Heterocyclic compounds for cancer treatment

Abstract

The present invention relates to heterocyclic amide derivatives and uses thereof in treating and preventing cancer, and to compositions containing the derivatives and methods for preparing the same.

Description

Field of the Invention

[0001] The present invention relates to heterocyclic amide derivatives and uses thereof in treating and preventing cancer, and to compositions containing the derivatives and methods for preparing the same. Background of the Invention

[0003] Stable repair of DNA double-strand breaks (DSBs) is essential for maintaining genome stability and cell viability. DSBs can be repaired by one of the following three main pathways: homologous recombination (HR), non-homologous end joining (NHEJ), and alternative NHEJ (alt-NHEJ). Microhomology-mediated end joining (MMEJ) is the most fully characterized alt-NHEJ mechanism. HR-mediated repair is a high-fidelity mechanism that is essential for accurate repair, thereby preventing cancer-prone genome stability. In contrast, NHEJ and MMEJ are error-prone pathways that can leave mutation scars at the repair site. MMEJ can work simultaneously with HR and NHEJ pathways (Truong et al. PNAS 2013, 110 (19), 7720-7725).

[0004] Unlike normal cells, cancer cells often rely on misregulation of DNA damage response (DDR) pathways for survival. For example, there is increased reliance on one pathway (usually mutagenic) in response to inactivation of another pathway, or enhanced replication stress due to increased proliferation. Aberrant DDR can also sensitize cancer cells to specific types of DNA damage, so defective DDR can be exploited to develop targeted cancer therapies. Crucially, cancer cells with impaired or inactivated HR and NHEJ become hyperdependent on MMEJ-mediated DNA repair. Genetic, cell biological and biochemical data have identified Polθ (UniProtKB-075417(DPOLQ_HUMAN) as a key protein in MMEJ (Kent et al., Nature Structural & Molecular Biology (2015), 22(3), 230-237, Mateos-Gomez et al. Nature (2015), 518(7538), 254-257). Polθ is a multifunctional enzyme that contains an N-terminal helicase domain (SF2 HEL308-type) and a C-terminal low-fidelity DNA polymerase domain (A-type) (Wood & Doublié DNA Repair (2016), 44, 22-32). These two domains have been shown to have consistent mechanistic functions in MMEJ. The helicase domain mediates the removal of RPA proteins from ssDNA ends and stimulates annealing. The polymerase domain extends the ssDNA ends and fills the remaining gaps.

[0005] Therefore, therapeutic inactivation of Pol θ will disable the ability of cells to perform MMEJ and provide new targeting strategies in a range of defined tumor environments. First, Pol θ has been shown to be essential for the survival of HR-deficient (HRD) cells (e.g., synthetic lethality with FA / BRCA defects) and is upregulated in HRD tumor cell lines (Ceccaldi et al. Nature (2015), 518(7538), 258-262). In vivo studies have also shown that Pol θ is significantly overexpressed in HRD ovarian, uterine, and breast cancer subgroups associated with poor prognosis (Higgins et al. Oncotarget (2010), 1, 175-184, Lemée et al. PNAS (2010), 107(30), 13390-13395, Ceccaldi et al. (2015), supra). Importantly, Pol θ is largely repressed in normal tissues but has been shown to be upregulated in matched cancer samples, thus correlating elevated expression with disease (Kawamura et al. International Journal of Cancer (2004), 109(1), 9-16). Second, its inhibition or blockade confers radiosensitivity to tumor cells. Finally, it is conceivable that inhibition of Pol θ could prevent the MMEJ-dependent functional reversal of BRCA2 mutations, which underlies the emergence of cisplatin and PARPi resistance in tumors.

[0006] Therefore, there is a need to provide effective Pol θ inhibitors for treating cancer. SUMMARY OF THE INVENTION

[0008] According to a first aspect of the present invention, there is provided a compound of formula (I):

[0009]

[0010] or a tautomer or stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein:

[0011] W represents = C (R 4 )-or=N-;

[0012] R 1 , R 2 , R 3 and R 4 independently represent hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, cyano or -NR x R y;

[0013] X represents -C(H)(R 6 )-、-N(R 14 )-or-O-;

[0014] R 5 Represents hydrogen, -CH 2 -R z or oxo, so that when X represents -N(R 14 )- or -O-, R 5 represents oxygen generation;

[0015] R 6 Represents hydrogen, -OR 15a , cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl alcohol, C 3-8 Cycloalkyl, halogen, -NR v R w 、-CH 2 -NR v R w , -Z-aryl or heterocyclic, wherein the aryl or heterocyclic can be optionally substituted with one or more oxo, hydroxyl C 1-6 Alkyl alcohol, -COC 1-6 Alkyl (e.g. -COMe) or -COOC 1-6 Alkyl (e.g. -COOtBu) group substitution;

[0016] Z represents a bond or a C optionally substituted by an oxygen atom 1-6 Alkylene;

[0017] R 7 Represents hydrogen, -CH 2 -R z OR 15b , so that when X represents -N(H)- or -O-, R 7 represents hydrogen;

[0018] R 8 Represents C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 3-8 Cycloalkyl;

[0019] Y represents -C(R 9 )=or-N=;

[0020] R 9 , R 10 , R 11 , R 12 and R 13independently represent hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, hydroxyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, halogen, halogenated C 1-6 Alkyl or -NR m R n , or the R 9 , R 10 , R 11 , R 12 and R 13 Two adjacent groups of the group may be linked to form a 5-7 membered saturated or unsaturated ring, which optionally contains one or more heteroatoms selected from O, N or S, and the ring may be optionally substituted by one or more C 1-6 Alkyl or halogen group substitution;

[0021] R 14 Represents hydrogen, C 1-6 Alkyl, C 1-6 Alkanol, -V-CO-NR m R n 、-V-NR m R n 、-V-SO 2 -C 1-6 Alkyl, -VO-SO 2 -NR m R n 、-V-SO 2 -NR m R n 、-VS(=NH)(=O)(C 1-6 Alkyl), -V-NH-SO 2 -C 1-6 Alkyl, -VN=S(=O)(C 1-6 alkyl) 2 , -V-heterocyclic group, wherein the heterocyclic group can be optionally substituted by one or more oxo, hydroxyl, halogen, cyano, C 1-6 Alkyl, -COC 1-6 Alkyl, -NR m -COC 1-6 Alkyl or C 1-6 Alkyl substitution;

[0022] V represents a bond or is selected from -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -and-CH 2 -CH(OH)-CH 2 - a linker;

[0023] R 15a and R 15b independently represents hydrogen or R 15a and R 15b are connected together to form a 5-7 membered saturated ring system, which may be optionally replaced by one or more C 1-6 Alkyl substitution;

[0024] R m and R n independently represents hydrogen or C 1-6 alkyl;

[0025] R v , R w , R x and R y independently represent hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, -COC 1-6 The alkyl or heterocyclyl group is optionally substituted with one or more hydroxyl, amino or sulfone groups, and the heterocyclyl ring is optionally substituted with one or more oxo, hydroxyl, C 1-6 Alkyl alcohol or -COC 1-6 Alkyl substituted; and

[0026] R z Represents hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or C 1-6 Alkyl alcohol. DETAILED DESCRIPTION OF THE INVENTION

[0028] definition

[0029] According to one aspect of the present invention, there is provided a compound of formula (I):

[0030]

[0031] or a tautomer or stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein:

[0032] W represents = C (R 4 )-or=N-;

[0033] R 1 , R 2 , R 3 and R 4 independently represent hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, cyano or -NR x Ry ;

[0034] X represents -C(H)(R 6 )-, -N(H)-, or -O-;

[0035] R 5 Represents hydrogen, -CH 2 -R z or oxo, so that when X represents -N(H)- or -O-, R 5 represents oxygen generation;

[0036] R 6 Represents hydrogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl alcohol, C 3-8 Cycloalkyl, halogen, -NR v R w or a heterocyclic group;

[0037] R 7 Represents hydrogen, -CH 2 -R z or hydroxyl, so that when X represents -N(H)- or -O-, R 7 represents hydrogen;

[0038] R 8 Represents C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 3-8 Cycloalkyl;

[0039] Y represents -C(R 9 )=or-N=;

[0040] R 9 , R 10 , R 11 , R 12 and R 13 independently represent hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, halogen or halogenated C 1-6 alkyl;

[0041] R v , R w , R x and R y independently represent hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, -COC 1-6Alkyl or heterocyclyl, wherein the alkyl group may be optionally substituted with one or more hydroxyl, amino or sulfone groups, and the heterocyclyl ring may be optionally substituted with one or more oxo or -COC 1-6 Alkyl substituted; and

[0042] R z Represents C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or C 1-6 Alkyl alcohol.

[0043] According to a first aspect of the present invention, there is provided a compound of formula (I):

[0044]

[0045] or a tautomer or stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein:

[0046] W represents = C (R 4 )-or=N-;

[0047] R 1 , R 2 , R 3 and R 4 independently represent hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, cyano or -NR x R y ;

[0048] X represents -C(H)(R 6 )-、-N(R 14 )-or-O-;

[0049] R 5 Represents hydrogen, -CH 2 -R z or oxo, so that when X represents -N(R 14 )- or -O-, R 5 represents oxygen generation;

[0050] R 6 Represents hydrogen, -OR 15a , cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl alcohol, C 3-8 Cycloalkyl, halogen, -NR v Rw 、-CH 2 -NR v R w , -Z-aryl or heterocyclic, wherein the aryl or heterocyclic can be optionally substituted by one or more oxo, hydroxyl, C 1-6 Alkyl alcohol, -COC 1-6 Alkyl (e.g. -COMe) or -COOC 1-6 Alkyl (e.g. -COOtBu) group substitution;

[0051] Z represents a bond or a C optionally substituted by an oxygen atom 1-6 Alkylene;

[0052] R 7 Represents hydrogen, -CH 2 -R z OR 15b , so that when X represents -N(H)- or -O-, R 7 represents hydrogen;

[0053] R 8 Represents C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 3-8 Cycloalkyl;

[0054] Y represents -C(R 9 )=or-N=;

[0055] R 9 , R 10 , R 11 , R 12 and R 13 independently represent hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, hydroxyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, halogen or halogenated C 1-6 Alkyl, or the R 9 , R 10 , R 11 , R 12 and R 13 Two adjacent groups of may be linked to form a 5-7 membered saturated or unsaturated ring, which optionally contains one or more heteroatoms selected from O, N or S;

[0056] R 14 Represents hydrogen, C 1-6 Alkyl, C 1-6 Alkyl alcohol or -SO 2 -C 1-6 alkyl;

[0057] R 15a and R15b independently represents hydrogen or R 15a and R 15b are connected together to form a 5-7 membered saturated ring system, which may be optionally replaced by one or more C 1-6 Alkyl substitution;

[0058] R v , R w , R x and R y independently represent hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, -COC 1-6 The alkyl or heterocyclyl group is optionally substituted with one or more hydroxyl, amino or sulfone groups, and the heterocyclyl ring is optionally substituted with one or more oxo, hydroxyl, C 1-6 Alkyl alcohol or -COC 1-6 Alkyl substituted; and

[0059] R z Represents C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or C 1-6 Alkyl alcohol.

[0060] The term "halo" or "halogen" as used herein refers to fluoro, chloro, bromo or iodo.

[0061] As used herein, the term "cyano" refers to a group in which a carbon atom is triple-bonded to a nitrogen atom.

[0062] As used herein, the term "C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

[0063] As used herein, the term "C 2-6 "Alkenyl" refers to a straight or branched unsaturated hydrocarbon group containing 2 to 6 carbon atoms and at least one double bond. Examples of such groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

[0064] As used herein, the term "C 1-6 "Alkoxy" refers to a C 1-6 Alkyl, where C 1-6 Alkyl is as defined herein. Examples of such groups include methoxy, ethoxy or propoxy.

[0065] As used herein, the term "C1-6 "Alkanol" refers to a C 1-6 Alkyl, where C 1-6 Alkyl is as defined herein.

[0066] As used herein, the term "halogenated C 1-6 "Alkyl" means a C 1-6 Alkyl in which one or more hydrogen atoms are replaced by halogen. Hence the term "halo-C 1-6 "Alkyl" includes a halo-C 1-6 Alkyl and also includes polyhalogenated C 1-6 Alkyl. One, two, three or more hydrogen atoms may be replaced by halogen, thereby halogenated C 1-6 The alkyl group may have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and the like.

[0067] As used herein, the term “C 3-8 "Cycloalkyl" refers to a saturated monocyclic hydrocarbon ring of 3-8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0068] As used herein, the term "oxo" refers to the group =0.

[0069] As used herein, the term "amino" refers to the group -NR'R", wherein R' and R" independently represent hydrogen or C 1-6 alkyl.

[0070] As used herein, the term "heterocyclyl" refers to a monocyclic or bicyclic non-aromatic, partially saturated or fully saturated ring system containing, for example, 3-12 ring members. Each ring may contain up to 5 heteroatoms typically selected from nitrogen, sulfur and oxygen.

[0071] Specific examples of “heterocyclic group” include morpholine, piperidine (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl), piperidone, pyrrolidine (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl), pyrrolidone, azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g., tetrahydropyran-4-yl), imidazoline, imidazolidinone, oxazoline, thiazoline, pyrazolin-2-yl, pyrazolidine, piperazinone and piperazine.

[0072] It is to be understood that the term "heterocyclyl" includes reference to spiro and bridged heterocyclic derivatives. Examples of such spiro and bridged heterocyclic derivatives include: hexahydropyrrolo[2,3-c]pyrrolidinyl, diazaspiro[3.4]octanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[3.4]octanyl, oxa-azaspiro[4.4]nonanyl, tetrahydrofuro[3,4-c]pyrrolidinyl, oxa-azaspiro[3.3]heptyl, diazaspiro[4.5]decanyl, diazaspiro[3.4]octanyl, octahydro-naphthyridinyl, tetrahydropyrazino-oxazinyl, oxadiazolospiro[5.5]undecyl and oxabicyclo[2.2.1]heptanyl.

[0073] As used herein, the term "optionally substituted" refers to a group that may or may not be substituted with substituents as defined herein.

[0074] Implementation

[0075] In one embodiment, the compound of formula (I) is a compound of formula (I)a:

[0076]

[0077] Where R 1 , R 2 , R 3 , R 4 , R 5 , X, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 As defined above or as defined in any of the embodiments defined herein.

[0078] In another embodiment, the compound of formula (I) is a compound of formula (I)b:

[0079]

[0080] Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 As defined above or as defined in any of the embodiments defined herein.

[0081] In one embodiment, W represents =C(R4 )-. In an alternative embodiment, W represents =N-. In one embodiment, W represents =C(H)-, =C(CN)- or =N-. In another embodiment, W represents =C(H)- or =C(CN)-.

