.79 (4H, m).

[0256] Scaffold 7: (R)-2-benzyl-1-(4-chloro-6-((4-methoxybenzyl)oxy)pyrimidin-2-yl)azepane

[0257] [ka]

[0258] Step 1: (R)-2-benzyl-1-(4-chloro-6-((4-methoxybenzyl)oxy)pyrimidin-2-yl)azepane Following Method G from 4-chloro-6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidine (1.72 g, 4.79 mmol, Scaffold 6, Step 1) and (R)-2-benzylazepane (906 mg, 4.79 mmol, Example 3, Step 2). The reaction was stirred at 80 °C for 4 days. Purification by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) gave the title compound.1 H NMR (400 MHz, CDCl3): δ 7.33 (2H, dd, J=5.3, 8.3 Hz), 7.28 - 7.13 (5H, m), 6.90 (2H, d, J=7.3 Hz), 5.96 (1H, d, J=6.6 Hz), 5.33 - 5.17 (2H, m), 4.79 - 4.63 (1H, m), 4.25 - 4.17 (1H, m), 3.82 (3H, s), 2.95 - 2.81 (2H, m), 2.72 - 2.61 (1H, m), 2.02 - 1.91 (1H, m), 1.81 - 1.68 (3H, m), 1.59 - 1.52 (1H, m), 1.52 - 1.36 (1H, m), 1.23 - 1.09 (2H, m).

[0259] 3. Synthesis of intermediates Intermediate 1 (1S*,2S*,5R*)-2-benzyl-3-azabicyclo[3.1.0]hexane and Intermediate 2 (1S*,2R*,5R*)-2-benzyl-3-azabicyclo[3.1.0]hexane

[0260] [ka]

[0261] Step 1: tert-Butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate A solution of Boc anhydride (2.6 g, 11.9 mmol) and NaHCO3 (3.32 g, 39.5 mmol) in water (78 mL) was added to a suspension of 3-azabicyclo[3.1.0]hexane hydrochloride (950 mg, 7.9 mmol) in THF (26 mL). The resulting biphasic mixture was vigorously stirred at rt overnight. The reaction mixture was diluted with water and DCM. The layers were separated, and the organic phase was dried (phase separator) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, 0-10% EtOAc / iso-hexane) to give the title compound.

[0262] Step 2: tert-Butyl (1S*,2S*,5R*)-2-benzyl-3-azabicyclo[3.1.0]hexane-3-carboxylate and tert-butyl (1S*,2R*,5R*)-2-benzyl-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (1.50 g, <7.9 mmol) in diethyl ether (27 mL) under a N atmosphere was added tetramethylethylenediamine (1.23 mL, 8.2 mmol), and the reaction mixture was cooled to −78 °C. sec-BuLi (11.8 mL, 10.6 mmol, 0.9 M in cyclohexane) was added, and the mixture was stirred at −78 °C for 30 minutes. Benzyl bromide (1.95 mL, 16.4 mmol) was added dropwise at −78 °C. After the addition was complete, the reaction was allowed to slowly warm to rt overnight. The reaction was quenched with saturated aqueous NH4Cl, the layers were separated, and the aqueous solution was further extracted with Et2O (x2). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The crude product material was purified by silica gel column chromatography (gradient elution, 0-10% EtOAc / iso-hexane) to afford the title compound as separate diastereomers, tert-butyl (1S,2R,5R)-2-benzyl-3-azabicyclo[3.1.0]hexane-3-carboxylate and tert-butyl (1S,2S,5R)-2-benzyl-3-azabicyclo[3.1.0]hexane-3-carboxylate.

[0263] Step 3: (1S*,2S*,5R*)-2-benzyl-3-azabicyclo[3.1.0]hexane To tert-butyl (1S,2S,5R)-2-benzyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (570 mg, 2.09 mmol) was added DCM (5 mL) and TFA (5 mL), and the resulting mixture was stirred at rt for 1 h. The solvent was evaporated and the residue was purified on an SCX cartridge eluting successively with 1:1 DCM:MeOH, followed by 3:1 DCM:7N ammonia in methanol. The ammonia in the methanol fractions was combined and concentrated under reduced pressure to give the title compound. The stereochemistry of the benzyl group relative to the cyclopropyl group was determined by nOe experiment. 1 H NMR (400 MHz, CDCl): δ 7.32–7.17 (5H, m), 3.41 (1H, ddd, J=3.0, 5.5, 8.1 Hz), 2.94 (2H, d, J=1.8 Hz), 2.82 (1H, dd, J=5.9, 13.0 Hz), 2.61 (1H, dd, J=7.8, 13.1 Hz), 1.38–1.32 (1H, m), 1.30–1.23 (1H, m), 0.40–0.34 (1H, m), 0.34–0.30 (1H, m). No NH was observed.

[0264] Step 4: (1S,2R,5R)-2-benzyl-3-azabicyclo[3.1.0]hexane To tert-butyl (1S,2R,5R)-2-benzyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (400 mg, 1.46 mmol) was added DCM (3.5 mL) and TFA (3.5 mL), and the resulting mixture was stirred at rt for 1 h. The solvent was evaporated and the residue was purified on an SCX cartridge eluting successively with DCM:MeOH, 1:1, then 3:1 DCM:7N ammonia in methanol. The ammonia in the methanol fractions was combined and concentrated under reduced pressure to give the title compound. The stereochemistry of the benzyl group relative to the cyclopropyl group was determined by nOe experiment. 1H NMR (400 MHz, CDCl3): δ 7.32 - 7.17 (5H, m), 3.29 (1H, t, J=7.2 Hz), 3.00 (1H, dd, J=3.2, 11.2 Hz), 2.87 (1H, d, J=11.0 Hz), 2.69 (1H, dd, J=7.2, 13.5 Hz), 2.60 (1H, dd, J=7.5, 13.4 Hz), 1.43 - 1.36 (1H, m), 1.29 (1H, ddd, J=4.0, 6.2, 7.9 Hz), 0.45 (1H, dt, J=5.0, 7.7 Hz), 0.15 (1H, dd, J=4.0, 8.7 Hz). NH is not observed.

[0265] Intermediate 3(1R*,2R*,5S*)-2-(4-fluorobenzyl)-3-azabicyclo[3.1.0]hexane and Intermediate 4(1R*,2S*,5S*)-2-(4-fluorobenzyl)-3-azabicyclo[3.1.0]hexane

[0266] [ka]

[0267] Step 1: tert-butyl (1R*,2R*,5S*)-2-(4-fluorobenzyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and tert-butyl (1R*,2S*,5S*)-2-(4-fluorobenzyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (-)-Sparteine ​​was freshly distilled with KOH to give a colorless oil whose optical rotation was that reported in the literature ([α] D 20The resulting mixture was stirred at −78 °C for 10 min and then transferred to a solution of tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (613 mg, 3.35 mmol) in Et2O (11 mL) at −78 °C. The resulting reaction mixture was stirred at −78 °C for 5 h, and then 4-fluorobenzyl bromide (0.63 mL, 5.02 mmol) was added. The mixture was then allowed to warm slowly to room temperature over 3 h. Water was then added, and the aqueous solution was extracted with Et2O (×2). The organic phase was dried (MgSO) and evaporated to give a crude oil that was purified by silica chromatography (gradient elution, 0–25% iso-Hex / EtOAc) to give tert-butyl (1R,2R,5S)-2-(4-fluorobenzyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and tert-butyl (1R,2S,5S)-2-(4-fluorobenzyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.

[0268] Step 2: (1R*,2R*,5S*)-2-(4-fluorobenzyl)-3-azabicyclo[3.1.0]hexane To tert-butyl (1R,2R,5S)-2-(4-fluorobenzyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (176 mg, 0.603 mmol) was added DCM (1.5 mL) and TFA (1.5 mL), and the resulting mixture was stirred at rt for 3 h. The solvent was evaporated, and the residue was partitioned between DCM and saturated aqueous sodium bicarbonate. The combined organic phases were passed through a phase separator and evaporated to give the title compound.

[0269] (1R*,2R*,5S*)-2-(4-fluorobenzyl)-3-azabicyclo[3.1.0]hexane 1H NMR δ (ppm) (400 MHz, CDCl3) 7.23–7.16 (2H, m), 7.00–6.94 (2H, m), 3.44–3.38 (1H, m), 2.96 (2H, d, J=1.9 Hz), 2.80 (1H, dd, J=6.0, 13.2 Hz), 2.61 (1H, dd, J=7.9, 13.3 Hz), 1.43–1.36 (1H, m), 1.30–1.23 (1H, m), 0.42–0.31 (2H, m). No NH is observed. The nOe observed between the cyclopropyl and benzyl CH2 is consistent with cis relative stereochemistry.

[0270] Step 3: (1R*,2S*,5S*)-2-(4-fluorobenzyl)-3-azabicyclo[3.1.0]hexane To tert-butyl (1R,2S,5S)-2-(4-fluorobenzyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (320 mg, 1.10 mmol) was added DCM (1.5 mL) and TFA (1.5 mL), and the resulting mixture was stirred at rt for 3 h. The solvent was evaporated, and the residue was partitioned between DCM and saturated aqueous sodium bicarbonate. The combined organic phase was passed through a phase separator and evaporated to give the title compound.

[0271] (1R*,2S*,5S*)-2-(4-Fluorobenzyl)-3-azabicyclo[3.1.0]hexane 1H NMR δ (ppm) (400 MHz, CDCl3) 7.21–7.14 (2H, m), 7.00–6.95 (2H, m), 3.26 (1H, t, J=7.2 Hz), 2.98 (1H, dd, J=3.4, 11.2 Hz), 2.87 (1H, d, J=11.2 Hz), 2.69–2.55 (2H, m), 1.45–1.34 (1H, m), 1.31–1.26 (1H, m), 0.48 (1H, dt, J=5.0, 7.7 Hz), 0.16 (1H, q, J=4.4 Hz), no NH. The nOe seen between the cyclopropyl CH2 and NCH is consistent with trans relative stereochemistry.

[0272] Intermediate 5: (R)-5-benzylpyrrolidin-2-one

[0273] [ka]

[0274] Intermediate 5 was prepared according to the route described in Journal of the American Chemical Society, Vol. 138, No. 51, pp. 16839-16848.

[0275] Intermediate 6: (2R*,3S*)-2-benzyl-3-methylpyrrolidine

[0276] [ka]

[0277] Step 1: tert-Butyl (2R*,3S*)-2-benzyl-3-methylpyrrolidine-1-carboxylate Palladium(II) acetate (18 mg, 0.08 mmol), Dpe-phos (86 mg, 0.16 mmol), and sodium tert-butoxide (884 mg, 9.2 mmol) were placed in a sealed reaction tube, which was evacuated and backfilled with nitrogen (x3). 3-Methylpent-4-en-1-yl)carbamate (798 mg, 4.0 mmol) was dissolved in dioxane (16 mL) and degassed. The solution, followed by bromobenzene (0.25 mL, 4.8 mmol), was added to the reaction tube, and the reaction was heated at 100 °C for 17.5 h. The reaction mixture was cooled to rt and diluted with NHCl. The reaction mixture was extracted with EtOAc (x3). The organic extracts were dried (phase separator) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution, 2-20% EtOAc / iso-hexane) to give the title compound.

[0278] Step 2: (2R*,3S*)-2-benzyl-3-methylpyrrolidine tert-Butyl (2R*,3S*)-2-benzyl-3-methylpyrrolidine-1-carboxylate (785 mg, 2.85 mmol) was dissolved in 4 M HCl in dioxane (7.1 mL) with stirring at rt. After 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with saturated NaHCO3 solution. The organic extract was dried (phase separator) and concentrated under reduced pressure to give the title compound. 1 H NMR (400 MHz, CDCl): δ 7.32–7.16 (5H, m), 3.00–2.79 (3H, m), 2.77–2.68 (1H, m), 2.59 (1H, dd, J=8.5, 13.3 Hz), 2.08–1.96 (1H, m), 1.76–1.66 (1H, m), 1.42–1.31 (1H, m), 1.00 (3H, d, J=6.6 Hz), no NH observed.

[0279] Intermediate 7: (2R*,3S*)-2-(2-methoxybenzyl)-3-methylpyrrolidine

[0280] [ka]

[0281] Step 1: tert-Butyl (2R*,3S*)-2-(2-methoxybenzyl)-3-methylpyrrolidine-1-carboxylate Palladium(II) acetate (4.5 mg, 0.02 mmol), Dpe-phos (22 mg, 0.04 mmol), and sodium tert-butoxide (221 mg, 2.30 mmol) were placed in a sealed reaction tube, which was evacuated and backfilled with nitrogen (x3). 3-Methylpent-4-en-1-yl)carbamate (199 mg, 1.00 mmol) was dissolved in dioxane (4 mL) and degassed. The solution, followed by 2-bromoanisole (0.15 mL, 1.2 mmol), was added to the reaction tube, and the reaction was heated at 100 °C for 17.25 h. The reaction mixture was cooled to rt and diluted with NH4Cl. The reaction mixture was extracted with EtOAc (x3). The organic extracts were dried (phase separator) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution, 2–20% EtOAc / iso-hexane) to give the title compound.

[0282] Step 2: (2R*,3S*)-2-(2-Methoxybenzyl)-3-methylpyrrolidine tert-Butyl (2R*,3S*)-2-(2-methoxybenzyl)-3-methylpyrrolidine-1-carboxylate (216 mg, 0.71 mmol) was dissolved in 4 M HCl in dioxane (1.8 mL) with stirring at rt. After 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved and purified on an SCX cartridge eluting with DCM (3 CV), methanol (3 CV), followed by 4:1 DCM:7N methanolic ammonia (6 CV). The methanolic ammonia fractions were combined and concentrated under reduced pressure to give the title compound. 1H NMR (400 MHz, CDCl3): δ 7.21 - 7.16 (2H, m), 6.91 - 6.82 (2H, m), 3.81 (3H, s), 3.01 - 2.78 (4H, m), 2.73 (1H, br s), 2.64 (1H, dd, J=8.1, 13.4 Hz), 2.06 - 1.94 (1H, m), 1.78 - 1.68 (1H, m), 1.42 - 1.30 (1H, m), 0.98 (3H, d, J=7.8 Hz).

[0283] Intermediate 8: 2-(4-fluoro-2-methoxybenzyl)azepane

[0284] [ka]

[0285] Step 1: tert-butyl 2-((4-fluoro-2-methoxyphenyl)(hydroxy)methyl)azepane-1-carboxylate TMEDA (0.75 mL, 5.01 mmol) was added to a solution of tert-butyl azepane-1-carboxylate (1 g, 5.01 mmol) in EtO (10 mL). The mixture was cooled to −78° C., and sec-BuLi (4.66 mL, 6.52 mmol, 1.4 M in cyclohexane) was added dropwise. After 2 h, 4-fluoro-2-methoxybenzaldehyde (0.85 g, 5.52 mmol) in EtO (5 mL) was added dropwise at −78° C. After 3 h, during which time the cooling bath temperature was raised to −20° C., the reaction was quenched with water. The ether was removed in vacuo, the remaining aqueous layer was extracted with DCM, and the layers were separated using a phase separator. The DCM was removed in vacuo to give the title compound, which was used in the next step without further purification.

[0286] Step 2: 1-(4-fluoro-2-methoxyphenyl)hexahydro-1H,3H-oxazolo[3,4-a]azepin-3-one KOtBu (56 mg, 0.50 mmol) was added to a solution of tert-butyl 2-((4-fluoro-2-methoxyphenyl)(hydroxy)methyl)azepane-1-carboxylate (1.22 g, 3.46 mmol) in i-PrOH (20 mL). The reaction mixture was heated to reflux for 4 h and then cooled to rt. The solvent was removed in vacuo to give an oily residue, which was purified by silica gel column chromatography (gradient elution, 0-30% EtOAc / iso-hexane) to give the title compound.

[0287] Step 3: 2-(4-fluoro-2-methoxybenzyl)azepane To a solution of 1-(4-fluoro-2-methoxyphenyl)hexahydro-1H,3H-oxazolo[3,4-a]azepin-3-one (700 mg, 2.51 mmol) in MeOH (5 mL) was added NaOMe (0.48 mL, 2.63 mmol, 5.5 M solution in methanol) and Pd(OH) (63 mg, 25 g / mol). The mixture was stirred under hydrogen (1 atmosphere) at room temperature for 48 hours. The reaction was filtered through Celite, washed with MeOH, and the collected solution was acidified to approximately pH 2 with 1 M HCl. The solvent was removed in vacuo, and the residue was purified by SCX chromatography (eluting with 50% MeOH / DCM followed by 10% 7N methanolic ammonia in methanol / methanol). Concentration of the ammonia fraction in vacuo afforded the title compound. 1 H NMR (400 MHz, CDCl): δ 7.07-7.04 (1H, m), 6.61-6.56 (2H, m), 3.79 (3H, s), 2.99-2.93 (1H, m), 2.91-2.84 (1H, m), 2.68-2.54 (3H, m), 1.80-1.44 (7H, m), 1.41-1.31 (1H, m), no NH observed.

[0288] The following examples were prepared using procedures similar to those described for intermediate 8 starting from the reported aldehyde.

[0289] [Table 6] TIFF0007727627000096.tif155169

[0290] Intermediate 20: 2-benzyl-4,4-dimethylazepane

[0291] [ka]

[0292] Step 1: 2-benzyl-4,4-dimethylcyclohexan-1-one 4,4-Dimethylcyclohexan-1-one (1 g, 7.93 mmol) in THF (15 mL) was added dropwise to a solution of LDA (4.36 mL, 8.73 mmol, 2 M in THF) at −40° C. After stirring at 40° C. for 1 h, benzyl bromide (1.04 mL, 8.73 mmol) was added dropwise and the reaction was allowed to warm to rt over 3 h. The reaction was quenched by the addition of 1 M HCl and the THF was removed in vacuo. The aqueous layer was extracted with DCM and the layers were separated using a phase separator. The DCM layer was concentrated in vacuo to give a residual oil that was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc / iso-hexane) to give the title compound.

[0293] Step 2: 7-benzyl-5,5-dimethylazepan-2-one To a solution of 2-benzyl-4,4-dimethylcyclohexan-1-one (850 mg, 3.93 mmol) in methanesulfonic acid (2 mL) was added sodium azide (270 mg, 4.13 mmol) in portions, maintaining the internal temperature below 30° C. After the addition was complete, the reaction was stirred at rt for 2 h. The reaction mixture was added to water, and the resulting white solid was collected by filtration. The solid was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) to provide the title compound.

[0294] Step 3: 2-benzyl-4,4-dimethylazepane To a solution of 7-benzyl-5,5-dimethylazepan-2-one (430 mg, 1.86 mmol) in THF (10 mL) was added LiAlH (3.7 mL, 3.72 mmol, 1 M in THF). The reaction was heated to reflux for 3 h. The reaction was cooled to 0 °C and quenched by the addition of water. The THF was removed in vacuo and the aqueous layer was extracted with EtOAc. The layers were separated and the EtOAc layer was dried (MgSO). The solvent was removed in vacuo to give a residual oil that was purified by silica gel column chromatography (gradient elution, 0-10% DCM / MeOH) to give the title compound. 1 H NMR (400 MHz, CDCl): δ 7.31-7.28 (2H, m), 7.22-7.19 (3H, m), 3.03-2.97 (1H, m), 2.94-2.87 (1H, m), 2.68-2.55 (3H, m), 1.61-1.39 (6H, m), 0.92 (3H, s), 0.89 (3H, s), NH absent.

[0295] The following examples were prepared using a similar procedure to that described for intermediate 20 starting from the appropriate aldehyde and cyclohexanone:

[0296] [Table 7]

[0297] Intermediate 26: 2-(thiophen-3-ylmethyl)azepane

[0298] [ka]

[0299] Step 1: (E)-2-(thiophen-3-ylmethylene)cyclohexan-1-one Sodium hydroxide (1.6 g, 40.12 mmol) was added to cyclohexanone (7.88 g, 80.25 mmol) suspended in water (150 mL) at rt. The reaction was stirred for 15 minutes before 3-thiophenecarboxaldehyde (3 g, 26.75 mmol) was added dropwise. After 18 hours, the resulting solid was collected by filtration and air-dried to give a yellow solid that was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc / iso-hexane) to give the title compound.

[0300] Step 2: 2-(Thiophen-3-ylmethyl)cyclohexan-1-one (£)-2-(Thiophen-3-ylmethylene)cyclohexan-1-one (800 mg, 4.17 mmol) was dissolved in MeOH (80 mL) and passed through an H-Cube reactor equipped with a 10% palladium on carbon CatCart (1 mL / min, 50 bar, rt). The collected eluent solvent was concentrated in vacuo to give a yellow solid, which was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc / iso-hexane) to give the title compound.

[0301] Step 3: 2-(Thiophen-3-ylmethyl)cyclohexan-1-one oxime 2-(Thiophen-3-ylmethyl)cyclohexan-1-one (800 mg, 4.12 mmol) was dissolved in MeOH (10 mL) and water (6 mL). Sodium carbonate (1.31 g, 12.35 mmol) was added, followed by hydroxylamine hydrochloride (572 mg, 8.24 mmol), and the reaction was stirred at rt overnight. The solvent was removed in vacuo, and the residue was suspended in DCM and water. The DCM layer was separated using a phase separator and concentrated in vacuo to give the title compound. It was used in the next step without further purification.

[0302] Step 4: 7-(Thiophen-3-ylmethyl)azepan-2-one 2-(Thiophen-3-ylmethyl)cyclohexan-1-one oxime (857 mg, 4.09 mmol) was dissolved in acetone (50 mL) and water (50 mL). Sodium carbonate (1.74 g, 16.38 mmol) was added, followed by tosyl chloride (1.56 g, 8.19 mmol), and the reaction was stirred at rt overnight. The solvent was removed in vacuo, and the residue was dissolved in DCM and washed with water. The layers were separated using a phase separator, and the DCM layer was concentrated in vacuo to give a yellow solid residue. Purification by silica gel column chromatography (gradient elution, 0-30% EtOAc / iso-hexane) afforded the title compound.

[0303] Step 5: 2-(Thiophen-3-ylmethyl)azepane To a solution of 7-(thiophen-3-ylmethyl)azepan-2-one (620 mg, 2.96 mmol) in THF (20 mL) was added lithium aluminum hydride (3 mL, 5.29 mmol, 2 M solution in THF) at rt. The reaction was heated to reflux for 3 h. The reaction was cooled to rt, then 0 °C and quenched by careful addition of water. The THF was removed in vacuo and the aqueous layer was extracted with EtOAc. The layers were separated and the EtOAc layer was dried (phase separator) and concentrated in vacuo to give a residual oil that was purified by SCX chromatography (eluting with 50% MeOH / DCM followed by 10% 7N methanolic ammonia in methanol / methanol). Concentration of the ammonia fraction in vacuo gave the title compound. 1 H NMR (400 MHz, CDCl): δ 7.27-7.25 (1H, m), 6.99 (1H, s), 6.96 (1H, d, J = 5.1 Hz), 2.99-2.94 (1H, m), 2.90-2.83 (1H, m), 2.75-2.56 (3H, m), 1.84-1.78 (1H, m), 1.74-1.47 (6H, m), 1.41-1.31 (1H, m), no NH observed.

[0304] Intermediate 27: 4,4-Difluoro-2-(2-methoxybenzyl)azepane

[0305] [ka]

[0306] Step 1: (E)-4,4-Difluoro-2-(2-methoxybenzylidene)cyclohexan-1-one Sodium hydroxide (0.75 g, 18.64 mmol) was added to a suspension of 4,4-difluorocyclohexan-1-one (5 g, 37.28 mmol) in water (100 mL) at rt. After 15 min, 2-methoxybenzaldehyde (1.69 g, 12.43 mmol) was added portionwise. After 72 h, the reaction mixture was extracted with DCM, and the DCM layer was separated using a phase separator. The DCM layer was concentrated in vacuo to give a residue that was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc / iso-hexane) to give the title compound.

[0307] Step 2: 4,4-Difluoro-2-(2-methoxybenzyl)cyclohexan-1-one (£)-4,4-Difluoro-2-(2-methoxybenzylidene)cyclohexan-1-one (1.8 g, 7.14 mmol) was dissolved in MeOH (180 mL) and passed through an H-Cube reactor equipped with a 10% palladium on carbon CatCart (1 mL / min, 50 bar, rt). The collected eluent was concentrated in vacuo to give a yellow solid, which was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc / iso-hexane) to give the title compound.

[0308] Step 3: 5,5-Difluoro-7-(2-methoxybenzyl)azepan-2-one To a solution of 4,4-difluoro-2-(2-methoxybenzyl)cyclohexan-1-one (1.1 g, 4.33 mmol) in methanesulfonic acid (8 mL) was added sodium azide (0.3 g, 4.54 mmol) in portions over 30 min at rt. After 1 h, the reaction was added to water. The aqueous layer was extracted with DCM, and the layers were separated using a phase separator. The DCM layer was concentrated in vacuo to give an oil that was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) to give the title compound.

[0309] Step 4: 4,4-Difluoro-2-(2-methoxybenzyl)azepane LiAlH4 (2.5 mL, 4.93 mmol, 2 M solution in THF) was added to a solution of 4,4-difluoro-2-(2-methoxybenzyl)azepane (664 mg, 2.47 mmol) in THF (10 mL) at rt. The reaction was heated to reflux for 3 h. The reaction was cooled to rt, then 0 °C and quenched by careful addition of water. THF was removed in vacuo and the aqueous layer was extracted with EtOAc. The layers were separated and the EtOAc layer was dried (phase separator) and concentrated in vacuo to give a residual oil that was purified by SCX chromatography (eluting with 50% MeOH / DCM followed by 10% 7N methanolic ammonia in methanol / methanol). Concentration of the ammonia fraction in vacuo gave the title compound. 1 H NMR (400 MHz, CDCl): δ 7.22 (1H, t, J = 7.8 Hz), 7.11 (1H, d, J = 6.8 Hz), 6.92-6.86 (2H, m), 3.83 (3H, s), 3.09-3.00 (2H, m), 2.75-2.64 (3H, m), 2.30-1.92 (4H, m), 1.72-1.66 (2H, m), no NH.

[0310] The following example was prepared using a similar procedure as described for intermediate 27 starting from 4-methylcyclohexanone and 2-methoxybenzaldehyde.

[0311] [Table 8]

[0312] Intermediate 29: (R)-2-benzyl-6,6-dimethylazepane, Intermediate 30: Diastereomer 1 of (2R)-2-benzyl-6-methylazepane, and Intermediate 31: Diastereomer 2 of (2R)-2-benzyl-6-methylazepane

[0313] [ka]

[0314] Step 1: tert-Butyl (R)-2-benzyl-7-oxoazepane-1-carboxylate (R)-7-benzylazepan-2-one (3 g, 14.8 mmol, Example 3, Step 1) was dissolved in MeCN (25 mL), di-tert-butyl dicarbonate (4.8 g, 22.2 mmol) and 4-(dimethylamino)pyridine (2.7 g, 22.2 mmol) were added, and the mixture was heated to reflux for 18 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc / iso-hexane) to give the title compound.