[0082] In one embodiment, R 1 express:

[0083] hydrogen;

[0084] C 1-6 Alkyl (e.g., methyl or ethyl);

[0085] C 2-6 Alkenyl (eg vinyl); C 1-6 Alkoxy (e.g. methoxy);

[0086] halogen (e.g. chlorine); or

[0087] -NR x R y (e.g. -N(Me) 2 or -N(Me)(Et)).

[0088] In one embodiment, R 1 express:

[0089] hydrogen;

[0090] C 1-6 Alkyl (e.g. methyl);

[0091] C 1-6 an alkoxy group (such as a methoxy group); or

[0092] -NR x R y (e.g. -N(Me) 2 or -N(Me)(Et)).

[0093] In another embodiment, R 1 Represents C 1-6 Alkyl (eg, methyl).

[0094] In one embodiment, R 2 represents: hydrogen; halogen (such as chlorine); or C 1-6 Alkyl (eg, methyl).

[0095] In one embodiment, R 2 Represents hydrogen.

[0096] In one embodiment, R 3 express:

[0097] C1-6 Alkyl (e.g., methyl, ethyl or isopropyl);

[0098] C 2-6 Alkenyl (e.g. -C(=CH 2 )(Me));

[0099] Halogens (e.g. bromine);

[0100] Halogenated C 1-6 Alkyl (e.g. trifluoromethyl or -C(H)(Me)-CF 3 );or

[0101] Halogenated C 1-6 Alkoxy (eg, difluoromethoxy).

[0102] In one embodiment, R 3 express:

[0103] C 1-6 Alkyl (for example, methyl, ethyl or isopropyl); or

[0104] Halogenated C 1-6 Alkyl (eg trifluoromethyl).

[0105] In another embodiment, R 3 Represents halogenated C 1-6 Alkyl (eg trifluoromethyl).

[0106] In one embodiment, R 4 It means: hydrogen; or cyano.

[0107] In another embodiment, R 4 Represents hydrogen.

[0108] In one embodiment, R x and R y Represents C 1-6 In another embodiment, R x and R y Both represent C 1-6 In another embodiment, R x and R y Both represent methyl or one represents methyl and the other represents ethyl.

[0109] In one embodiment, W represents =C(R 4 )-,and;

[0110] R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 Represents hydrogen, R 3Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 4 represents a cyano group; or

[0111] R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 Represents hydrogen, R 3 Represents C 1-6 alkyl (such as methyl or isopropyl), and R 4 represents a cyano group; or

[0112] R 1 Represents C 1-6 Alkyl (such as methyl or ethyl), R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 Alkyl (e.g. trifluoromethyl or -CH(Me)-CF 3 ), and R 4 represents hydrogen; or

[0113] R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 Represents hydrogen, R 3 Represents C 1-6 alkyl (e.g. isopropyl), and R 4 represents hydrogen; or

[0114] R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 represents a halogen (e.g., chlorine), R 3 Represents C 1-6 alkyl (eg, methyl), and R 4 represents hydrogen; or

[0115] R 1 Represents C 1-6 Alkoxy (e.g. methoxy), R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 4 represents a cyano group; or

[0116] R 1 Indicates -NR x R y (e.g. -N(Me) 2 or -N(Me)(Et)), R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 4 represents a cyano group; or

[0117] R 1 Represents hydrogen, R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 4 represents a cyano group; or

[0118] R 1 Represents hydrogen, R 2 Represents C 1-6 Alkyl (e.g. methyl), R 3 Represents C 1-6 alkyl (eg ethyl), and R 4 represents hydrogen; or

[0119] R 1 represents a halogen (e.g., chlorine), R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 4 represents hydrogen; or

[0120] R 1 represents a halogen (e.g., chlorine), R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 Alkoxy (eg, difluoromethoxy), and R 4 represents hydrogen; or

[0121] R 1 Represents C 2-6 Alkenyl (e.g. vinyl), R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 4 represents hydrogen; or

[0122] R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 Alkoxy (eg, difluoromethoxy), and R 4 represents hydrogen; or

[0123] R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 Represents hydrogen, R 3 Represents C 2-6 Alkenyl (e.g. -C(Me)(=CH 2 )), and R 4 represents hydrogen; or

[0124] R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 Represents hydrogen, R 3 represents a halogen (e.g., bromine), and R 4 Represents hydrogen.

[0125] In one embodiment, W represents =C(R 4 )-,and;

[0126] R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 4 represents a cyano group; or

[0127] R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 Represents hydrogen, R 3 Represents C 1-6 alkyl (such as methyl or isopropyl), and R 4 represents a cyano group; or

[0128] R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 4 represents hydrogen; or

[0129] R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 Represents hydrogen, R 3 Represents C 1-6 alkyl (e.g. isopropyl), and R 4 represents hydrogen; or

[0130] R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 represents a halogen (e.g., chlorine), R 3 Represents C 1-6 alkyl (eg, methyl), and R 4 represents hydrogen; or

[0131] R 1 Represents C 1-6 Alkoxy (e.g. methoxy), R 2 Represents hydrogen, R3 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 4 represents a cyano group; or

[0132] R 1 Indicates -NR x R y (e.g. -N(Me) 2 or -N(Me)(Et)), R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 4 represents a cyano group; or

[0133] R 1 Represents hydrogen, R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 4 represents a cyano group; or

[0134] R 1 Represents hydrogen, R 2 Represents C 1-6 Alkyl (e.g. methyl), R 3 Represents C 1-6 alkyl (eg ethyl), and R 4 Represents hydrogen.

[0135] In another embodiment, W represents =C(R 4 )-, and R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 4 Represents hydrogen R 1 Represents hydrogen.

[0136] In an alternative embodiment, W represents =N-, and R 1 Represents C 1-6 Alkyl (e.g. methyl), R 2 represents hydrogen, and R 3 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 4 Represents hydrogen.

[0137] In one embodiment, X represents -C(H)(R 6 )- or -O-. In another embodiment, X represents -C(H)(R 6)-. In an alternative embodiment, X represents -O-. In another alternative embodiment, X represents -N(R 14 )-.

[0138] In one embodiment, R 5 Means: hydrogen; or oxo.

[0139] In an alternative embodiment, R 5 In another alternative embodiment, R 5 In another alternative embodiment, R 5 Indicates -CH 2 -R z .

[0140] In one embodiment, R z Represents hydrogen.

[0141] In one embodiment, R 6 express:

[0142] hydrogen;

[0143] -OR 15a (e.g. hydroxyl);

[0144] Halogens (e.g. fluorine);

[0145] C 1-6 Alkanol (e.g. CH 2 OH);

[0146] C 1-6 Alkoxy (e.g. methoxy);

[0147] -NR v R w (e.g. -NH 2 、-NMe 2 , -N(H)(Me), -N(H)(COMe), -N(H)((CH 2 ) 2 OH), -N(H)((CH 2 ) 2 SO 2 Me), N(Me)((CH 2 ) 2 SO 2Me), -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), -N(H)(azetidinyl), -N(H)(oxetanyl), -N(Me)(oxetanyl), -N(H)(cyclopentyl), -N(Me)(cyclopentyl), -N(H)(tetrahydropyranyl), -N(Me)(tetrahydropyranyl, or -N(H)((CH 2 ) 2 NH 2 ), wherein the pyrrolidinyl, tetrahydropyranyl or cyclopentyl ring may be optionally substituted with one or more oxo, hydroxyl, -COC 1-6 Alkyl (e.g. -COMe) or -COOC 1-6 Alkyl (e.g. -COOtBu) group substitution;

[0148] -CH 2 -NR v R w (e.g. -CH 2 -N(Me) 2 );

[0149] -Z-aryl (e.g. -CH 2 -O-CH 2 -phenyl); or

[0150] Heterocyclyl (eg azetidinyl, pyrrolidinyl, morpholinyl or piperazinyl), optionally substituted by one or more hydroxyl or C 1-6 Alkanol (e.g. CH 2 OH) group substitution.

[0151] In one embodiment, R 6 express:

[0152] hydrogen;

[0153] Hydroxyl;

[0154] Halogens (e.g. fluorine);

[0155] C 1-6 Alkoxy (e.g. methoxy);

[0156] -NR v R w (e.g. -NH 2 、-NMe 2 , -N(H)(Me), -N(H)(COMe), -N(H)((CH 2 ) 2 OH), -N(H)((CH 2 ) 2 SO 2 Me), N(Me)((CH 2) 2 SO 2 Me), -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), -N(H)(azetidinyl), -N(H)((CH 2 ) 2 NH 2 ), wherein the pyrrolidinyl ring may be optionally substituted with oxo or -COC 1-6 Alkyl (eg, -COMe) group substitution; or

[0157] Heterocyclic groups (eg morpholinyl or piperazinyl).

[0158] In another embodiment, R 6 Represents hydroxyl.

[0159] In one embodiment, R 7 Means: Hydrogen; or -OR 15b (e.g. hydroxyl).

[0160] In one embodiment, R 7 Means: hydrogen; or hydroxyl.

[0161] In another embodiment, R 7 Indicates -OR 15b (e.g. hydroxyl).

[0162] In one embodiment, X represents -C(H)(R 6 )-,and;

[0163] R 5 , R 6 and R 7 each represents hydrogen; or

[0164] R 5 and R 7 Both represent hydrogen, and R 6 Indicates -OR 15a (e.g. hydroxyl); or

[0165] R 5 and R 6 Both represent hydrogen, and R 7 Indicates -OR 15b (e.g. hydroxyl); or

[0166] R 5 and R 7 Both represent hydrogen, and R 6 represents a halogen (e.g. fluorine); or

[0167] R 5 and R 7 Both represent hydrogen, and R 6 Represents C1-6 an alkoxy group (such as a methoxy group); or

[0168] R 5 and R 7 Both represent hydrogen, and R 6 Indicates -NR v R w (e.g. -NH 2 、-NMe 2 、-N(H)(Me),-N(H)((CH 2 ) 2 OH), -N(H)((CH 2 ) 2 SO 2 Me), N(Me)((CH 2 ) 2 SO 2 Me), -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), -N(H)(azetidinyl), -N(H)(oxetanyl), -N(Me)(oxetanyl), -N(H)(cyclopentyl), -N(Me)(cyclopentyl), -N(H)(tetrahydropyranyl), -N(Me)(tetrahydropyranyl, or -N(H)((CH 2 ) 2 NH 2 ), wherein the pyrrolidinyl, tetrahydropyranyl or cyclopentyl ring may be optionally substituted with one or more oxo, hydroxyl, -COC 1-6 Alkyl (e.g. -COMe) or -COOC 1-6 Alkyl (eg, -COOtBu) group substitution; or

[0169] R 5 and R 7 Both represent hydrogen, and R 6 represents a heterocyclic group (e.g. azetidinyl, pyrrolidinyl, morpholinyl or piperazinyl, which is optionally substituted by one or more hydroxyl or C 1-6 Alkanol (CH 2 OH) group substitution); or

[0170] R 5 Represents hydrogen, R 6 Indicates -OR 15a (e.g. hydroxyl), and R 7 Indicates -OR 15b (e.g. hydroxyl); or

[0171] R 5 represents oxo, and R 6 and R 7 all represent hydrogen; or

[0172] R5 Represents oxo, R 6 Indicates -NR v R w (e.g. -NH 2 or -N(H)(COMe)), and R 7 represents hydrogen; or

[0173] R 5 Represents oxo, R 6 represents a heterocyclic group (e.g., morpholinyl), and R 7 represents hydrogen; or

[0174] R 5 Represents oxo, R 6 Indicates -OR 15a (e.g. hydroxyl), and R 7 Indicates -OR 15b (e.g. hydroxyl); or

[0175] R 5 Represents oxo, R 6 Indicates -OR 15a (e.g. hydroxyl), and R 7 represents hydrogen; or

[0176] R 5 Represents oxo, R 6 represents a -Z-aryl group (e.g., -CH 2 -O-CH 2 -phenyl), and R 7 represents hydrogen; or

[0177] R 5 Represents oxo, R 6 Represents C 1-6 Alkanol (e.g. CH 2 OH), and R 7 represents hydrogen; or

[0178] R 5 Represents oxo, R 6 represents hydrogen, and R 7 Indicates -OR 15b (e.g. hydroxyl); or

[0179] R 5 Represents oxo, R 6 Indicates -CH 2 -NR v R w (e.g. -CH 2 -N(Me) 2 ), and R 7 represents hydrogen; or

[0180] R 5 Represents oxo, R6 Indicates -OR 15a And R 7 Indicates -OR 15b , where R 15a and R 15b are connected together to form a 5-7 (e.g. 5) membered saturated ring system (e.g. dioxolanyl), which may be optionally replaced by one or more C 1-6 Alkyl (e.g. two methyl) substitution; or

[0181] R 6 and R 7 Both represent hydrogen, and R 5 Indicates -CH 2 -R z (e.g. methyl).

[0182] In one embodiment, X represents -C(H)(R 6 )-,and;

[0183] R 5 , R 6 and R 7 each represents hydrogen; or

[0184] R 5 and R 7 Both represent hydrogen, and R 6 Indicates -OR 15a (e.g. hydroxyl); or

[0185] R 5 and R 6 Both represent hydrogen, and R 7 Indicates -OR 15b (e.g. hydroxyl); or

[0186] R 5 and R 7 Both represent hydrogen, and R 6 represents a halogen (e.g. fluorine); or

[0187] R 5 and R 7 Both represent hydrogen, and R 6 Represents C 1-6 an alkoxy group (such as a methoxy group); or

[0188] R 5 and R 7 Both represent hydrogen, and R 6 Indicates -NR v R w (e.g. -NH 2 、-NMe 2 、-N(H)(Me),-N(H)((CH 2 )2 OH), -N(H)((CH 2 ) 2 SO 2 Me), N(Me)((CH 2 ) 2 SO 2 Me), -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), -N(H)(azetidinyl), -N(H)(oxetanyl), -N(Me)(oxetanyl), -N(H)(cyclopentyl), -N(Me)(cyclopentyl), -N(H)(tetrahydropyranyl), -N(Me)(tetrahydropyranyl, or -N(H)((CH 2 ) 2 NH 2 ), wherein the pyrrolidinyl, tetrahydropyranyl or cyclopentyl ring may be optionally substituted with one or more oxo, hydroxyl, -COC 1-6 Alkyl (e.g. -COMe) or -COOC 1-6 Alkyl (eg, -COOtBu) group substitution; or

[0189] R 5 and R 7 Both represent hydrogen, and R 6 represents a heterocyclic group (e.g. azetidinyl, pyrrolidinyl, morpholinyl or piperazinyl, which is optionally substituted by one or more hydroxyl or C 1-6 Alkanol (CH 2 OH) group); or

[0190] R 5 Represents hydrogen, R 6 Indicates -OR 15a (e.g. hydroxyl), and R 7 Indicates -OR 15b (e.g. hydroxyl); or

[0191] R 5 represents oxo, and R 6 and R 7 all represent hydrogen; or

[0192] R 5 Represents oxo, R 6 Indicates -NR v R w (e.g. -NH 2 or -N(H)(COMe)), and R 7 represents hydrogen; or

[0193] R 5 Represents oxo, R 6 represents a heterocyclic group (e.g., morpholinyl), and R 7 represents hydrogen; or

[0194] R 5 Represents oxo, R 6 Indicates -OR 15a (e.g. hydroxyl), and R 7 Indicates -OR 15b (e.g. hydroxyl); or

[0195] R 5 Represents oxo, R 6 Indicates -OR 15a (e.g. hydroxyl), and R 7 represents hydrogen; or

[0196] R 5 Represents oxo, R 6 represents a -Z-aryl group (e.g., -CH 2 -O-CH 2 -phenyl), and R 7 represents hydrogen; or

[0197] R 5 Represents oxo, R 6 Represents C 1-6 Alkanol (e.g. CH 2 OH), and R 7 represents hydrogen; or

[0198] R 5 Represents oxo, R 6 represents hydrogen, and R 7 Indicates -OR 15b (e.g. hydroxyl); or

[0199] R 5 Represents oxo, R 6 Indicates -CH 2 -NR v R w (e.g. -CH 2 -N(Me) 2 ), and R 7 represents hydrogen; or

[0200] R 5 Represents oxo, R 6 Indicates -OR 15a and R 7 Indicates -OR 15b , where R 15a and R 15b are connected together to form a 5-7 (e.g. 5) membered saturated ring system (e.g. dioxolanyl), which may be optionally replaced by one or more C 1-6 Alkyl (eg, two methyl) substitutions.

[0201] In one embodiment, X represents -C(H)(R 6 )-,and

[0202] R 5 , R 6 and R 7 each represents hydrogen; or

[0203] R 5 and R 7 Both represent hydrogen, and R 6 represents a hydroxyl group; or

[0204] R 5 and R 6 Both represent hydrogen, and R 7 represents a hydroxyl group; or

[0205] R 5 and R 7 Both represent hydrogen, and R 6 represents a halogen (e.g. fluorine); or

[0206] R 5 and R 7 Both represent hydrogen, and R 6 Represents C 1-6 an alkoxy group (such as a methoxy group); or

[0207] R 5 and R 7 Both represent hydrogen, and R 6 Indicates -NR v R w (e.g. -NH 2 、-NMe 2 、-N(H)(Me),-N(H)((CH 2 ) 2 OH), -N(H)((CH 2 ) 2 SO 2 Me), N(Me)((CH 2 ) 2 SO 2 Me), -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), -N(H)(azetidinyl), -N(H)((CH 2 ) 2 NH 2 ), wherein the pyrrolidinyl ring may be optionally substituted with oxo or -COC 1-6 Alkyl (eg, -COMe) group substitution; or

[0208] R 5 and R 7 Both represent hydrogen, and R 6represents a heterocyclic group (for example morpholinyl or piperazinyl); or

[0209] R 5 represents hydrogen, and R 6 and R 7 All represent hydroxyl group; or

[0210] R 5 represents oxo, and R 6 and R 7 all represent hydrogen; or

[0211] R 5 Represents oxo, R 6 Indicates -NR v R w (e.g. -NH 2 or -N(H)(COMe)), and R 7 represents hydrogen; or

[0212] R 5 Represents oxo, R 6 represents a heterocyclic group (e.g., morpholinyl), and R 7 represents hydrogen; or

[0213] R 5 represents oxo, and R 6 and R 7 All represent hydroxyl groups.

[0214] In another embodiment, X represents -C(H)(R 6 )-, and R 5 represents oxo, and R 6 and R 7 All represent hydroxyl groups.

[0215] In one embodiment, X represents -O-, and R 5 represents oxo, and R 7 Represents hydrogen.

[0216] In one embodiment, X represents -N(R 14 )-,and;

[0217] R 5 represents oxo, and R 7 and R 14 all represent hydrogen; or

[0218] R 5 Represents oxo, R 7 represents hydrogen, and R 14 express:

[0219] C 1-6 Alkanol (e.g. -CH 2 -CH(oH)Me, -(CH2 ) 2 -OH, -CH 2 -CHOH-CH 2 OH or -(CH 2 ) 2 -CHOH-CH 2 OH);

[0220] -V-SO 2 -C 1-6 Alkyl (e.g. -SO 2 -Me or -(CH 2 ) 2 -SO 2 -Me);

[0221] -V-SO 2 -NR m R n (For example -(CH 2 ) 2 -SO 2 -N(Me) 2 );

[0222] -V-NR m R n (For example -(CH 2 ) 2 -N(Me) 2 、-(CH 2 ) 3 -N(Me) 2 or -CH 2 -CHOH-CH 2 -NMe 2 );

[0223] -V-CO-NR m R n (e.g. -CH 2 -CONH 2 、-CH 2 -CON(Me) 2 、-(CH 2 ) 2 -CON(Me) 2 or -(CH 2 ) 2 -CON(H)(Me));

[0224] -V-NH-SO 2 -C 1-6 Alkyl (e.g. -(CH 2 ) 2 -NH-SO 2 -Me);

[0225] -VS(=NH)(=O)(C 1-6 Alkyl) (e.g. -(CH 2 ) 2 -S(=NH)(=O)(Me));

[0226] -VO-SO 2 -NR m R n (For example -(CH 2 ) 2 -O-SO 2 -NH 2 );

[0227] -VN=S(=O)(C 1-6 alkyl) 2 (For example -(CH 2 ) 2 -N=S(=O)(Me) 2 );or

[0228] -V-heterocyclic group (e.g. -CH 2 -Oxetane, -CH 2 -azetidinyl, -(CH 2 ) 2 -azetidinyl, -CH 2 -oxazolidinyl, -(CH 2 ) 2 -piperidinyl, -(CH 2 ) 2 -piperazinyl, -(CH 2 ) 3 -piperazinyl, -CH 2 -morpholinyl, -(CH 2 ) 2 -morpholinyl, -CH 2 -CHOH-CH 2 -morpholinyl, -(CH 2 ) 2 -thiomorpholinyl, -CH 2 -pyrrolidinyl, -(CH 2 ) 2 -pyrrolidinyl or -CH 2 -CHOH-CH 2 -pyrrolidinyl), wherein the heterocyclic group may be optionally substituted with one or more oxo, hydroxy, halogen (e.g. fluorine), cyano, C 1-6 Alkyl (such as methyl), -COC 1-6 Alkyl (e.g. -COMe), -NR m -COC 1-6 Alkyl (e.g. -NMe-COMe) or C1-6 Alkanol (e.g. -CH 2 OH or -(CH 2 ) 2 -OH) group substitution.

[0229] In one embodiment, X represents -N(R 14 )-,and

[0230] R 5 represents oxo, and R 7 and R 14 all represent hydrogen; or

[0231] R 5 Represents oxo, R 7 represents hydrogen, and R 14 Represents C 1-6 Alkanol (e.g. -CH 2 -CH(OH)Me); or

[0232] R 5 Represents oxo, R 7 represents hydrogen, and R 14 Indicates -SO 2 -C 1-6 Alkyl (e.g. -SO 2 -Me).

[0233] In one embodiment, R v and R w represents hydrogen, C 1-6 Alkyl (such as methyl), -COC 1-6 Alkyl (e.g. -COMe), C 3-8 Cycloalkyl (e.g. cyclopentyl) or heterocyclyl (e.g. oxetanyl, azetidinyl, tetrahydropyranyl or pyrrolidinyl), wherein the alkyl group may be optionally substituted with one or more hydroxy groups (e.g. (CH 2 ) 2 OH), amino groups (e.g. (CH 2 ) 2 NH 2 ) or sulfone (e.g. (CH 2 ) 2 SO 2 Me) group, and the heterocyclyl ring may be optionally substituted with one or more oxo or -COC 1-6 In one embodiment, R v and R w Represents hydrogen, C 1-6 Alkyl (such as methyl), -COC 1-6alkyl (e.g., -COMe) or heterocyclic (e.g., azetidinyl or pyrrolidinyl), wherein the alkyl group may be optionally substituted with one or more hydroxy groups (e.g., (CH 2 ) 2 OH), amino groups (e.g. (CH 2 ) 2 NH 2 ) or sulfone (e.g. (CH 2 ) 2 SO 2 Me) group, and the heterocyclyl ring may be optionally substituted with one or more oxo or -COC 1-6 In one embodiment, R v and R w Both represent hydrogen or C 1-6 alkyl (e.g. methyl) or one represents hydrogen and the other represents C 1-6 Alkyl (eg methyl) or a hydrogen or C 1-6 alkyl (e.g. methyl) and the other represents -COC 1-6 Alkyl (e.g. -COMe), C 3-8 Cycloalkyl (e.g. cyclopentyl) or heterocyclyl (e.g. azetidinyl, tetrahydropyranyl or pyrrolidinyl), wherein the alkyl group may be optionally substituted with one or more hydroxy groups (e.g. (CH 2 ) 2 OH), amino groups (e.g. (CH 2 ) 2 NH 2 ) or sulfone (e.g. (CH 2 ) 2 SO 2 Me) group, and the heterocyclyl ring may be optionally substituted with one or more oxo or -COC 1-6 In one embodiment, R v and R w Both represent hydrogen or C 1-6 alkyl (e.g. methyl) or one represents hydrogen and the other represents C 1-6 Alkyl (eg methyl) or a hydrogen or C 1-6 alkyl (e.g. methyl) and the other represents -COC 1-6 alkyl (e.g., -COMe) or heterocyclic (e.g., azetidinyl or pyrrolidinyl), wherein the alkyl group may be optionally substituted with one or more hydroxy groups (e.g., (CH 2 ) 2 OH), amino groups (e.g. (CH 2 ) 2 NH 2 ) or sulfone (e.g. (CH 2 )2 SO 2 Me) group, and the heterocyclyl ring may be optionally substituted with one or more oxo or -COC 1-6 Alkyl (eg, -COMe) groups are substituted.

[0234] In one embodiment, R 8 Represents C 1-6 Alkyl (e.g. CH 3 , CD 3 , ethyl or isopropyl) or C 3-8 In one embodiment, R 8 Represents C 1-6 In another embodiment, R 8 Represents C 1-6 Alkyl (e.g. CH 3 , CD 3 In another embodiment, R 8 Represents C 1-6 In another embodiment, R 8 Represents C 1-6 Alkyl (e.g. CH 3 or CD 3 ).

[0235] In one embodiment, Y represents -C(R 9 )=. In an alternative embodiment, Y represents -N=.

[0236] In one embodiment, R 9 represents: hydrogen; halogen (such as fluorine or chlorine); or C 1-6 Alkoxy (eg, methoxy).

[0237] In one embodiment, R 9 represents: hydrogen; halogen (such as fluorine); or C 1-6 Alkoxy (eg, methoxy).

[0238] In one embodiment, R 9 represents: hydrogen; or halogen (such as fluorine).

[0239] In another embodiment, R 9 Represents hydrogen.

[0240] In one embodiment, R 10 express:

[0241] hydrogen;

[0242] Halogen (for example, fluorine, bromine or chlorine);

[0243] C 1-6 Alkyl (e.g., methyl or ethyl);

[0244] C 2-6 alkenyl (e.g. vinyl);

[0245] Hydroxyl;

[0246] C 1-6 Alkoxy (e.g. methoxy);

[0247] -NR m R n (e.g. -NH 2 , -NHMe or -NMe 2 );or

[0248] R 10 and R 11 connected to form a 5-7 membered saturated or unsaturated ring, which optionally contains one or more heteroatoms selected from O, N or S (e.g., a pyrrolinyl, tetrahydropyranyl, pyrazolyl, morpholinyl, pyridyl, furanyl or thienyl ring, which is optionally substituted with one or more methyl or fluoro groups).

[0249] In one embodiment, R 10 express:

[0250] hydrogen;

[0251] Halogen (for example, fluorine, bromine or chlorine);

[0252] C 1-6 Alkyl (e.g., methyl or ethyl);

[0253] C 2-6 alkenyl (e.g. vinyl);

[0254] Hydroxyl;

[0255] C 1-6 an alkoxy group (such as a methoxy group); or

[0256] R 10 and R 11 They are linked to form a 5-7 membered saturated or unsaturated ring, which optionally contains one or more heteroatoms selected from O, N or S (eg, a pyrroline or tetrahydropyranyl ring).

[0257] In one embodiment, R 10 represents: hydrogen; halogen (such as fluorine or chlorine); or C 1-6 Alkyl (eg, methyl).

[0258] In another embodiment, R 10 represents a halogen (eg, chlorine).

[0259] In one embodiment, R m and R n In another embodiment, R m and R n Both represent hydrogen or R m and R n Both represent methyl or R m and R n One represents hydrogen and the other represents methyl.

[0260] In one embodiment, R 11 express:

[0261] hydrogen;

[0262] Halogen (for example, fluorine, bromine or chlorine);

[0263] C 1-6 Alkyl (e.g., methyl or ethyl);

[0264] C 2-6 alkenyl (e.g. vinyl);

[0265] C 3-8 Cycloalkyl (e.g. cyclopropyl);

[0266] Halogenated C 1-6 Alkyl (eg trifluoromethyl); or

[0267] R 11 and R 10 connected to form a 5-7 membered saturated or unsaturated ring, which optionally contains one or more heteroatoms selected from O, N or S (e.g., a pyrrolinyl, tetrahydropyranyl, pyrazolyl, morpholinyl, pyridyl, furanyl or thienyl ring, which is optionally substituted with one or more methyl or fluoro groups).

[0268] In one embodiment, R 11 express:

[0269] hydrogen;

[0270] Halogen (for example, fluorine, bromine or chlorine);

[0271] C 1-6 Alkyl (e.g., methyl or ethyl);

[0272] C 2-6 alkenyl (e.g. vinyl);

[0273] Halogenated C 1-6 Alkyl (eg trifluoromethyl); or

[0274] R 11 and R10 They are linked to form a 5-7 membered saturated or unsaturated ring, which optionally contains one or more heteroatoms selected from O, N or S (eg, a pyrroline or tetrahydropyranyl ring).

[0275] In one embodiment, R 11 represents: hydrogen; halogen (such as fluorine or chlorine); or halogenated C 1-6 Alkyl (eg trifluoromethyl).

[0276] In another embodiment, R 11 represents a halogen (eg, fluorine).

[0277] In one embodiment, R 12 represents: hydrogen; halogen (such as fluorine or chlorine); C 1-6 Alkyl (eg methyl); halo 1-6 alkyl (e.g. fluoromethyl, difluoromethyl or trifluoromethyl); or C 1-6 Alkoxy (eg, methoxy).

[0278] In another embodiment, R 12 Represents hydrogen.

[0279] In one embodiment, R 13 represents: hydrogen; or halogen (such as fluorine).

[0280] In one embodiment, R 13 Represents hydrogen.