[0315] Step 2: tert-butyl (R)-7-benzyl-3,3-dimethyl-2-oxoazepane-1-carboxylate, tert-butyl (7R)-7-benzyl-3-methyl-2-oxoazepane-1-carboxylate diastereomer 1 and tert-butyl (7R)-7-benzyl-3-methyl-2-oxoazepane-1-carboxylate diastereomer 2 tert-Butyl (R)-2-benzyl-7-oxoazepane-1-carboxylate (960 mg, 3.17 mmol) was dissolved in THF and cooled to -78 °C. LHMDS (7.9 mL, 7.9 mmol, 1 M in THF) was added, and the resulting mixture was stirred at -78 °C for 1 h. MeI (490 μL, 7.9 mmol) was added, and the reaction was allowed to warm to rt over 19 h. Water and EtO were added, the two phases were separated, and the aqueous phase was re-extracted with EtO (×1). The combined organic phases were dried (MgSO) and evaporated to give a crude oil, which was purified by silica gel column chromatography (gradient elution, 0–4% EtOAc / iso-hexane) to give the title compound. The first eluting component, tert-butyl (R)-7-benzyl-3,3-dimethyl-2-oxoazepane-1-carboxylate, was obtained. The second and third eluting compounds were tert-butyl (7R)-7-benzyl-3-methyl-2-oxoazepane-1-carboxylate diastereomer 1 and tert-butyl (7R)-7-benzyl-3-methyl-2-oxoazepane-1-carboxylate diastereomer 2, respectively.

[0316] Step 3: (R)-7-benzyl-3,3-dimethylazepan-2-one DCM (1.5 mL) and TFA (1.5 mL) were added to tert-butyl (R)-7-benzyl-3,3-dimethyl-2-oxoazepane-1-carboxylate (200 mg, 0.60 mmol), and the resulting mixture was stirred at rt. After 3 h, the solvent was evaporated, and the residue was partitioned between DCM and saturated aqueous NaHCO3 and extracted again with DCM. The combined organic phases were dried (phase separator) and evaporated to give the title compound.

[0317] Step 4: (7R)-7-benzyl-3-methylazepan-2-one diastereomer 1 The title compound was obtained following the procedure described for Intermediate 29, Step 3 starting from tert-butyl (7R)-7-benzyl-3-methyl-2-oxoazepane-1-carboxylate diastereomer 1 (60 mg, 0.189 mmol).

[0318] Step 5: (7R)-7-benzyl-3-methylazepan-2-one diastereomer 2 The title compound was obtained following the procedure described for Intermediate 29, Step 3 starting from tert-butyl (7R)-7-benzyl-3-methyl-2-oxoazepane-1-carboxylate diastereomer 2 (150 mg, 0.473 mmol).

[0319] Step 6: (R)-2-benzyl-6,6-dimethylazepane Lithium aluminum hydride (1.2 mL, 1.2 mmol, 1 M solution in THF) was added to a solution of (R)-2-benzyl-6,6-dimethylazepane (140 mg, 0.61 mmol) in THF (3 mL) and heated to 70° C. for 3 h. The mixture was carefully quenched with aqueous NaOH (15% solution) and the THF was evaporated. The aqueous phase was extracted with EtOAc (×2). The organic phase was dried (MgSO4) and evaporated to give the title compound, which was used in the next step without purification. 1 H NMR (400 MHz, CDCl3): δ 7.32 - 7.26 (2H, m), 7.23 - 7.16 (3H, m), 2.87 - 2.77 (1H, m), 2.70 (1H, dd, J=5.1, 13.5 Hz), 2.64 - 2.53 (2H, m), 2.30 (1H, d, J=13.6 Hz), 1.77 - 1.26 (6H, m), 0.91 (3H, s), 0.79 (3H, s).

[0320] Step 7: (2R)-2-benzyl-6-methylazepane diastereomer 1 Following the procedure described for Intermediate 29, Step 6 starting from (7R)-7-benzyl-3-methylazepan-2-one diastereomer 1 (42 mg, 0.19 mmol) gave the title compound. 1H NMR (400 MHz, CDCl): δ 7.32–7.25 (2H, m), 7.23–7.15 (3H, m), 2.96–2.87 (1H, m), 2.76–2.55 (4H, m), 1.87–1.56 (4H, m), 1.44–1.14 (3H, m), 0.88 (3H, d, J=6.6 Hz), no NH observed.

[0321] Step 8: (2R)-2-benzyl-6-methylazepane diastereomer 2 Following the procedure described for Intermediate 29, Step 6 starting from (7R)-7-benzyl-3-methylazepan-2-one diastereomer 2 (84 mg, 0.39 mmol) gave the title compound. 1 H NMR (400 MHz, CDCl): δ 7.32–7.25 (2H, m), 7.24–7.17 (3H, m), 2.95–2.84 (2H, m), 2.72 (1H, dd, J=5.2, 13.5 Hz), 2.57 (1H, dd, J=8.6, 13.4 Hz), 2.16 (1H, dd, J=10.5, 13.3 Hz), 1.82–1.71 (3H, m), 1.63–1.19 (4H, m), 0.80 (3H, d, J=6.6 Hz), no NH observed.

[0322] 4.General method

[0323] [ka]

[0324] Method C A suspension of aryl halide (1.0 eq.), amine (1.0 eq.), and CsCO (1.5 eq.) in dry 1,4-dioxane (0.2 M) was sparged with N for 15 min. Pd(dba) (0.053 eq.) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.2 eq.) were then added, and the reaction tube was sealed under N and stirred at 100 °C for 16–40 h. After cooling to rt, the mixture was filtered through Celite, washed thoroughly with CHCl, and the filtrate was concentrated.

[0325] Method D For solid amines, the following procedure was followed: A mixture of amine (1.0–1.4 eq), aryl halide (1.0 eq), CsCO or NaOtBu (1.1 eq), RuPhos (0.05–0.1 eq), and RuPhos palladacycle G1 methyl tert-butyl ether adduct (0.05–0.1 eq) was placed in a stem-block tube and sealed. The tube was evacuated and backfilled with nitrogen (x3). 1,4-Dioxane (0.08–0.15 M) was added, and the reaction was heated at 85 °C for 16 h. The reaction mixture was cooled to rt and filtered through Celite. The mixture was concentrated under reduced pressure.

[0326] In the case of the amine, which was an oil, it was introduced as a solution in dry 1,4-dioxane.

[0327] Method E To a solution of the PMB-protected compound (1.0 eq.) in ethanol (0.15 M) was added 5% palladium on carbon (100 wt. % of the PMB compound), and the reaction mixture was purged with N2 for 20 min. 1-Methylcyclohexa-1,4-diene (10 eq.) was added, and the reaction was heated at 75 °C for 1-18 h. The reaction was cooled to rt, filtered through Celite, and washed with methanol. The solution was concentrated under reduced pressure.

[0328] 5. Synthesis of Example Compounds Example 1: (R)-6-(2-benzylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 2: (S)-6-(2-benzylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0329] [ka]

[0330] Step 1: 4-(2-(2-benzylpyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Method C was followed, starting with 2-benzylpyrrolidine (53 mg, 0.30 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (101 mg, 0.30 mmol, scaffold 1). After heating at 105 °C for 18.5 h, an additional 0.5 eq. pyrrolidine, 1.6 eq. cesium carbonate, 0.025 eq. Pd2(dba)3, and 0.1 eq. BINAP were added, and the reaction was heated at 105 °C for an additional 23 h. The reaction was cooled to rt, filtered through Celite, washed with DCM, and the reaction was concentrated under reduced pressure. The reaction was repeated on an identical scale using 1,4-dioxane as the solvent. The crude mixtures from both reactions were combined and purified by silica gel column chromatography (gradient elution, 0-25% EtOAc / iso-hexane) to give the title compound (170 mg, 61%).

[0331] Step 2: (S)-6-(2-benzylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and (R)-6-(2-benzylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one Following method E from 4-(2-(2-benzylpyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (150 mg, 0.32 mmol). Purification by reverse phase preparative HPLC followed by SFC gave the title compound:

[0332] 6-[(2S)-2-benzylpyrrolidin-1-yl]-4-morpholino-1H-pyridin-2-one; LCMS (ES+) 340 (M+H) + , RT 2.96 min (analytical method B); RT 5.78 min (analytical method SFC1, YMC Cellulose-SC, 45 / 55 IPA (0.1% DEA) / CO2); 1 H NMR (400 MHz, DMSO-d6): δ 9.68 (1H, s), 7.32 - 7.29 (4H, m), 7.25 - 7.19 (1H, m), 5.15 (2H, s), 4.22 - 4.19 (1H, m), 3.71 - 3.67 (4H, m), 3.42 - 3.36 (1H, m), 3.21 - 3.14 (5H, m), 2.97 (1H, dd, J=3.5, 13.1 Hz), 2.56 (1H, dd, J=9.3, 13.2 Hz), 1.83 - 1.68 (4H, m).

[0333] 6-[(2R)-2-benzylpyrrolidin-1-yl]-4-morpholino-1H-pyridin-2-one; LCMS (ES+) 340 (M+H) + , RT 2.97 min (Analysis Method B); RT 4.62 min (Analysis Method SFC1, YMC Cellulose-SC, 45 / 55 IPA (0.1% DEA) / CO2); 1 H NMR (400 MHz, DMSO-d6): δ 9.68 (1H, s), 7.32 - 7.29 (4H, m), 7.25 - 7.19 (1H, m), 5.15 (2H, s), 4.22 - 4.19 (1H, m), 3.71 - 3.67 (4H, m), 3.42 - 3.36 (1H, m), 3.21 - 3.14 (5H, m), 2.97 (1H, dd, J=3.5, 13.1 Hz), 2.56 (1H, dd, J=9.3, 13.2 Hz), 1.83 - 1.68 (4H, m).

[0334] Example 2: (S)-6-(2-benzylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0335] [ka]

[0336] Step 1: tert-Butyl (S)-2-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate Phenylmagnesium bromide (15 mL, 15 mmol, 1.0 M in THF) was added dropwise to a solution of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (2.00 g, 10 mmol) in dry THF (20 mL) at −78° C. The reaction mixture was stirred at −78° C. for 2.5 h before being quenched with saturated aqueous NH4Cl and diluted with water (10 mL). The mixture was extracted with EtOAc (×2), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (gradient elution, 0-25% EtOAc / iso-hexane) afforded the title compound.

[0337] Step 2: tert-Butyl (S)-2-(((1H-imidazole-1-carbonothioyl)oxy)(phenyl)methyl)pyrrolidine-1-carboxylate To a solution of tert-butyl (R)-2-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (242 mg, 0.87 mmol) in anhydrous THF (10 mL) was added DMAP (11 mg, 0.087 mmol) and diimidazolethiocarbonyl (233 mg, 1.31 mmol). The resulting solution was heated to reflux overnight. The solution was cooled to rt and the solvent was removed in vacuo. The residue was dissolved in DCM, washed with water, and the layers were separated and dried (phase separator). The DCM was removed in vacuo and the resulting residue was purified by silica gel column chromatography (gradient 0-50% EtOAc / iso-hexane) to give the title compound.

[0338] Step 3: tert-Butyl (S)-2-benzylpyrrolidine-1-carboxylate To a solution of tert-butyl (R)-2-(((1H-imidazole-1-carbonothioyl)oxy)(phenyl)methyl)pyrrolidine-1-carboxylate (195 mg, 0.5 mmol) in anhydrous toluene (2 mL) was added tributyltin hydride (0.41 mL, 1.51 mmol) and AIBN (16 mg, 0.1 mmol). The solution was heated to reflux for 6 h and then cooled to rt. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (gradient 0-20% EtOAc / iso-hexane) to give the product.

[0339] Step 4: (S)-2-Benzylpyrrolidine tert-Butyl (S)-2-benzylpyrrolidine-1-carboxylate (82 mg, 0.31 mmol) was dissolved in 4N HCl / dioxane (5 ml) and stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was purified by SCX chromatography (eluted with MeOH / DCM 1:1, then recovered with 10% 7N NH3 in MeOH / MeOH) to give the title compound.

[0340] Step 5: (S)-4-(2-(2-benzylpyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method C, starting with (S)-2-benzylpyrrolidine (26 mg, 0.16 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (53 mg, 0.16 mmol, scaffold 1). After heating at 105 °C for 115 h, the reaction mixture was cooled to rt, filtered through Celite, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc / iso-hexane) to give the title compound.

[0341] Step 6: (S)-6-(2-benzylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one Following Method E starting with (S)-4-(2-(2-benzylpyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (35 mg, 0.08 mmol). The crude material was purified by reverse phase preparative HPLC and lyophilized from MECN / H2O to give the title compound. LCMS (ES+) 340 (M+H) + , RT 2.74 min (Analysis Method A); RT 7.62 min (Analysis Method SFC1, YMC Cellulose-SC, 45 / 55 IPA (0.1% DEA) / CO2); 1 H NMR (400 MHz, DMSO-d6): δ 9.68 (1H, s), 7.32 - 7.29 (4H, m), 7.25 - 7.19 (1H, m), 5.15 (2H, s), 4.22 - 4.19 (1H, m), 3.71 - 3.67 (4H, m), 3.42 - 3.36 (1H, m), 3.21 - 3.14 (5H, m), 2.97 (1H, dd, J=3.5, 13.1 Hz), 2.56 (1H, dd, J=9.3, 13.2 Hz), 1.83 - 1.68 (4H, m).

[0342] Example 3: (R)-6-(2-benzylazepan-1-yl)-4-morpholinopyridin-2(1H)-one

[0343] [ka]

[0344] Step 1: tert-butyl (R)-(5-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-5-oxo-1-phenylpentan-2-yl)carbamate (R)-4-((tert-butoxycarbonyl)amino)-5-phenylpentanoic acid (3.0 g, 10.2 mmol) was dissolved in DCM (50 mL) and cooled to 0 °C. Meldrum's acid (1.47 g, 10.2 mmol), EDC hydrochloride (2.94 g, 15.3 mmol), and DMAP (1.87 g, 15.3 mmol) were added sequentially to the reaction. The reaction mixture was stirred for 19 h, and the ice bath was removed after 1 h. The reaction was transferred to a separatory funnel and washed with 1 M aqueous potassium hydrogen sulfate. The organic extract was dried (phase separator) and concentrated under reduced pressure to give the title compound. It was used in the next step without further purification.

[0345] Step 2: tert-butyl (R)-(5-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-phenylpentan-2-yl)carbamate tert-Butyl (R)-(5-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-5-oxo-1-phenylpentan-2-yl)carbamate (2.1 g, 5.01 mmol) was dissolved in DCM (50 mL) and cooled to 0 °C. Acetic acid (3.16 mL, 55.1 mmol) was added, followed by the portionwise addition of NaBH (759 mg, 20.05 mmol). The reaction was stirred at 0 °C for 3.5 h. The reaction mixture was carefully quenched by the dropwise addition of water (5 mL), followed by brine (ca. 100 mL). The layers were separated and the aqueous layer was extracted with DCM. The combined layers were washed with brine, dried (MgSO), filtered, and concentrated under reduced pressure to provide the title compound. Used in the next step without further purification.

[0346] Step 3: tert-Butyl (R)-6-((tert-butoxycarbonyl)amino)-7-phenylheptanoate tert-Butyl (R)-(5-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-phenylpentan-2-yl)carbamate (1.86 g, 4.59 mmol) was dissolved in toluene (5 mL) and t-BuOH (5 mL). The reaction mixture was refluxed for 6 h. After this time, the solvent was removed under reduced pressure. The resulting oil was dissolved in toluene and heated to reflux for 25 h. The reaction mixture was concentrated under reduced pressure. The oil was dissolved in DCM and NaHCO3 (sat. aq.) was added. The layers could not be separated. A small amount of brine was added and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried (phase separator) and concentrated under reduced pressure. The crude oil was purified by silica gel column chromatography (gradient elution 0-30% EtOAc / iso-hexane) to give the title compound.

[0347] Step 4: (R)-6-amino-7-phenylheptanoic acid TFA (2 mL) was added to tert-butyl (R)-6-((tert-butoxycarbonyl)amino)-7-phenylheptanoate (457 mg, 1.21 mmol) in DCM (2 mL) with stirring at rt. After 1.5 h, the reaction mixture was concentrated under reduced pressure to give a yellow oil. The oil was dissolved in 4 M HCl in dioxane (10 mL) and stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure and dissolved in 4 M HCl in dioxane (10 mL). After 6 h, the reaction mixture was concentrated under reduced pressure and used in the next step without further purification.

[0348] Step 5: (R)-7-Benzylazepan-2-one EDC (348 mg, 1.82 mmol) and HOPO (201 mg, 1.82 mmol) were added to a solution of (R)-6-amino-7-phenylheptanoic acid (1.21 mmol) and triethylamine (1.01 mL, 7.26 mmol) in DMF (13 mL) with stirring at rt. After 54.5 h, the reaction mixture was transferred to a separatory funnel and diluted with DCM. The reaction mixture was washed successively with 1 M HCl (aq), NaHCO3 (sat. aq.), and brine. The organics were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution 50-70% EtOAc / iso-hexane) to give the title compound.

[0349] Step 6: (R)-2-Benzylazepane Lithium aluminum hydride (0.59 mL, 0.59 mmol, 1 M solution in THF) was added dropwise to an ice-cold solution of (R)-7-benzylazepan-2-one (60 mg, 0.30 mmol) in THF (2 mL). The reaction mixture was warmed to rt and heated at reflux for 3 h. The reaction mixture was cooled to rt, then to 0 °C, and carefully quenched with water. THF was removed under reduced pressure. The mixture was diluted with water and EtOAc. The layers were separated, and the organic extract was dried (MgSO), filtered, and concentrated under reduced pressure. The resulting oil was purified by SCX cartridge. The sample was loaded into DCM and eluted with 3 column volumes of DCM, 3 column volumes of methanol, and 3 column volumes of 7N NH in MeOH / DCM (1:9). The basic fractions were combined and concentrated under reduced pressure to give the title compound. This was used in the next step without further purification.

[0350] Step 7: (R)-4-(2-(2-benzylazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D starting with 2-(R)-benzylazepane (64 mg, 0.19 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (40 mg, 0.21 mmol, scaffold 1). The residue was purified by silica gel column chromatography (gradient elution 0-100% EtO / iso-hexane) to give the title compound.

[0351] Step 8: (R)-6-(2-benzylazepan-1-yl)-4-morpholinopyridin-2(1H)-one Method E was followed, starting with (R)-4-(2-(2-benzylazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (31 mg, 0.064 mmol). The reaction was filtered through Celite and washed thoroughly with MeOH. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (gradient elution 0-20% MeOH / EtOAc) to give the title compound. LCMS (ES+) 368 (M+H)+, RT 2.91 min (Analytical Method A); RT 2.02 min (85.8% ee) (Analytical Method SFC1, YMC Amylose-C, 35 / 65 IPA + 0.1% DEAISO / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.31 - 7.21 (3H, m), 7.16 - 7.12 (2H, m), 5.17 (1H, d, J=2.0 Hz), 4.89 (1H, d, J=2.0 Hz), 3.80 - 3.75 (6H, m), 3.40 - 3.35 (1H, m), 3.22 - 3.18 (4H, m), 2.99 (1H, dd, J=11.7, 16.0 Hz), 2.87 - 2.76 (2H, m), 2.15 - 2.05 (1H, m), 1.84 - 1.70 (2H, m), 1.57 - 1.45 (2H, m), 1.31 - 1.13 (2H, m).

[0352] Chiral Compounds: For all subsequent chiral compounds in which the enantiomers were separated by chiral SFC purification, stereochemical assignments were made based on the biological activity of each enantiomer in biochemical assays: all R enantiomers were assigned as the biologically active conformation based on the biological activity results obtained with chirally pure synthesized (R)-6-(2-benzylazepan-1-yl)-4-morpholinopyridin-2(1H)-one (Example 3) and the lack of biological activity shown by (S)-6-(2-benzylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one (Example 2).

[0353] Example 3: (R)-6-(2-benzylazepan-1-yl)-4-morpholinopyridin-2(1H)-one and Example 4: (S)-6-(2-benzylazepan-1-yl)-4-morpholinopyridin-2(1H)-one

[0354] [ka]

[0355] Step 1: 7-Benzylazepan-2-one Sodium azide (1.05 g, 16.17 mmol) was added to a solution of 2-benzylcyclohexan-1-one (2.9 g, 15.4 mmol) in methanesulfonic acid (12 mL) and the reaction temperature was maintained below 25° C. After 2 hours, the reaction was diluted with water (100 mL) to give a white solid suspension. The solid was collected by filtration, washed with water, and air-dried overnight to give the title compound.

[0356] Using a reference sample of chiral material from Example 3, Step 5, the enantiomers were subjected to chiral separation by SFC in comparison with the racemate, followed by enantiomerically pure 2-(R)-benzylazepane.

[0357] Step 2: 2-Benzylazepane Lithium aluminum hydride (23.2 mL, 23.2 mmol, 1 M in THF) was added dropwise to a solution of 7-benzylazepan-2-one (2.36 g, 11.61 mmol) in anhydrous THF (85 mL) at 0 °C. After the addition was complete, the reaction was allowed to warm to rt. The reaction was heated to reflux for 2 h and then cooled to rt. The reaction was cooled to 0 °C and quenched by the dropwise addition of water (CAUTION!). After effervescence subsided, the THF was removed in vacuo. The mixture was dissolved in EtOAc / water and the layers were separated. The organic layer was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (gradient 0-10% 7N ammonia in methanol / DCM) to give the title compound.

[0358] Step 3: 4-(3-(2-benzylazepan-1-yl)-5-((4-methoxybenzyl)oxy)phenyl)morpholine A flask containing 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (2.67 g, 7.97 mmol, scaffold 1), 2-benzylazepane (1.48 g, 7.82 mmol), NaOtBu (834 mg, 8.68 mmol), RuPhos (192 mg, 0.41 mmol), and RuPhos Pd G3 (330 mg, 0.39 mmol) in dioxane (50 mL) was evacuated and refilled with N2 three times. The mixture was stirred at 85 °C for 20 h. After cooling to rt, the mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated and purified by silica gel column chromatography (gradient elution, 0-50% EtOAc / iso-hexane) to give the title compound.

[0359] Step 4: (R)-6-(2-benzylazepan-1-yl)-4-morpholinopyridin-2(1H)-one and (S)-6-(2-benzylazepan-1-yl)-4-morpholinopyridin-2(1H)-one Following Method E from 4-(3-(2-benzylazepan-1-yl)-5-((4-methoxybenzyl)oxy)phenyl)morpholine (200 mg, 0.41 mmol). The reaction was filtered through Celite and washed thoroughly with MeOH. The solvent was removed in vacuo and the residue was purified by reverse-phase preparative HPLC. The resulting sample was further purified by SFC to give the title compound.

[0360] (R)-6-(2-benzylazepan-1-yl)-4-morpholinopyridin-2(1H)-one. LCMS (ES+) 368 (M+H) + , RT 2.86 min (Analysis method A); RT 2.88 min (Analysis method SFC1,YMC Amylose-C, 35 / 65 IPA + 0.1%DEA / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.32-7.21 (3H, m), 7.16-7.11 (2H, m), 5.17 (1H, d, J=2.0 Hz), 4.89 (1H, d, J=1.9 Hz), 3.81-3.75 (5H, m), 3.41-3.33 (1H, m), 3.20 (4H, t, 5.0 Hz), 2.99 (1H, dd, J= 12.2, 15.9 Hz), 2.86-2.76 (2H, m), 2.14-2.05 (1H, m), 1.87-1.67 (3H, m), 1.60-1.45 (2H, m), 1.31-1.12 (3H, m).

[0361] (S)-6-(2-benzylazepan-1-yl)-4-morpholinopyridin-2(1H)-one. LCMS (ES+) 368 (M+H) + , RT 2.86 min (Analytical method A); RT 2.06 min (Analytical method SFC1,YMC Amylose-C, 35 / 65 IPA +0.1%DEAISO) / CO2) 1H NMR (400 MHz, CDCl3): δ 7.32-7.21 (3H, m), 7.16-7.11 (2H, m), 5.17 (1H, d, J=2.0 Hz), 4.89 (1H, d, J=1.9 Hz), 3.81-3.75 (5H, m), 3.41-3.33 (1H, m), 3.20 (4H, t, 5.0 Hz), 2.99 (1H, dd, J= 12.2, 15.9 Hz), 2.86-2.76 (2H, m), 2.14-2.05 (1H, m), 1.87-1.67 (3H, m), 1.60-1.45 (2H, m), 1.31-1.12 (3H, m).

[0362] Example 5: (S)-7-benzyl-1-(4-morpholino-6-oxo-1,6-dihydropyridin-2-yl)azepan-2-one and Example 6: (R)-7-benzyl-1-(4-morpholino-6-oxo-1,6-dihydropyridin-2-yl)azepan-2-one

[0363] [ka]

[0364] Step 1: 7-benzyl-1-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)azepan-2-one A suspension of 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (163 mg, 0.49 mmol, scaffold 1), 7-benzylazepan-2-one (100 mg, 0.49 mmol, Example 3, Step 1), and CsCO (0.98 mmol) in dry 1,4-dioxane (3.3 mL) was purged with N for 15 min. Pd(OAc) (0.024 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.10 mmol) were then added, and the reaction tube was sealed under N and stirred at 100 °C for 16 h. After cooling to rt, the mixture was filtered through Celite and thoroughly washed with CHCl. The filtrate was concentrated and the residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) to afford the impure title compound.

[0365] Step 2: (S)-7-benzyl-1-(4-morpholino-6-oxo-1,6-dihydropyridin-2-yl)azepan-2-one and (R)-7-benzyl-1-(4-morpholino-6-oxo-1,6-dihydropyridin-2-yl)azepan-2-one Following Method E starting with 7-benzyl-1-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)azepan-2-one (168 mg, <0.33 mmol). Purification by reverse-phase preparative HPLC followed by SFC and lyophilization of the enantiomers from MECN / HO gave the title compound.

[0366] (S)-7-Benzyl-1-(4-morpholino-6-oxo-1,6-dihydropyridin-2-yl)azepan-2-one. LCMS (ES+) 382 (M+H) + , RT 2.82 min (Analytical method B), RT 2.11 min (Analytical method SFC1, YMC Cellulose-C + 0.1% DEAISO 30% MeOH SOL3); 1H NMR (400 MHz, CDCl3): δ 9.89 (1H, br s), 7.32 (2H, dd, J=7.3, 7.3 Hz), 7.27 - 7.21 (1H, m), 7.18 - 7.14 (2H, m), 5.49 (1H, d, J=2.3 Hz), 5.11 (1H, d, J=1.8 Hz), 4.00 - 3.92 (1H, m), 3.73 - 3.69 (4H, m), 3.29 (1H, dd, J=8.8, 13.9 Hz), 3.08 - 3.03 (4H, m), 2.90 - 2.79 (3H, m), 2.06 - 1.89 (4H, m), 1.87 - 1.78 (2H, m).

[0367] (R)-7-ベンジル-1-(4-モルホリノ-6-オキソ-1,6-ジヒドロピリジン-2-イル)アゼパン-2-オン. LCMS (ES+) 382 (M+H) + , RT 2.82 points (analytical method B), RT 1.56 points (analytical method SFC1, YMC セルロース-C + 0.1% DEAISO 30% MeOH SOL3); 1 H NMR (400 MHz, CDCl3): δ 9.74 (1H, br s), 7.35 - 7.29 (2H, m), 7.26 - 7.22 (1H, m), 7.18 - 7.14 (2H, m), 5.49 (1H, d, J=2.3 Hz), 5.12 (1H, d, J=1.8 Hz), 4.00 - 3.93 (1H, m), 3.73 - 3.69 (4H, m), 3.29 (1H, dd, J=9.0, 13.8 Hz), 3.05 (4H, dd, J=3.8, 5.8 Hz), 2.90 - 2.79 (3H, m), 2.04 - 1.90 (4H, m), 1.85 - 1.78 (2H, m).

[0368] The following examples were prepared using procedures similar to those described in Example 1 starting from commercial amines and Scaffold 1 or Scaffold 2, as appropriate. The amines are coupled using Buchwald conditions, Method C or Method D. Isomers were isolated after purification by chiral SFC unless otherwise stated (*); in these cases, chirally pure amines were purchased.

[0369] [Table 9] TIFF0007727627000110.tif221167TIFF0007727627000111.tif245167TIFF0007727627000112.tif245167TIFF0007727 627000113.tif245167TIFF0007727627000114.tif254167TIFF0007727627000115.tif196167TIFF0007727627000116.t if214168TIFF0007727627000117.tif246167TIFF0007727627000118.tif178167TIFF0007727627000119.tif246167TIF F0007727627000120.tif246167TIFF0007727627000121.tif186168TIFF0007727627000122.tif255159TIFF00077276270 00123.tif229168TIFF0007727627000124.tif242170TIFF0007727627000125.tif240170TIFF0007727627000126.tif25 5170TIFF0007727627000127.tif241170TIFF0007727627000128.tif248170TIFF0007727627000129.tif242170TIFF000 7727627000130.tif247170TIFF0007727627000131.tif254170TIFF0007727627000132.tif229170TIFF00077276270001 33.tif203170TIFF0007727627000134.tif250170TIFF0007727627000135.tif250170TIFF0007727627000136.tif152170

[0370] The following intermediate compounds were prepared in the same manner as before and the amines were used without purification in the Buchwald coupling.

[0371] [Table 10]

[0372] Example 88: 6-((2S,3R)-2-benzyl-3-methoxypyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 89: 6-((2R,3S)-2-benzyl-3-methoxypyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0373] [ka]

[0374] Step 1: Benzyl 2-benzyl-3-oxopyrrolidine-1-carboxylate KOtBu (1.58 g, 14.04 mmol) was added to a solution of ((benzyloxy)carbonyl)-L-phenylalanine (4.0 g, 12.7 mmol) in anhydrous THF (30 mL) at rt. After 15 min, a solution of methyl acrylate (1.16 mL, 12.76 mmol) in anhydrous THF (5 mL) was added dropwise, and the resulting solution was heated to reflux for 2.5 h. The reaction mixture was cooled to rt and diluted with 1 M aqueous HCl. The solvent was removed under reduced pressure and extracted with aqueous EtOAc. The organic extract was washed with brine and dried (MgSO). The solvent was removed in vacuo to give an oil, which was vigorously stirred with 0.3 M HCl at reflux for 4 days. The mixture was cooled to rt, and the aqueous layer was extracted with EtOAc. The organic layer was washed with NaHCO (saturated aqueous solution), brine, dried (MgSO), and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution 0-50% EtOAc / iso-hexane) to afford the title compound.

[0375] Step 2: Benzyl (2S*,3S*)-2-benzyl-3-hydroxypyrrolidine-1-carboxylate Benzyl 2-benzyl-3-oxopyrrolidine-1-carboxylate (613 mg, 1.98 mmol) was dissolved in MeOH (0.2 M) and the resulting mixture was cooled in an ice bath. NaBH4 (1.1 eq.) was added in one portion and the reaction was allowed to warm to rt over 1 h. The reaction was quenched by careful addition of water and MeOH was removed under reduced pressure. The aqueous layer was extracted with DCM and the layers were separated. The organic extract was dried (phase separator) and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography eluting with a gradient of 0-50% EtOAc / iso-hexane to give the title compound.

[0376] Step 3: Benzyl (2S*,3R*)-3-(benzoyloxy)-2-benzylpyrrolidine-1-carboxylate Benzoic acid (1.92 mmol) and triphenylphosphine (1.92 mmol) were added to a solution of benzyl (2S,3S)-2-benzyl-3-hydroxypyrrolidine-1-carboxylate (498 mg, 1.60 mmol) in THF (10 mL) and cooled to 0 °C. DIAD (1.92 mmol) was added dropwise and the reaction was allowed to warm to rt over 5 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (gradient elution, 0-50% EtOAc / iso-hexane) to give the title compound.

[0377] Step 4: Benzyl (2S*,3R*)-2-benzyl-3-hydroxypyrrolidine-1-carboxylate Benzyl (2S*,3R*)-3-(benzoyloxy)-2-benzylpyrrolidine-1-carboxylate (465 mg, 1.12 mmol) was dissolved in MeOH (10 mL) and water (5 mL). Lithium hydroxide monohydrate (70.5 mg, 1.68 mmol) was added in one portion and the reaction was heated at 50°C for 3 h. The methanol was removed in vacuo and the aqueous layer was extracted with DCM. The layers were separated, dried (phase separator), and concentrated in vacuo. Purification by silica gel chromatography (gradient elution, 0-30% EtOAc / iso-hexane) gave the title compound.

[0378] Step 5: Benzyl (2S*,3R*)-2-benzyl-3-methoxypyrrolidine-1-carboxylate NaH (77 mg, 1.93 mmol, 60% dispersion in mineral oil) was added in one portion to benzyl (2S*,3R*)-2-benzyl-3-hydroxypyrrolidine-1-carboxylate (300 mg, 0.96 mmol) in anhydrous DMF (5 mL) at 0 °C. After 20 min, methyl iodide (0.09 mL, 1.45 mmol) was added and the reaction was allowed to warm to rt over 2 h. The reaction was cooled in an ice bath and quenched by the addition of water. DMF was removed in vacuo and the residue was dissolved in DCM. The DCM was washed with water and the layers were separated. The organic extract was dried (phase separator) and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient 0-30% EtOAc / iso-hexane) to give the title compound.

[0379] Step 6: (2S*,3R*)-2-benzyl-3-methoxypyrrolidine Following Method E, starting with rac-benzyl (2R,3S)-2-benzyl-3-methoxypyrrolidine-1-carboxylate (250 mg, 0.77 mmol). After filtering the reaction mixture through Celite, the solvent was removed in vacuo to give the title compound, which was used without further purification.

[0380] Step 7: 4-(2-((2S*,3R*)-2-benzyl-3-methoxypyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D starting with (2S*,3R*)-2-benzyl-3-methoxypyrrolidine (94 mg, 0.49 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (150 mg, 0.45 mmol, scaffold 1). The residue was purified by silica gel column chromatography (gradient 0-50% EtOAc / iso-hexane) to give the title compound.

[0381] Step 8: 6-((2S,3R)-2-benzyl-3-methoxypyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and 6-((2R,3S)-2-benzyl-3-methoxypyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one Following method E starting from 4-(2-((2S*,3R*)-2-benzyl-3-methoxypyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (190 mg, 0.39 mmol). The residue was purified by reverse phase preparative HPLC. The sample was further purified by SFC chiral chromatography to give the title compound.

[0382] 6-((2S,3R)-2-benzyl-3-methoxypyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 370 (M+H) + , RT 2.85 min (Analytical method A); RT 3.37 min (Analytical method SFC4, YMC Amylose-C, 30 / 70 IPA (0.1%DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.36-7.17 (5H, m), 5.21 (1H, d, J= 2.1 Hz), 4.88 (1H, d, J= 2.1 Hz), 4.07 (1H, dd, J= 4.1, 8.5 Hz), 3.78 (4H, t, J= 4.9 Hz), 3.74 (1H, d, J= 4.0 Hz), 3.51-3.39 (2H, m), 3.23 (4H, dd, J= 3.7, 6.0 Hz), 3.16 (3H, s), 2.99 (1H, dd, J= 4.2, 14.2 Hz), 2.66 (1H, dd, J= 8.5, 14.2 Hz), 2.10-2.05 (1H, m), 1.89-1.80 (1H, m), NH not observed.

[0383] 6-((2R,3S)-2-benzyl-3-methoxypyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 370 (M+H) +, RT 2.85 min (Analytical method A); RT 2.52 min (Analytical method SFC4,YMC Amylose-C, 30 / 70 IPA (0.1%DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.36-7.17 (5H, m), 5.21 (1H, d, J= 2.1 Hz), 4.88 (1H, d, J= 2.1 Hz), 4.07 (1H, dd, J= 4.1, 8.5 Hz), 3.78 (4H, t, J= 4.9 Hz), 3.74 (1H, d, J= 4.0 Hz), 3.51-3.39 (2H, m), 3.23 (4H, dd, J= 3.7, 6.0 Hz), 3.16 (3H, s), 2.99 (1H, dd, J= 4.2, 14.2 Hz), 2.66 (1H, dd, J= 8.5, 14.2 Hz), 2.10-2.05 (1H, m), 1.89-1.80 (1H, m), NH not observed.

[0384] Example 90: 6-((2S,3R)-2-benzyl-3-(difluoromethoxy)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 91: 6-((2R,3S)-2-benzyl-3-(difluoromethoxy)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0385] [ka]

[0386] Step 1: Benzyl (2S*,3R*)-2-benzyl-3-(difluoromethoxy)pyrrolidine-1-carboxylate Benzyl (2S*,3R*)-2-benzyl-3-hydroxypyrrolidine-1-carboxylate (227 mg, 0.73 mmol, Example 88, Step 4) was dissolved in MeCN (6 mL) and copper(I) iodide (0.14 mmol) was added. The resulting mixture was heated to 50°C, and 2,2-difluoro-2-(fluorosulfyl) acetic acid (1.1 mmol) in MeCN (4 mL) was added dropwise over 20 minutes. The resulting mixture was stirred at 50°C for an additional 1 hour. The reaction was cooled to rt, and the solvent was removed in vacuo to give a residue that was dissolved in DCM, washed with water, and the layers were separated using a phase separator. The DCM layer was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (gradient elution, 0-30% EtOAc / iso-hexane) to give the title compound.

[0387] Step 2: (2S*,3R*)-2-benzyl-3-(difluoromethoxy)pyrrolidine Following method E using rac-benzyl (2S*,3R*)-2-benzyl-3-(difluoromethoxy)pyrrolidine-1-carboxylate (110 mg, 0.3 mmol). After filtration through Celite, the solvent was removed in vacuo to give the title compound, which was used without further purification.

[0388] Step 3: 4-(2-((2S*,3R*)-2-benzyl-3-(difluoromethoxy)pyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D, starting with (2S*,3R*)-2-benzyl-3-(difluoromethoxy)pyrrolidine (50 mg, 0.2 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (65 mg, 0.2 mmol, scaffold 1). The residue was dissolved in DCM and washed with water. The organic extract was dried (phase separator) and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution, 0-30% EtOAc / iso-hexane) to give the title compound.

[0389] Step 4: 6-((2S,3R)-2-benzyl-3-(difluoromethoxy)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and 6-((2R,3S)-2-benzyl-3-(difluoromethoxy)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one Following method E starting from 4-(2-((2S*,3R*)-2-benzyl-3-(difluoromethoxy)pyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (50 mg, 0.1 mmol). The residue was purified by reverse phase preparative HPLC followed by SFC to give the title compound.

[0390] 6-((2S,3R)-2-benzyl-3-(difluoromethoxy)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 406 (M+H) + , RT 3.01 min (Analytical method B); RT 1.43 min (Analytical method SFC4,YMC Amylose-C, 30 / 70 EtOH (0.1%DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.34-7.29 (3H, m), 7.18-7.16 (2H, m), 6.13 (1H, t, J= 73.6 Hz), 5.24 (1H, d, J= 2.1 Hz), 4.88 (1H, d, J= 2.0 Hz), 4.67 (1H, d, J= 4.0 Hz), 4.18 (1H, dd, J= 4.5, 7.8 Hz), 3.78 (4H, t, J= 4.8 Hz), 3.54-3.44 (2H, m), 3.24-3.21 (4H, m), 2.99 (1H, dd, J= 4.5, 14.7Hz), 2.78 (1H, dd, J= 8.1, 14.4 Hz), 2.15-2.09 (1H, m), 1.97-1.87 (2H, m).

[0391] 6-((2R,3S)-2-benzyl-3-(difluoromethoxy)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 406 (M+H) + , RT 2.87 min (Analytical method A); RT 1.79 min (Analytical method SFC4,YMC Amylose-C, 30 / 70 EtOH (0.1%DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.34-7.29 (3H, m), 7.18-7.16 (2H, m), 6.13 (1H, t, J= 73.6 Hz), 5.24 (1H, d, J= 2.1 Hz), 4.88 (1H, d, J= 2.0 Hz), 4.67 (1H, d, J= 4.0 Hz), 4.18 (1H, dd, J= 4.5, 7.8 Hz), 3.78 (4H, t, J= 4.8 Hz), 3.54-3.44 (2H, m), 3.24-3.21 (4H, m), 2.99 (1H, dd, J= 4.5, 14.7Hz), 2.78 (1H, dd, J= 8.1, 14.4 Hz), 2.15-2.09 (1H, m), 1.97-1.87 (2H, m).

[0392] Example 92: 6-((2S,3S)-2-benzyl-3-methoxypyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 93: 6-((2R,3R)-2-benzyl-3-methoxypyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0393] [ka]

[0394] Step 1: Benzyl (2S*,3S*)-2-benzyl-3-methoxypyrrolidine-1-carboxylate Following the procedure described for the preparation of Example 88, Step 4 from benzyl (2S*,3S*)-2-benzyl-3-hydroxypyrrolidine-1-carboxylate (338 mg, 1.09 mmol, Example 88, Step 2), the mixture was purified by silica gel column chromatography (gradient 0-50% EtOAc / iso-hexane) to give the title compound.

[0395] Step 2: (2S*,3S*)-2-benzyl-3-methoxypyrrolidine Following Method E starting with benzyl (2S,3S)-2-benzyl-3-methoxypyrrolidine-1-carboxylate (300 mg, 0.92 mmol), the mixture was purified by SCX chromatography (eluting with MeOH / DCM 1:1, then recovered with 10% 7N NH / methanol in MeOH) to give the title compound.

[0396] Step 3: 4-(2-((2S*,3S*)-2-benzyl-3-methoxypyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D, starting with (2S*,3S*)-2-benzyl-3-methoxypyrrolidine (146 mg, 0.76 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (255 mg, 0.76 mmol, scaffold 1). The residue was dissolved in DCM and washed with water. The organic extract was dried (phase separator) and the DCM layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient 0-50% EtOAc / iso-hexane) to give the title compound.

[0397] Step 4: 6-((2S,3S)-2-benzyl-3-methoxypyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and 6-((2R,3R)-2-benzyl-3-methoxypyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one Following method E starting from 4-(2-((2S*,3S*)-2-benzyl-3-methoxypyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (130 mg, 0.26 mmol). The residue was purified by reverse phase preparative HPLC followed by SFC to give the title compound.

[0398] 6-((2S,3S)-2-benzyl-3-methoxypyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 370 (M+H) + , RT 2.84 min (Analytical method A); RT 2.23 min (Analytical method SFC1, YMC Amylose-C, 30 / 70 MeOH (0.1%DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.29-7.16 (5H, m), 5.15 (1H, d, J=1.9 Hz), 4.68 (1H, d, J= 2.1 Hz), 4.12 (1H, q, J= 5.8 Hz), 3.91-3.85 (1H, m), 3.73 (4H, t, 5 Hz), 3.53-3.47 (1H, m), 3.38 (3H, s), 3.30 (1H, q, J= 8.5 Hz), 3.18-3.06 (5H, m), 2.77 (1H, dd, J= 5.6, 14 Hz), 2.18-2.09 (1H, m), 1.90-1.79 (2H, m).

[0399] 6-((2R,3R)-2-benzyl-3-methoxypyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 370 (M+H) + , RT 2.84 min (Analytical method A); RT 2.96 min (Analytical method SFC1, YMC Amylose-C, 30 / 70 MeOH (0.1%DEAISO) / CO2); 1H NMR (400 MHz, CDCl3): δ 7.29-7.16 (5H, m), 5.15 (1H, d, J=1.9 Hz), 4.68 (1H, d, J= 2.1 Hz), 4.12 (1H, q, J= 5.8 Hz), 3.91-3.85 (1H, m), 3.73 (4H, t, 5 Hz), 3.53-3.47 (1H, m), 3.38 (3H, s), 3.30 (1H, q, J= 8.5 Hz), 3.18-3.06 (5H, m), 2.77 (1H, dd, J= 5.6, 14 Hz), 2.18-2.09 (1H, m), 1.90-1.79 (2H, m).

[0400] Example 94: 6-((2S,3S)-2-benzyl-3-hydroxy-3-methylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 95: 6-((2R,3R)-2-benzyl-3-hydroxy-3-methylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0401] [ka]

[0402] Step 1: Benzyl (2S*,3S*)-2-benzyl-3-hydroxy-3-methylpyrrolidine-1-carboxylate Methylmagnesium bromide (1.18 mL, 1.18 mmol, 3 M in diethyl ether) was added dropwise to a suspension of cerium(III) chloride (960 mg, 3.91 mmol) in dry THF (10 mL) at −78° C., ensuring that the temperature did not rise above −70° C. After 30 min, a solution of benzyl 2-benzyl-3-oxopyrrolidine-1-carboxylate (500 mg, 1.62 mmol, Example 88, Step 1) in dry THF (10 mL) was added dropwise, maintaining the temperature below −70° C. After the addition was complete, the reaction was stirred for an additional 2 h, allowing the reaction to warm to 0° C. EtOAc was added and the insoluble material was filtered through Celite. THF was removed in vacuo, and the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient 0-50% EtOAc / iso-hexane) to afford the title compound.

[0403] Step 3: (2S*,3S*)-2-benzyl-3-methylpyrrolidin-3-ol Method E was followed starting from benzyl (2S,*3S*)-2-benzyl-3-hydroxy-3-methylpyrrolidine-1-carboxylate (284 mg, 0.97 mmol) to give the title compound.

[0404] Step 4: (2S*,3S*)-2-benzyl-1-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)-3-methylpyrrolidin-3-ol Following Method D starting with (2S*,3S*)-2-benzyl-3-methylpyrrolidin-3-ol (94 mg, 0.49 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (150 mg, 0.45 mmol, scaffold 1), the crude material was purified by silica gel column chromatography (gradient 0-50% EtOAc / iso-hexane) to give the title compound.

[0405] Step 5: 6-((2S,3S)-2-benzyl-3-hydroxy-3-methylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and 6-((2R,3R)-2-benzyl-3-hydroxy-3-methylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one Following Method E starting from (2S*,3S*)-2-benzyl-1-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)-3-methylpyrrolidin-3-ol (200 mg, 0.4 mmol). The crude material was purified by reverse phase preparative HPLC followed by SFC to give the title compound.

[0406] 6-((2S,3S)-2-benzyl-3-hydroxy-3-methylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 370 (M+H) + , RT 2.51 min (Analytical method A); RT 1.36 min (Analytical method SFC4, YMC Amylose-C, 25 / 75 MeOH (0.1%DEAISO) / CO2); 1 H NMR (400 MHz, CDCl): δ 7.29–7.17 (5H, m), 5.17 (1H, d, J= 2.2 Hz), 4.67 (1H, d, J= 2.2 Hz), 3.77 (1H, t, J= 5.6 Hz), 3.72 (4H, t, J= 4.8 Hz), 3.53 (1H, dt, J= 4, 9.3 Hz), 3.29–3.05 (6H, m), 2.84 (1H, dd, J= 5.2, 14.3 Hz), 2.01–1.85 (2H, m), 1.30 (3H, s), no NH or OH.

[0407] 6-((2R,3R)-2-benzyl-3-hydroxy-3-methylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 370 (M+H) +, RT 2.51 min (Analytical method A); RT 1.98 min (Analytical method SFC4, YMC Amylose-C, 25 / 75 MeOH (0.1%DEAISO) / CO2); 1 H NMR δ (ppm) (400 MHz, CDCl) 7.29-7.17 (5H, m), 5.17 (1H, d, J = 2.2 Hz), 4.67 (1H, d, J = 2.2 Hz), 3.77 (1H, t, J = 5.6 Hz), 3.72 (4H, t, J = 4.8 Hz), 3.53 (1H, dt, J = 4, 9.3 Hz), 3.29-3.05 (6H, m), 2.84 (1H, dd, J = 5.2, 14.3 Hz), 2.01-1.85 (2H, m), 1.30 (3H, s), no NH or OH.

[0408] Example 96: 6-((2S,3R)-2-benzyl-3-fluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 97: 6-((2R,3S)-2-benzyl-3-fluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0409] [ka]

[0410] Step 1: Benzyl (2S*,3R*)-2-benzyl-3-fluoropyrrolidine-1-carboxylate DAST (2.28 mmol) was added dropwise to a solution of benzyl (2S*,3S*)-2-benzyl-3-hydroxypyrrolidine-1-carboxylate (203 mg, 0.65 mmol, Example 88, Step 2) in anhydrous DCM at -78 °C, and the reaction was allowed to warm to rt overnight. The reaction was cooled in an ice bath and quenched by the addition of NaHCO3 (saturated aqueous solution). The phases were separated, and the organic extract was dried (phase separator). The DCM layer was concentrated in vacuo. The mixture was purified by silica gel column chromatography (gradient elution with 0-50% EtOAc / iso-hexane) to give the title compound.

[0411] Step 2: (2S*,3R*)-2-benzyl-3-fluoropyrrolidine Method E was followed starting from benzyl (2S,*3R*)-2-benzyl-3-fluoropyrrolidine-1-carboxylate (120 mg, 0.38 mmol) to give the title compound.

[0412] Step 3: 4-(2-((2S*,3R*)-2-benzyl-3-fluoropyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D starting with (2S*,3R*)-2-benzyl-3-fluoropyrrolidine (43 mg, 0.24 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (73 mg, 0.22 mmol, scaffold 1). The residue was purified by silica gel column chromatography (gradient 0-50% EtOAc / iso-hexane) to give the title compound.

[0413] Step 4: 6-((2S,3R)-2-benzyl-3-fluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and 6-((2R,3S)-2-benzyl-3-fluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one Following method E starting from 6-((2S*,3R*)-2-benzyl-3-fluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one (100 mg, 0.21 mmol). The residue was purified by reverse phase preparative HPLC followed by SFC to give the title compound.

[0414] 6-((2S,3R)-2-benzyl-3-fluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 358 (M+H) + , RT 2.77 min (Analytical method A); RT 1.75 min (Analytical method SFC4, YMC Amylose-C, 30 / 70 MeOH (0.1%DEAISO) / CO2);1 H NMR (400 MHz, CDCl3): δ 7.34-7.24 (3H, m), 7.18-7.16 (2H, m), 5.25 (1H, d, J= 2.2 Hz), 5.02 (1H, dd, J= 51.6, 2.9 Hz), 4.91 (1H, d, J= 2.2 Hz), 4.32 (1H, dq, J= 4.1, 10.4 Hz), 3.79 (4H, t, J= 5.2 Hz), 3.63 (1H, t, J= 9.2 Hz), 3.51 (1H, dt, J= 7.0, 9.7 Hz), 3.24 (4H, dd, J= 4.1, 5.9 Hz), 3.05-2.99 (1H, m), 2.70 (1H, dd, J = 8.1, 14.0 Hz), 2.26-2.16 (1H, m), 1.95-1.75 (1H, m), NH not observed.

[0415] 6-((2R,3S)-2-benzyl-3-fluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 358 (M+H) + , RT 2.76 min (Analytical method A); RT 2.23 min (Analytical method SFC4, YMC Amylose-C, 30 / 70 MeOH (0.1%DEAISO) / CO2); 1H NMR (400 MHz, CDCl3): δ 7.34-7.24 (3H, m), 7.18-7.16 (2H, m), 5.25 (1H, d, J= 2.2 Hz), 5.02 (1H, dd, J= 51.6, 2.9 Hz), 4.91 (1H, d, J= 2.2 Hz), 4.32 (1H, dq, J= 4.1, 10.4 Hz), 3.79 (4H, t, J= 5.2 Hz), 3.63 (1H, t, J= 9.2 Hz), 3.51 (1H, dt, J= 7.0, 9.7 Hz), 3.24 (4H, dd, J= 4.1, 5.9 Hz), 3.05-2.99 (1H, m), 2.70 (1H, dd, J = 8.1, 14.0 Hz), 2.26-2.16 (1H, m), 1.95-1.75 (1H, m), NH not observed.

[0416] Example 98: (S)-6-(2-benzyl-3,3-difluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 99: (R)-6-(2-benzyl-3,3-difluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0417] [ka]

[0418] Step 1: Benzyl 2-benzyl-3,3-difluoropyrrolidine-1-carboxylate DAST (3.55 mmol) was added dropwise to a solution of benzyl 2-benzyl-3-oxopyrrolidine-1-carboxylate (500 mg, 1.62 mmol, Example 88, Step 1) in anhydrous DCM at -78 °C, and the reaction was allowed to warm to rt overnight. The reaction was cooled to 0 °C and quenched with NaHCO (saturated aqueous solution). The phases were separated and the organic extract was dried (phase separator). The DCM layer was concentrated in vacuo. The crude product was purified by silica gel column chromatography (gradient 0-50% EtOAc / iso-hexane) to give the title compound.

[0419] Step 2: 2-Benzyl-3,3-difluoropyrrolidine Following Method E starting with benzyl 2-benzyl-3,3-difluoropyrrolidine-1-carboxylate (515 mg, 1.55 mmol). The reaction mixture was filtered through Celite and the solvent removed in vacuo to give the title compound, which was used without further purification.

[0420] Step 3: 4-(2-(2-benzyl-3,3-difluoropyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D, starting with 2-benzyl-3,3-difluoropyrrolidine (97 mg, 0.49 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (150 mg, 0.45 mmol, scaffold 1). The residue was dissolved in DCM and washed with water. The organic extract was dried (phase separator) and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient 0-50% EtOAc / iso-hexane) to give the title compound.

[0421] Step 4: (S)-6-(2-benzyl-3,3-difluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and (R)-6-(2-benzyl-3,3-difluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one Following Method E starting from 4-(2-(2-benzyl-3,3-difluoropyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (208 mg, 0.42 mmol). The residue was purified by reverse-phase preparative HPLC followed by separation of enantiomers by SFC to give the title compound.

[0422] (S)-6-(2-benzyl-3,3-difluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 376 (M+H) +, RT 2.84 points (analytical method A); RT 2.09 points (analytical method SFC1, YMC Amiro-C, 25 / 75 MeOH (0.1% DEA) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.29-7.20 (3H, m), 7.17-7.15 (2H, m), 5.27 (1H, d, J= 2.2 Hz), 4.80 (1H, d, J= 1.8 Hz), 4.35 (1H, dt, J= 4.6, 18.2 Hz), 3.76 (4H, t, J= 5.1 Hz), 3.51 (1H, dt, J= 2.2, 9.8 Hz), 3.42-3.35 (1H, m), 3.28-3.13 (5H, m), 2.88 (1H, td, J= 3, 14.3 Hz), 2.32-2.22 (1H, m), 1.92-1.74 (2H, m).

[0423] (R)-6-(2-ベンジル-3,3-ジフルオロピロリジン-1-イル)-4-モルホリノピジン-2(1H)-オン;LCMS (ES+) 376 (M+H) + , RT 2.84 points (analytical method A); RT 2.99 points (analytical method SFC1, YMC Amiro-C, 25 / 75 MeOH (0.1% DEA) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.29-7.20 (3H, m), 7.17-7.15 (2H, m), 5.27 (1H, d, J= 2.2 Hz), 4.80 (1H, d, J= 1.8 Hz), 4.35 (1H, dt, J= 4.6, 18.2 Hz), 3.76 (4H, t, J= 5.1 Hz), 3.51 (1H, dt, J= 2.2, 9.8 Hz), 3.42-3.35 (1H, m), 3.28-3.13 (5H, m), 2.88 (1H, td, J= 3, 14.3 Hz), 2.32-2.22 (1H, m), 1.92-1.74 (2H, m).

[0424] Example 100: Stereoisomer 1 of 6-((2R,4R*)-2-benzyl-4-methylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 101: Stereoisomer 2 of 6-((2R,4R*)-2-benzyl-4-methylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0425] [ka]

[0426] Step 1: tert-butyl (S)-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-oxo-3-phenylpropan-2-yl)carbamate EDC.HCl (3.25 g, 16.96 mmol) and DMAP (2.07 g, 19.96 mmol) were added to a solution of (tert-butoxycarbonyl)-L-phenylalanine (3 g, 11.3 mmol) in DCM (50 mL). Meldrum's acid (1.63 g, 11.3 mmol) was added, and the resulting mixture was stirred at rt overnight. The reaction was washed with 1 M potassium hydrogen sulfate, water, and brine. The DCM layer was concentrated in vacuo to give the title compound.