[0281] In one embodiment, Y represents -C(R 9 )=, and:

[0282] R 9 , R 10 , R 11 , R 12 and R 13 represents hydrogen; or

[0283] R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12 Represents C 1-6 an alkyl group (e.g. a methyl group); or

[0284] R 9 , R 10 and R 13 Each of represents hydrogen, and R 11 and R 12 represents halogen (e.g. fluorine or chlorine); or

[0285] R9 , R 10 and R 13 Each of R represents hydrogen, 11 represents a halogen (e.g., fluorine), and R 12 Represents C 1-6 an alkyl group (e.g. a methyl group); or

[0286] R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents a halogen (e.g., fluorine), and R 12 Represents halogenated C 1-6 Alkyl (eg fluoromethyl or trifluoromethyl); or

[0287] R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12 Represents halogenated C 1-6 Alkyl (eg fluoromethyl or difluoromethyl); or

[0288] R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12 represents a halogen (e.g. chlorine); or

[0289] R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents a halogen (e.g., fluorine), and R 12 Represents C 1-6 an alkoxy group (such as a methoxy group); or

[0290] R 9 , R 11 and R 13 Each of represents hydrogen, and R 10 and R 12 represents halogen (e.g. fluorine or chlorine); or

[0291] R 9 , R 10 and R 13 Each of R represents hydrogen, 11 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 12 represents a halogen (e.g. fluorine); or

[0292] R 9 , R 11 , R12 and R 13 Each of represents hydrogen, and R 10 Represents C 1-6 Alkyl (e.g. methyl);

[0293] R 9 , R 11 , R 12 and R 13 Each of represents hydrogen, and R 10 represents a halogen (e.g., chlorine);

[0294] R 9 , R 12 and R 13 Each of represents hydrogen, and R 10 and R 11 all represent halogen (e.g. fluorine, bromine or chlorine);

[0295] R 9 , R 10 and R 13 Each of R represents hydrogen, 11 Represents C 1-6 alkyl (eg, methyl), and R 12 represents a halogen (e.g., chlorine);

[0296] Every R 9 , R 12 and R 13 Represents hydrogen, R 10 Represents C 1-6 alkyl (eg, methyl or ethyl), and R 11 represents a halogen (e.g., chlorine or fluorine);

[0297] R 9 , R 12 and R 13 Each of R represents hydrogen, 10 Represents C 1-6 Alkoxy (eg, methoxy), and R 11 represents a halogen (e.g., fluorine);

[0298] R 9 , R 12 and R 13 Each of R represents hydrogen, 10 Represents C 1-6 Alkoxy (eg, methoxy), and R 11 Represents C 1-6 Alkyl (e.g. methyl);

[0299] R 9 , R 12 and R 13 Each of R represents hydrogen, 10represents a halogen (e.g., chlorine), and R 11 Represents C 1-6 Alkyl (e.g. methyl);

[0300] R 12 and R 13 Both represent hydrogen, R 9 and R 11 Both represent halogen (e.g. fluorine), and R 10 Represents C 1-6 Alkyl (e.g., methyl or ethyl);

[0301] R 10 , R 12 and R 13 Each of represents hydrogen, and R 9 and R 11 Both represent halogen (e.g. chlorine, bromine or fluorine);

[0302] R 9 and R 12 Both represent hydrogen, and R 10 , R 11 and R 13 Each of represents a halogen (e.g., chlorine or fluorine);

[0303] R 11 , R 12 and R 13 Each of represents hydrogen, and R 9 and R 10 Both represent halogen (e.g. chlorine or fluorine);

[0304] R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents a hydroxyl group, and R 11 represents a halogen (e.g., fluorine);

[0305] R 9 , R 12 and R 13 Each of R represents hydrogen, 10 Represents C 2-6 alkenyl (eg, vinyl), and R 11 Represents a halogen (e.g. fluorine)

[0306] R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents a hydroxyl group, and R 11 Represents C 1-6 Alkyl (e.g. methyl);

[0307] R10 , R 11 and R 13 Each of represents hydrogen, and R 9 and R 12 Both represent halogen (e.g. fluorine or chlorine);

[0308] R 10 and R 13 Both represent hydrogen, R 11 and R 12 Both represent halogen (e.g. fluorine or chlorine), and R 9 Represents C 1-6 Alkoxy (e.g. methoxy);

[0309] R 12 and R 13 Both represent hydrogen, and R 9 , R 10 and R 11 Each of represents a halogen (e.g., fluorine or chlorine);

[0310] R 12 and R 13 Both represent hydrogen, R 9 and R 11 Both represent halogen (e.g. fluorine), and R 10 Represents C 2-6 alkenyl (e.g. vinyl);

[0311] R 9 , R 12 and R 13 Each of represents hydrogen, and R 10 and R 11 connected to form a pyrrolinyl, tetrahydropyranyl, pyrazolyl or pyridinyl ring, which is optionally substituted with methyl;

[0312] R 10 and R 13 Both represent hydrogen, and R 9 , R 11 and R 12 represents a halogen (eg, chlorine or fluorine); or

[0313] R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents a halogen (e.g., chlorine), and R 11 Represents C 3-8 Cycloalkyl (eg cyclopropyl).

[0314] In one embodiment, Y represents -C(R 9 )=, and:

[0315] R 9 , R 10 , R 11 , R 12 and R 13 represents hydrogen; or

[0316] R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12 Represents C 1-6 an alkyl group (e.g. a methyl group); or

[0317] R 9 , R 10 and R 13 Each of represents hydrogen, and R 11 and R 12 represents halogen (e.g. fluorine or chlorine); or

[0318] R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents a halogen (e.g., fluorine), and R 12 Represents C 1-6 an alkyl group (e.g. a methyl group); or

[0319] R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents a halogen (e.g., fluorine), and R 12 Represents halogenated C 1-6 Alkyl (eg fluoromethyl or trifluoromethyl); or

[0320] R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12 Represents halogenated C 1-6 Alkyl (eg fluoromethyl or difluoromethyl); or

[0321] R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12 represents a halogen (e.g. chlorine); or

[0322] R 9 , R 10 and R 13 Each of R represents hydrogen, 11represents a halogen (e.g., fluorine), and R 12 Represents C 1-6 an alkoxy group (such as a methoxy group); or

[0323] R 9 , R 11 and R 13 Each of represents hydrogen, and R 10 and R 12 represents halogen (e.g. fluorine or chlorine); or

[0324] R 9 , R 10 and R 13 Each of R represents hydrogen, 11 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 12 represents a halogen (e.g. fluorine); or

[0325] R 9 , R 11 , R 12 and R 13 Each of represents hydrogen, and R 10 Represents C 1-6 Alkyl (e.g. methyl);

[0326] R 9 , R 11 , R 12 and R 1 Every 3 represents hydrogen, and R 10 represents a halogen (e.g., chlorine);

[0327] R 9 , R 12 and R 13 Each of represents hydrogen, and R 10 and R 11 all represent halogen (e.g. fluorine, bromine or chlorine);

[0328] R 9 , R 10 and R 13 Each of R represents hydrogen, 11 Represents C 1-6 alkyl (eg, methyl), and R 12 represents a halogen (e.g., chlorine);

[0329] R 9 , R 12 and R 13 Each of R represents hydrogen, 10 Represents C 1-6 alkyl (eg, methyl or ethyl), and R 11 represents a halogen (e.g., chlorine or fluorine);

[0330] R 9 , R 12 and R 13 Each of R represents hydrogen, 10 Represents C 1-6 Alkoxy (eg, methoxy), and R 11 represents a halogen (e.g., fluorine);

[0331] R 9 , R 12 and R 13 Each of R represents hydrogen, 10 Represents C 1-6 Alkoxy (eg, methoxy), and R 11 Represents C 1-6 Alkyl (e.g. methyl);

[0332] R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents a halogen (e.g., chlorine), and R 11 Represents C 1-6 Alkyl (e.g. methyl);

[0333] R 12 and R 13 Both represent hydrogen, R 9 and R 11 Both represent halogen (e.g. fluorine), and R 10 Represents C 1-6 Alkyl (e.g., methyl or ethyl);

[0334] R 10 , R 12 and R 13 Each of represents hydrogen, and R 9 and R 11 Both represent halogen (e.g. chlorine, bromine or fluorine);

[0335] R 9 and R 12 Both represent hydrogen, and R 10 , R 11 and R 13 Each of represents a halogen (e.g., chlorine or fluorine);

[0336] R 11 , R 12 and R 13 Each of represents hydrogen, and both are R 9 and R 10 represents a halogen (e.g., chlorine or fluorine);

[0337] R 9, R 12 and R 13 Each of R represents hydrogen, 10 represents a hydroxyl group, and R 11 represents a halogen (e.g., fluorine);

[0338] R 9 , R 12 and R 13 Each of R represents hydrogen, 10 Represents C 2-6 alkenyl (eg, vinyl), and R 11 Represents a halogen (e.g. fluorine)

[0339] R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents a hydroxyl group, and R 11 Represents C 1-6 Alkyl (e.g. methyl);

[0340] R 10 , R 11 and R 13 Each of represents hydrogen, and R 9 and R 12 Both represent halogen (e.g. fluorine or chlorine);

[0341] R 10 and R 13 Both represent hydrogen, R 11 and R 12 Both represent halogen (e.g. fluorine or chlorine), and R 9 Represents C 1-6 Alkoxy (e.g. methoxy);

[0342] R 12 and R 13 Both represent hydrogen, and R 9 , R 10 and R 11 Each of represents a halogen (e.g., fluorine or chlorine);

[0343] R 12 and R 13 Both represent hydrogen, R 9 and R 11 Both represent halogen (e.g. fluorine), and R 10 Represents C 2-6 alkenyl (e.g. vinyl);

[0344] R 9 , R 12 and R 13 Each of represents hydrogen, and R 10 and R11 connected to form a pyrroline or tetrahydropyranyl ring; or

[0345] R 10 and R 13 Both represent hydrogen, and R 9 , R 11 and R 12 Each of represents a halogen (eg, chlorine or fluorine).

[0346] In one embodiment, Y represents -C(R 9 )=, and:

[0347] R 9 , R 10 , R 11 , R 12 and R 13 represents hydrogen; or

[0348] R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12 Represents C 1-6 an alkyl group (e.g. a methyl group); or

[0349] R 9 , R 10 and R 13 Each of represents hydrogen, and R 11 and R 12 represents halogen (e.g. fluorine or chlorine); or

[0350] R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents a halogen (e.g., fluorine), and R 12 Represents C 1-6 an alkyl group (e.g. a methyl group); or

[0351] R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents a halogen (e.g., fluorine), and R 12 Represents halogenated C 1-6 Alkyl (eg fluoromethyl or trifluoromethyl); or

[0352] R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12 Represents halogenated C 1-6Alkyl (eg fluoromethyl or difluoromethyl); or

[0353] R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12 represents a halogen (e.g. chlorine); or

[0354] R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents a halogen (e.g., fluorine), and R 12 Represents C 1-6 an alkoxy group (such as a methoxy group); or

[0355] R 9 , R 11 and R 13 Each of represents hydrogen, and R 10 and R 12 represents halogen (e.g. fluorine); or

[0356] R 9 , R 10 and R 13 Each of R represents hydrogen, 11 Represents halogenated C 1-6 alkyl (e.g. trifluoromethyl), and R 12 represents a halogen (e.g. fluorine); or

[0357] R 9 , R 11 , R 12 and R 13 Each of represents hydrogen, and R 10 Represents C 1-6 an alkyl group (e.g. a methyl group); or

[0358] R 9 , R 12 and R 13 Each of represents hydrogen, and R 10 and R 11 All represent halogen (eg, fluorine or chlorine).

[0359] In another embodiment, Y represents -C(R 9 )=, and R 9 , R 12 and R 13 Each of represents hydrogen, and R 10 and R 11 All represent halogen (such as fluorine or chlorine), such as R 9 , R 12 and R 13Each of R represents hydrogen, 10 represents a halogen (e.g., chlorine), and R 11 represents a halogen (eg, fluorine).

[0360] In an alternative embodiment, Y represents -N=, and:

[0361] R 11 and R 13 Both represent hydrogen, R 10 Represents C 1-6 alkyl (eg, methyl), and R 12 Represents halogenated C 1-6 Alkyl (e.g. trifluoromethyl);

[0362] R 10 and R 11 connected to form a pyrroline ring, and R 12 and R 13 All represent hydrogen;

[0363] R 12 and R 13 Both represent hydrogen, R 10 Represents C 1-6 alkyl (eg, methyl), and R 11 represents a halogen (e.g., fluorine);

[0364] R 11 , R 12 and R 13 Each of represents hydrogen, and R 10 Indicates -NR m R n (e.g. -NH 2 , -NHMe or -NMe 2 );

[0365] R 12 and R 13 Both represent hydrogen, and R 10 and R 11 connected to form a pyrrolinyl, morpholinyl, furanyl or thienyl ring, which is optionally substituted with a methyl, fluoro or chloro group; or

[0366] R 13 Represents hydrogen, R 12 represents a halogen (e.g., chlorine), and R 10 and R 11 The pyrroline ring is optionally substituted with a methyl group.

[0367] In one embodiment that can be mentioned, Y represents -N=, and:

[0368] R 11 and R 13 Both represent hydrogen, R10 Represents C 1-6 alkyl (eg, methyl), and R 12 Represents halogenated C 1-6 Alkyl (eg trifluoromethyl); or

[0369] R 10 and R 11 connected to form a pyrroline ring, and R 12 and R 13 All represent hydrogen.

[0370] In one embodiment, Y represents -N=, and R 11 and R 13 Both represent hydrogen, R 10 Represents C 1-6 alkyl (eg, methyl), and R 12 Represents halogenated C 1-6 Alkyl (eg trifluoromethyl).

[0371] In one embodiment, the invention provides a compound of formula (I) which is the free base of a compound of Examples 1-245 or a pharmaceutically acceptable salt or solvate thereof.

[0372] In one illustrative embodiment, the present invention provides a compound of formula (I), which is a free base of a compound of Examples 1-163 or a pharmaceutically acceptable salt or solvate thereof.

[0373] In one illustrative embodiment, the present invention provides a compound of formula (I), which is a free base of a compound of Examples 1-167 or a pharmaceutically acceptable salt or solvate thereof.

[0374] In one embodiment, the compound of formula (I) is a compound other than Example 65.

[0375] In one embodiment, the compound of formula (I) is a compound other than Example 163.

[0376] In one embodiment, the compound of formula (I) is a compound other than Examples 65 and 163.

[0377] Reference to compounds of formula (I) and subgroups thereof also includes their ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms, such as described below; preferably, their salts or tautomers or isomers or N-oxides or solvates; more preferably, their salts or tautomers or N-oxides or solvates, and even more preferably, their salts or tautomers or solvates. Hereinafter, compounds as defined in any aspect of the present invention and their ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms (except for intermediate compounds in chemical processes) are referred to as "compounds of the present invention".

[0378] Salt

[0379] Some compounds of formula (I) may exist in the form of salts, for example acid addition salts or salts of organic and inorganic bases in some cases, such as carboxylates, sulfonates and phosphates. All these salts are within the scope of the present invention, and references to compounds of formula (I) include the salt forms of the compounds.