[0427] Step 2: tert-butyl (R)-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-phenylpropan-2-yl)carbamate NaBH4 (1.55 g, 40.92 mmol) was added portionwise over 20 min to a solution of tert-butyl (S)-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-oxo-3-phenylpropan-2-yl)carbamate (4 g, 10.23 mmol) and acetic acid (6.4 mL, 112 mmol) in DCM (100 mL) at 0 °C. After 3 h, the reaction was quenched with water and the layers were separated. The DCM layer was washed with saturated sodium bicarbonate and the layers were separated. The DCM layer was dried (phase separator) and concentrated in vacuo to give the title compound.

[0428] Step 3: tert-butyl (S)-(1-phenyl-3-(2,2,5-trimethyl-4,6-dioxo-1,3-dioxan-5-yl)propan-2-yl)carbamate K2CO3 (0.44 g, 3.18 mmol) was added to a solution of tert-butyl (R)-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-phenylpropan-2-yl)carbamate (1 g, 2.65 mmol) in DMF (10 mL). The reaction mixture was cooled to 0 °C and methyl iodide (0.49 mL, 7.95 mmol) was added. The reaction was allowed to warm to rt overnight. DMF was removed in vacuo, the residue was dissolved in DCM, washed with water, and the layers were separated. The organic extract was dried (phase separator) and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution, 0-40% EtOAc / iso-hexane) to give the title compound.

[0429] Step 4: tert-Butyl (5R)-5-benzyl-3-methyl-2-oxopyrrolidine-1-carboxylate tert-Butyl (S)-(1-phenyl-3-(2,2,5-trimethyl-4,6-dioxo-1,3-dioxan-5-yl)propan-2-yl)carbamate (750 mg, 1.92 mmol) was dissolved in toluene (10 mL) and the reaction was heated to reflux for 48 h. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (gradient elution, 0-10% EtOAc / iso-hexane) to give the title compound.

[0430] Step 5: (5R)-5-benzyl-3-methylpyrrolidin-2-one tert-Butyl (5R)-5-benzyl-3-methyl-2-oxopyrrolidine-1-carboxylate (530 mg, 1.83 mmol) was dissolved in 4 M HCl in dioxane (5 mL) and the reaction was stirred at rt for 1 h. The solvent was removed in vacuo, and the residue was dissolved in DCM and washed with saturated NaHCO. The layers were separated, and the organic extract was dried (phase separator) and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) to give the title compound.

[0431] Step 6: (2R)-2-benzyl-4-methylpyrrolidine LiAlH4 (3.28 mL, 3.27 mmol, 1 M in THF) was added dropwise to a solution of (5R)-5-benzyl-3-methylpyrrolidin-2-one (310 mg, 1.64 mmol) in THF (10 mL). The reaction was heated to reflux for 5 h and then cooled to rt. The reaction was cooled to 0 °C and quenched by the addition of water. The THF was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated under reduced pressure to provide the title compound. Used without further purification.

[0432] Step 7: 4-(2-((2R)-2-benzyl-4-methylpyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D, starting with (2R)-2-benzyl-4-methylpyrrolidine (86 mg, 0.49 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (150 mg, 0.48 mmol, scaffold 1). The reaction was cooled to rt and the solvent removed in vacuo. The residue was dissolved / suspended in DCM, washed with water and the layers separated. The organic extract was dried (phase separator) and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution, 0-50% EtOAc / iso-hexane) to give the title compound.

[0433] Step 8: Stereoisomer 1 of 6-((2R,4R*)-2-benzyl-4-methylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and Stereoisomer 2 of 6-((2R,4R*)-2-benzyl-4-methylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one Following method E starting from 4-(2-((2R)-2-benzyl-4-methylpyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (200 mg, 0.42 mmol). Purification by SFC gave the title compound.

[0434] Diastereomer 1 of 6-((2R,4R*)-2-benzyl-4-methylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 354 (M+H) + , RT 3.09 min (Analytical method B); RT 2.19 min (Analytical method SFC4,YMC Amylose-C, 30% (IPA / ACN, 1:1) / (0.1%DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.32-7.23 (3H, m), 7.18-7.16 (2H, m), 5.20 (1H, d,J= 2.0 Hz), 4.85 (1H, d, J= 2.2 Hz), 4.11-4.05 (1H, m), 3.79 (4H, t, J= 4.8 Hz), 3.54 (1H, J= 8.4 Hz), 3.25-3.23 (4H, m), 2.98 (1H, dd, J=3.9, 13.8 Hz), 2.82 (1H, t, J= 8.9 Hz), 2.71 (1H, dd, J= 8.4, 13.8 Hz), 2.35-2.25 (1H, m), 1.97 (1H, dd, J = 6.1, 12.4 Hz), 1.64-1.56 (1H, m), 1.06 (3H, d, J = 6.8 Hz), no NH was observed.

[0435] Diastereomer 2 of 6-((2R,4R*)-2-benzyl-4-methylpyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 354 (M+H) + , RT 3.09 min (Analytical method B); RT 3.14 min (Analytical method SFC1,YMC Amylose-C, 30% (IPA / ACN, 1:1) / (0.1%DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.30-7.20 (3H, m), 7.16-7.14 (2H, m), 5.24 (1H, d, J= 2.2 Hz), 4.91 (1H, d, J= 2.2 Hz), 4.17-4.10 (1H, m), 3.77 (4H, t, J= 5.1 Hz), 3.54-3.49 (1H, m), 3.27-3.25 (4 H, m), 3.19 (1H, dd, J=3.4, 13.9Hz), 2.90 (1H, t, J= 9.6Hz), 2.64 (1H, dd, J= 8.9, 13.6 Hz), 2.22-2.11 (2H, m), 1.47-1.38 (1H, m), 1.03 (3H, d, J= 6.6 Hz), NH not observed.

[0436] Example 102: (S)-6-(2-benzyl-4,4-difluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 103: (R)-6-(2-benzyl-4,4-difluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0437] [ka]

[0438] Step 1: tert-Butyl 4,4-difluoro-2-formylpyrrolidine-1-carboxylate Dess-Martin periodinane (4.92 g, 11.60 mmol) was added portionwise to a solution of tert-butyl 4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.5 g, 10.55 mmol) in DCM (30 mL) at 0 °C. After the addition was complete, the reaction was warmed to rt and stirred for 2 h. Saturated NaHCO was added and the layers were separated using a phase separator. The DCM was removed in vacuo to give a clear oil that was used for the next step without further purification.

[0439] Step 2: tert-Butyl 4,4-difluoro-2-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate Phenylmagnesium bromide (9.4 mL, 9.40 mmol, 1 M in THF) was added dropwise to a solution of tert-butyl 4,4-difluoro-2-formylpyrrolidine-1-carboxylate (1.7 g, 7.23 mmol) in THF (15 mL) at −78° C. After 3 h, the reaction was warmed to rt and quenched with water. The THF was removed in vacuo. The aqueous layer was extracted with EtOAc, and the organic layer was dried (MgSO). The solvent was removed in vacuo to give a residue that was purified by silica gel column chromatography (gradient elution, 0-30% EtOAc / iso-hexane) to give the title compound.

[0440] Step 3: 6,6-Difluoro-1-phenyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one To a solution of tert-butyl 4,4-difluoro-2-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (1.23 g, 3.93 mmol) in isopropanol (20 mL) was added KOtBu (44 mg, 0.39 mmol). The reaction was heated to reflux for 3 h. Additional KOtBu (440 mg, 3.93 mmol) was added and the reaction was heated to reflux for an additional 2 h. The reaction was cooled to rt and the solvent removed to give a residual oil that was purified by silica gel column chromatography (gradient elution, 0-30% EtOAc / iso-hexane) to give the title compound.

[0441] Step 4: 2-Benzyl-4,4-difluoropyrrolidine To a solution of 6,6-difluoro-1-phenyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one (310 mg, 1.29 mmol) in MeOH (5 mL) was added NaOMe (0.25 mL, 1.36 mmol, 5.5 M in methanol) and 20% palladium hydroxide on carbon. The reaction was stirred under a hydrogen atmosphere (1 atmosphere) for 48 hours. The reaction was filtered through Celite, and the Celite was washed with additional MeOH. The collected filtrate was acidified with 1 M HCl (to approximately pH 3), and the solvent was removed to give a residue that was purified by SCX chromatography (eluting with 50% MeOH / DCM, followed by 10% 7N methanolic ammonia in methanol / methanol). Concentration of the ammonia fraction in vacuo gave the title compound.

[0442] Step 5: 4-(2-(2-benzyl-4,4-difluoropyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Method D was followed starting from 2-benzyl-4,4-difluoropyrrolidine and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (Scaffold 1). The reaction was cooled to rt and the solvent removed in vacuo. The residue was dissolved / suspended in DCM, washed with water and the layers separated. The organic extract was dried (phase separator) and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution, 0-50% EtOAc / iso-hexane) to give the title compound.

[0443] Step 6: (S)-6-(2-benzyl-4,4-difluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and (R)-6-(2-benzyl-4,4-difluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one Follow Method E starting from 4-(2-(2-benzyl-4,4-difluoropyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine

[0444] (S)-6-(2-benzyl-4,4-difluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 376 (M+H)+, RT 3.03 min (Analytical Method B); RT 4.65 min (Analytical Method SFC4, YMC Cellulose-C, 15 / 85 IPA (0.1% DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.30-7.22 (5H, m), 5.32 (1H, d, J= 2.0 Hz), 4.91 (1H, d, J= 1.2 Hz), 4.73-4.66 (1H, m), 3.90-3.74 (6H, m), 3.29-3.26 (4H, m), 3.19 (1H, dd, J= 4.3, 14.2 Hz), 2.50-2.25 (2H, m).

[0445] (R)-6-(2-benzyl-4,4-difluoropyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 376 (M+H)+, RT 3.03 min (Analytical Method B); RT 5.53 min (Analytical Method SFC4, YMC Cellulose-C, 15 / 85 IPA (0.1% DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.30-7.22 (5H, m), 5.32 (1H, d, J= 2.0 Hz), 4.91 (1H, d, J= 1.2 Hz), 4.73-4.66 (1H, m), 3.90-3.74 (6H, m), 3.29-3.26 (4H, m), 3.19 (1H, dd, J= 4.3, 14.2 Hz), 2.50-2.25 (2H, m).

[0446] Example 104: (R)-6-(2-benzyl-3,3-difluoroazepan-1-yl)-4-morpholinopyridin-2(1H)-one and Example 105: (S)-6-(2-benzyl-3,3-difluoroazepan-1-yl)-4-morpholinopyridin-2(1H)-one

[0447] [ka]

[0448] Step 1: tert-Butyl (E)-2-benzylidene-3-oxoazepane-1-carboxylate LDA (2.58 mL, 5.16 mmol, 2 M in THF) was added dropwise to a solution of tert-butyl 3-oxoazepane-1-carboxylate (1 g, 4.69 mmol) in dry THF (15 mL) at −40° C. The reaction was stirred at −40° C. for 1 h before benzaldehyde (1.43 mL, 14.08 mmol) was added dropwise. The reaction was allowed to warm to rt over 3 h. The reaction was quenched by the addition of water and the THF was removed under reduced pressure. The aqueous layer was extracted with DCM and the layers were separated. The organic extract was dried (phase separator) and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc / iso-hexane) to give the title compound.

[0449] Step 2: tert-Butyl 2-benzyl-3-oxoazepane-1-carboxylate tert-Butyl (E)-2-benzylidene-3-oxoazepane-1-carboxylate (300 mg, 1 mmol) was dissolved in MeOH (100 mL), and the resulting solution was passed through an H-Cube (30 bar, rt, 1 mL / min) using a Pd / C (10%) cartridge. The collected solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc / iso-hexane) to give the title compound.

[0450] Step 3: tert-Butyl 2-benzyl-3,3-difluoroazepane-1-carboxylate tert-Butyl 2-benzyl-3-oxoazepane-1-carboxylate (1.95 g, 6.4 mmol) was dissolved in deoxofluor (21 mL, 50% in THF) and the reaction was stirred at rt for 4 days. The reaction was cooled in an ice bath and quenched by careful addition of saturated NaHCO3. The resulting aqueous layer was extracted with DCM, and the organic extract was dried (phase separator) and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc / iso-hexane) to give the title compound.

[0451] Step 4: 2-benzyl-3,3-difluoroazepane Following the procedure described for the preparation of Example 5, Step 2, starting with tert-butyl 2-benzyl-3,3-difluoroazepane-1-carboxylate (15 mg, 0.046 mmol), the title compound was obtained and used without further purification.

[0452] Step 5: 4-(2-(2-benzyl-3,3-difluoroazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D starting from 2-benzyl-3,3-difluoroazepane (270 mg, 1.2 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (401 mg, 1.2 mmol, scaffold 1). The crude product material was purified by silica gel column chromatography (gradient elution 0-50% EtOAc / iso-hexane) to give the title compound.

[0453] Step 6: (S)-6-(2-benzyl-3,3-difluoroazepan-1-yl)-4-morpholinopyridin-2(1H)-one and (R)-6-(2-benzyl-3,3-difluoroazepan-1-yl)-4-morpholinopyridin-2(1H)-one Following Method E starting from 4-(2-(2-benzyl-3,3-difluoroazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (264 mg, 0.5 mmol). The crude product material was purified by reverse-phase preparative HPLC followed by SFC to give the title compound.

[0454] (R)-6-(2-benzyl-3,3-difluoroazepan-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 404 (M+H) + , RT 3.02 min (Analysis Method A); RT 2.27 min (Analysis Method SFC4, LUX Cellulose-4, 35 / 65 IPA (0.1% DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.27 - 7.12 (5H, m), 5.17 (1H, d, J= 1.9 Hz), 4.75 (1H, d, J= 1.8 Hz), 4.35 - 4.20 (1H,m), 3.71 (4H, t, J= 5.1 Hz), 3.60 - 3.51 (1H, m), 3.34 - 3.25 (1H, m), 3.19 (1H, dd, J= 3.6, 13.5 Hz), 3.11 - 3.00 (4H, m), 2.93 (1H, dd, J= 10.2, 14.6 Hz), 2.24 - 1.98 (2H, m), 1.82 - 1.65 (4H, m), NH not recognized.

[0455] (S)-6-(2-benzyl-3,3-difluoroazepan-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 404 (M+H) + , RT 3.02 min (Analysis Method A); RT 2.74 min (Analysis Method SFC4, LUX Cellulose-4, 35 / 65 IPA (0.1% DEAISO) / CO2); 1H NMR (400 MHz, CDCl3): δ 7.27 - 7.12 (5H, m), 5.17 (1H, d, J= 1.9 Hz), 4.75 (1H, d, J= 1.8 Hz), 4.35 - 4.20 (1H,m), 3.71 (4H, t, J= 5.1 Hz), 3.60 - 3.51 (1H, m), 3.34 - 3.25 (1H, m), 3.19 (1H, dd, J= 3.6, 13.5 Hz), 3.11 - 3.00 (4H, m), 2.93 (1H, dd, J= 10.2, 14.6 Hz), 2.24 - 1.98 (2H, m), 1.82 - 1.65 (4H, m), NH not recognized.

[0456] Example 106: 6-((2S*,3S*)-2-benzyl-3-(difluoromethoxy)azepan-1-yl)-4-morpholinopyridin-2(1H)-one

[0457] [ka]

[0458] Step 1: tert-Butyl-(2S*,3S*)-2-benzyl-3-hydroxyazepane-1-carboxylate Following the procedure described for the preparation of Example 88, Step 2, starting with tert-butyl-2-benzyl-3-oxoazepane-1-carboxylate (118 mg, 0.39 mmol, Example 104, Step 2), the residue was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc / iso-hexane) to give the title compound.

[0459] Step 2: tert-Butyl-(2S*,3S*)-2-benzyl-3-(difluoromethoxy)azepane-1-carboxylate Following the procedure described for the preparation of Example 90, Step 1, starting with tert-butyl-(2S*,3S*)-2-benzyl-3-hydroxyazepane-1-carboxylate (100 mg, 0.33 mmol), the mixture was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc / iso-hexane) to give the title compound.

[0460] Step 3: (2S*,3S*)-2-benzyl-3-(difluoromethoxy)azepane Following the procedure described for the preparation of Example 73, Step 5, starting with tert-butyl-(2S,3S)-2-benzyl-3-(difluoromethoxy)azepane-1-carboxylate (60 mg, 0.17 mmol), the title compound was obtained after freebasing with saturated aqueous sodium bicarbonate.

[0461] Step 4: 4-(2-((2S*,3S*)-2-benzyl-3-(difluoromethoxy)azepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D, starting with (2S*,3S*)-2-benzyl-3-(difluoromethoxy)azepane (30 mg, 0.18 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (36 mg, 0.11 mmol, scaffold 1). The residue was purified by silica gel column chromatography (gradient elution, 0-50% EtOAc / iso-hexane) to give the title compound.

[0462] Step 5: 6-((2S*,3S*)-2-benzyl-3-(difluoromethoxy)azepan-1-yl)-4-morpholinopyridin-2(1H)-one Following method E starting from 4-(2-((2S*,3S*)-2-benzyl-3-(difluoromethoxy)azepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (35 mg, 0.06 mmol). The residue was purified by reverse phase preparative HPLC to give the title compound (1.33 mg, 5%). LCMS (ES+) 434 (M+H) + , RT 2.99 minutes (Analysis method A); 1 H NMR (400 MHz, CDCl3): δ 7.28-7.16 (5H, m), 6.16 (1H, dd, J= 72.9, 76.9 Hz), 5.20 (1H, d, J= 2.0 Hz), 4.91 (1H, d, J= 2Hz), 4.54-4.50 (1H, m), 4.16-4.11 (1H, m), 3.76 (4H, t, J= 5 Hz), 3.5-3.36 (2H, m), 3.16 (4H, dd, J= 3.7, 6.1Hz), 3.01-2.99 (2H, m), 2.07-1.99 (1H, m), 1.94-1.83 (1H, m), 1.78-1.66 (3H, m), 1.59-1.52 (1H, m), NH not observed.

[0463] Example 107: 6-((2S,3R)-2-benzyl-3-methoxyazepan-1-yl)-4-morpholinopyridin-2(1H)-one, stereoisomer 1 and Example 108: 6-((2S,3R)-2-benzyl-3-methoxyazepan-1-yl)-4-morpholinopyridin-2(1H)-one, stereoisomer 2

[0464] [ka]

[0465] Step 1: tert-Butyl-(2S*,3R*)-3-(benzoyloxy)-2-benzylazepane-1-carboxylate Following the procedure described for the preparation of Example 88, Step 3, starting with tert-butyl-(2S,3S)-2-benzyl-3-hydroxyazepane-1-carboxylate (1.19 g, 3.9 mmol, Example 106, Step 1), purification by silica gel column chromatography (gradient elution, 0-20% EtOAc / iso-hexane) afforded the title compound.

[0466] Step 2: tert-Butyl-(2S*,3R*)-2-benzyl-3-hydroxyazepane-1-carboxylate Following the procedure described for the preparation of Example 88, Step 4, starting with tert-butyl-(2S,3R)-3-(benzoyloxy)-2-benzylazepane-1-carboxylate (1.09 g, 2.66 mmol), purification by silica gel column chromatography (gradient elution, 0-30% EtOAc / iso-hexane) afforded the title compound.

[0467] Step 3: tert-Butyl-(2S*,3R*)-2-benzyl-3-methoxyazepane-1-carboxylate Following the procedure described for the preparation of Example 88, Step 5, starting with tert-butyl-(2S,3R)-2-benzyl-3-hydroxyazepane-1-carboxylate (200 mg, 0.65 mmol), purification by silica gel chromatography (gradient elution, 0-30% EtOAc / iso-hexane) afforded the title compound.

[0468] Step 4: (2S*,3R*)-2-benzyl-3-methoxyazepane Following the procedure described for the preparation of Example 73, Step 5, starting with tert-butyl-(2S,3R)-2-benzyl-3-methoxyazepane-1-carboxylate (102 mg, 0.38 mmol), the residue was partitioned between DCM and saturated aqueous NaHCO, dried (phase separator), and concentrated under reduced pressure to give the title compound.

[0469] Step 5: 4-(2-((2S*,3R*)-2-benzyl-3-methoxyazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D, starting with (2S*,3R*)-2-benzyl-3-methoxyazepane (98 mg, 0.48 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (150 mg, 0.48 mmol, scaffold 1). The residue was purified by silica gel column chromatography (gradient elution, 0-50% EtOAc / iso-hexane) to give the title compound.

[0470] Step 6: 6-((2S*,3R*)-2-benzyl-3-methoxyazepan-1-yl)-4-morpholinopyridin-2(1H)-one, stereoisomer 1 and 6-((2S*,3R*)-2-benzyl-3-methoxyazepan-1-yl)-4-morpholinopyridin-2(1H)-one, stereoisomer 2 Following Method E starting from 4-(2-((2S*,3R*)-2-benzyl-3-methoxyazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (52 mg, 0.1 mmol). The crude material was purified by reverse-phase preparative HPLC followed by SFC to give the title compound.

[0471] 6-((2S*,3R*)-2-benzyl-3-methoxyazepan-1-yl)-4-morpholinopyridin-2(1H)-one, diastereomer 1; LCMS (ES+) 398 (M+H) + , RT 2.98 min (Analytical method A); RT 0.99 min (Analytical method SFC4, YMC Cellulose-C, 30 / 70 MeOH (0.1%DEAISO) / CO2); 1H NMR (400 MHz, CDCl3): δ 7.27-7.18 (3H, m), 7.13-7.11 (2H, m), 5.14 (1H, d, J= 2.2 Hz), 4.75 (1H, d, J= 2.2 Hz), 3.76-3.71 (5H, m), 3.41 (3H, s), 3.39-3.33 (1H, m), 3.22 (1H, t, J= 8.1 Hz), 3.15-3.06 (5H, m), 2.90 (1H, dd, J= 7.6, 14.2 Hz), 2.79-2.72 (1H, m), 1.96-1.80 (2H, m), 1.68-1.52 (3H, m), 1.39-1.28 (1H, m), NH not observed.

[0472] 6-((2S*,3R*)-2-benzyl-3-methoxyazepan-1-yl)-4-morpholinopyridin-2(1H)-one, diastereomer 2; LCMS (ES+) 398 (M+H) + , RT 2.98 min (Analysis method A); RT 1.47 min (Analysis method SFC4, YMC Cellulose-C, 30 / 70 MeOH (0.1%DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.27-7.18 (3H, m), 7.13-7.11 (2H, m), 5.14 (1H, d, J= 2.2 Hz), 4.75 (1H, d, J= 2.2 Hz), 3.76-3.71 (5H, m), 3.41 (3H, s), 3.39-3.33 (1H, m), 3.22 (1H, t, J= 8.1 Hz), 3.15-3.06 (5H, m), 2.90 (1H, dd, J= 7.6, 14.2 Hz), 2.79-2.72 (1H, m), 1.96-1.80 (2H, m), 1.68-1.52 (3H, m), 1.39-1.28 (1H, m), NH not observed.

[0473] Example 109: 6-((2S*,3R*)-2-benzyl-3-(difluoromethoxy)azepan-1-yl)-4-morpholinopyridin-2(1H)-one, stereoisomer 1 and Example 110: 6-((2S*,3R*)-2-benzyl-3-(difluoromethoxy)azepan-1-yl)-4-morpholinopyridin-2(1H)-one, stereoisomer 2

[0474] [ka]

[0475] Step 1: tert-Butyl-(2S*,3R*)-2-benzyl-3-(difluoromethoxy)azepane-1-carboxylate Following the procedure described for the preparation of Example 90, Step 1, starting with tert-butyl-(2S,3R)-2-benzyl-3-hydroxyazepane-1-carboxylate (250 mg, 0.82 mmol, Example 107, Step 2), purification by silica gel column chromatography (gradient elution, 0-30% EtOAc / iso-hexane) afforded the title compound.

[0476] Step 2: (2S*,3R*)-2-benzyl-3-(difluoromethoxy)azepane Following the procedure described for the preparation of Example 73, Step 5, starting with tert-butyl-(2S,3R)-2-benzyl-3-(difluoromethoxy)azepane-1-carboxylate (210 mg, 0.59 mmol), the residue was partitioned between DCM and saturated aqueous NaHCO, dried (phase separator), and concentrated under reduced pressure to give the title compound.

[0477] Step 3: 4-(2-((2S*,3R*)-2-benzyl-3-(difluoromethoxy)azepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D, starting with rac-(2S,3R)-2-benzyl-3-(difluoromethoxy)azepane (70 mg, 0.27 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (92 mg, 0.27 mmol, scaffold 1). The residue was purified by silica gel column chromatography (gradient elution, 0-30% EtOAc / iso-hexane) to afford a mixture (75 mg) of approximately 70% rac-(2S,3R)-2-benzyl-3-(difluoromethoxy)azepane and approximately 20% of the title compound as a clear oil. The reaction was repeated with this mixture using Method D using CsCO as the base. The residue was purified by silica gel column chromatography (gradient elution, 0-30% EtOAc / iso-hexane) to afford the title compound.

[0478] Step 4: 6-((2S*,3R*)-2-benzyl-3-(difluoromethoxy)azepan-1-yl)-4-morpholinopyridin-2(1H)-one, stereoisomer 1 and 6-((2S*,3R*)-2-benzyl-3-(difluoromethoxy)azepan-1-yl)-4-morpholinopyridin-2(1H)-one, stereoisomer 2 Following method E starting from 4-(2-((2S*,3R*)-2-benzyl-3-(difluoromethoxy)azepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (60 mg, 0.11 mmol). The residue was purified by reverse phase preparative HPLC followed by SFC to give the title compound.

[0479] 6-((2S*,3R*)-2-benzyl-3-(difluoromethoxy)azepan-1-yl)-4-morpholinopyridin-2(1H)-one, diastereomer 1; LCMS (ES+) 434 (M+H) + , RT 3.11 min (Analytical method B); RT 3.64 min (Analytical method SFC1, YMC Amylose-C, 20 / 80 IPA (0.1%DEAISO) / CO2); 1H NMR (400 MHz, CDCl3): δ 7.25-7.18 (3H, m), 7.13-7.11 (2H, m), 6.34 (1H, t, J= 73.9 Hz), 5.14 (1H, d, J= 2.0 Hz). 4.76 (1H, d, J= 2.1 Hz), 4.21 (1H, t, J=8.9 Hz), 3.88-3.83 (1H, m), 3.73 (4H, t, J= 4.5 Hz), 3.46-3.42 (1H, m), 3.16-3.05 (5H, m), 2.88 (1H, d, J= 8.1, 13.8 Hz), 2.76-2.69 (1H,m), 2.04-1.99 (1H, m), 1.88-1.72 (2H, m), 1.65-1.60 (2H, m), 1.49-1.38 (1H, m), NH not observed

[0480] 6-((2S*,3R*)-2-benzyl-3-(difluoromethoxy)azepan-1-yl)-4-morpholinopyridin-2(1H)-one, diastereomer 2; LCMS (ES+) 434 (M+H) + , RT 3.03 min (Analytical method A); RT 3.14 min (Analytical method SFC1, YMC Amylose-C, 20 / 80 IPA (0.1%DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.25-7.18 (3H, m), 7.13-7.11 (2H, m), 6.34 (1H, t, J= 73.9 Hz), 5.14 (1H, d, J= 2.0 Hz). 4.76 (1H, d, J= 2.1 Hz), 4.21 (1H, t, J=8.9 Hz), 3.88-3.83 (1H, m), 3.73 (4H, t, J= 4.5 Hz), 3.46-3.42 (1H, m), 3.16-3.05 (5H, m), 2.88 (1H, d, J= 8.1, 13.8 Hz), 2.76-2.69 (1H,m), 2.04-1.99 (1H, m), 1.88-1.72 (2H, m), 1.65-1.60 (2H, m), 1.49-1.38 (1H, m), NH not observed

[0481] Example 111: 6-(2-((6-fluoropyridin-3-yl)methyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0482] [ka]

[0483] Step 1: tert-Butyl 2-((6-fluoropyridin-3-yl)methyl)pyrrolidine-1-carboxylate To a solution of N-Boc-pyrrolidine (751 mg, 4.4 mmol) in diethyl ether (0.3 M) under a N atmosphere was added sec-BuLi (1.3 eq., 0.86 M solution in cyclohexane) at −78 °C, and the mixture was stirred at −78 °C for 30 min. 5-(Bromomethyl)-2-fluoropyridine (1.00 g, 5.2 mmol) was added dropwise at −78 °C. After the addition was complete, the reaction was allowed to slowly warm to rt overnight. The reaction was quenched with saturated aqueous NH4Cl, the layers were separated, and the aqueous solution was further extracted with Et2O (x2). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (gradient elution, 0–100% EtOAc / iso-hexane) to give the title compound.

[0484] Step 2: 2-Fluoro-5-(pyrrolidin-2-ylmethyl)pyridine To a solution of tert-butyl 2-((6-fluoropyridin-3-yl)methyl)pyrrolidine-1-carboxylate (150 mg, 0.53 mmol) in DCM (0.42 M) was added TFA (0.42 M) and the mixture was stirred at rt for 1 h. The reaction was evaporated to dryness. Purification was performed on an SCX cartridge eluting successively with DCM:MeOH, 1:1, then 3:1 DCM:7N ammonia in methanol. The ammonia in methanol fractions were combined and concentrated under reduced pressure to give the title compound.

[0485] Step 3: 4-(2-(2-((6-fluoropyridin-3-yl)methyl)pyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method C, starting with 2-fluoro-5-(pyrrolidin-2-ylmethyl)pyridine (60 mg, 0.33 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (110 mg, 0.33 mmol, scaffold 1). Purification by silica gel column chromatography (gradient elution, 0-30% EtOAc / iso-hexane) afforded the title compound.

[0486] Step 4: 6-(2-((6-fluoropyridin-3-yl)methyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one Following Method E starting with 4-(2-(2-((6-fluoropyridin-3-yl)methyl)pyrrolidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (119 mg, 0.25 mmol). Purification by reverse phase preparative HPLC followed by lyophilization from MeCN / H2O gave the title compound. LCMS (ES+) 359 (M+H) + , RT 2.57 minutes (Analysis method A); 1 H NMR (400 MHz, CDCl3): δ 8.05 (1H, d, J=2.3 Hz), 7.73 (1H, dt, J=2.5, 8.1 Hz), 6.85 (1H, dd, J=2.9, 8.5 Hz), 5.21 (1H, d, J=2.0 Hz), 4.86 (1H, d, J=2.0 Hz), 4.42 - 4.38 (1H, m), 3.82 - 3.78 (4H, m), 3.46 - 3.39 (1H, m), 3.28 - 3.23 (5H, m), 3.00 (1H, dd, J=3.9, 14.0 Hz), 2.69 (1H, dd, J=8.5, 14.0 Hz), 2.02 - 1.91 (2H, m), 1.82 - 1.75 (2H, m), NH not observed.

[0487] The following examples were prepared using a procedure similar to that described in Example 111, using the alkyl halides listed below. An amine is coupled to scaffold 1 using Buchwald conditions, Method C or Method D. Purification by reverse-phase preparative HPLC affords the title compound.

[0488] [Table 11]

[0489] Intermediate 32: (R)-4-(2-((1S,3S,4R)-3-benzyl-2-azabicyclo[2.2.1]heptan-2-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-methylmorpholine Intermediate 33: (R)-4-(2-((1R,3R,4S)-3-benzyl-2-azabicyclo[2.2.1]heptan-2-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-methylmorpholine Intermediate 34: (R)-4-(2-((1R,3S,4S)-3-benzyl-2-azabicyclo[2.2.1]heptan-2-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-methylmorpholine Intermediate 35: (R)-4-(2-((1S,3R,4R)-3-benzyl-2-azabicyclo[2.2.1]heptan-2-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-methylmorpholine

[0490] [ka]

[0491] Step 1: tert-Butyl 3-azabicyclo[2.2.1]heptane-3-carboxylate A solution of Boc anhydride (1.05 eq.) and NaHCO (5 eq.) in water (0.2 M) was added to a suspension of 3-azabicyclo[2.2.1]heptane hydrochloride (2.0 g, 15.0 mmol) in THF (0.6 M). The resulting biphasic mixture was vigorously stirred at rt overnight. The reaction mixture was diluted with water and DCM. The layers were separated, and the organic phase was dried (phase separator) and concentrated under reduced pressure to give the title compound. This was used in the next step without further purification.

[0492] Step 2: tert-Butyl 2-benzyl-3-azabicyclo[2.2.1]heptane-3-carboxylate Follow the procedure described for the preparation of Intermediate 1, Step 2, starting with tert-butyl 3-azabicyclo[2.2.1]heptane-3-carboxylate (3.0 g, 15 mmol) and benzyl bromide (3.6 mL, 30.4 mmol). Purification by silica gel column chromatography (gradient elution, 0-5% EtOAc / iso-hexane) affords the title compound.

[0493] Step 3: 2-Benzyl-3-azabicyclo[2.2.1]heptane Following the procedure described for the preparation of Intermediate 1, Step 3 starting from tert-butyl 2-benzyl-3-azabicyclo[2.2.1]heptane-3-carboxylate (615 mg, 2.14 mmol) gave the title compound.

[0494] Step 4: (R)-4-(2-((1R,3R,4S)-3-benzyl-2-azabicyclo[2.2.1]heptan-2-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-methylmorpholine, (R)-4-(2-((1R,3S,4S)-3-benzyl-2-azabicyclo[2.2.1]heptan-2-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-methylmorpholine morpholine, (R)-4-(2-((1S,3R,4R)-3-benzyl-2-azabicyclo[2.2.1]heptan-2-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-methylmorpholine, (R)-4-(2-((1S,3S,4R)-3-benzyl-2-azabicyclo[2.2.1]heptan-2-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-methylmorpholine Following Method D, starting with 3-benzyl-2-azabicyclo[2.2.1]heptane (430 mg, <2.14 mmol, Example 62, Step 3) and (R)-4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-methylmorpholine (746 mg, 2.14 mmol, Scaffold 1). Purification by reverse-phase preparative HPLC followed by SFC gave Intermediate 32 (192 mg, 18%), Intermediate 33 (185 mg, 17%), Intermediate 34 (105 mg, 10%), and Intermediate 35 (137 mg, 13%), respectively.

[0495] Example 115: 6-((1S,3S,4R)-3-benzyl-2-azabicyclo[2.2.1]heptan-2-yl)-4-((R)-2-methylmorpholino)pyridin-2(1H)-one

[0496] [ka]

[0497] Method E was followed starting from intermediate 32 (192 mg, 0.38 mmol). Purification by reverse-phase preparative HPLC followed by lyophilization from MeCN / H2O gave the title compound (relative stereochemistry between the benzyl group and the bridgehead protons assigned by NMR nOe experiments). LCMS (ES+) 380 (M+H) + , RT 3.19 min (analytical method B), RT 2.23 min (analytical method SFC1, YMC Cellulose-C 25 / 75 IPA (0.1% DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.30 (2H, m), 7.27 - 7.19 (3H, m), 5.21 (1H, d, J=2.1 Hz), 4.88 (1H, d, J=2.1 Hz), 4.53 (1H, s), 3.94 (1H, dd, J=2.3, 11.5 Hz), 3.71 - 3.60 (2H, m), 3.42 (2H, dd, J=14.5, 14.5 Hz), 3.20 (1H, dd, J=3.8, 9.2 Hz), 2.99 - 2.84 (2H, m), 2.65 - 2.54 (2H, m), 2.45 - 2.42 (1H, m), 2.02 (1H, d, J=10.8 Hz), 1.72 - 1.59 (3H, m), 1.45 (1H, d, J=10.2 Hz), 1.26 - 1.21 (4H, m), NH not observed.

[0498] Example 116: 6-((1R,3R,4S)-3-benzyl-2-azabicyclo[2.2.1]heptan-2-yl)-4-((R)-2-methylmorpholino)pyridin-2(1H)-one

[0499] [ka]

[0500] Method E was followed, starting with Intermediate 33 (185 mg, 0.37 mmol). The crude material was treated with DMSO / water, and the resulting solid was collected by filtration. The solid was purified by silica gel column chromatography (gradient elution, 0-5% MeOH / DCM) to give the title compound (relative stereochemistry between the benzyl group and the bridgehead protons as assigned by NMR nOe experiment). LCMS (ES+) 380 (M+H). + , RT 3.04 min (analysis method A), RT 2.52 min (analysis method SFC1, YMC Cellulose-C 25 / 75 IPA (0.1% DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.32 (2H, dd, J=7.2, 7.2 Hz), 7.28 - 7.18 (3H, m), 5.20 (1H, d, J=2.0 Hz), 4.86 (1H, d, J=2.0 Hz), 4.42 (1H, s), 3.94 (1H, dd, J=2.1, 11.5 Hz), 3.68 - 3.60 (2H, m), 3.41 (2H, dd, J=12.5, 28.4 Hz), 3.20 (1H, dd, J=3.9, 9.0 Hz), 2.98 - 2.87 (2H, m), 2.67 - 2.52 (2H, m), 2.45 - 2.45 (1H, m), 2.03 (1H, d, J=10.5 Hz), 1.71 - 1.60 (3H, m), 1.45 (1H, d, J=10.1 Hz), 1.30 - 1.24 (1H, m), 1.22 (3H, d, J=6.3 Hz), NH not observed.

[0501] Example 117: 6-((1R,3S,4S)-3-benzyl-2-azabicyclo[2.2.1]heptan-2-yl)-4-((R)-2-methylmorpholino)pyridin-2(1H)-one

[0502] [ka]

[0503] Method E was followed starting from intermediate 34 (105 mg, 0.21 mmol). Purification by reverse-phase preparative HPLC followed by lyophilization from MeCN / H2O gave the title compound (relative stereochemistry between the benzyl group and the bridgehead protons assigned by NMR nOe experiments). LCMS (ES+) 380 (M+H) + , RT 3.20 min (analytical method B), RT 2.59 min (analytical method SFC1, YMC Cellulose-C 25 / 75 IPA (0.1% DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 10.39 (1H,br s), 7.33 - 7.28 (2H, m), 7.25 - 7.21 (3H, m), 5.19 (1H, d, J=2.1 Hz), 4.80 (1H, d, J=2.0 Hz), 4.31 (1H, s), 3.95 (1H, dd, J=2.3, 11.5 Hz), 3.86 - 3.79 (1H, m), 3.72 - 3.60 (2H, m), 3.44 (2H, d, J=12.4 Hz), 3.19 (1H, dd, J=4.1, 14.1 Hz), 2.94 - 2.86 (1H, m), 2.65 - 2.53 (2H, m), 2.44 (1H, s), 2.04 - 1.98 (1H, m), 1.86 - 1.80 (2H, m), 1.63 - 1.55 (2H, m), 1.47 (1H, d, J=9.7 Hz), 1.22 (3H, d, J=6.1 Hz).

[0504] Example 118: 6-((1S,3R,4R)-3-benzyl-2-azabicyclo[2.2.1]heptan-2-yl)-4-((R)-2-methylmorpholino)pyridin-2(1H)-one

[0505] [ka]

[0506] Method E was followed starting from intermediate 35 (137 mg, 0.27 mmol). Purification by silica gel column chromatography (gradient elution, 0-15% MeOH / EtOAc), followed by a second silica gel column chromatography (gradient elution, 0-6% MeOH / DCM) and lyophilization from MeCN / HO gave the title compound (relative stereochemistry between the benzyl group and the bridgehead protons assigned by NMR nOe experiment). LCMS (ES+) 380 (M+H). + , RT 3.03 min (analysis method A), RT 3.04 min (analysis method SFC1, YMC Cellulose-C 25 / 75 IPA (0.1% DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.31 (2H, dd, J=7.2, 7.2 Hz), 7.25 - 7.19 (3H, m), 5.20 (1H, d, J=2.3 Hz), 4.81 (1H, d, J=2.0 Hz), 4.23 (1H, s), 3.94 (1H, ddd, J=1.3, 3.4, 11.6 Hz), 3.83 - 3.77 (1H, m), 3.68 - 3.61 (2H, m), 3.48 (1H, td, J=2.0, 12.7 Hz), 3.39 - 3.33 (1H, m), 3.16 (1H, dd, J=4.2, 14.3 Hz), 2.91 (1H, dt, J=3.6, 12.1 Hz), 2.64 (1H, dd, J=9.9, 14.1 Hz), 2.57 (1H, dd, J=10.5, 12.6 Hz), 2.47 (1H, s), 2.06 - 1.98 (1H, m), 1.84 - 1.77 (2H, m), 1.65 - 1.56 (2H, m), 1.48 (1H, d, J=9.9 Hz), 1.22 (3H, d, J=6.3 Hz), NH not observed.

[0507] The following examples were prepared using a procedure similar to that described in Example 115 starting from 2-benzyl-3-azabicyclo[2.2.1]heptane and scaffold 1. Relative cis / trans stereochemistry was determined by NMR nOe experiments.

[0508] [Table 12]

[0509] The following examples were prepared using a procedure similar to that described in Example 115, starting with the listed Boc-protected pyrrolidine and alkyl halide, using scaffold 1 or 2 as appropriate. Boc deprotection was achieved using 4 M HCl in dioxane instead of TFA. In these examples, diastereomers were separated in the final step, followed by separation of the enantiomers of each diastereomer. Relative cis / trans stereochemistry was determined by NMR nOe experiments.

[0510] [Table 13] TIFF0007727627000159.tif248168TIFF0007727627000160.tif230167TIFF0007727627000161.tif230167 TIFF0007727627000162.tif212167TIFF0007727627000163.tif245167TIFF0007727627000164.tif192167

[0511] Example 142: 6-((1S,2R,4R,5R)-2-benzyl-4-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-4-morpholinopyridin-2(1H)-one and Example 143: 6-((1R,2S,4S,5S)-2-benzyl-4-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-4-morpholinopyridin-2(1H)-one

[0512] [ka]

[0513] Step 1: tert-Butyl (1R,2S,5S)-2-benzyl-4-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate Tetramethylethylenediamine (540 μL, 3.6 mmol) was added to a solution of tert-butyl (1R,2S,5S)-2-benzyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (982 mg, 3.6 mmol, Intermediate 1, Step 2) in EtO (12 mL) under nitrogen. The reaction was cooled to −78 °C, sec-BuLi (3.3 mL, 4.7 mmol, 1.4 M in cyclohexane) was added, and the reaction was warmed to −35 °C for 1 h. The reaction was cooled to −78 °C, and methyl iodide (450 μL, 7.2 mmol) was added dropwise. After the addition was complete, the reaction was allowed to slowly warm to rt overnight. The reaction was quenched with aqueous NH4Cl, the layers were separated, and the aqueous solution was further extracted with EtO (×2). The combined organic extracts were dried (MgSO4) and evaporated. Purification by silica gel column chromatography (gradient elution, 0-3% EtOAc / iso-hexane) afforded the title compound.

[0514] Step 2: (1R*,2S*,5S*)-2-benzyl-4-methyl-3-azabicyclo[3.1.0]hexane tert-Butyl (1R,2S,5S)-2-benzyl-4-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (130 mg, 0.45 mmol) was dissolved in HCl (3 mL, 4 M in dioxane). After 1.5 h, the reaction was concentrated under reduced pressure. The residue was dissolved in DCM and washed with saturated NaHCO (saturated aqueous solution). The DCM layer was dried (phase separator) and concentrated under reduced pressure to give the title compound. It was used in the next step without further purification.

[0515] Step 3: 4-(2-((1R,2S,5S)-2-benzyl-4-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D from (1R,2S,5S)-2-benzyl-4-methyl-3-azabicyclo[3.1.0]hexane (75 mg, 0.40 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (134 mg, 0.40 mmol, scaffold 1). Purification by silica gel column chromatography (gradient elution, 0-15% EtOAc / iso-hexane) afforded the title compound.

[0516] Step 4: 6-((1S,2R,4R,5R)-2-benzyl-4-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-4-morpholinopyridin-2(1H)-one and 6-((1R,2S,4S,5S)-2-benzyl-4-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-4-morpholinopyridin-2(1H)-one According to Method E from 4-(2-((1R*,2S*,5S*)-2-benzyl-4-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (53 mg, 0.11 mmol). The crude product material was purified by chiral SFC to separate the isomers.

[0517] 6-((1S,2R,4R,5R)-2-benzyl-4-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-4-morpholinopyridin-2(1H)-one was lyophilized from MECN / HO to give the title compound. LCMS (ES+) 366 (M+H) + , RT 3.10 min (Analytical Method B), RT 1.44 min (Analytical Method SFC4, YMC Cellulose-SC 35 / 65 MeOH [0.1% DEAISO] / CO2); 1H NMR (400 MHz, CDCl3): δ 7.22 - 7.15 (3H, m), 7.15 - 7.10 (2H, m), 5.30 (1H, d, J=2.0 Hz), 4.99 (1H, d, J=2.0 Hz), 4.44 (1H, dd, J=3.2, 9.2 Hz), 3.83 - 3.71 (5H, m), 3.29 - 3.23 (4H, m), 2.97 - 2.89 (1H, m), 2.55 (1H, dd, J=9.3, 13.1 Hz), 1.61 - 1.54 (1H, m), 1.44 - 1.38 (1H, m), 1.21 (3H, d, J=5.6 Hz), 0.50 - 0.45 (2H, m), NH not recognized.

[0518] 6-((1R,2S,4S,5S)-2-benzyl-4-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-4-morpholinopyridin-2(1H)-one was repurified by silica gel chromatography (gradient elution, 0-10% MeOH / EtOAc) and lyophilized from MECN / HO to give the title compound. LCMS (ES+) 366 (M+H) + , RT 3.11 min (Analytical Method B), RT 3.16 min (Analytical Method SFC1, YMC Cellulose-SC 35 / 65 MeOH [0.1% DEAISO] / CO2); 1H NMR (400 MHz, CDCl3): δ 7.22 (3H, dd, J=6.9, 13.3 Hz), 7.13 (2H, d, J=7.8 Hz), 5.29 (1H, d, J=1.5 Hz), 5.00 (1H, d, J=1.8 Hz), 4.27 (1H, dd. dd, J=9.1, 13.4 Hz), 1.63 - 1.56 (1H, m), 1.49 - 1.42 (1H, m), 1.21 (3H, d, J=5.8 Hz), 0.55 - 0.43 (2H, m), NH not observed.

[0519] Example 144: 6-((S)-2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 145: 6-((R)-2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0520] [ka]

[0521] Step 1: 2,2,2-trifluoro-1-(2-(4-methoxybenzyl)pyrrolidin-1-yl)ethan-1-one To a solution of 2-(4-methoxybenzyl)pyrrolidine (376 mg, 1.97 mmol) in dry DCM (0.1 M) was added TFAA (2.0 eq.) at 0 °C under N. The mixture was allowed to warm to rt over 24 h with stirring. The reaction was quenched by cooling to 0 °C and treated with HO followed by saturated aqueous NaHCO. The mixture was diluted with DCM and the layers were separated. The organic layer was dried (phase separator) and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) to give the impure title compound, which was used without further purification.

[0522] Step 2: 2,2,2-trifluoro-1-(2-(4-hydroxybenzyl)pyrrolidin-1-yl)ethan-1-one A solution of 2,2,2-trifluoro-1-(2-(4-methoxybenzyl)pyrrolidin-1-yl)ethan-1-one (243 mg, 0.85 mmol) in dry DCM (0.2 M) was cooled to 0 °C under N. Boron tribromide (4.25 mL, 4.25 mmol, 1 M solution in DCM) was added. After 2 h, the reaction mixture was poured into saturated aqueous NaHCO and stirred vigorously for 1 h. The layers were separated, dried (phase separator), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) to give the impure title compound, which was used without further purification.

[0523] Step 3: 2,2,2-trifluoro-1-(2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)ethan-1-one A solution of 2,2,2-trifluoro-1-(2-(4-hydroxybenzyl)pyrrolidin-1-yl)ethan-1-one (250 mg, 0.92 mmol) and (S)-1-methoxypropan-2-ol (1.83 mmol) alcohol in dry THF (3 mL) was treated with PPh3 (1.3 mmol) and DIAD (1.3 mmol) at rt. The reaction was stirred at rt for 3 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) to give the impure title compound, which was used without further purification.

[0524] Step 4: 2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidine A solution of 2,2,2-trifluoro-1-(2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)ethan-1-one (224 mg) in MeOH (7 mL) was treated with KCO (420 mg, 3.04 mmol) at rt. The mixture was stirred at 60° C. for 1 h. After cooling to rt, the mixture was concentrated and partitioned between DCM (20 mL) and water (10 mL). The residue was passed through a hydrophobic frit and the organic layer was concentrated to give the title compound.

[0525] Step 5: 4-(2-((4-methoxybenzyl)oxy)-6-(2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)pyridin-4-yl)morpholine Following Method C, starting with 2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidine (155 mg, 0.62 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (211 mg, 0.63 mmol, scaffold 1). After 16 h, additional BINAP (0.13 mmol) and Pd(dba) (64 μmol) were added, the tube was degassed three times with N, and heating was continued at 100 °C for 22 h. After cooling to rt, the mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated and used without further purification.

[0526] Step 6: 6-((S)-2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and 6-((R)-2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one A solution of 4-(2-((4-methoxybenzyl)oxy)-6-(2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)pyridin-4-yl)morpholine (the crude product from the previous step was used) in TFA (5 mL) was stirred at rt for 1-17 h. The reaction mixture was then concentrated. The crude mixture was purified by reverse-phase preparative HPLC followed by SFC to give the title compound.

[0527] 6-((S)-2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 428 (M+H) + , RT 2.79 minutes (Analysis method A); 1 H NMR (400 MHz, CDCl3): δ 7.06 (2H, d, J=8.5 Hz), 6.86 (2H, d, J=8.5 Hz), 5.21 (1H, d, J=2.0 Hz), 4.88 (1H, d, J=2.0 Hz), 4.55 - 4.46 (1H, m), 4.09 - 4.01 (1H, m), 3.79 (4H, dd, J=4.9, 4.9 Hz), 3.58 (1H, dd, J=5.9, 10.2 Hz), 3.49 - 3.42 (2H, m), 3.41 (3H, s), 3.32 - 3.23 (5H, m), 2.89 (1H, dd, J=3.7, 13.9 Hz), 2.63 (1H, dd, J=8.4, 13.9 Hz), 1.97 - 1.75 (5H, m), 1.30 (3H, d, J=6.3 Hz).

[0528] 6-((R)-2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 428 (M+H) + , RT 2.79 minutes (Analysis method A); 1 H NMR (400 MHz, CDCl3): δ 7.05 (2H, d, J=8.5 Hz), 6.86 (2H, d, J=8.7 Hz), 5.21 (1H, d, J=2.0 Hz), 4.87 (1H, d, J=2.0 Hz), 4.51 (1H, qt, J=5.6, 6.1 Hz), 4.05 (1H, dd, J=8.5, 8.5 Hz), 3.79 (4H, dd, J=4.9, 4.9 Hz), 3.58 (1H, dd, J=5.8, 10.2 Hz), 3.50 - 3.42 (2H, m), 3.41 (3H, s), 3.32 - 3.22 (5H, m), 2.89 (1H, dd, J=3.8, 13.9 Hz), 2.64 (1H, dd, J=8.3, 13.9 Hz), 1.97 - 1.75 (4H, m), 1.29 (3H, d, J=6.3 Hz), NH not observed.

[0529] Example 146: (R)-4-Morpholino-6-(2-(3-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidin-1-yl)pyridin-2(1H)-one and Example 147: (S)-4-Morpholino-6-(2-(3-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidin-1-yl)pyridin-2(1H)-one

[0530] [ka]

[0531] Step 1: 2-(3-Methoxybenzyl)pyrrolidinium hydrochloride A solution of tert-butyl 2-(3-methoxybenzyl)pyrrolidine-1-carboxylate (3.68 g, 12.6 mmol) in 4 M HCl / dioxane (25 mL) was stirred at rt for 1 h. Evaporation of the volatiles gave the impure title compound.

[0532] Step 2: 2,2,2-trifluoro-1-(2-(3-methoxybenzyl)pyrrolidin-1-yl)ethan-1-one DIPEA (4.4 mL, 25.3 mmol) was added to a solution of 2-(3-methoxybenzyl)pyrrolidinium hydrochloride (2.87 g mixture from the previous step) in dry DCM (120 mL) at 0 °C. TFAA (3.5 mL, 25.2 mmol) was added over 5 min, and the reaction was allowed to warm to rt over 16 h. After 17 h, TFAA (3.5 mL, 25.2 mL) was added. After an additional 4 h, TFAA (1.3 mL) was added at rt. The reaction mixture was stirred at rt for an additional 1.5 h before being cooled to 0 °C. The reaction mixture was quenched with water (5 mL) and saturated aqueous NaHCO3 (15 mL). The layers were separated, and the organic extract was dried (phase separator) and concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL), washed with 1M Na2CO3 (2x30 mL), 1M HCl (30 mL), dried (Na2SO4) and concentrated to give the title compound.

[0533] Step 3: 2,2,2-trifluoro-1-(2-(3-hydroxybenzyl)pyrrolidin-1-yl)ethan-1-one Following the procedure described for the preparation of Example 11, Step 2, starting from 2,2,2-trifluoro-1-(2-(3-methoxybenzyl)pyrrolidin-1-yl)ethan-1-one (2.42 g, 8.42 mmol), the reaction mixture was quenched with 20 mL of saturated aqueous NaHCO3. The residue was dried (phase separator) and concentrated to give the title compound.

[0534] Step 4: 2,2,2-trifluoro-1-(2-(3-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidin-1-yl)ethan-1-one Following the procedure described for the preparation of Example 11, Step 3, starting with 2,2,2-trifluoro-1-(2-(3-hydroxybenzyl)pyrrolidin-1-yl)ethan-1-one (550 mg mixture from the previous step) and tetrahydro-2H-pyran-4-ol (3.98 mmol), the mixture was concentrated and the residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) to give the impure title compound, which was used without further purification.

[0535] Step 5: 2-(3-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidine Following the procedure described for the preparation of Example 11, Step 4, starting from 2,2,2-trifluoro-1-(2-(3-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidin-1-yl)ethan-1-one (564 mg mixture from the previous step), impure title compound was obtained and used without further purification.

[0536] Step 6: 4-(2-((4-methoxybenzyl)oxy)-6-(2-(3-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidin-1-yl)pyridin-4-yl)morpholine Following Method D starting from 2-(3-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidine (159 mg, 0.61 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (201 mg, 0.61 mmol, scaffold 1). Purification by silica gel column chromatography (gradient elution, 0-40% EtOAc / iso-hexane) afforded the impure title compound, which was used without further purification.