[0380] The salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods, such as those described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent or a mixture of the two; usually a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used.

[0381] Acid addition salts (mono or di-salts) can be formed with a variety of acids, including inorganic and organic acids. Examples of acid addition salts include mono or di-salts formed with acids selected from acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+) camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, galactaric acid, succinic ... acid), gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrohalogen acids (e.g., hydrobromic acid, hydrochloric acid, hydroiodic acid), isethionic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyruvic acid, L-pyroglutamic acid acid), salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid, as well as acylated amino acids and cation exchange resins.

[0382] A particular group of salts consists of salts formed with acetic, hydrochloric, hydroiodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylic), ethanesulfonic, naphthylsulfonic, valeric, acetic, propionic, butyric, malonic, glucuronic and lactobionic acids.

[0383] If the compounds of formula (I) contain amine functions, they can form quaternary ammonium salts, for example by reaction with alkylating agents according to methods well known to those skilled in the art. Such quaternary ammonium compounds fall within the scope of formula (I).

[0384] The compounds of the present invention may exist as mono- or di-salts, depending on the pK of the acid forming the salt. a .

[0385] It should be understood that for medical use, the salt of the compound of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts are obvious to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J.Pharm.Sci.1977, 66, pp.1-19. Such pharmaceutically acceptable salts include acid addition salts with inorganic acids and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, and organic acids such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthalenesulfonic acid. Other salts, such as oxalates or formates, can be used, for example, in the process of separating the compound of formula (I), and are included within the scope of the present invention. However, non-pharmaceutically acceptable salts can also be prepared into intermediate forms, which can then be converted into pharmaceutically acceptable salts. Such pharmaceutically unacceptable salts can be used, for example, to purify or separate the compounds of the present invention, and also constitute an integral part of the present invention.

[0386] Certain compounds of formula (I) may form acid addition salts with one or more equivalents of an acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0387] Solvate

[0388] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they react or precipitate or crystallize. These complexes are referred to as "solvates". For example, complexes with water are referred to as "hydrates". Pharmaceutically acceptable solvates of the compounds of the invention are within the scope of the invention. In one embodiment, pharmaceutically acceptable solvates of the compounds of the invention include hydrates thereof.

[0389] In one embodiment, the crystalline form of the compound of formula (I) is a co-crystal or co-former. Such co-crystals or co-formers can be prepared using water-soluble molecules such as saccharin, caffeine, nicotinamide or carboxylic acids. Co-formers can be prepared as described in Emami S et al. (2018) BioImpacts 8(4), 305-320, the techniques of which are incorporated herein by reference.

[0390] It will be understood that the present invention includes pharmaceutically acceptable derivatives of the compounds of formula (I) and that these are included within the scope of the invention.

[0391] As used herein, "pharmaceutically acceptable derivatives" include any pharmaceutically acceptable esters of a compound of formula (I) which, when administered to a recipient, is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.

[0392] N-oxides

[0393] Compounds of formula (I) comprising nitrogen containing functional groups / moieties may also form N-oxides. Reference herein to compounds of formula (I) comprising nitrogen containing functional groups / moieties also includes N-oxides.

[0394] If the compound contains several nitrogen containing functional groups / moieties, one or more nitrogen atoms may be oxidized to N-oxides. Specific examples of N-oxides are N-oxides of a nitrogen atom of a tertiary amine or a nitrogen containing heterocycle.

[0395] N-oxides can be formed by treating the corresponding nitrogen-containing functional group / moiety with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, e.g., Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience. More specifically, N-oxides can be prepared by the method of LW Deady (Syn. Commun. 1977, 7, 509-514), wherein a compound comprising a nitrogen-containing functional group / moiety is reacted with meta-chloroperoxybenzoic acid (mCPBA), e.g., in an inert solvent such as dichloromethane.

[0396] Prodrug

[0397] It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I) which may be prepared before the final deprotection stage may not themselves be pharmacologically active, but in some cases may be administered orally or parenterally, and then metabolized in vivo to form pharmacologically active compounds of the invention. Therefore, such derivatives may be described as "prodrugs". All these prodrugs of compounds of the invention are included within the scope of the invention. Examples of prodrug functional groups suitable for compounds of the invention are described in Drugs of Today, 19, 9, 1983, 499-538 and Topics in Chemistry, Chapter 31, pp. 306-316 and "Design of Prodrugs", H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in these documents are incorporated herein by reference). It will be further appreciated by those skilled in the art that certain parts referred to by those skilled in the art as "front-parts", such as those described by H. Bundgaard in "Design of Prodrugs" (the disclosures in these documents are incorporated herein by reference), when present in compounds of the invention, may be located on appropriate functional groups.

[0398] The compounds of the present invention also include their polymorphic forms within their scope.

[0399] Enantiomers

[0400] If there is a chiral center in the compound of formula (I), the present invention includes within its scope all possible enantiomers and diastereomers, including mixtures thereof. The different isomeric forms may be separated or resolved from each other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or stereospecific or asymmetric synthesis. The present invention also extends to any tautomeric form or mixtures thereof.

[0401] isotope

[0402] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are the same as those listed in formula (I), but one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0403] Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen such as 2 H(D) and 3 H(T); isotopes of carbon, such as 11 C. 13 C and 14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I. 125 I and 131 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O. 17 O and 18 O; isotopes of phosphorus, such as 32 P; and sulfur isotopes, such as 35 S.

[0404] Certain isotopically labeled compounds of formula (I), for example those containing radioactive isotopes, can be used in drug and / or substrate tissue distribution studies. Compounds of formula (I) can also have valuable diagnostic properties because they can be used to detect or identify the formation of complexes between labeled compounds and other molecules, peptides, proteins, enzymes or receptors. The detection or identification methods can use compounds labeled with labeling agents such as radioactive isotopes, enzymes, fluorescent materials, luminescent materials (e.g., luminol, luminol derivatives, fluorescein, aequorin and luciferase), etc. The radioactive isotope tritium, i.e. 3 H(T), and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and readily available means of detection.

[0405] Using heavier isotopes such as deuterium 2 H(D) substitution may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0406] Using positron-emitting isotopes (e.g. 11 C. 18 F. 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine target site occupancy.

[0407] Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0408] purity

[0409] Since it is contemplated that the compounds of formula (I) are used in pharmaceutical compositions, it will be readily appreciated that each of them is preferably provided in substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure, and preferably at least 85%, especially at least 98% pure (given as % by weight on a weight basis). Impure preparations of the compounds may be used to prepare purer forms for use in pharmaceutical compositions.

[0410] method

[0411] Another aspect of the present invention provides a method for preparing compounds of formula (I) and derivatives thereof. The following scheme is an example of a synthetic scheme that can be used to synthesize compounds of the present invention. In the following scheme, the reactive group can be protected with a protecting group and deprotected according to well-established techniques.

[0412] Another aspect of the present invention provides a process for preparing a compound of formula (I) as defined herein, the process comprising:

[0413] (a) making a compound of formula (II):

[0414]

[0415] Where R 1 , R 2 , R 3 , W, R 5 , X and R 7 As defined herein, reacting with a compound of formula (III):

[0416]

[0417] Where R 8 , Y, R 10 , R 11 , R 12 and R 13 As defined herein;

[0418] (b) making a compound of formula (IV):

[0419]

[0420] Where R 5 ,X,R 7 , R 8 , Y, R 10 , R 11 , R 12 and R 13 As defined herein, reacting with a compound of formula (V):

[0421]

[0422] Where R 1 , R 2 , R 3 and W are as defined herein, and L 1 represents a suitable leaving group, for example a halogen atom (e.g. chlorine);

[0423] (c) deprotecting a protected derivative of a compound of formula (I);

[0424] (d) interconverting a compound of formula (I) or a protected derivative thereof into another compound of formula (I) or a protected derivative thereof; and

[0425] (e) optionally forming a pharmaceutically acceptable salt of the compound of formula (I).

[0426] Process (a) typically comprises reacting a compound of formula (II) with a compound of formula (II) in the presence of a suitable reagent, for example EtOAc, pyridine and T3P.

[0427] Process (b) typically comprises reacting a compound of formula (IV) with a compound of formula (V) in the presence of a suitable reagent, such as DIPEA in NMP, under suitable conditions, such as heating to a suitable temperature (eg 100°C).

[0428] Compounds of formula (II) and (IV) can be prepared according to the methods described herein. For example, compounds of formula (II) can be prepared according to the experimental method described in Example 1, and compounds of formula (IV) can be prepared according to the experimental method described in Example 2.

[0429] The compounds of formula (III) and (V) are known or can be prepared by known methods.

[0430] Various well-known functional group interchanges of process (c) are known to those skilled in the art for converting precursors to compounds of formula (I) and are described in Advanced Organic Chemistry by Jerry March, 4th edition, John Wiley & Sons, 1992. For example, possible metal-catalyzed functionalizations, such as the use of organo-tin reagents (Stille reactions), Grignard reagents and reactions with nitrogen nucleophiles are described in 'Palladium Reagents and Catalysts' [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 1, Ei-ichi Negishi ed., Wiley, ISBN 0-471-31506-0].

[0431] The reactions described herein are followed or preceded, if appropriate, by one or more reactions known to those skilled in the art and carried out in a suitable order to achieve R as defined herein. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 The essential substitutions on the above give other compounds of formula (I). Non-limiting examples of such reactions whose conditions can be found in the literature include:

[0432] Protection of reactive functional groups;

[0433] Deprotection of reactive functional groups;

[0434] Halogenation;

[0435] Dehalogenation;

[0436] Dealkylation;

[0437] Alkylation or arylation of amines, anilines, alcohols, and phenols;

[0438] Mitsunobu reaction on hydroxyl groups;

[0439] Cycloaddition reactions on appropriate groups;

[0440] Reduction of nitro groups, esters, cyano groups, and aldehydes;

[0441] Transition metal-catalyzed coupling reactions;

[0442] Acylation;

[0443] Sulfonylation / introduction of sulfonyl groups;

[0444] saponification / hydrolysis of ester groups;

[0445] Amidation or transesterification of ester groups;

[0446] Esterification or amidation of carboxyl groups;

[0447] Halogen exchange;

[0448] nucleophilic substitution with amines, thiols, or alcohols;

[0449] Reductive amination;

[0450] Oxime formation on carbonyl and hydroxylamine groups;

[0451] S-oxidation;

[0452] N-oxidation;

[0453] Salinization.

[0454] It is recognized that the order of reactions involving aryl coupling and reduction may vary. It is also recognized that a wide range of palladium-based catalysts are suitable for carrying out aryl coupling reactions.

[0455] It will also be appreciated that isomer separation can occur at any suitable stage of the synthetic sequence. It should be emphasized that this chiral separation constitutes a key aspect of the present invention, and this separation can be performed according to the methods described herein or can be performed according to known methods. It is also appreciated that it may be beneficial to temporarily form protected derivatives of intermediates in the synthesis, for example, Boc-protected amines or SEM-protected amides, to facilitate chromatographic separation, chiral resolution, or to obtain improved solubility or yield in a particular step.

[0456] In many of the reactions described above, it may be necessary to protect one or more groups to prevent the reaction from occurring at undesired locations on the molecule. Examples of protecting groups and methods for protecting and deprotecting functional groups can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2007).

[0457] For example, a hydroxyl group may be protected as an ether (—OR) or an ester (—OC(═O)R), such as tert-butyl ether; tetrahydropyranyl (THP) ether; benzyl, diphenylmethyl (diphenylmethyl) or triphenylmethyl (triphenylmethyl) ether; trimethylsilyl or tert-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH 3 ).

[0458] Amine groups can be protected as amides (-NRCO-R) or carbamates (-NRCO-OR), for example, methyl amide (-NHCO-CH 3 ); benzyl carbamate (-NHCO-OCH 2 C 6 H 5 , -NH-Cbz or NH-Z); tert-butyl carbamate (-NHCO-OC(CH 3 ) 3 , -NH-Boc); 2-biphenyl-2-propyl carbamate (-NHCO-OC(CH 3 ) 2 C 6 H 4 C 6 H 5 , -NH-Boc), 9-fluorenylmethyl carbamate (-NH-Fmoc), 6-nitroveratryl carbamate (-NH-Nvoc), 2-trimethylsilylethyl carbamate (-NH-Teoc), 2,2,2-trichloroethyl carbamate (-NH-Troc), allyl carbamate (-NH-Alloc), or 2-(phenylsulfonyl)ethyl carbamate (-NH-Psec).

[0459] Other protecting groups for amines, such as cyclic amines and heterocyclic NH groups include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl), benzyl groups such as p-methoxybenzyl (PMB), and tetrahydropyranyl (THP).

[0460] The carboxylic acid group can be protected as an ester, for example: C 1-7 Alkyl ester (eg methyl ester; tert-butyl ester); C 1-7 Haloalkyl esters (e.g. 1-7 trihaloalkyl ester); triC 1-7 Alkylsilyl-C 1-7 Alkyl ester; or C 5-20 Aryl-C 1-7 Alkyl esters (e.g., benzyl esters; nitrobenzyl esters; p-methoxybenzyl esters.

[0461] Those skilled in the art will appreciate that certain compounds of the invention can be converted to other compounds of the invention according to standard chemical methods.

[0462] Pharmaceutically acceptable salts can be conventionally prepared by reaction with a suitable acid or acid derivative.

[0463] Therapeutic Uses

[0464] The compounds of the present invention, its subgroups and embodiments thereof are inhibitors of Pol θ polymerase activity and can be used to prevent or treat disease states or conditions described herein. In addition, the compounds of the present invention and its subgroups will be used to prevent or treat diseases or conditions mediated by Pol θ. Prevention or prevention or treatment of disease states or conditions such as cancer includes within its scope the reduction or reduction of the incidence of cancer.

[0465] Thus, for example, the compounds of the invention are expected to be useful in ameliorating or reducing the incidence of cancer.

[0466] The compounds of the present invention may be used to treat the adult population. The compounds of the present invention may be used to treat the pediatric population.

[0467] Due to their inhibitory effect on Pol θ, these compounds can be used to provide a method of rendering cells incapable of performing MMEJ. Therefore, it is expected that these compounds may prove useful in treating or preventing proliferative diseases, such as cancer. In addition, the compounds of the invention may be used to treat diseases where there is a disorder associated with cell accumulation.

[0468] Without being bound by theory, it is expected that the Pol θ inhibitors of the present invention exhibit certain properties that make them particularly useful in the treatment of certain cancers. For example, in one embodiment, the Pol θ inhibitors of the present invention are moderately lethal in BRCA1 and BRCA2 deficient primary and secondary solid tumors, including breast, ovarian, prostate, and pancreatic.

[0469] In another embodiment, the Polθ inhibitors of the invention have moderate lethality in a variety of primary and secondary solid tumors that are HRD by mechanisms other than BRCA deficiency, such as those with promoter hypermethylation. In these tumors where no DSB repair pathways may be completely downregulated, Polθi may be administered together with another DDR modulator such as a PARP inhibitor, DNA-PK inhibitor, ATR inhibitor, ATM inhibitor, wee1 inhibitor, or CHK1 inhibitor.

[0470] In another embodiment, the Polθ inhibitors of the invention are moderately lethal in primary and secondary breast, ovarian, prostate, and pancreatic tumors that retain BRCA1 deficiency but are resistant to PARPi treatment with or without exposure to PARPi drugs.

[0471] In another embodiment, the Polθ inhibitors of the present invention appropriately increase the ORR, including CRR, will delay the onset of PARPi resistance, will increase the time to relapse and DFS, and will increase the OS of HRD (BRCA1 / 2 deficiency and other HRD mechanisms) primary and secondary tumors (breast, ovarian, prostate and pancreatic) when administered with a PARPi treatment regimen.

[0472] In another embodiment, the Polθ inhibitors of the present invention have ATM activity (ATM - / - ) are lost, particularly in the case of WT p53, and synthetic sickness and / or synthetic lethality are appropriately displayed. Tumor types include approximately 10% of all solid tumors, including gastric, lung, breast and CRC, as well as CLL. This activity can be further enhanced by co-administration with another DDR modulator, such as a DNA-PK inhibitor, a PARP inhibitor or an ATR inhibitor. Polθ inhibitors resensitize CLL to typical chemotherapy and chemoimmunotherapy to which resistance has emerged. Therefore, according to another embodiment, the pharmaceutical composition of the present invention further comprises a DNA-PK inhibitor, a PARP inhibitor or an ATR inhibitor.

[0473] In another embodiment, the Polθ inhibitors of the present invention appropriately show synthetic disease and / or synthetic lethality in a variety of tumors defective in the DNA double-strand break repair process of non-homologous end joining (NHEJ-D). Tumor types include approximately 2-10% of all solid tumors, including prostate, pancreas, cervix, breast, lung, bladder, and esophagus. This activity can be further enhanced by co-administration with another DDR regulator, such as a PARP inhibitor, an ATM inhibitor, a wee1 inhibitor, a CHK inhibitor, or an ATR inhibitor. Polθ inhibitors further sensitize NHEJD cancer cells to DNA DSB-inducing chemotherapy and ionizing radiation-based therapies. Therefore, according to another embodiment, the pharmaceutical composition of the present invention also comprises a PARP inhibitor, an ATM inhibitor, a wee1 inhibitor, a CHK inhibitor, or an ATR inhibitor.

[0474] In another embodiment, the Polθ inhibitor of the present invention appropriately reduces the DNA replication stress response during chemotherapy of HR-effective (HR proficient) tumors such as breast, ovarian, and NSCL tumors that overexpress Polθ. This will increase the ORR to treatment and increase OS. This effect may be particularly related to cytarabine (Ara-C) and hydroxyurea used for a wide range of leukemias including CML and treatment of squamous cell carcinoma.

[0475] In another embodiment, the Polθ inhibitors of the invention appropriately selectively sensitize solid tumors to radiation therapy, including EBRT and brachytherapy and radioligand-based therapies, while leaving normal tissues with little or no sensitivity. In fractionated curative-intent situations, this will increase locoregional control, driving increased survival. This is particularly evident in the treatment of NSCLC, SCCH&N, colorectal cancer, prostate cancer, and pancreatic cancer.

[0476] In another embodiment, the Polθ inhibitors of the present invention appropriately show synthetic disease and / or synthetic lethality in PTEN-deficient tumors such as CaP, whether or not co-administered with PARPi. In addition, through PTEN deficiency and the radiosensitivity induced by Polθ inhibitors, such tumors will show extremely high sensitivity to radiotherapy.

[0477] In another embodiment, the Pol θ inhibitors of the invention appropriately inhibit TLS polymerase activity, sensitize primary and secondary solid tumors (e.g., breast, lung, ovarian, CRC) to drugs (e.g., cisplatin, mitomycin and cyclophosphamide) and reduce the acquisition of drug-induced mutations that are involved in tumor resistance, resulting in prolonged remission and increased TTR.

[0478] In another embodiment, the Pol θ inhibitors of the invention appropriately resensitize BCR-ABL-positive CML that has developed imatinib resistance, as well as other solid tumors with elevated ligase IIIα levels, decreased ligase IV levels, and increased dependency on altEJDSB repair.

[0479] In another embodiment, Pol θ inhibitors of the invention suitably exhibit synthetic disease and / or synthetic lethality in aromatase inhibitor-resistant ER-primary and secondary breast cancers that also exhibit elevated ligase IIIα levels, decreased ligase IV levels, and increased dependency on altEJ DSB repair.

[0480] Another aspect of the invention provides a compound of formula (I) as defined herein for use in the treatment of a tumour characterised by homologous recombination (HRD) deficiency.

[0481] It should be understood that "homologous recombination deficiency (HRD)" referred to herein refers to any genetic variation that results in a defect or loss of homologous recombination gene function. Examples of such genetic variations include mutations (e.g., point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosomal abnormalities, copy number variations (CNVs), epigenetics, DNA inversions, reduced expression, and misplaced distributions.

[0482] In one embodiment, the homologous recombination gene is selected from any one of the following: ATM, ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), PTEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4, LIG1, RPA1, RPA2, BRIP1 and PTEN.

[0483] It should be understood that "non-homologous end joining deficiency (NHEJD)" referred to herein refers to any genetic variation that results in a defect or loss of function of the resulting homologous recombination gene. Examples of the genetic variation include mutations (e.g., point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosomal abnormalities, copy number variations (CNVs), epigenetics, DNA inversions, reduced expression, and misplaced distributions.

[0484] In one embodiment, the non-homologous end joining gene is selected from any one or more of the following: LIG4, NHEJ1, POLL, POLM, PRKDC, XRCC4, XRCC5, XRCC6 and DCLRE1C.

[0485] Another aspect of the invention provides a compound of formula (I) as defined herein for use in treating a tumour overexpressing Polθ.

[0486] Another aspect of the invention provides a compound of formula (I) as defined herein for use in treating a tumour having elevated ligase IIIa levels, reduced ligase IV levels and increased dependency on altEJ DSB repair.

[0487] Examples of cancers (and their benign counterparts) that may be treated (or inhibited) include, but are not limited to, tumors of epithelial origin (adenomas and carcinomas of various types, including adenocarcinomas, squamous cell carcinomas, transitional cell carcinomas, and other carcinomas), such as bladder and urinary tract cancer, breast cancer, gastrointestinal cancer (including esophageal cancer, stomach / gastric cancer, small intestine cancer, colon cancer, rectal cancer, and anal cancer), liver cancer (hepatocellular carcinoma), gallbladder cancer and cancer of the biliary system, exocrine pancreatic cancer, kidney cancer, lung cancer (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung cancer, bronchioloalveolar carcinoma, and pulmonary carcinoma). carcinoma and mesothelioma), head and neck cancer (e.g., tongue cancer, buccal cancer, laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, tonsil cancer, salivary gland cancer, nasal cancer, and paranasal sinus cancer), ovarian cancer, fallopian tube cancer, peritoneal cancer, vaginal cancer, vulvar cancer, penis cancer, cervical cancer, myometrial cancer, endometrial cancer, thyroid cancer (e.g., follicular thyroid cancer), adrenal gland cancer, prostate cancer, skin cancer, and adnexal cancer (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic naevus); hematological malignancies (i.e., leukemias, lymphomas) and premalignant hematological disorders and disorders of borderline malignancies malignancy), including hematologic malignancies and conditions of the lymphoid lineage (e.g., acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, MALT lymphoma, T-cell lymphomas and leukemias, natural killer [NK]-cell lymphoma, Hodgkin's lymphoma, hairy cell leukemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorder), and hematologic malignancies and conditions of the myeloid lineage (e.g., acute myeloid leukemia [AML], chronic myeloid leukemia [CML], chronic myelomonocytic leukemia [CMML / chronic myelomonocyticleukemia], hypereosinophilic syndrome, myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia);Tumors of mesenchymal origin, such as sarcomas of soft tissue, bone, or cartilage, such as osteosarcoma, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma, Kaposi sarcoma, Ewing's sarcoma, synovial sarcoma, epithelioid sarcoma, gastrointestinal stromal tumors, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans protuberans); tumors of the central or peripheral nervous system (e.g., astrocytomas, gliomas and glioblastomas, meningiomas, ependymomas, pinealomas, and schwannomas); endocrine tumors (e.g., pituitary tumors, adrenal tumors, pancreatic islet cell tumors, parathyroid tumors, carcinoid tumors, and medullary thyroid carcinoma); ocular and adnexal tumors (e.g., retinoblastoma); germ cell and trophoblastic tumors (e.g., teratomas, seminoma, dysgerminoma, hydatidiform mole, and choriocarcinoma); and pediatric and embryonal tumors (e.g., medulloblastoma, neuroblastoma, Wilms tumor, and primitive neuroectodermal tumor); or congenital or other syndromes that predispose a patient to malignancy (e.g., xeroderma pigmentosum).

[0488] Many diseases are characterized by persistent and dysregulated angiogenesis. Chronic proliferative diseases are often accompanied by significant angiogenesis, which can lead to or maintain an inflammatory and / or proliferative state, or which can cause tissue destruction via invasive proliferation of blood vessels. It has been found that tumor growth and metastasis are angiogenesis-dependent. The compounds of the present invention can therefore be used to prevent and disrupt the initiation of tumor angiogenesis. In particular, the compounds of the present invention can be used to treat metastatic lesions and metastatic cancers.

[0489] Metastasis or metastatic disease is the spread of disease from one organ or part to another non-adjacent organ or part. Cancers that can be treated with the compounds of the invention include primary tumors (i.e., cancer cells at the site of origin), locally invasive (cancer cells penetrate and infiltrate surrounding normal tissues in a local area) and metastatic (or secondary) tumors, i.e., tumors formed by malignant cells that circulate through the bloodstream (hematogenous spread) or through lymphatic vessels or through body cavities (transcavitary) to other parts and tissues of the body.

[0490] Particular cancers include hepatocellular carcinoma, melanoma, esophageal cancer, renal cancer, colon cancer, colorectal cancer, lung, such as mesothelioma or lung adenocarcinoma, breast cancer, bladder cancer, gastrointestinal cancer, ovarian cancer, and prostate cancer.

[0491] Another aspect provides the use of a compound in the preparation of a medicament for treating a disease or condition as described herein, particularly cancer.

[0492] The compounds may also be used to treat tumor growth, pathogenesis, resistance to chemotherapy and radiotherapy by sensitizing cells to chemotherapy and as antimetastatic agents.

[0493] The efficacy of the compounds of the invention as Pol θ inhibitors can be measured using the biological and biophysical assays set forth in the Examples herein, and the level of affinity exhibited by a given compound can be measured based on the IC 50 The specific compounds of the present invention are those having IC 50 Compounds having a value of less than 1 μM, more particularly less than 0.1 μM.

[0494] WO 2017 / 062754 describes the effect of loss of Polθ in enhancing the efficacy of CRISPR-mediated gene editing. Therefore, Polθ inhibitory compounds may help to enhance the efficiency of CRISPR-based editing methods and / or CRISPR-based editing treatments. In addition, compound-mediated Polθ inhibition may reduce the frequency of random integration events, thereby providing a way to improve any safety issues of CRISPR-mediated technology. Therefore, another aspect of the present invention provides the use of a compound of formula (I) as defined herein in a CRISPR-based editing method and / or a CRISPR-based editing treatment, for example, enhancing the efficiency of a CRISPR-based editing method and / or a CRISPR-based editing treatment.

[0495] Pharmaceutical composition

[0496] While it is possible to administer the active compound alone, it is preferably presented as a pharmaceutical composition (eg formulation). In one embodiment, this is a sterile pharmaceutical composition.

[0497] Therefore, the present invention also provides pharmaceutical compositions as defined above, and methods for preparing pharmaceutical compositions, said pharmaceutical compositions comprising (e.g., mixed with) at least one compound of formula (I) (and subgroups thereof as defined herein), and one or more pharmaceutically acceptable excipients and optionally other therapeutic or prophylactic agents as described herein.

[0498] One or more pharmaceutically acceptable excipients can be selected from, for example, carriers (for example, solid, liquid or semisolid carriers), adjuvants, diluents, fillers or extenders, granulating agents, coating agents, release control agents, adhesives, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickeners, flavoring agents, sweeteners, taste masking agents, stabilizers or any other excipients conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are described in more detail below.

[0499] The term "pharmaceutically acceptable" as used herein relates to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of subjects (e.g., humans) without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0500] Pharmaceutical compositions containing compounds of formula (I) may be formulated according to known techniques, see for example Remington's Pharmaceutical Science, Mack Publishing Company, Easton, PA, USA.

[0501] The pharmaceutical composition can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, auricular, rectal, intravaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery to a target organ or target tissue by injection, infusion or other delivery means. The delivery can be by push, short-term infusion or longer-term infusion and can be delivered via passive delivery or via utilizing a suitable infusion pump or syringe driver.

[0502] Pharmaceutical preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, cosolvents, surfactants, organic solvent mixtures, cyclodextrin complexing agents, emulsifiers (for forming and stabilizing emulsion preparations), liposome components for forming liposomes, gelling polymers for forming polymer gels, lyoprotectants, and combinations of agents, in particular, for stabilizing the active ingredient in soluble form and making the preparation isotonic with the blood of the intended recipient. Pharmaceutical preparations for parenteral administration may also be in the form of aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents (RG Strickly, Solubilizing Excipients inoral and injectable formulations, Pharmaceutical Research, Vol. 21(2) 2004, pp. 201-230).

[0503] The formulation can be present in single-dose or multi-dose containers such as sealed ampoules, vials and prefilled syringes, and can be stored in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. In one embodiment, the formulation is provided in a bottle as an active pharmaceutical ingredient for subsequent reconstitution with an appropriate diluent.

[0504] The pharmaceutical formulation may be prepared by lyophilizing a compound of formula (I) or a subgroup thereof. Lyophilization refers to the process of freeze drying a composition. Therefore, freeze drying and lyophilization are used as synonyms herein.

[0505] Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

[0506] The pharmaceutical compositions of the present invention for parenteral injection may also include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use.

[0507] Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (e.g., sunflower oil, safflower oil, corn oil or olive oil) and injectable organic esters, such as ethyl oleate. For example, appropriate fluidity can be maintained by the use of thickening or coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by the use of surfactants.

[0508] Compositions of the present invention may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. Can be ensured to prevent the action of microorganisms by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include tonicity agents, such as sugar, sodium chloride, etc. Can be extended to absorb injectable drug forms by including delayed absorption agents such as aluminum monostearate and gelatin.

[0509] In a specific embodiment of the present invention, the pharmaceutical composition is in a form suitable for iv administration, such as by injection or infusion. For intravenous administration, the solution can be administered as is or can be injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or 5% glucose) before administration.