[0537] Step 7: (R)-4-morpholino-6-(2-(3-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidin-1-yl)pyridin-2(1H)-one and (S)-4-morpholino-6-(2-(3-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidin-1-yl)pyridin-2(1H)-one Following Method E starting from 4-(2-((4-methoxybenzyl)oxy)-6-(2-(3-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidin-1-yl)pyridin-4-yl)morpholine (171 mg from the previous step). Purification by reverse phase HPLC followed by chiral SFC gave the title compound.

[0538] (R)-4-Morpholino-6-(2-(3-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidin-1-yl)pyridin-2(1H)-one. LCMS (ES+) 440 (M+H) + , RT 2.78 min (Analytical method A), RT 1.92 min (Analytical method SFC4, YMC Amylose-C 50 / 50 IPA (0.1% DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.21 (1H, t, J=7.8 Hz), 6.82 - 6.73 (3H, m), 5.20 (1H, d, J=2.3 Hz), 4.85 (1H, d, J=2.0 Hz), 4.49 - 4.42 (1H, m), 4.05 - 3.93 (3H, m), 3.78 (4H, t, J=4.9 Hz), 3.60 - 3.53 (2H, m), 3.42 (1H, dd, J=6.7, 9.0 Hz), 3.29 - 3.25 (1H, m), 3.23 (4H, dd, J=4.2, 5.7 Hz), 2.92 (1H, dd, J=4.2, 13.8 Hz), 2.66 (1H, dd, J=8.3, 13.6 Hz), 2.04 - 1.86 (6H, m), 1.81 - 1.71 (3H, m).

[0539] (S)-4-Morpholino-6-(2-(3-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidin-1-yl)pyridin-2(1H)-one. LCMS (ES+) 440 (M+H) + , RT 2.79 min (Analytical method A), RT 0.94 min (Analytical method SFC4, YMC Amylose-C 50 / 50 IPA (0.1% DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.21 (1H, t, J=7.8 Hz), 6.82 - 6.73 (3H, m), 5.20 (1H, d, J=2.3 Hz), 4.85 (1H, d, J=2.0 Hz), 4.49 - 4.42 (1H, m), 4.05 - 3.93 (3H, m), 3.78 (4H, t, J=4.9 Hz), 3.60 - 3.53 (2H, m), 3.42 (1H, dd, J=6.7, 9.0 Hz), 3.29 - 3.25 (1H, m), 3.23 (4H, dd, J=4.2, 5.7 Hz), 2.92 (1H, dd, J=4.2, 13.8 Hz), 2.66 (1H, dd, J=8.3, 13.6 Hz), 2.04 - 1.86 (6H, m), 1.81 - 1.71 (3H, m).

[0540] Example 148: 6-((R)-2-(3-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 149: 6-((S)-2-(3-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0541] [ka]

[0542] Step 1: 2,2,2-trifluoro-1-(2-(3-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)ethan-1-one Following the procedure described for the preparation of Example 11, Step 3, starting with 2,2,2-trifluoro-1-(2-(3-hydroxybenzyl)pyrrolidin-1-yl)ethan-1-one (550 mg, Example 13, Step 3) and (S)-1-methoxypropan-2-ol (3.99 mmol), the mixture was concentrated and the residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) to give the title compound.

[0543] Step 2: 2-(3-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidine Following the procedure described for the preparation of Example 11, Step 4, starting from 2,2,2-trifluoro-1-(2-(3-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)ethan-1-one (381 mg), the title compound was obtained.

[0544] Step 3: 4-(2-((4-methoxybenzyl)oxy)-6-(2-(3-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)pyridin-4-yl)morpholine Following Method D from 2-(3-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidine (249 mg, 0.75 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (181 mg, 0.73 mmol, scaffold 1). Purification by silica gel column chromatography (gradient elution, 0-50% EtOAc / iso-hexane) afforded the title compound.

[0545] Step 4: 6-((R)-2-(3-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one and 6-((S)-2-(3-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one Following method E from 4-(2-((4-methoxybenzyl)oxy)-6-(2-(3-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)pyridin-4-yl)morpholine (289 mg, 0.53 mmol). Purification by reverse phase HPLC followed by chiral SFC gave the title compound.

[0546] 6-((R)-2-(3-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 428 (M+H)+, RT 2.83 min (Analytical Method A), RT 1.34 min (Analytical Method SFC4, YMC Amylose-C 50 / 50 IPA (0.1% DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.20 (1H, t, J=8.0 Hz), 6.83 - 6.79 (1H, m), 6.77 - 6.73 (2H, m), 5.21 (1H, d, J=2.1 Hz), 4.88 (1H, d, J=2.1 Hz), 4.52 (1H, dd, J=6.1, 10.5, 12.3 Hz), 4.04 (1H, dd, J=4.0, 8.0 Hz), 3.79 (4H, t, J=4.9 Hz), 3.57 (1H, dd, J=5.9, 10.2 Hz), 3.47 (2H, dd, J=4.4, 10.2 Hz), 3.41 (3H, s), 3.31 - 3.22 (6H, m), 2.95 (1H, dd, J=3.8, 13.7 Hz), 2.61 (1H, dd, J=8.6, 13.7 Hz), 1.99 - 1.84 (4H, m), 1.29 (3H, d, J=6.3 Hz).

[0547] 6-((S)-2-(3-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 428 (M+H) + , RT 2.84 min (Analytical method A), RT 0.77 min (Analytical method SFC4, YMC Amylose-C 50 / 50 IPA (0.1% DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.20 (1H, t, J=7.8 Hz), 6.81 (1H, dd, J=2.1, 8.1 Hz), 6.78 - 6.73 (2H, m), 5.21 (1H, d, J=2.1 Hz), 4.89 (1H, d, J=2.1 Hz), 4.56 - 4.50 (1H, m), 4.02 (1H, dd, J=3.6, 8.0 Hz), 3.79 (4H, t, J=4.9 Hz), 3.57 (1H, dd, J=5.9, 10.2 Hz), 3.50 - 3.43 (2H, m), 3.41 (3H, s), 3.30 - 3.22 (5H, m), 2.94 (1H, dd, J=3.9, 13.7 Hz), 2.62 (1H, dd, J=8.6, 13.7 Hz), 2.00 - 1.84 (4H, m), 1.29 (3H, d, J=6.1 Hz), no NH was observed.

[0548] Example 150: 6-((S)-2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)azepan-1-yl)-4-morpholinopyridin-2(1H)-one and Example 151: 6-((R)-2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)azepan-1-yl)-4-morpholinopyridin-2(1H)-one

[0549] [ka]

[0550] Step 1: 2,2,2-trifluoro-1-(2-(4-methoxybenzyl)azepan-1-yl)ethan-1-one TFAA (0.63 mL, 4.53 mmol) was added to a solution of 2-(4-methoxybenzyl)azepane oxalate (619 mg, 2.00 mmol) in dry DCM (25 mL) at 0 °C under nitrogen (Note: Strongly exothermic). The mixture was stirred at rt for 18 h. DIPEA (3 × 199 μL, 3 × 1.14 mmol, at 3 h intervals) was added until complete conversion was observed. The reaction was quenched by cooling to 0 °C and treating with 1 mL HO, followed by 1 mL saturated aqueous NaHCO solution. The reaction mixture was diluted with 10 mL DCM and dried (phase separator). The crude material was purified by silica gel column chromatography (gradient elution, 0–60% EtOAc / iso-hexane) to give the product, which was used without further purification.

[0551] Step 2: 2,2,2-trifluoro-1-(2-(4-hydroxybenzyl)azepan-1-yl)ethan-1-one Following the procedure described for the preparation of Example 11, Step 2 starting from 2,2,2-trifluoro-1-(2-(4-methoxybenzyl)azepan-1-yl)ethan-1-one, the organic layer was dried (phase separator) and concentrated under reduced pressure to give the title compound.

[0552] Step 3: 2,2,2-trifluoro-1-(2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)azepan-1-yl)ethan-1-one Following the procedure described for the preparation of Example 11, Step 3, starting with 2,2,2-trifluoro-1-(2-(4-hydroxybenzyl)azepan-1-yl)ethan-1-one (1.37 mmol) and (S)-1-methoxypropan-2-ol (270 μL, 2.76 mmol), the mixture was purified by silica gel column chromatography (gradient elution, 0-50% EtOAc / iso-hexane) to give the title compound.

[0553] Step 4: 2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)pyrrolidine Following the procedure described for the preparation of Example 11, Step 4 starting from 2,2,2-trifluoro-1-(2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)azepan-1-yl)ethan-1-one (0.93 mmol). After 18 h, HO (2 mL) and KOH (3.70 mmol) were added and the reaction was stirred at 60 °C. After 43 h, the reaction mixture was concentrated, diluted with 20 mL HO and 20 mL DCM, passed through a hydrophobic frit and the organic layer was concentrated to give the title compound.

[0554] Step 5: 4-(2-((4-methoxybenzyl)oxy)-6-(2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)azepan-1-yl)pyridin-4-yl)morpholine Following Method D, starting with 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (221 mg, 0.66 mmol, scaffold 1) and 2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)azepane (189 mg, 0.68 mmol) added as a solution in dry dioxane (4.5 mL). The filtrate was concentrated and then purified by silica gel column chromatography (gradient elution, 0-25% EtOAc / iso-hexane) to give the impure title compound, which was used without further purification.

[0555] Step 6: 6-((S)-2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)azepan-1-yl)-4-morpholinopyridin-2(1H)-one and 6-((R)-2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)azepan-1-yl)-4-morpholinopyridin-2(1H)-one Following Method E starting from 4-(2-((4-methoxybenzyl)oxy)-6-(2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)azepan-1-yl)pyridin-4-yl)morpholine (the crude product from the previous step was used). The residue was partially purified by silica gel column chromatography (gradient elution, 0-20% MeOH / EtOAc) and the fractions containing the title compound were further purified by SFC to give the title compound.

[0556] 6-((R)-2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)azepan-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 456 (M+H) + , RT 2.90 min (Analysis method A); 1 H NMR (400 MHz, DMSO-d6): δ 9.39 (1H, s), 7.18 (2H, d, J=8.3 Hz), 6.87 (2H, d, J=8.6 Hz), 5.34 (1H, s), 5.25 (1H, s), 4.62 - 4.55 (1H, m), 4.33 (1H, s), 3.72 (4H, t, J=4.8 Hz), 3.52 (1H, dd, J=5.7, 10.9 Hz), 3.45 (1H, dd, J=4.2, 10.4 Hz), 3.38 (3H, s), 3.19 - 3.13 (4H, m), 3.02 - 2.92 (1H, m), 2.78 - 2.72 (1H, m), 2.66 - 2.58 (1H, m), 1.90 - 1.86 (1H, m), 1.77 - 1.62 (3H, m), 1.48 - 1.38 (2H, m), 1.30 - 1.25 (1H, m), 1.23 (3H, d, J=6.1 Hz), 1.11 - 1.01 (1H, m), 1H not observed.

[0557] 6-((S)-2-(4-(((R)-1-methoxypropan-2-yl)oxy)benzyl)azepan-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 456 (M+H) + , RT 2.91 minutes (Analysis method A); 1 H NMR (400 MHz, DMSO-d6): δ 9.41 (1H, s), 7.18 (2H, d, J=8.6 Hz), 6.87 (2H, d, J=8.6 Hz), 5.38 - 5.31 (1H, m), 5.25 (1H, s), 4.62 - 4.55 (1H, m), 4.34 (1H, s), 3.72 (4H, t, J=4.9 Hz), 3.52 (1H, dd, J=5.8, 10.3 Hz), 3.45 (1H, dd, J=4.5, 10.3 Hz), 3.39 (3H, s), 3.19 - 3.13 (4H, m), 2.96 (1H, t, J=13.0 Hz), 2.74 (1H, dd, J=4.4, 13.0 Hz), 2.63 (1H, dd, J=8.0, 13.1 Hz), 1.91 - 1.83 (1H, m), 1.77 - 1.59 (3H, m), 1.51 - 1.38 (2H, m), 1.31 - 1.20 (4H, m), 1.12 - 1.01 (1H, m), 1H not observed.

[0558] Example 152: 6-[(2R)-2-benzyl-2-(methoxymethyl)pyrrolidin-1-yl]-4-morpholino-1H-pyridin-2-one and Example 153: 6-[(2S)-2-benzyl-2-(methoxymethyl)pyrrolidin-1-yl]-4-morpholino-1H-pyridin-2-one

[0559] [ka]

[0560] Step 1: Methyl-1-[6-[(4-methoxyphenyl)methoxy]-4-morpholino-2-pyridyl]pyrrolidine-2-carboxylate Following Method C, starting with L-proline methyl ester hydrochloride (545 mg, 3.29 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (1.10 g, 3.29 mmol, scaffold 1). The mixture was purified by silica gel column chromatography (gradient elution, 0-50% EtOAc / iso-hexane) to give the impure title compound, which was reacted directly in the next step.

[0561] Step 2: Methyl 2-benzyl-1-[6-[(4-methoxyphenyl)methoxy]-4-morpholino-2-pyridyl]pyrrolidine-2-carboxylate LHMDS (3.1 mL, 3.06 mmol, 1 M solution in THF) was added to a solution of methyl (2S)-1-[6-[(4-methoxyphenyl)methoxy]-4-morpholino-2-pyridyl]pyrrolidine-2-carboxylate (770 mg, 1.8 mmol) in dry THF (7 mL) at −25° C. under a N atmosphere. After 1 h, benzyl bromide (0.43 mL, 3.6 mmol) was added and the mixture was allowed to warm to rt. After 1 h, the mixture was cooled to 0° C. and quenched with saturated aqueous NH4Cl. The reaction mixture was diluted with water (10 mL) and extracted with DCM (×2). The organic extracts were dried (phase separator) and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (gradient elution, 0–20% EtOAc / iso-hexane) to give the title compound.

[0562] Step 3: [2-benzyl-1-[6-[(4-methoxyphenyl)methoxy]-4-morpholino-2-pyridyl]pyrrolidin-2-yl]methanol LiAlH4 (0.68 mL, 1.36 mmol, 2 M solution in THF) was added to a solution of methyl 2-benzyl-1-[6-[(4-methoxyphenyl)methoxy]-4-morpholino-2-pyridyl]pyrrolidine-2-carboxylate (701 mg, 1.36 mmol) in dry THF (6.8 mL) at rt. After stirring for 1 h, the mixture was quenched with saturated aqueous NH4Cl and diluted with water (10 mL). The reaction mixture was extracted with DCM (x3). The organic extracts were dried (phase separator) and concentrated to give the title compound.

[0563] Step 4: 4-[2-[2-benzyl-2-(methoxymethyl)pyrrolidin-1-yl]-6-[(4-methoxyphenyl)methoxy]-4-pyridyl]morpholine To a stirred solution of [2-benzyl-1-[6-[(4-methoxyphenyl)methoxy]-4-morpholino-2-pyridyl]pyrrolidin-2-yl]methanol (250 mg, 0.51 mmol) in dry DMF (3.4 mL) was added sodium hydride (31 mg, 0.77 mmol, 60% dispersion in mineral oil) in portions. The resulting mixture was stirred for 15 minutes, and then iodomethane (35 μL, 0.56 mmol) was added. After 1.5 hours, additional iodomethane (35 μL, 0.56 mmol) was added. After another 1.5 hours, additional iodomethane (18 μL, 0.28 mmol) was added. After 2 hours, the reaction mixture was partitioned between 4% aqueous LiCl and extracted with DCM (×3). The organic extract was dried (phase separator) and concentrated to give the title compound.

[0564] Step 5: 6-[2-benzyl-2-(methoxymethyl)pyrrolidin-1-yl]-4-morpholino-1H-pyridin-2-one Following Method E starting from 4-[2-[2-benzyl-2-(methoxymethyl)pyrrolidin-1-yl]-6-[(4-methoxyphenyl)methoxy]-4-pyridyl]morpholine (259 mg, 0.51 mmol), the crude material was purified by reverse-phase preparative HPLC followed by SFC to give the title compound.

[0565] 6-[(2R)-2-benzyl-2-(methoxymethyl)pyrrolidin-1-yl]-4-morpholino-1H-pyridin-2-one; LCMS (ES+) 384 (M+H) + , RT 2.97 min (analytical method A); RT 1.62 min (analytical method SFC1, YMC Cellulose-C, 45 / 55 IPA + 0.1% DEAISO / CO2); 1 H NMR (400 MHz, CDCl3): δ 10.89 (1H, s), 7.29 - 7.22 (3H, m), 7.15 - 7.12 (2H, m), 5.33 (1H, d, J=2.0 Hz), 4.91 (1H, d, J=2.1 Hz), 3.81 - 3.77 (4H, m), 3.58 (3H, s), 3.47 (1H, d, J=9.7 Hz), 3.38 - 3.22 (8H, m), 2.82 (1H, d, J=13.6 Hz), 2.11 (1H, ddd, J=7.1, 9.4, 13.0 Hz), 1.83 - 1.73 (1H, m), 1.72 - 1.66 (1H, m), 1.53 (1H, ddd, J=5.0, 7.3, 12.7 Hz).

[0566] 6-[(2S)-2-benzyl-2-(methoxymethyl)pyrrolidin-1-yl]-4-morpholino-1H-pyridin-2-one; LCMS (ES+) 384 (M+H) + , RT 2.98 min (analytical method A); RT 3.00 min (analytical method SFC1, YMC Cellulose-C, 45 / 55 IPA + 0.1% DEAISO / CO2); 1H NMR (400 MHz, CDCl3): δ 10.89 (1H, s), 7.29 - 7.22 (3H, m), 7.15 - 7.12 (2H, m), 5.33 (1H, d, J=2.0 Hz), 4.91 (1H, d, J=2.1 Hz), 3.81 - 3.77 (4H, m), 3.58 (3H, s), 3.47 (1H, d, J=9.7 Hz), 3.38 - 3.22 (8H, m), 2.82 (1H, d, J=13.6 Hz), 2.11 (1H, ddd, J=7.1, 9.4, 13.0 Hz), 1.83 - 1.73 (1H, m), 1.72 - 1.66 (1H, m), 1.53 (1H, ddd, J=5.0, 7.3, 12.7 Hz).

[0567] Example 154: (S)-6-(2-benzyl-3,3-difluoropiperidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 155: (R)-6-(2-benzyl-3,3-difluoropiperidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0568] [ka]

[0569] Step 1: tert-Butyl 5-(pyrrolidin-1-yl)-3,4-dihydropyridine-1(2H)-carboxylate Pyrrolidine (3.13 mL, 37.5 mmol) was added to a solution of tert-butyl 3-oxopiperidine-1-carboxylate (5 g, 25 mmol) in toluene (50 mL). The reaction was heated to reflux in a Dean-Stark apparatus. After 5.5 hours, the reaction mixture was cooled to rt and concentrated under reduced pressure to give the title compound. This was used in the next step without further purification.

[0570] Step 2: tert-Butyl 2-benzyl-3-oxopiperidine-1-carboxylate Benzyl bromide (1.63 mL, 13.8 mmol) was added to a solution of tert-butyl 5-(pyrrolidin-1-yl)-3,4-dihydropyridine-1(2H)-carboxylate (3.15 g, 12.5 mmol) in acetonitrile (25 mL). The reaction mixture was heated at 65 °C. After 15.5 h, the reaction was cooled to RT. Brine was added, and the reaction mixture was transferred to a separatory funnel with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NH4Cl, dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting brown oil was purified by silica gel column chromatography (gradient elution 0-60% EtOAc / iso-hexane) to provide the title compound.

[0571] Step 3: tert-Butyl 2-benzyl-3,3-difluoropiperidine-1-carboxylate Following the procedure described for the preparation of Example 40, Step 3, starting with tert-butyl 2-benzyl-3-oxopiperidine-1-carboxylate (500 mg, 1.73 mmol), the crude material was purified by silica gel column chromatography (gradient 0-20% EtOAc / iso-hexane) to afford the title compound.

[0572] Step 4: 2-Benzyl-3,3-difluoropiperidine Following the procedure described for the preparation of Example 5, Step 2, starting with tert-butyl 2-benzyl-3,3-difluoropiperidine-1-carboxylate (320 mg, 1.03 mmol), the title compound was obtained and used in the next step without further purification.

[0573] Step 5: 4-(2-(2-benzyl-3,3-difluoropiperidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D, starting with 2-benzyl-3,3-difluoropiperidine (127 mg, 0.60 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (200 mg, 0.60 mmol, scaffold 1). The residue was purified by silica gel column chromatography (gradient elution 0-55% EtO / iso-hexane) to give the title compound.

[0574] Step 6: (S)-6-(2-benzyl-3,3-difluoropiperidin-1-yl)-4-morpholinopyridin-2(1H)-one and (R)-6-(2-benzyl-3,3-difluoropiperidin-1-yl)-4-morpholinopyridin-2(1H)-one TFA (29 μL, 0.38 mmol) was added to 4-(2-(2-benzyl-3,3-difluoropiperidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (192 mg, 0.38 mmol) in DCM (2 mL). After 19 h, the reaction mixture was concentrated under reduced pressure. The oil was dissolved in DCM, washed with saturated aqueous sodium bicarbonate solution, dried (phase separator), and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography (gradient elution with 0-10% MeOH in EtOAc), followed by SFC to separate the enantiomers, to give the title compound.

[0575] (S)-6-(2-benzyl-3,3-difluoropiperidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 390 (M+H) + , RT 2.83 min (Analytical method A), RT 1.10 min (Analytical method SFC4, YMC Amylose-C 30% MeOH (0.1% DEAISO) / CO2; 1H NMR (400 MHz, DMSO-d6): δ 9.59 (1H, s), 7.37 (2H, d, J=7.1 Hz), 7.25 (2H, dd, J=7.3, 7.3 Hz), 7.20 - 7.15 (1H, m), 5.41 - 5.40 (1H, m), 5.32 - 5.28 (1H, m), 5.14 - 5.09 (1H, m), 4.12 - 4.03 (1H, m), 3.70 - 3.65 (4H, m), 3.15 - 2.99 (7H, m), 2.42 - 2.24 (1H, m), 2.13 - 2.04 (1H, m), 1.81 - 1.68 (2H, m). Rotamers are observed.

[0576] (R)-6-(2-benzyl-3,3-difluoropiperidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 390 (M+H) + , RT 2.83 min (Analytical method A), RT 1.85 min (Analytical method SFC4, YMC Amylose-C 30% MeOH (0.1% DEAISO) / CO2; 1 H NMR (400 MHz, 105℃, DMSO-d6): δ 9.04 (1H, s), 7.28 (2H, d, J=7.3 Hz), 7.19 (2H, dd, J=7.3, 7.3 Hz), 7.13 - 7.09 (1H, m), 5.30 (1H, s), 5.27 (1H, s), 4.97 - 4.95 (1H, m), 4.06 - 3.99 (1H, m), 3.65 - 3.62 (4H, m), 3.13 - 2.96 (6H, m), 2.32 - 2.14 (1H, m), 2.05 - 2.04 (1H, m), 1.78 - 1.70 (2H, m), NH is not recognized.

[0577] Example 156: (S)-6-(3,3-difluoro-2-(4-methoxybenzyl)piperidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 157: (R)-6-(3,3-difluoro-2-(4-methoxybenzyl)piperidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0578] [ka]

[0579] Step 1: tert-Butyl 2-(4-methoxybenzyl)-3-oxopiperidine-1-carboxylate 4-Methoxybenzyl bromide (1.99 mL, 13.8 mmol) was added to a solution of tert-butyl 5-(pyrrolidin-1-yl)-3,4-dihydropyridine-1(2H)-carboxylate (3.15 g, 12.5 mmol, Example 132, Step 1) in acetonitrile (25 mL). The reaction mixture was heated at 65° C. After 15.5 h, the reaction was cooled to RT. Brine was added, and the reaction mixture was transferred to a separatory funnel with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NH4Cl, dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting brown oil was purified by silica gel column chromatography (gradient elution 0-40% EtOAc / iso-hexane) to provide the title compound.

[0580] Step 2: tert-Butyl 3,3-difluoro-2-(4-methoxybenzyl)piperidine-1-carboxylate Following the procedure described for the preparation of Example 40, Step 3, starting from tert-butyl 2-(4-methoxybenzyl)-3-oxopiperidine-1-carboxylate (1.56 mmol), the mixture was purified by silica gel column chromatography (gradient elution 0-20% EtOAc / iso-hexane) to give the title compound.

[0581] Step 3: 3,3-Difluoro-2-(4-methoxybenzyl)piperidine Following the procedure described for the preparation of Example 5, Step 3, starting with tert-butyl 3,3-difluoro-2-(4-methoxybenzyl)piperidine-1-carboxylate (313 mg, 0.92 mmol), the title compound was obtained and used in the next step without further purification.

[0582] Step 4: 4-(2-(2-benzyl-3,3-difluoropiperidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D starting with 3,3-difluoro-2-(4-methoxybenzyl)piperidine (145 mg, 0.60 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (200 mg, 0.60 mmol, scaffold 1). The residue was purified by silica gel column chromatography (gradient elution 0-55% EtO / iso-hexane) to give the title compound.

[0583] Step 5: (S)-6-(3,3-difluoro-2-(4-methoxybenzyl)piperidin-1-yl)-4-morpholinopyridin-2(1H)-one and (R)-6-(3,3-difluoro-2-(4-methoxybenzyl)piperidin-1-yl)-4-morpholinopyridin-2(1H)-one Following the procedure described for the preparation of Example 132, Step 6, starting with 4-(2-(3,3-difluoro-2-(4-methoxybenzyl)piperidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (129 mg, 0.24 mmol), the resulting oil was purified by silica gel column chromatography (gradient elution 0-10% MeOH / EtOAc). The two enantiomers were separated by SFC.

[0584] (S)-6-(3,3-difluoro-2-(4-methoxybenzyl)piperidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 420 (M+H) + , RT 2.82 min (Analytical method A); RT 1.21 min (Analytical method SFC4, YMC Amylose-C 30% MeOH (0.1% DEAISO) / CO2)); 1 H NMR (400 MHz, DMSO-d6): δ 9.52 (1H, s), 7.23 (2H, d, J=8.5 Hz), 6.77 (2H, d, J=8.7 Hz), 5.43 - 4.91 (3H, m), 4.18 - 3.94 (1H, m), 3.69 (3H, s), 3.66 - 3.61 (4H, m), 3.10 - 2.96 (6H, m), 2.90 - 2.85 (1H, m), 2.22 (1H, s), 2.07 - 2.02 (1H, m), 1.73 - 1.64 (2H, m). Rotamers are observed.

[0585] (R)-6-(3,3-difluoro-2-(4-methoxybenzyl)piperidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 420 (M+H) + , RT 2.82 min (Analytical method A); RT 1.96 min (Analytical method SFC4, YMC Amylose-C 30% MeOH (0.1% DEAISO) / CO2; 1 H NMR (400 MHz, 105℃, DMSO-d6): δ 9.01 (1H, s), 7.18 (2H, d, J=8.0 Hz), 6.75 (2H, d, J=8.5 Hz), 5.30 - 5.23 (2H, m), 4.93 - 4.82 (1H, m), 4.05 - 3.98 (1H, m), 3.70 (3H, s), 3.66 - 3.61 (4H, m), 3.11 - 3.00 (6H, m), 2.28 - 2.12 (1H, m), 2.07 - 1.95 (1H, m), 1.77 - 1.72 (2H, m), 1H is obscured by the water peak.

[0586] Example 158: 6-((2S,3S)-2-benzyl-3-methoxypiperidin-1-yl)-4-morpholinopyridin-2(1H)-one and Example 159: 6-((2R,3R)-2-benzyl-3-methoxypiperidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0587] [ka]

[0588] Step 1: tert-Butyl (2R*,3R*)-2-benzyl-3-hydroxypiperidine-1-carboxylate Following the procedure described for the preparation of Example 30, Step 2, starting with tert-butyl 2-benzyl-3-oxopiperidine-1-carboxylate (1.0 g, 3.45 mmol, Step 2), the reaction mixture was purified by silica gel column chromatography (gradient elution 10-80% EtOAc / iso-hexane) to give the title compound.