[0510] In another specific embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (sc) administration.

[0511] Suitable pharmaceutical dosage forms for oral administration include tablets (coated or uncoated), capsules (hard shell or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0512] Thus, tablet compositions may contain a unit dose of active compound with an inert diluent or carrier, such as a sugar or sugar alcohol, for example: lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent, such as calcium carbonate, calcium phosphate, calcium carbonate, or cellulose or derivatives such as microcrystalline cellulose (MCC), methylcellulose or ethylcellulose, hydroxypropyl methylcellulose, and starch such as corn starch. Tablets may also contain standard ingredients as binding and granulating agents such as polyvinyl pyrrolidone, disintegrants (e.g., swellable cross-linked polymers such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and need not be discussed in detail herein.

[0513] Tablets may be designed to release the drug upon contact with gastric fluid (immediate release tablets) or in a controlled manner over a longer period of time or in a specific area of ​​the gastrointestinal tract (controlled release tablets).

[0514] Capsule formulations may be of hard or soft gelatin variety and may contain the active ingredient in solid, semisolid, or liquid form. Gelatin capsules may be formed from animal gelatin or its synthetic or plant-derived equivalents.

[0515] Solid dosage forms (e.g., tablets, capsules, etc.) may be coated or uncoated. Coatings may serve as protective films (e.g., polymers, waxes, or varnishes) or as mechanisms for controlling drug release or for aesthetic or identification purposes. Coatings (e.g., Eudragit TM Type polymers) can be designed to release the active ingredient at a desired location in the gastrointestinal tract. Thus, the coating can be selected to degrade under certain pH conditions in the gastrointestinal tract, thereby selectively releasing the compound in the stomach or in the ileum, duodenum, jejunum or colon.

[0516] In place of or in addition to coating, the drug may be present in a solid matrix comprising a release control agent, such as a release delay agent, which may be suitable for releasing the compound in a controlled manner in the gastrointestinal tract. Alternatively, the drug may be present in a polymer coating, such as a polymethacrylate polymer coating, which may be suitable for selectively releasing the compound under conditions of acidity or alkalinity that vary in the gastrointestinal tract. Alternatively, the matrix material or release delay coating may be in the form of an erodible polymer (such as a maleic anhydride polymer) that is substantially continuously eroded when the dosage form passes through the gastrointestinal tract. In another alternative, the coating may be designed to disintegrate under the action of microorganisms in the intestinal tract. As another alternative, the active compound may be formulated in a delivery system that provides an osmotic control of the compound release. Osmotic release and other delayed release or sustained release formulations (such as formulations based on ion exchange resins) may be prepared according to methods known to those skilled in the art.

[0517] Formula (I) compound can be formulated with carrier and applied in the form of nanoparticles, the increased surface area of ​​nanoparticles contributes to their absorption. In addition, nanoparticles provide the possibility of penetrating directly into cells. Nanoparticle drug delivery system is described in "Nanoparticle Technology for Drug Delivery", Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published on March 13, 2006. Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91 (1-2), 167-172; and Sinha et al., Mol. Cancer Ther. August 1, (2006) 5, 1909.

[0518] The pharmaceutical composition generally comprises about 1% (w / w) to about 95% active ingredient and 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient or combination of excipients. Specifically, the composition comprises about 20% (w / w) to about 90% (w / w) of an active ingredient and 80% (w / w) to 10% of a pharmaceutically acceptable excipient or combination of excipients. The pharmaceutical composition comprises about 1% to about 95%, specifically about 20% to about 90% of an active ingredient. The pharmaceutical composition according to the present invention can be, for example, in the form of a unit dosage form such as an ampoule, a vial, a suppository, a prefilled syringe, a dragee, a tablet or a capsule.

[0519] One or more pharmaceutically acceptable excipients may be selected according to the desired physical form of the formulation and may, for example, be selected from diluents (e.g., solid diluents such as fillers or extenders; and liquid diluents such as solvents and co-solvents), disintegrants, buffers, lubricants, glidants, release controlling agents (e.g., release retarding or delaying polymers or waxes), binders, granulating agents, pigments, plasticizers, antioxidants, preservatives, flavoring agents, taste masking agents, tonicity adjusting agents, and coating agents.

[0520] Those skilled in the art will have the expertise to select the appropriate amount of ingredients for the formulation. For example, tablets and capsules typically contain 0%-20% disintegrant, 0%-5% lubricant, 0%-5% glidant and / or 0%-99% (w / w) filler / or extender (depending on the drug dose). They may also contain 0%-10% (w / w) polymer binder, 0%-5% (w / w) antioxidant, 0%-5% (w / w) pigment. Slow release tablets will additionally contain 0%-99% (w / w) release controlling (e.g., delayed) polymer (depending on the dose). The film coating of a tablet or capsule typically contains 0%-10% (w / w) polymer, 0%-3% (w / w) pigment, and / or 0%-2% (w / w) plasticizer.

[0521] Parenteral formulations typically contain 0%-20% (w / w) buffer, 0%-50% (w / w) cosolvent, and / or 0%-99% (w / w) water for injection (WFI) (depending on the dose and whether it is lyophilized). Formulations for intramuscular depots may also contain 0%-99% (w / w) oil.

[0522] Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with a solid carrier, granulating the resulting mixture if necessary, and processing the mixture into tablets, dragee cores or capsules after adding suitable excipients if necessary or necessary. They can also be incorporated into a polymer or wax matrix to diffuse or release the active ingredient in a measurable amount.

[0523] The compounds of the present invention can also be formulated into solid dispersions. Solid dispersions are uniform, finely dispersed phases of two or more solids. Solid solutions (molecular dispersion systems) are a type of solid dispersions, which are well known for use in pharmaceutical technology (see (Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300 (1971)), and can be used to increase dissolution rate and increase the bioavailability of poorly water-soluble drugs.

[0524] The present invention also provides a solid dosage form comprising the above-mentioned solid solution. Solid dosage forms include tablets, capsules, chewable tablets and dispersible tablets or effervescent tablets. Known excipients can be blended with the solid solution to obtain the desired dosage form. For example, a capsule can contain a solid solution blended with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. In addition, a capsule can contain a filler, such as lactose or microcrystalline cellulose. Tablets can contain a solid solution blended with at least one disintegrant, a lubricant, a surfactant, a filler and a glidant. Chewable tablets can contain a solid solution blended with a filler, a lubricant and, if desired, another sweetener (e.g., an artificial sweetener) and a suitable flavor. The solid solution can also be formed by spraying a drug and a suitable polymer solution onto the surface of an inert carrier such as sugar beads ("non-pareils"). These beads can then be filled into capsules or pressed into tablets.

[0525] Drug preparations may be given to patients in a "patient pack" that contains the entire course of treatment in a single package, usually a blister pack. Patient packs are superior to traditional prescriptions (where the pharmacist separates the patient's supply of medication from the bulk supply) because the patient always has access to the package insert included in the patient pack, which is often missing from patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with physician orders.

[0526] Compositions for topical use and nasal delivery include ointments, creams, sprays, patches, gels, drops and inserts (eg, intraocular inserts). Such compositions can be formulated according to known methods.

[0527] Examples of formulations for rectal or intravaginal administration include pessaries and suppositories, which may be formed, for example, from shaped moldable or waxy materials containing the active compound. Solutions of the active compound may also be used for rectal administration.

[0528] Compositions for administration by inhalation can take the form of inhalable powder compositions or liquid or powder sprays and can be administered in standard form using dry powder inhalation devices or aerosol dispensing devices. Such devices are well known. For example, for administration by inhalation, powdered formulations typically comprise the active compound with an inert solid powdered diluent such as lactose.

[0529] The compound of formula (I) is usually present in a unit dosage form, and in this regard usually contains enough compound to provide the desired level of biological activity. For example, the formulation can contain 1 nanogram to 2 grams of active ingredient, such as 1 nanogram to 2 milligrams of active ingredient. Within these ranges, a specific subrange of the compound is 0.1 milligram to 2 grams of active ingredient (more generally 10 milligrams to 1 gram, such as 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (e.g. 1 microgram to 10 milligrams, such as 0.1 milligram to 2 milligrams of active ingredient).

[0530] For oral compositions, unit dosage forms may contain 1 mg to 2 g, more typically 10 mg to 1 g, for example 50 mg to 1 g, for example 100 mg to 1 g, of active compound.

[0531] The active compound will be administered to a patient (eg, a human or animal patient) in need thereof in an amount sufficient to achieve the desired therapeutic effect.

[0532] Treatment

[0533] The compounds of formula (I) and subgroups defined herein can be used to prevent or treat a range of disease states or conditions mediated by Pol θ. Therefore, another aspect of the invention provides a method for treating a disease state or condition mediated by Pol θ (e.g., cancer), the method comprising administering a compound of formula (I) as described herein to a subject in need thereof. Examples of such disease states and conditions are as described above, and in particular include cancer.

[0534] The compounds are typically administered to a subject in need of such administration, such as a human or animal patient, particularly a human.

[0535] The compounds are generally administered in amounts useful for treatment or prevention and are generally non-toxic. However, in certain circumstances (e.g., in the case of life-threatening diseases), the benefits of administering a compound of formula (I) may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer an amount of the compound associated with a certain toxicity.

[0536] The compounds may be administered chronically to maintain a beneficial therapeutic effect, or may be administered only short term. Alternatively, they may be administered in a continuous manner or in a manner providing intermittent administration (eg, pulsed manner).

[0537] A typical daily dose of a compound of formula (I) may be between 100 pg and 100 mg / kg body weight, more typically between 5 ng and 25 mg / kg body weight, and more typically between 10 ng and 15 mg / kg (e.g., between 10 ng and 10 mg, and more typically between 1 mg / kg and 20 mg / kg, e.g., between 1 mg and 10 mg / kg) / kg body weight, although higher or lower doses may be used if desired. A compound of formula (I) may be used on a daily or repeated basis, e.g., every 2 or 3 or 4 or 5 or 6 or 7 or 10 or 14 or 21 or 28 days.

[0538] The compound of the present invention can be administered orally in a certain dosage range, such as 1-1500mg, 2-800mg or 5-500mg, such as 2-200mg or 10-1000mg, and specific dosage examples include 10, 20, 50 and 80mg. The compound can be administered once or more than once a day, for example, a suitable dosage regimen may require 1000mg-1500mg, 2 or 3 times a day. The compound can be administered continuously (i.e., taken every day without interruption during the treatment regimen). Alternatively, the compound can be administered intermittently (i.e., taken continuously for a specified period of time within the period of the entire treatment regimen, such as one week, then stopped for a period of time, such as one week, and then taken continuously for another period of time such as one week, etc.). Examples of treatment regimens involving intermittent administration include regimens in which administration is in cycles of one week on, one week off; or two weeks on, one week off; or three weeks on, one week off; or two weeks on, two weeks off; or four weeks on, two weeks off; or one week on, three weeks off, for one or more cycles, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more cycles.

[0539] In a specific dosing regimen, the patient is given an infusion of a compound of formula (I) for a duration of one hour per day for up to ten days, particularly up to five days, for a week, and the treatment is repeated at desired intervals, for example every two to four weeks, particularly every three weeks.

[0540] More specifically, the compound of formula (I) may be administered to the patient by infusion for a period of 1 hour daily for 5 days, with the treatment being repeated every three weeks.

[0541] In another specific dosing regimen, the patient is given an infusion over 30 minutes to 1 hour, followed by a maintenance infusion for a variable period of time, such as 1-5 hours, for example 3 hours.

[0542] In another specific dosing regimen, the patient is given a continuous infusion for 12 hours to 5 days, particularly a continuous infusion for 24 hours to 72 hours.

[0543] In another specific dosing regimen, the compound is administered orally to the patient once a week.

[0544] In another specific dosing regimen, the compound is administered orally to a patient once daily for 7-28 days, such as 7, 14 or 28 days.

[0545] In another specific dosing regimen, the compound is administered orally once daily to a patient for 1 day, 2 days, 3 days, 5 days or 1 week, followed by rest days as needed to complete a one or two week cycle.

[0546] In another specific dosing regimen, the compound is administered orally once daily to a patient for 2 weeks, followed by a 2 week rest period.

[0547] In another specific dosing regimen, the compound is administered orally once daily to a patient for 2 weeks followed by a 1 week rest period.

[0548] In another specific dosing regimen, the compound is administered orally once daily to a patient for 1 week, followed by 1 week rest.

[0549] However, the ultimate amount of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be determined by the clinician.

[0550] It will be appreciated that Pol 0 inhibitors may be used as single agents or in combination with other anticancer agents. Combination experiments may be performed, for example as described in Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regulat 1984; 22: 27-55.

[0551] The compounds defined herein may be administered as a single therapeutic agent, or they may be administered in combination therapy with one or more other compounds (or therapies) to treat a particular disease state, such as a neoplastic disease, such as cancer as defined above. For the treatment of the above-mentioned conditions, the compounds of the invention may advantageously be used in combination with one or more other agents, more specifically, with other anticancer agents or adjuvants (supporting agents in therapy) in cancer therapy. Examples of other therapeutic agents or treatments that may be administered together with the compounds of formula (I) (whether simultaneously or at different time intervals) include, but are not limited to:

[0552] Topoisomerase I inhibitors

[0553] Antimetabolites

[0554] Tubulin targeting agents

[0555] DNA binding agents and topoisomerase II inhibitors

[0556] Alkylating agent

[0557] Monoclonal antibodies

[0558] Antihormonal agents

[0559] Signal transduction inhibitors

[0560] Proteasome inhibitors

[0561] DNA methyltransferase inhibitors

[0562] Cytokines and retinoids

[0563] Chromatin-targeted therapy

[0564] Radiation therapy, and

[0565] Other therapeutic or prophylactic agents.