[0589] Step 2: tert-Butyl (2R*,3R*)-2-benzyl-3-methoxypiperidine-1-carboxylate Following the procedure described for the preparation of Example 30, Step 5, starting with tert-butyl (2R,3R)-2-benzyl-3-hydroxypiperidine-1-carboxylate (150 mg, 0.51 mmol), the reaction mixture was purified by silica gel column chromatography (gradient elution 10-80% EtOAc / iso-hexane) to give the title compound.

[0590] Step 3: (2R*,3R*)-2-benzyl-3-methoxypiperidine The procedure described for the preparation of Example 73, Step 5, was followed, starting with tert-butyl (2R*,3R*)-2-benzyl-3-methoxypiperidine-1-carboxylate (120 mg, 0.39 mmol). The reaction mixture was purified on an SCX cartridge (1 g) eluting with 3 column volumes of DCM, 3 column volumes of methanol, 2 column volumes of 7N NH3 in 9:1 DCM:MeOH, and 2 column volumes of 7N NH3 in 4:1 DCM:MeOH. The ammonia fractions were combined and concentrated under reduced pressure to give a colorless oil (40 mg). Additional target material was isolated from the methanol layer, which was concentrated under reduced pressure, dissolved in DCM, and washed with saturated aqueous NaHCO3. The organic extract was dried (phase separator) and concentrated under reduced pressure. The combined fractions gave the title compound.

[0591] Step 4: 4-(2-((2R*,3R*)-2-benzyl-3-methoxypiperidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D starting with (2R*,3R*)-2-benzyl-3-methoxypiperidine (75 mg, 0.36 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (111 mg, 0.33 mmol, scaffold 1), the crude product material was purified by silica gel column chromatography (gradient elution 10-60% EtOAc / iso-hexane) to give the title compound.

[0592] Step 5: 6-((2S,3S)-2-benzyl-3-methoxypiperidin-1-yl)-4-morpholinopyridin-2(1H)-one and 6-((2R,3R)-2-benzyl-3-methoxypiperidin-1-yl)-4-morpholinopyridin-2(1H)-one Following Method E, starting with 4-(2-((2R*,3R*)-2-benzyl-3-methoxypiperidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (110 mg, 0.22 mmol). The crude material was purified by silica gel column chromatography (gradient elution 0-25% methanol / EtOAc). The resulting product was purified by SFC to separate the enantiomers.

[0593] 6-((2S,3S)-2-benzyl-3-methoxypiperidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 384 (M+H) + , RT 3.02 min (analysis method B), RT 2.34 min (analysis method SFC4, YMC Cellulose-C 35% IPA SOL4 (0.1% DEAISO) / CO2); 1 H NMR (400 MHz, CDCl3): δ 7.25 - 7.20 (2H, m), 7.18 - 7.13 (3H, m), 5.10 (1H, d, J=2.0 Hz), 4.71 (1H, d, J=2.3 Hz), 4.19 - 4.13 (1H, m), 3.71 (4H, dd, J=4.9, 4.9 Hz), 3.50 - 3.35 (5H, m), 3.28 - 3.20 (1H, m), 3.08 - 3.03 (4H, m), 3.00 - 2.85 (2H, m), 2.00 - 1.96 (1H, m), 1.86 - 1.81 (1H, m), 1.75 - 1.62 (2H, m), NH are not observed.

[0594] 6-((2R,3R)-2-benzyl-3-methoxypiperidin-1-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 384 (M+H) + , RT 2.92 min (Analysis Method B), RT 1.42 min (Analysis Method SFC14 YMC Cellulose-C 30% IPA SOL4 (0.1% DEAISO) / CO2); 1H NMR (400 MHz, CDCl): δ 7.23–7.11 (5H, m), 5.08 (1H, d, J=1.9 Hz), 4.68 (1H, s), 4.25–4.22 (1H, m), 3.72–3.69 (4H, m), 3.51–3.48 (1H, m), 3.42 (4H, s), 3.25–3.19 (1H, m), 3.07–3.01 (4H, m), 3.01–2.85 (2H, m), 2.01–1.97 (1H, m), 1.85–1.82 (1H, m), 1.74–1.60 (2H, m), no NH observed.

[0595] Example 160: 6-(2-benzyl-4,4-difluoropiperidin-1-yl)-4-morpholinopyridin-2(1H)-one

[0596] [ka]

[0597] Step 1: tert-Butyl 2-benzyl-4,4-difluoropiperidine-1-carboxylate Following the procedure described for the preparation of Example 132, Step 3, starting with tert-butyl 2-benzyl-4-oxopiperidine-1-carboxylate (434 mg, 1.5 mmol), the reaction mixture was purified by silica gel column chromatography (gradient elution 5-40% EtOAc in iso-hexane) to give the title compound.

[0598] Step 2: 2-Benzyl-4,4-difluoropiperidine Starting with tert-butyl 2-benzyl-4,4-difluoropiperidine-1-carboxylate (360 mg, 1.16 mmol), the procedure described for the preparation of Example 5, Step 2, was followed using 5 eq. TFA. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM, washed with saturated aqueous NaHCO3, and dried (phase separator) to give the product, which was used in the next step without further purification.

[0599] Step 3: 4-(2-(2-benzyl-4,4-difluoropiperidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D, starting with 2-benzyl-4,4-difluoropiperidine (186 mg, 0.88 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (267 mg, 0.80 mmol, scaffold 1). The reaction mixture was purified by silica gel column chromatography (gradient elution 10-80% EtOAc / iso-hexane) to give the title compound contaminated with unreacted 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine. It was used in the next step without further purification.

[0600] Step 4: 6-(2-benzyl-4,4-difluoropiperidin-1-yl)-4-morpholinopyridin-2(1H)-one Following Method E starting with 4-(2-(2-benzyl-4,4-difluoropiperidin-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (260 mg, 0.51 mmol). The crude material was purified by reverse phase preparative HPLC to give the title compound. LCMS (ES+) 390 (M+H) + , RT 3.11 minutes (Analysis method B); 1H NMR (400 MHz, CDCl): δ 7.25–7.22 (2H, m), 7.21–7.15 (3H, m), 5.29 (1H, d, J=2.0 Hz), 5.14 (1H, d, J=2.0 Hz), 4.36–4.32 (1H, m), 3.80–3.76 (4H, m), 3.65–3.60 (1H, m), 3.43–3.34 (1H, m), 3.24–3.19 (4H, m), 2.98–2.82 (2H, m), 2.20–1.98 (4H, m), no NH.

[0601] Example 161: (R)-2-benzyl-4-methyl-1-(4-morpholino-6-oxo-1,6-dihydropyridin-2-yl)-1,4-diazepan-5-one, Example 162: (S)-2-benzyl-4-methyl-1-(4-morpholino-6-oxo-1,6-dihydropyridin-2-yl)-1,4-diazepan-5-one, Example 163: 7-benzyl-4-methyl-1-(4-morpholino-6-oxo-1,6-dihydropyridin-2-yl)-1,4-diazepan-5-one

[0602] [ka]

[0603] Step 1: tert-Butyl 2-benzyl-4-(hydroxyimino)piperidine-1-carboxylate Na2CO3 (2.20 g, 20.73 mmol) was added to a solution of tert-butyl 2-benzyl-4-oxopiperidine-1-carboxylate (2.0 g, 6.91 mmol) in MeOH (13 mL) and water (8 mL) at rt. Hydroxylamine hydrochloride (960 mg, 13.8 mmol) was added and the reaction was stirred for 21 h. The reaction mixture was concentrated under reduced pressure, diluted with DCM, and washed with water. The organic extract was dried (phase separator) and concentrated under reduced pressure to give the title compound. It was used in the next step without further purification.

[0604] Step 2: tert-butyl 7-benzyl-5-oxo-1,4-diazepane-1-carboxylate and tert-butyl 2-benzyl-5-oxo-1,4-diazepane-1-carboxylate tert-Butyl 2-benzyl-4-(hydroxyimino)piperidine-1-carboxylate (2.07 g, 6.8 mmol) was dissolved in acetone (68 mL) and water (68 mL) and cooled to 0 °C. Na2CO3 (2.88 g, 27.2 mmol) was added portionwise, followed by tosyl chloride (2.59 g, 13.6 mmol). The reaction was allowed to warm to rt. After 22 h, the reaction was concentrated under reduced pressure. The residue was dissolved in DCM and washed with water. The organic extract was dried (phase separator) and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (gradient elution 5-80% EtOAc / iso-hexane to 10% MeOH / EtOAc) to give the title compound.

[0605] Step 3: tert-butyl 7-benzyl-4-methyl-5-oxo-1,4-diazepane-1-carboxylate and tert-butyl 2-benzyl-4-methyl-5-oxo-1,4-diazepane-1-carboxylate NaH (131 mg, 3.29 mmol, 60% dispersion in mineral oil) was added to an ice-cooled solution of tert-butyl 7-benzyl-5-oxo-1,4-diazepane-1-carboxylate and tert-butyl 2-benzyl-5-oxo-1,4-diazepane-1-carboxylate (500 mg, 1.64 mmol, inseparable mixture) in DMF (5 mL). After stirring at 0 °C for 20 min, methyl iodide (123 μL, 1.97 mmol) was added and the reaction mixture was allowed to warm to RT. After 2 h, the reaction was cooled to 0 °C and carefully quenched with water. The reaction mixture was diluted with DCM and the layers were separated. The organic extract was dried (phase separator) and concentrated under reduced pressure. It was used in the next step without further purification.

[0606] Step 4: 7-benzyl-4-methyl-1,4-diazepan-5-one and 2-benzyl-4-methyl-1,4-diazepan-5-one The procedure described for the preparation of Example 73, Step 5, was followed, starting with impure tert-butyl 7-benzyl-4-methyl-5-oxo-1,4-diazepane-1-carboxylate and tert-butyl 2-benzyl-4-methyl-5-oxo-1,4-diazepane-1-carboxylate (1.64 mmol). The crude material was purified on a 5 g SCX cartridge eluting with 3 column volumes of DCM, 3 column volumes of methanol, 2 column volumes of 7N NH in 9:1 DCM:MeOH, and 2 column volumes of 7N NH in 4:1 DCM:MeOH. The ammonia fractions were combined and concentrated under reduced pressure to provide the title compounds. This was an inseparable mixture and was used in the next step without further purification.

[0607] Step 5: 2-benzyl-1-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)-4-methyl-1,4-diazepan-5-one and 7-benzyl-1-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)-4-methyl-1,4-diazepan-5-one Following Method D starting from 7-benzyl-4-methyl-1,4-diazepan-5-one and 2-benzyl-4-methyl-1,4-diazepan-5-one (360 mg, 1.08 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (360 mg, 1.08 mmol, scaffold 1). The crude product material was purified by silica gel column chromatography (gradient elution 10-100% EtOAc / iso-hexane) to give the title compound. The first eluting compound was 7-benzyl-1-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)-4-methyl-1,4-diazepan-5-one, and the second eluting compound was 2-benzyl-1-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)-4-methyl-1,4-diazepan-5-one.

[0608] Step 6: (S)-2-benzyl-4-methyl-1-(4-morpholino-6-oxo-1,6-dihydropyridin-2-yl)-1,4-diazepan-5-one and (R)-2-benzyl-4-methyl-1-(4-morpholino-6-oxo-1,6-dihydropyridin-2-yl)-1,4-diazepan-5-one Method E was followed, starting with 2-benzyl-1-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)-4-methyl-1,4-diazepan-5-one (253 mg, 0.49 mmol). The crude material was purified by silica gel column chromatography (gradient elution 0-4% 7N NH3 / DCM in MeOH). The resulting product was purified by SFC to separate the enantiomers and lyophilized from acetonitrile / water.

[0609] (S)-2-Benzyl-4-methyl-1-(4-morpholino-6-oxo-1,6-dihydropyridin-2-yl)-1,4-diazepan-5-one; LCMS (ES+) 397 (M+H) + , RT 2.72 min (Analytical Method B), RT 1.35 min (Analytical Method SFC1, YMC Amylose-C + 0.1% DEAISO 35% MeOH SOL3); 1 H NMR (400 MHz, CDCl): δ 7.27–7.17 (5H, m), 5.21 (1H, d, J=2.0 Hz), 4.88 (1H, d, J=2.0 Hz), 4.53–4.45 (1H, m), 3.78–3.73 (5H, m), 3.64–3.55 (1H, m), 3.49–3.35 (2H, m), 3.18–3.13 (4H, m), 2.91–2.90 (7H, m), no NH observed.

[0610] (R)-2-benzyl-4-methyl-1-(4-morpholino-6-oxo-1,6-dihydropyridin-2-yl)-1,4-diazepan-5-one; LCMS (ES+) 397 (M+H) +, RT 2.72 min (Analytical Method B), RT 2.02 min (Analytical Method SFC1, YMC Amylose-C + 0.1% DEAISO 35% MeOH SOL3); 1 H NMR (400 MHz, CDCl): δ 7.25–7.17 (5H, m), 5.21 (1H, d, J=2.0 Hz), 4.88 (1H, d, J=1.8 Hz), 4.51–4.45 (1H, m), 3.81–3.74 (5H, m), 3.62–3.55 (1H, m), 3.48–3.35 (2H, m), 3.17–3.13 (4H, m), 3.06–2.73 (7H, m), no NH.

[0611] Step 7: 7-benzyl-4-methyl-1-(4-morpholino-6-oxo-1,6-dihydropyridin-2-yl)-1,4-diazepan-5-one Following Method E starting with 7-benzyl-1-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)-4-methyl-1,4-diazepan-5-one (76 mg, 0.15 mmol). The crude product material was purified by silica gel column chromatography (gradient elution 0-4% 7N NH3 / DCM in MeOH). This material was purified by reverse-phase preparative HPLC to give the title compound.

[0612] LCMS (ES+) 397 (M+H) + , RT 2.60 min (Analysis method A); 1H NMR (400 MHz, CDCl): δ 7.26–7.19 (5H, m), 5.23 (1H, d, J=2.0 Hz), 4.87 (1H, d, J=1.8 Hz), 4.19–4.14 (1H, m), 3.87–3.77 (2H, m), 3.74 (4H, dd, J=4.9, 4.9 Hz), 3.49–3.43 (1H, m), 3.43–3.35 (1H, m), 3.13 (4H, dd, J=3.7, 5.9 Hz), 3.05 (3H, s), 2.97–2.88 (3H, m), 2.81–2.74 (1H, m), no NH.

[0613] Example 164: (S)-6-(3-benzyl-1,4-oxazepan-4-yl)-4-morpholinopyridin-2(1H)-one

[0614] [ka]

[0615] Step 1: tert-butyl (S)-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)propanoate Tert-butyl acrylate (2.52 mL, 17.19 mmol) was added to a solution of tert-butyl (S)-(1-hydroxy-3-phenylpropan-2-yl)carbamate (2.88 g, 11.45 mmol) in NaOH (445 μL, 5 M aqueous solution) and dioxane (3 mL). After 30 min, dioxane (1.5 mL) was added, and stirring was continued at rt for 18 h. NaOH (445 μL) and tert-butyl acrylate (0.5 mL) were added, and stirring was continued. After 7.5 h, NaOH (100 μL) and tert-butyl acrylate (0.5 mL) were added, and stirring was continued for 18 h. The reaction mixture was partitioned between DCM and water. The layers were separated, dried (phase separator), and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (gradient elution 10-60% EtOAc / iso-hexane) to give the title compound.

[0616] Step 2: (S)-3-(2-amino-3-phenylpropoxy)propanoic acid TFA (2 mL) was added to a solution of tert-butyl (S)-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)propanoate (546 mg, 1.44 mmol) in DCM (2 mL) with stirring at rt. After 2 h, the reaction was concentrated under reduced pressure to provide the title compound as the TFA salt. The oil was dissolved in EtOAc (5 mL). EtN (200 μL, 1.44 mmol) was added with stirring at rt. After 2 h, the resulting white precipitate was collected by filtration and air-dried to provide the title compound. It was used without further purification.

[0617] Step 3: (S)-3-benzyl-1,4-oxazepan-5-one (S)-3-(2-amino-3-phenylpropoxy)propanoic acid (230 mg, 1.03 mmol) was dissolved in DMF (5 mL) and cooled to 0 °C. N-Methylmorpholine (226 μL, 2.06 mmol), HOBt (139 mg, 1.03 mmol), and EDC (296 mg, 1.54 mmol) were added, and the reaction was stirred for 15 min before warming to rt. After 25 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (gradient elution 20-100% EtOAc / iso-hexane). The product containing fractions were reduced to approximately 50 mL. EtOAc (20 mL) was added, and the organics were washed with NaHCO (sat. aq.). The organic extract was dried (phase separator) and concentrated under reduced pressure to give the product.

[0618] Step 4: (S)-3-benzyl-1,4-oxazepane Lithium aluminum hydride (1.22 mL, 1.22 mmol, 1 M solution in THF) was added to (S)-3-benzyl-1,4-oxazepan-5-one (125 mg, 0.61 mmol) in THF (4 mL) at 0 °C. The reaction was warmed to rt and stirred for 19 h. The reaction mixture was cooled to 0 °C and carefully quenched with water. THF was removed under reduced pressure. The crude mixture was diluted with EtOAc / water and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried (phase separator) and concentrated under reduced pressure. The crude product material was purified by SCX eluting with 3 column volumes of DCM, 3 column volumes of methanol, 2 column volumes of 7N NH3 in 9:1 DCM:MeOH, and 2 column volumes of 7N NH3 in 4:1 DCM:MeOH. The ammonia fractions were combined and concentrated under reduced pressure to give the product.

[0619] Step 5: (S)-3-benzyl-4-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)-1,4-oxazepane Following Method D, starting with (S)-3-benzyl-1,4-oxazepane (110 mg, 0.57 mmol) and 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (175 mg, 0.52 mmol, scaffold 1). The reaction mixture was purified by silica gel column chromatography (gradient elution 10-50% diethyl ether in iso-hexane) to give the title compound.

[0620] Step 6: (S)-6-(3-benzyl-1,4-oxazepan-4-yl)-4-morpholinopyridin-2(1H)-one Following Method E starting with (S)-3-benzyl-4-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)-1,4-oxazepane (160 mg, 0.33 mmol). The crude material was purified by reverse phase preparative HPLC to afford the title compound as a salt. The solid was dissolved in DCM, washed with NaHCO (sat. aq.), dried (Phase separator) and concentrated under reduced pressure to afford the title compound.

[0621] (S)-6-(3-benzyl-1,4-oxazepan-4-yl)-4-morpholinopyridin-2(1H)-one; LCMS (ES+) 370 (M+H) + , RT 2.76 minutes (Analysis method A); 1 H NMR (400 MHz, CDCl): δ 7.32–7.21 (3H, m), 7.18–7.14 (2H, m), 5.20 (1H, d, J=2.0 Hz), 4.91 (1H, d, J=1.8 Hz), 4.10–3.91 (3H, m), 3.75 (4H, dd, J=4.9, 4.9 Hz), 3.67–3.48 (3H, m), 3.30–3.21 (1H, m), 3.19–3.14 (4H, m), 2.92–2.78 (2H, m), 2.03–1.93 (1H, m), 1.78–1.70 (1H, m), no NH.

[0622] Example 165: Stereoisomer 1 of 6-(2-benzylazepan-1-yl)-4-((2R,6R)-2,6-dimethylmorpholino)pyridin-2(1H)-one

[0623] [ka]

[0624] Step 1: (2R,6R)-4-(2,6-dichloropyridin-4-yl)-2,6-dimethylmorpholine Following Method B starting with (2R,6R)-2,6-dimethylmorpholine (0.5 g, 4.5 mmol) and 2,6-dichloro-4-iodopyridine (1.3 g, 4.5 mmol), purified by silica gel column chromatography (gradient elution, 2-20% EtOAc / iso-hexane) to give the title compound.

[0625] Step 2: (2R,6R)-4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2,6-dimethylmorpholine Following Method A, starting with (2R,6R)-4-(2,6-dichloropyridin-4-yl)-2,6-dimethylmorpholine (0.4 g, 1.5 mmol) and (4-methoxyphenyl)methanol (231 mg, 2.1 mmol), purified by silica gel column chromatography (gradient elution, 1-25% EtOAc / iso-hexane) to give the title compound.

[0626] Step 3: (2R,6R)-4-(2-(2-benzylazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2,6-dimethylmorpholine Following Method D starting with (2R,6R)-4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2,6-dimethylmorpholine (0.21 g, 1.1 mmol) and 2-benzylazepane (209 mg, 1.1 mmol). Purification by silica gel column chromatography (gradient elution, 10-30% EtOAc / iso-hexane) gave the title compound.

[0627] Step 4: Stereoisomer 1 of 6-(2-benzylazepan-1-yl)-4-((2R,6R)-2,6-dimethylmorpholino)pyridin-2(1H)-one Following Method E starting with (2R,6R)-4-(2-(2-benzylazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2,6-dimethylmorpholine (0.31 g, 0.6 mmol). The crude material was purified by reverse phase HPLC to give a brown solid. The sample was further purified by SFC chiral chromatography to give the title compound as a single isomer. LCMS (ES+) 396 (M+H)+, RT 2.99 min 97% (Analytical Method A); 1H NMR δ (ppm) (400 MHz, CDCl3) 7.31 - 7.21 (3H, m), 7.16 - 7.13 (2H, m), 5.11 (1H, dd, J=2.0, 2.0 Hz), 4.84 (1H, dd, J=2.0, 16.1 Hz), 4.12 - 4.05 (2H, m), 3.82 - 3.73 (1H, m), 3.43 (1H, d, J=15.7 Hz), 3.33 - 3.25 (1H, m), 3.05 - 2.95 (3H, m), 2.89 - 2.74 (2H, m), 2.16 - 2.04 (1H, m), 1.86 - 1.72 (4H, m), 1.56 - 1.44 (2H, m), 1.32-1.13 (8H, m); NH not visible.

[0628] Example 166: 6-(2-benzylazepan-1-yl)-4-(2-(difluoromethyl)morpholino)pyridin-2(1H)-one

[0629] [ka]

[0630] Step 1: 4-(2,6-dichloropyridin-4-yl)-2-(difluoromethyl)morpholine Following Method B starting with 2-difluoromethylmorpholine (0.4 g, 2.9 mmol) and 2,6-dichloro-4-iodopyridine (822 mg, 3 mmol), purified by silica gel column chromatography (gradient elution 10-40% EtOAc / iso-hexane) to give the title compound.

[0631] Step 2: 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-(difluoromethyl)morpholine Following Method A starting with 4-(2,6-dichloropyridin-4-yl)-2-(difluoromethyl)morpholine (0.5 g, 1.8 mmol) and (4-methoxyphenyl)methanol (269 mg, 1.95 mmol), purified by silica gel column chromatography (gradient elution, 1-20% EtOAc / iso-hexane) to give the title compound.

[0632] Step 3: 4-(2-(2-benzylazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-(difluoromethyl)morpholine Following Method D starting from 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-(difluoromethyl)morpholine (0.19 g, 1.0 mmol) and 2-benzylazepane (190 mg, 1 mmol) (Example 3, step 2). Purification by silica gel column chromatography (gradient elution 10-25% EtOAc / iso-hexane) gave the title compound.

[0633] Step 4: Mixture of two stereoisomers of 6-(2-benzylazepan-1-yl)-4-(2-(difluoromethyl)morpholino)pyridin-2(1H)-one Following Method E starting with 4-(2-(2-benzylazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-(difluoromethyl)morpholine (0.4 g, 0.74 mmol). The crude material was purified by reverse phase preparative HPLC to give the title compound. LCMS (ES+) 418 (M+H)+, RT 3.12 min, 98% (analytical Method A); 1H NMR δ (ppm) (400 MHz, CDCl3) 7.30 - 7.20 (3H, m), 7.14 (2H, d, J=7.7 Hz), 5.92 (1H, dd, J=2.1, 4.1 Hz), 5.80 (1H, dddd, J=55.0 Hz; J=2.1 Hz; J=4.0 Hz), 5.19 - 5.18 (1H, m), 4.88 (1H, dd, J=2.0, 7.2 Hz), 4.05 - 4.01 (1H, m), 3.83 - 3.57 (4H, m), 3.43 (2H, d, J=13.1 Hz), 3.09 - 2.73 (4H, m), 2.17 - 2.00 (1H, m), 1.84 - 1.79 (3H, m), 1.58 - 1.45 (2H, m), 1.32 - 1.13 (2H, m); NH not visible.

[0634] Example 167: (R)-6-(2-benzylazepan-1-yl)-4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2(1H)-one and Example 168: (S)-6-(2-benzylazepan-1-yl)-4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2(1H)-one

[0635] [ka]

[0636] Step 1: 2-(tert-butoxy)-6-chloro-4-iodopyridine A solution of 2,6-dichloro-4-iodopyridine (1.0 g, 3.65 mmol) in dry THF (15 mL) was treated with KOtBu (4.0 mL, 4.0 mmol, 1 M in THF) at rt. The mixture was heated to reflux for 2 h. After cooling to rt, the reaction was diluted with EtOAc (100 mL), washed with water (30 mL) and brine (30 mL), and dried (NaSO). The mixture was concentrated to give the title compound.

[0637] Step 2: 2-(tert-butoxy)-6-chloro-4-(3,6-dihydro-2H-pyran-4-yl)pyridine A mixture of 2-(tert-butoxy)-6-chloro-4-iodopyridine (661 mg, 2.12 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (540 mg, 2.57 mmol), XPhos PdG (23.3 mg, 30 μmol), KCO (885 mg, 6.40 mmol), dioxane (9.4 mL), and water (2.4 mL) was degassed three times with N, sealed, and heated to 80 °C for 45 min. After cooling to rt, the mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated and purified by silica gel chromatography (gradient elution, 0–50% EtOAc / iso-hexane) to give the impure title compound, which was used without further purification.

[0638] Step 3: 2-benzyl-1-(6-(tert-butoxy)-4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)azepane Following Method D, starting with 2-(tert-butoxy)-6-chloro-4-(3,6-dihydro-2H-pyran-4-yl)pyridine (447 mg, 1.67 mmol) and 2-benzylazepane (316 mg, 1.67 mmol, Example 3, Step 2). The mixture was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) to give the impure title compound, which was used without further purification.

[0639] Step 4: (R)-6-(2-benzylazepan-1-yl)-4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2(1H)-one and (S)-6-(2-benzylazepan-1-yl)-4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2(1H)-one A solution of 2-benzyl-1-(6-(tert-butoxy)-4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)azepane (148 mg, 0.35 mmol) in DCM (1.5 mL) was treated with TiCl (0.53 mL, 0.53 mmol, 1 M in DCM) at 0 °C under N and stirred for 2.5 h. The reaction was quenched with 2 mL saturated aqueous NaHCO, diluted with DCM (10 mL), and the layers were separated. The organic extract was dried (phase separator) and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane, then 0-20% MeOH / DCM). The target material was further purified by reverse-phase preparative HPLC followed by SFC to give the title compound.

[0640] (R)-6-(2-benzylazepan-1-yl)-4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2(1H)-one; LCMS (ES+) 365 (M+H) + 3.31 min (Analytical method A), RT 1.75 min (Analytical method SFC4, YMC Amylose-C 50 / 50MeOH (0.1% DEA) / CO2); 1H NMR (400 MHz, CDCl3): δ 7.31 - 7.26 (2H, m), 7.25 - 7.20 (1H, m), 7.17 - 7.13 (2H, m), 6.17 - 6.15 (1H, m), 5.76 (1H, d, J=1.3 Hz), 5.44 (1H, d, J=1.3 Hz), 4.30 (2H, q, J=2.8 Hz), 3.97 - 3.91 (1H, m), 3.89 (2H, t, J=5.4 Hz), 3.51 - 3.43 (1H, m), 3.01 (1H, dd, J=11.7, 15.5 Hz), 2.86 (1H, dd, J=5.5, 13.4 Hz), 2.79 (1H, dd, J=7.5, 13.4 Hz), 2.43 - 2.37 (2H, m), 2.14 - 2.04 (1H, m), 1.87 - 1.69 (3H, m), 1.60 - 1.45 (3H, m), 1.33 - 1.12 (2H, m).

[0641] LCMS (ES+) 365 (M+H) + , RT 3.31 min (analytical method A), RT 1.28 (analytical method SFC4, YMC アミロース-C 50 / 50 MeOH (0.1% DEA) / CO2); 1H NMR (400 MHz, CDCl3): δ 7.31 - 7.26 (2H, m), 7.25 - 7.20 (1H, m), 7.17 - 7.13 (2H, m), 6.17 - 6.15 (1H, m), 5.76 (1H, d, J=1.3 Hz), 5.44 (1H, d, J=1.3 Hz), 4.30 (2H, q, J=2.8 Hz), 3.97 - 3.91 (1H, m), 3.89 (2H, t, J=5.4 Hz), 3.51 - 3.43 (1H, m), 3.01 (1H, dd, J=11.7, 15.5 Hz), 2.86 (1H, dd, J=5.5, 13.4 Hz), 2.79 (1H, dd, J=7.5, 13.4 Hz), 2.43 - 2.37 (2H, m), 2.14 - 2.04 (1H, m), 1.87 - 1.69 (3H, m), 1.60 - 1.45 (3H, m), 1.33 - 1.12 (2H, m).

[0642] Example 169: (R)-2-(2-(2-methoxybenzyl)piperidin-1-yl)-6-morpholinopyrimidin-4(3H)-one

[0643] [ka]

[0644] Step 1: 2-chloro-4-iodo-6-((4-methoxybenzyl)oxy)pyridine NaH (0.68 g, 17.1 mmol, 60% dispersion in mineral oil) was suspended in THF (17 mL) and cooled to 0 °C. (4-Methoxyphenyl)methanol (1.4 mL, 11.25 mmol) was added, and the reaction was stirred at 0 °C for 20 min. 2,6-Dichloro-4-iodopyridine (2.8 g, 10.2 mmol) in THF (10 mL) was slowly added to the reaction, and the mixture was allowed to warm to rt. After 18 h, the reaction was cooled to 0 °C and carefully quenched with NH4Cl (sat. aq.). The reaction was allowed to warm to rt and extracted with EtOAc. The combined organic extracts were dried (phase separator) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, 2-20% EtOAc / iso-hexane) to give the title compound.

[0645] Step 2: (1R,5S)-3-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane A reaction tube containing 2-chloro-4-iodo-6-((4-methoxybenzyl)oxy)pyridine (292 mg, 0.78 mmol), (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (121 mg, 0.81 mmol), Pd(OAc) (10.2 mg, 45 μmol), PPh (23.9 mg, 91 μmol), and KPO (765 mg, 3.60 mmol) in dry DMF (5 mL) was evacuated and refilled with N three times. The reaction was stirred at 100 °C for 1 h. After cooling to rt, the reaction mixture was diluted with DCM (40 mL) and water (20 mL). The layers were separated by passage through a hydrophobic frit, and the DCM layer was concentrated. The residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) to give the title compound.

[0646] Step 3: (1R,5S)-3-(2-((R)-2-benzylazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane Following Method D from (1R,5S)-3-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (102 mg, 0.28 mmol) and (R)-2-benzylazepane (57.3 mg, 0.30 mmol, Example 3, Step 2). After 16 h, additional (R)-2-benzylazepane (0.86 equiv), RuPhos Pd G1 (0.06 equiv), RuPhos (0.06 equiv), and NaOtBu (1 equiv) were added to achieve complete conversion of the heteroaryl chloride. Purification by silica gel chromatography (gradient elution, 0-100% EtOAc / iso-hexane) afforded the impure title compound, which was used without further purification.

[0647] Step 4: (R)-2-(2-(2-methoxybenzyl)piperidin-1-yl)-6-morpholinopyrimidin-4(3H)-one Following Method E from (1R,5S)-3-(2-((R)-2-benzylazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (116 mg from the previous step). Purification by reverse phase HPLC gave the title compound. LCMS (ES+) 394 (M+H) + , RT 2.97 minutes (Analysis method A); 1 H NMR (400 MHz, CDCl3) 7.32 - 7.20 (3H, m), 7.17 - 7.10 (2H, m), 5.11 (1H, d, J=1.8 Hz), 4.82 (1H, d, J=1.3 Hz), 4.48 - 4.41 (2H, m), 3.82 - 3.73 (1H, m), 3.37 (1H, d, J=16.4 Hz), 3.25 (2H, dd, J=2.9, 11.7 Hz), 3.12 - 2.94 (3H, m), 2.85 - 2.74 (2H, m), 2.15 - 2.05 (1H, m), 1.97 - 1.70 (7H, m), 1.60 - 1.44 (2H, m), 1.31 - 1.14 (2H, m), NH not observed.

[0648] Example 170: 6-((R)-2-benzylazepan-1-yl)-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-2(1H)-one

[0649] [ka]

[0650] Step 1: (1S,4S)-5-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane A tube containing 2-chloro-4-iodo-6-((4-methoxybenzyl)oxy)pyridine (304 mg, 0.81 mmol, Step 1), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (116 mg, 0.86 mmol), Pd(OAc) (20.7 mg, 92 μmol), PPh (44.8 mg, 0.17 mmol), and KPO (753 mg, 3.55 mmol) in dry DMF (5 mL) was evacuated and refilled with N three times. The reaction was stirred at 100 °C for 1 h. After cooling to RT, the reaction mixture was diluted with DCM (40 mL) and water (20 mL). The layers were separated by passage through a hydrophobic frit, and the DCM layer was concentrated. The residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) to give the title compound.

[0651] Step 2: (1S,4S)-5-(2-((R)-2-benzylazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane Following Method D from (1S,4S)-5-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (231 mg, 0.67 mmol) and (R)-2-benzylazepane (124 mg, 0.66 mmol). Purification by silica gel chromatography (gradient elution, 0-100% EtOAc / iso-hexane) afforded the impure title compound, which was used without further purification.

[0652] Step 3: 6-((R)-2-benzylazepan-1-yl)-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-2(1H)-one Following Method E from (1S,4S)-5-(2-((R)-2-benzylazepan-1-yl)-6-((4-methoxybenzyl)oxy)pyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (118 mg from the previous step). Purification by reverse phase HPLC gave the title compound. LCMS (ES+) 380 (M+H) + , RT 2.85 min (Analysis method A); 1 H NMR (400 MHz, DMSO) 9.25 (1H, s), 7.36 - 7.19 (5H, m), 5.05 (1H, s), 4.95 (1H, s), 4.65 (1H, s), 4.55 (1H, s), 4.30 (1H, br s), 3.76 (2H, d, J=7.1 Hz), 3.68 (1H, d, J=7.1 Hz), 3.43 (1H, d, J=9.6 Hz), 3.08 (1H, d, J=10.4 Hz), 3.00 (1H, t, J=12.7 Hz), 2.84 (1H, dd, J=4.5, 12.9 Hz), 2.68 (1H, dd, J=8.5, 12.8 Hz), 1.95 - 1.82 (3H, m), 1.78 - 1.60 (3H, m), 1.53 - 1.39 (2H, m), 1.26 (1H, dd, J=3.4, 11.5 Hz), 1.09 (1H, q, J=11.7 Hz).

[0653] Example 171: (R)-6-(2-benzylazepan-1-yl)-3-fluoro-4-morpholinopyridin-2(1H)-one

[0654] [ka]

[0655] Step 1: 4-(6-chloro-3-fluoro-2-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine A mixture of 4-(2-chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (1.00 g, 2.99 mmol, scaffold 1) and Selectfluor (1.27 g, 3.58 mmol) in DMF (6 mL) and MeCN (6 mL) was stirred at rt for 18 h. The mixture was partitioned between EtOAc (50 mL) and water (30 mL). The layers were separated and the aqueous solution was extracted with additional EtOAc (2×40 mL). The combined organics were dried (NaSO) and concentrated. Trituration with EtO gave the title compound. 1 H NMR (400 MHz, CDCl3): δ 7.41 (2H, d, J=8.6 Hz), 6.90 (2H, d, J=8.6 Hz), 6.42 (1H, d, J=4.6 Hz), 5.33 (2H, s), 3.84 - 3.79 (7H, m), 3.26 - 3.22 (4H, m).

[0656] Step 2: (R)-4-(6-(2-benzylazepan-1-yl)-3-fluoro-2-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine Following Method D from 4-(6-chloro-3-fluoro-2-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (107 mg, 0.30 mmol) and (R)-2-benzylazepane (62.3 mg, 0.33 mmol) heated at 80 °C for 17 h. After cooling to rt, the mixture was filtered through Celite, washed with MeOH, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / iso-hexane) to give the impure title compound, which was used without further purification.

[0657] Step 3: (R)-6-(2-benzylazepan-1-yl)-3-fluoro-4-morpholinopyridin-2(1H)-one A mixture of (R)-4-(6-(2-benzylazepan-1-yl)-3-fluoro-2-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (70 mg), 1-methyl-1,4-cyclohexadiene (156 μL, 1.39 mmol), and 5% Pd / C (50 wt% HO, 86.2 mg) in EtOH (1.4 mL) was deoxygenated by evacuating the reaction vessel and refilling with N four times. The reaction was stirred at 75 °C for 3.5 h. After cooling to rt, the mixture was filtered through Celite, washing with MeOH, and the filtrate was concentrated. The residue was purified by reverse-phase HPLC to give the title compound. LCMS (ES+) 386 (M+H) + , RT 3.25 min (Analysis method A); 1 H NMR (400 MHz, CDCl3): δ 7.30 - 7.20 (3H, m), 7.15 - 7.10 (2H, m), 4.72 (1H, d, J=4.8 Hz), 3.80 (5H, dd, J=4.7, 4.7 Hz), 3.50 - 3.42 (1H, m), 3.22 - 3.17 (4H, m), 3.03 (1H, dd, J=12.4, 15.4 Hz), 2.85 - 2.73 (2H, m), 2.16 - 2.07 (1H, m), 1.86 - 1.70 (3H, m), 1.56 - 1.44 (2H, m), 1.32 - 1.12 (2H, m), NH is not recognized.

[0658] Example 172: (S)-6-(2-benzylpyrrolidin-1-yl)-1-methyl-4-morpholinopyridin-2(1H)-one and Example 173: (R)-6-(2-benzylpyrrolidin-1-yl)-1-methyl-4-morpholinopyridin-2(1H)-one

[0659] [ka]

[0660] Step 1: 6-chloro-4-morpholinopyridin-2(1H)-one 4-(2-Chloro-6-((4-methoxybenzyl)oxy)pyridin-4-yl)morpholine (1 g, 2.99 mmol, Scaffold 1) was dissolved in DCM (10 mL). TFA (0.23 mL, 2.99 mmol) was added and the reaction was stirred at rt for 5 h. A white precipitate formed during the reaction and was collected by filtration. The filtrate was diluted with DCM and washed with saturated sodium bicarbonate solution. The layers were separated, dried (phase separator), and concentrated under reduced pressure. The resulting product was triturated with diethyl ether to give another product. The two products were combined and used in the next step without further purification.

[0661] Step 2: 6-chloro-1-methyl-4-morpholinopyridin-2(1H)-one 6-Chloro-4-morpholinopyridin-2(1H)-one (400 mg, 1.87 mmol) was dissolved in dioxane (5 mL). Lithium tert-butoxide (299 mg, 3.74 mmol) was added to the reaction mixture with stirring at rt, followed by iodomethane (116 μL, 1.87 mmol). The reaction mixture was then heated at 85° C. for 22.5 h. After this time, the reaction mixture was cooled to rt and quenched with water. The reaction was transferred to a separatory funnel and diluted with DCM. The layers were separated, and the aqueous layer was extracted with DCM. The combined organics were dried (phase separator) and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (gradient elution 0-9% MeOH / EtOAc) to give the title compound.

[0662] Step 3: (S)-6-(2-benzylpyrrolidin-1-yl)-1-methyl-4-morpholinopyridin-2(1H)-one and (R)-6-(2-benzylpyrrolidin-1-yl)-1-methyl-4-morpholinopyridin-2(1H)-one DIPEA (91 μL, 0.53 mmol) was added to a solution of 6-chloro-1-methyl-4-morpholinopyridin-2(1H)-one (80 mg, 0.35 mmol) and 2-benzylpyrrolidine (56 mg, 0.35 mmol) in NMP (0.5 mL) in a stem-block tube. The reaction mixture was sealed and heated at 150° C. for 53.5 h. After this time, the reaction was cooled to rt and diluted with EtOAc and water. The layers were separated, and the organic extract was dried (phase separator) and concentrated under reduced pressure. The crude product material was purified by silica gel column chromatography (gradient elution 0-10% MeOH / EtOAc) to give the target compound. This material was purified by SFC to give two enantiomers.

[0663] (R)-6-(2-benzylpyrrolidin-1-yl)-1-methyl-4-morpholinopyridin-2(1H)-one; CMS (ES+) 354 (M+H) + , RT 3.09 min (Analysis method A), RT 2.76 min (Analysis method SFC1, YMC Amylose-C 30% IPA (0.1% DEA) / CO2); 1 H NMR δ (ppm) (400 MHz, DMSO-d6) 1H NMR δ (ppm) (400 MHz, DMSO-d6) 7.35 - 7.29 (2H, m), 7.26 - 7.21 (1H, m), 7.20 - 7.17 (2H, m), 5.74 (1H, d, J=2.5 Hz), 5.35 (1H, d, J=2.3 Hz), 3.99 - 3.90 (1H, m), 3.73 (4H, dd, J=4.8, 4.8 Hz), 3.52 - 3.43 (1H, m), 3.32 - 3.17 (7H, m), 2.89 - 2.82 (2H, m), 2.62 - 2.58 (1H, m), 1.96 - 1.87 (2H, m), 1.82 - 1.59 (2H, m).

[0664] (S)-6-(2-ベンジルピロリジン-1-イル)-1-メチル-4-モルホリノピリジン-2(1H)-オン;LCMS (ES+) 354 (M+H) + , RT 3.09 points (analytical method A), RT 2.23 points (analytical method SFC1, YMC アミロース-C 30% IPA (0.1% DEA) / CO2); 1 H NMR δ (ppm) (400 MHz, DMSO-d6) 1 H NMR (400 MHz, DMSO) 7.34 - 7.30 (2H, m), 7.24 (1H, dd, J=7.3, 7.3 Hz), 7.20 - 7.17 (2H, m), 5.74 (1H, d, J=2.5 Hz), 5.35 (1H, d, J=2.3 Hz), 3.99 - 3.90 (1H, m), 3.75 - 3.71 (4H, m), 3.51 - 3.43 (1H, m), 3.32 - 3.17 (7H, m), 2.89 - 2.82 (2H, m), 2.62 - 2.57 (1H, m), 1.97 - 1.86 (2H, m), 1.82 - 1.58 (2H, m).

[0665] Example 174: Stereoisomer 1 of 6-((2R*,3S*)-2-benzyl-3-methylpyrrolidin-1-yl)-1-(3-methoxypropyl)-4-morpholinopyridin-2(1H)-one and Example 175: Stereoisomer 2 of 6-((2R*,3S*)-2-benzyl-3-methylpyrrolidin-1-yl)-1-(3-methoxypropyl)-4-morpholinopyridin-2(1H)-one

[0666] [ka]

[0667] Step 1: 4,6-Dichloro-1-(3-methoxypropyl)pyridin-2(1H)-one 1-Bromo-3-methoxypropane (0.56 mL, 5.00 mmol) was added to 4,6-dichloropyridin-2(1H)-one (410 mg, 2.50 mmol) and potassium carbonate (691 mg, 5.0 mmol) in acetone (8 mL) and heated at 60 °C. After 24 h, the reaction was cooled to rt, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, 7-60% EtOAc in iso-hexane) to give the title compound.

[0668] Step 2: 6-((2S*,3R*)-2-benzyl-3-methylpyrrolidin-1-yl)-4-chloro-1-(3-methoxypropyl)pyridin-2(1H)-one 4,6-Dichloro-1-(3-methoxypropyl)pyridin-2(1H)...

Claims

1. Formula I: 【Chemical 1】 [In formula: Ring B is a heterocycloalkyl ring optionally having 1 to 3 additional heteroatoms selected from O, N, and S; X is CH or N; (i) Z is N and Y is -CH(R 1 )- or -CH 2 -is; or (ii) ZY is -C=C(R 1 )- or -C=C(H)-; L is C 1 ~ 4 C optionally substituted with alkoxy 1～3 is alkylene; Each R 1 independently, C 1 ~ 4 Alkyl, Halo-C 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy, Halo-C 1 ~ 4 Alkoxy or C 3～6 is cycloalkyl; or two R's 1 together with the carbon atoms to which they are attached, combine to form a cycloalkyl ring; Each R 2 are hydroxy, halo, C 1 ~ 4 C optionally substituted with alkoxy 1 ~ 4 Alkyl, C 1 ~ 4 Halo-C optionally substituted with alkoxy 1 ~ 4 C optionally substituted with alkyl, cycloalkyl 1 ~ 4 Alkoxy, Halo-C 1 ~ 4 Alkoxy, C 3～6 Cycloalkyl, and C 3～6 independently selected from cycloalkoxy; or two R's 2 When present on the same carbon atom, they combine to form oxo; or two R's 2 taken together with the carbon atoms to which they are attached, join to form a ring optionally substituted with 1 to 3 halo; R 3 is H, or -N(R 8 )(R 9 ), C 1 ~ 4 Alkoxy or C 3～6 C optionally substituted with cycloalkyl 1 ~ 6 is alkyl; R 4 is H or halo; R 5 is an aryl or heteroaryl ring, each of which is substituted by one to three R 6 optionally substituted with; Each R 6 independently, halo, C 1 ~ 6 Alkyl, Halo-C 1 ~ 6 Alkyl or -OR 7 and; Each R 7 is heterocycloalkyl and C 1 ~ 4 C optionally substituted with alkoxy or halo 1 ~ 6 independently selected from alkyl; R 8 and R 9 is H and C 1 ~ 6 are each independently selected from alkyl; p is 0, 1, 2 or 3; m is 0, 1, 2 or 3. or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof.

2. Formula II: 【Chemistry 2】 [In formula: X is CH or N; (i) Z is N and Y is -CH(R 1 )- or -CH 2 -is; or (ii) ZY is -C=C(R 1 )- or -C=C(H)-; L is C 1 ~ 4 C optionally substituted with alkoxy 1～3 is alkylene; Each R 1 independently, C 1 ~ 4 Alkyl, Halo-C 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy, Halo-C 1 ~ 4 Alkoxy or C 3～6 is cycloalkyl; or two R's 1 together with the carbon atoms to which they are attached, combine to form a cycloalkyl ring; Each R 2 are hydroxy, halo, C 1 ~ 4 C optionally substituted with alkoxy 1 ~ 4 Alkyl, C 1 ~ 4 Halo-C optionally substituted with alkoxy 1 ~ 4 C optionally substituted with alkyl, cycloalkyl 1 ~ 4 Alkoxy, Halo-C 1 ~ 4 Alkoxy, C 3～6 Cycloalkyl, and C 3～6 independently selected from cycloalkoxy; or two R's 2 When present on the same carbon atom, they combine to form oxo; or two R's 2 taken together with the carbon atoms to which they are attached, join to form a ring optionally substituted with 1 to 3 halo; R 3 is H, or -N(R 8 )(R 9 ), C 1 ~ 4 Alkoxy or C 3～6 C optionally substituted with cycloalkyl 1 ~ 6 is alkyl; R 4 is H or halo; R 5 is an aryl or heteroaryl ring, each of which is substituted by one to three R 6 optionally substituted with; Each R 6 independently, halo, C 1 ~ 6 Alkyl, Halo-C 1 ~ 6 Alkyl or -OR 7 and; Each R 7 is heterocycloalkyl and C 1 ~ 4 C optionally substituted with alkoxy or halo 1 ~ 6 independently selected from alkyl; R 8 and R 9 is H and C 1 ~ 6 are each independently selected from alkyl; p is 0, 1, 2 or 3; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4. or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof.

3. Formula II(a): 【Chemistry 3】 3. The compound of claim 2, wherein

4. Formula II(b): 【Chemistry 4】 3. The compound of claim 2, wherein

5. Formula II(a)(i): 【Chemistry 5】 4. The compound of claim 3,

6. Formula II(a)(ii): 【Chemistry 6】 4. The compound of claim 3,

7. Formula II(b)(i): 【Chemistry 7】 5. The compound of claim 4,

8. Formula II(b)(ii): 【Chemistry 8】 5. The compound of claim 4,

9. Formula III: 【Chemistry 9】 [In formula: X is CH or N; (i) Z is N and Y is -CH(R 1 )- or -CH 2 -is; or (ii) ZY is -C=C(R 1 )-and; R 1 is H, C 1 ~ 4 Alkyl, Halo-C 1 ~ 4 Alkyl, C 1 ~ 4 Alkoxy, Halo-C 1 ~ 4 Alkoxy or C 3～6 is cycloalkyl; or two R's 1 together with the carbon atoms to which they are attached, combine to form a cycloalkyl ring; Each R 2 are hydroxy, halo, C 1 ~ 4 C optionally substituted with alkoxy 1 ~ 4 Alkyl, C 1 ~ 4 Halo-C optionally substituted with alkoxy 1 ~ 4 C optionally substituted with alkyl, cycloalkyl 1 ~ 4 Alkoxy, Halo-C 1 ~ 4 Alkoxy, C 3～6 Cycloalkyl, and C 3～6 independently selected from cycloalkoxy; or two R's 2 When present on the same carbon atom, they combine to form oxo; or two R's 2 taken together with the carbon atoms to which they are attached, join to form a ring optionally substituted with 1 to 3 halo; R 3 is H, or -N(R 8 )(R 9 ), C 1 ~ 4 Alkoxy or C 3～6 C optionally substituted with cycloalkyl 1 ~ 3 is alkyl; R 4 is H or halo; R 5 is an aryl or heteroaryl ring, each of which is substituted by one to three R 6 optionally substituted with; Each R 6 independently, halo, C 1 ~ 6 Alkyl, Halo-C 1 ~ 6 Alkyl or -OR 7 and; Each R 7 is heterocycloalkyl and C 1 ~ 4 C optionally substituted with alkoxy or halo 1 ~ 6 independently selected from alkyl; R 8 and R 9 is H and C 1 ~ 6 are each independently selected from alkyl; R 10 and R 11 is H or C 1 ~ 3 are each independently selected from alkyl; p is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4. or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof.

10. Formula III(a): 【Chemistry 10】 10. The compound of claim 9,

11. Formula III(b): 【Chemistry 11】 10. The compound of claim 9,

12. Formula III(a)(i): 【Chemistry 12】 11. The compound of claim 10,

13. Formula III(a)(ii): 【Chemistry 13】 11. The compound of claim 10,

14. Formula III(b)(i): 【Chemistry 14】 12. The compound of claim 11,

15. Formula III(b)(ii): 【Chemistry 15】 12. The compound of claim 11,

16. Formula IV: 【Chemistry 16】 [In formula: X is CH or N; R 1 is H or C 1 ~ 3 is alkyl; Each R 2 are hydroxy, halo, C 1 ~ 4 C optionally substituted with alkoxy 1 ~ 4 Alkyl, C 1 ~ 4 Halo-C optionally substituted with alkoxy 1 ~ 4 C optionally substituted with alkyl, cycloalkyl 1 ~ 4 Alkoxy, Halo-C 1 ~ 4 Alkoxy, C 3～6 Cycloalkyl, and C 3～6 independently selected from cycloalkoxy; or two R's 2 When present on the same carbon atom, they combine to form oxo; or two R's 2 taken together with the carbon atoms to which they are attached, join to form a ring optionally substituted with 1 to 3 halo; R 3 is H or C 1 ~ 3 is alkyl; R 4 is H or halo; R 5 is an aryl or heteroaryl ring, each of which is substituted by one to three R 6 optionally substituted with; Each R 6 independently halo, C 1 ~ 6 Alkyl, Halo-C 1 ~ 6 Alkyl or -OR 7 and; Each R 7 is heterocycloalkyl and C 1 ~ 4 C optionally substituted with alkoxy or halo 1 ~ 6 independently selected from alkyl; R 10 and R 11 are each independently selected from H or methyl; p is 0, 1, 2 or 3; n is 2, 3 or 4. or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof.

17. m is 1 and R 1 The compound of any one of claims 1 to 8, wherein is methyl.

18. R 1 The compound of any one of claims 9 to 16, wherein is H or methyl.

19. R 1 19. The compound of claim 18, wherein is H.

20. R 3 The compound of any one of claims 1 to 19, wherein is H or methyl.

21. R 4 The compound of any one of claims 1 to 20, wherein is H or fluoro.

22. R 5 is one to three R 6 22. The compound of any one of claims 1 to 21, wherein R is aryl optionally substituted with R.

23. R 5 The compound of any one of claims 1 to 22, wherein is aryl.

24. R 5 However, one to three R 6 24. The compound of any one of claims 1 to 23, wherein the phenyl is optionally substituted with

25. R 5 The compound of any one of claims 1 to 24, wherein is phenyl.

26. 26. The compound of any one of claims 2 to 25, wherein n is 2, 3 or 4.

27. 26. The compound of any one of claims 2 to 25, wherein n is 2.

28. 26. The compound of any one of claims 2 to 25, wherein n is 3.

29. 26. The compound of any one of claims 2 to 25, wherein n is 4.

30. A compound selected from the compounds in Table 1 below, or a pharmaceutically acceptable salt thereof. 【Table 1】

31. A pharmaceutical composition comprising the compound of any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

32. 32. A pharmaceutical composition for treating a condition or disorder mediated by ATM kinase, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 30 or a pharmaceutical composition according to claim 31.

33. The condition or disorder may be Huntington's disease, Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NIID), dentatorubral-pallidoluysian atrophy (DRPLA), Friedreich's ataxia, Rubenstein-Taubi syndrome, polyglutamine disease, spinocerebellar ataxia 1 (SCA1), spinocerebellar ataxia 7 (SCA7), seizures, striatonigral degeneration, progressive supranuclear palsy, torsion dystonia, spasmodic torticollis, dyskinesia, familial tremor, Gilles de la Tourette syndrome, diffuse Lewy body disease, progressive supranuclear palsy, Pick's disease, primary lateral sclerosis, progressive neuromuscular atrophy, spinal muscular atrophy, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic nerve damage, or optic nerve damage.

33. The pharmaceutical composition of claim 32, wherein the disease is amyloidosis, hereditary spastic paraplegia, Shy-Drager syndrome, Kennedy's disease, protein aggregation-associated neurodegeneration, Machado-Joseph disease, spongiform encephalopathy, prion-related disease, multiple sclerosis (MS), progressive supranuclear palsy (Steele-Richardson-Olszewski disease), Hallervorden-Spatz disease, progressive familial myoclonic epilepsy, cerebellar degeneration, motor neuron disease, Werdnig-Hoffmann disease, Wohlfahrt-Kugelberg-Welander disease, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, retinitis pigmentosa, Leber's disease, progressive systemic sclerosis, dermatomyositis, or mixed connective tissue disease.

34. 33. The pharmaceutical composition of claim 32, wherein the condition or disorder is Huntington's disease.

35. 33. The pharmaceutical composition of claim 32, wherein the condition or disorder is cancer.

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