[0566] Specific examples of anticancer agents or adjuvants (or their salts) include, but are not limited to, any agent selected from the following groups (i) to (xlvi) and optionally group (xlvii):

[0567] (i) a platinum compound, such as cisplatin (optionally in combination with amifostine), carboplatin or oxaliplatin;

[0568] (ii) Taxane compounds, such as paclitaxel, paclitaxel protein-bound particles (Abraxane TM ), docetaxel, cabazitaxel, or larotaxel;

[0569] (iii) topoisomerase I inhibitors, such as camptothecin compounds, such as camptothecin, irinotecan (CPT11), SN-38, or topotecan;

[0570] (iv) topoisomerase II inhibitors, such as antitumor epipodophyllotoxin or podophyllotoxin derivatives, such as etoposide or teniposide;

[0571] (v) vinca alkaloids, for example vinblastine, vincristine, Onco-TCS, vinorelbine, vindesine, vinflunine or vinvesir;

[0572] (vi) nucleoside derivatives, such as 5-fluorouracil (5-FU, optionally in combination with leucovorin), gemcitabine, capecitabine, tegafur, UFT, S1, cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine, or nelarabine;

[0573] (vii) antimetabolites, such as clofarabine, aminopterin, or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine, thiopurine, 6-mercaptopurine, or hydroxyurea (hydroxycarbamide);

[0574] (viii) alkylating agents, such as nitrogen mustards or nitrosoureas, for example cyclophosphamide, chlorambucil, carmustine (BCNU), bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), altretamine, busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil, mechlorethamine, methylcyclohexylchloroethylnitrosourea, or nimustine (ACNU);

[0575] (ix) anthracyclines, anthracenediones and related drugs, such as daunorubicin, doxorubicin (optionally in combination with dexrazoxane), liposomal formulations of doxorubicin (e.g. Caelyx TM 、Myocet TM , Doxil TM ), idarubicin, mitoxantrone, epirubicin, amsacrine, or valrubicin;

[0576] (x) an epothilone, such as ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO, epothilone A, epothilone B, deoxyepothilone B (also known as epothilone D or KOS-862), azaepothilone B (also known as BMS-247550), aulimalide, isolaulimalide, or luetherobin;

[0577] (xi) DNA methyltransferase inhibitors, such as temozolomide, azacytidine or decitabine, or SGI-110;

[0578] (xii) antifolates, such as methotrexate, pemetrexed disodium, or raltitrexed;

[0579] (xiii) cytotoxic antibiotics, for example, antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, or mithramycin;

[0580] (xiv) tubulin binding agents, such as combrestatin, colchicine or nocodazole;

[0581] (xv) signal transduction inhibitors, such as kinase inhibitors (e.g., EGFR (epidermal growth factor receptor) inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, MTKI (multi-targeted kinase inhibitors), Raf inhibitors, mTOR inhibitors such as imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, temsirolimus, everolimus) (RAD 001), vemurafenib (PLX4032 or RG7204), dabrafenib, encorafenib, or IκB kinase inhibitors such as SAR-113945, bardoxolone, BMS-066, BMS-345541, IMD-0354, IMD-2560, or IMD-1041, or MEK inhibitors such as selumetinib (AZD6244) and trametinib (Selumetinib) (GSK121120212);

[0582] (xvi) Aurora kinase inhibitors, such as AT9283, barasertib (AZD1152), TAK-901, MK0457 (VX680), cenisertib (R-763), danusertib (PHA-739358), alisertib (MLN-8237), or MP-470;

[0583] (xvii) CDK inhibitors, such as AT7519, roscovitine, seliciclib, avocidib (flavopiridol), dinaciclib (SCH-727965), 7-hydroxy-staurosporine (UCN-01), JNJ-7706621, BMS-387032 (also known as SNS-032), PHA533533, PD332991, ZK-304709, or AZD-5438;

[0584] (xviii) PKA / B inhibitors and PKB (akt) pathway inhibitors, for example, AKT inhibitors such as KRX-0401 (perifosin / NSC 639966), ipatasertib (GDC-0068; RG-7440), afuresertib (GSK-2110183; 2110183), MK-2206, MK-8156, AT13148, AZD-5363, triciribine phosphate ( phosphate) (VQD-002; triciribine phosphate monohydrate (API-2; TCN-P; TCN-PM; VD-0002), RX-0201, NL-71-101, SR-13668, PX-316, AT13148, AZ-5363, Semaphore, SF1126, or enzastaurin HCl (LY317615), or MTOR inhibitors such as rapamycin analogs, such as RAD 001 (everolimus), CCI 779 (temsirolimus), AP23573, and ridaforolimus, sirolimus (originally called rapamycin), AP23841, and AP23573, calmodulin inhibitors such as CBP-501 (forkhead translocation inhibitor), enzastaurin HCl (LY317615), or mTOR inhibitors such as rapamycin analogs, such as RAD 001 (everolimus), CCI 779 (temsirolimus), AP23573, and ridaforolimus, sirolimus (originally called rapamycin), AP23841, and AP23573, or calmodulin inhibitors such as CBP-501 (forkhead translocation inhibitor), enzastaurin HCl (LY317615). HCl) (LY317615), or PI3K inhibitors such as dactolisib (BEZ235), buparlisib (BKM-120; NVP-BKM-120), BYL719, copanlisib (BAY-80-6946), ZSTK-474, CUDC-907, apitolisib (GDC-0980; RG-7422), pictilisib (pictrelisib, GDC-0941, RG-7321), GDC-0032, GDC-0068, GSK-2636771, idelalisib (previously CAL-101, GS 1101, GS-1101), MLN1117 (INK1117), MLN0128 (INK128), IPI-145 (INK1197), LY-3023414, ipatacept, ericetib, MK-2206, MK-8156, LY-3023414, LY294002, SF1126 or PI-103 or sonolisib (PX-866);

[0585] (xix) Hsp90 inhibitors, such as AT13387, herbimycin, geldanamycin (GA), 17-allylamino-17-demethoxygeldanamycin (17-AAG), such as NSC-330507, Kos-953 and CNF-1010, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), such as NSC-707545 and Kos-1022, NVP-AUY922 (VER-52296), NVP-BEP800, CNF-2024 (BIIB-021, an oral purine), ganetespib (STA-9090), SNX-5422 (SC-102112) or IPI-504;

[0586] (xx) monoclonal antibodies (unconjugated or conjugated with radioisotopes, toxins or other agents), antibody derivatives and related agents, such as anti-CD antibodies, anti-VEGFR antibodies, anti-HER2 antibodies, anti-CTLA4 antibodies, anti-PD-1 or anti-EGFR antibodies, for example, rituximab (CD20), ofatumumab (CD20), ibritumomab tiuxetan (CD20), GA101 (CD20), tositumomab (CD20), epratuzumab (CD22), lintuzumab (CD33), gemtuzumab ozogamicin (CD34), and rituximab (CD20). ozogamicin (CD33), alemtuzumab (CD52), galiximab (CD80), trastuzumab (HER2 antibody), pertuzumab (HER2), trastuzumab-DM1 (HER2), ertumaxomab (HER2 and CD3), cetuximab (EGFR), panitumumab (EGFR), necitumumab (EGFR), nimotuzumab (EGFR), bevacizumab ( izumab (VEGF), catumaxumab (EpCAM and CD3), abagovomab (CA125), farletuzumab (folate receptor), elotuzumab (CS1), denosumab (RANK ligand), figitumumab (IGF1R), CP751,871 (IGF1R), mapatumumab (TRAIL receptor), metMAB (met), mitumomab (GD3 ganglioside), naptumomab (metomab) estafenatox (5T4), or siltuximab (IL6), or immunomodulators, such as CTLA-4 blocking antibodies and / or antibodies against PD-1 and PD-L1 and / or PD-L2, such as ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly lambrolizumab,anti-PD-1), nivolumab (anti-PD-1), BMS-936559 (anti-PD-L1), MPDL320A, AMP-514, or MEDI4736 (anti-PD-L1), or tremelimumab (formerly known as ticilimumab, CP-675, 206, anti-CTLA-4);

[0587] (xxi) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or estrogen synthesis inhibitors, such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, or raloxifene;

[0588] (xxii) aromatase inhibitors and related drugs, such as exemestane, anastrozole, letrozole, testolactone, aminoglutethimide, mitotane, or vorozole;

[0589] (xxiii) anti-androgens (i.e., androgen receptor antagonists) and related agents, such as bicalutamide, nilutamide, flutamide, cyproterone, or ketoconazole;

[0590] (xxiv) hormones and their analogues, such as medroxyprogesterone, diethylstilbestrol (also known as diethylstilbestrol), or octreotide;

[0591] (xxv) steroids, for example dromostanolone propionate, megestrol acetate, nandrolone (decanoate, phenylpropionate), fluoxymestrone or gossypol;

[0592] (xxvi) steroidal cytochrome P450 17α-hydroxylase-17,20-lyase inhibitors (CYP17), for example abiraterone;

[0593] (xxvii) gonadotropin-releasing hormone agonists or antagonists (GnRA), such as abarelix, goserelin acetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin, or deslorelin;

[0594] (xxviii) glucocorticoids, such as prednisone, prednisolone, dexamethasone;

[0595] (xxix) Differentiating agents such as retinoids, retinoids, vitamin D or retinoic acid and retinoic acid metabolism blockers (RAMBAs), for example, accutane, alitretinoin, bexarotene, or tretinoin;

[0596] (xxx) Farnesyl transferase inhibitors, such as tipifarnib;

[0597] (xxxi) Chromatin-targeted therapies, such as histone deacetylase (HDAC) inhibitors, such as panobinostat, resminostat, abexinostat, vorinostat, romidepsin, belinostat, entinostat, quisinostat, pracinostat, tefinostat, mocetinostat, givinostat, CUDC-907, CUDC-101, ACY-1215, MGCD-290, EVP-0334, RG-2833, 4SC-202, romidepsin, AR-42 (Ohio State University), CG-200745, valproic acid, CKD-581, sodium butyrate, suberoylanilide hydroxamic acid (SAHA), decapeptide (FR 901228), dacinostat (NVP-LAQ824), R306465 / JNJ-16241199, JNJ-26481585, trichostatin A, chlamydocin, A-173, JNJ-MGCD-0103, PXD-101, or apicidin;

[0598] (xxxii) proteasome inhibitors, such as bortezomib, carfilzomib, delanzomib (CEP-18770), ixazomib (MLN-9708), oprozomib (ONX-0912), or marizomib;

[0599] (xxxiii) photodynamic drugs, such as porfimer sodium or temoporfin;

[0600] (xxxiv) Anticancer agents derived from marine organisms, such as trabectidin;

[0601] (xxxv) radiolabelled drugs for use in radioimmunotherapy, for example with isotopes that emit beta particles (e.g. iodine-131, yttrium-90) or alpha particles (e.g. bismuth-213 or actinium-225), for example ibritumomab or tositumomab;

[0602] (xxxvi) telomerase inhibitors, such as telomestatin;

[0603] (xxxvii) matrix metalloproteinase inhibitors, for example batimastat, marimastat, prinostat or metastat;

[0604] (xxxviii) recombinant interferons (such as interferon-γ and interferon α) and interleukins (such as interleukin 2), such as aldesleukin, denileukin diftitox, interferon α2a, interferon α2b, or pegylated interferon α2b;

[0605] (xxxix) Selective immune response modifiers, such as thalidomide or lenalidomide;

[0606] (xl) Therapeutic vaccines, such as sipuleucel-T (Provenge) or OncoVex;

[0607] (xli) Cytokine activators, including Picibanil, Romurtide, Sizofiran, Virulizin, or Thymosin;

[0608] (xlii) arsenic trioxide;

[0609] (xliii) G protein-coupled receptor (GPCR) inhibitors, such as atrasentan;

[0610] (xliv) enzymes, such as L-asparaginase, pegaspargase, rasburicase, or pegademase;

[0611] (xlv) DNA repair inhibitors, such as PARP inhibitors, for example olaparib, velaparib, iniparib, rucaparib (AG-014699 or PF-01367338), talazoparib or AG-014699;

[0612] (xlvi) DNA damage response inhibitors, such as ATM inhibitors AZD0156MS3541, ATR inhibitors AZD6738, M4344, M6620 wee1 inhibitor AZD1775;

[0613] (xlvii) death receptor (e.g., TNF-related apoptosis-inducing ligand (TRAIL) receptor) agonists, such as mapamumab (formerly known as HGS-ETR1), conatumumab (formerly known as AMG 655), PRO95780, lexatumumab, dulanermin, CS-1008, apomab, or recombinant TRAIL ligands, such as recombinant human TRAIL / Apo2 ligand;

[0614] (xlvii) Prophylactic (adjuvant) agents; i.e., agents that reduce or alleviate some of the side effects associated with chemotherapeutic agents, e.g.

[0615] - Antiemetics;

[0616] - Agents that prevent chemotherapy-related neutropenia or shorten the duration of chemotherapy-related neutropenia and prevent complications caused by decreased levels of platelets, red blood cells or white blood cells, such as interleukin-11 (e.g., oprelvekin), erythropoietin (EPO) and its analogs (e.g., darbepoetin alfa), colony stimulating factor analogs such as granulocyte macrophage colony stimulating factor (GM-CSF) (e.g., sargramostim), and granulocyte colony stimulating factor (G-CSF) and its analogs (e.g., filgrastim, pegfilgrastim);

[0617] - agents that inhibit bone resorption, such as denosumab or bisphosphonates, for example zoledronate, zoledronic acid, pamidronate and ibandronate;

[0618] -Agents that suppress inflammation, such as dexamethasone, prednisone, and prednisolone;

[0619] - Agents used to reduce blood levels of growth hormone and IGF-I (and other hormones) in patients with acromegaly or other rare hormone-producing tumors, such as synthetic forms of the hormone somatostatin, for example octreotide acetate;

[0620] -Antidotes for drugs that lower folate levels, such as leucovorin or folinic acid;

[0621] - Medications for pain, for example opiates, such as morphine, diamorphine and fentanyl;

[0622] - nonsteroidal anti-inflammatory drugs (NSAIDs), such as COX-2 inhibitors, for example celecoxib, etoricoxib and lumiracoxib;

[0623] -Agents used for mucositis, such as palifermin;

[0624] -Agents used to treat side effects including anorexia, cachexia, edema, or thromboembolic events, such as megestrol acetate.

[0625] In one embodiment, the anticancer agent is selected from recombinant interferons (e.g., interferon-γ and interferon α) and interleukins (e.g., interleukin 2), such as aldesleukin, denileukin, interferon α2a, interferon α2b or pegylated interferon α2b; interferon-α2 (500 μ / ml), in particular interferon-β; and signal transduction inhibitors, such as kinase inhibitors (e.g., EGFR (epidermal growth factor receptor) inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, MTKI (multi-targeted kinase inhibitors), Raf inhibitors, mTOR inhibitors, such as imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovitinib, axitinib, nilotinib, vandetanib, vatalanib, pazopanib, sorafenib, sunitinib, temsirolimus, everolimus (RAD 001), vemurafenib (PLX4032 / RG7204), dabrafenib, anrafenib or IκB kinase inhibitors such as SAR-113945, bardoxolone, BMS-066, BMS-345541, IMD-0354, IMD-2560 or IMD-1041, or MEK inhibitors such as selumetinib (AZD6244) and trametinib (GSK121120212), in particular Raf inhibitors (e.g. vemurafenib) or MEK inhibitors (e.g. trametinib).

[0626] Each of the compounds present in the combination of the present invention can be given according to a dosage regimen that varies individually and via different routes. Thus, the posology of each of the two or more medicaments may be different: each can be administered simultaneously or at different times. Those skilled in the art will know the dosage regimen and combined therapy to be used via his or her common sense. For example, the compound of the present invention can be used in combination with one or more other medicaments, and the one or more other medicaments are administered according to the combination regimen they already exist. Examples of standard combination regimens are provided below.

[0627] The taxane compound is advantageously administered at a dose of 50 mg to 400 mg per square meter of body surface area (mg / m 2 ) dose, for example, 75 mg / m per course of treatment 2 Up to 250 mg / m 2 , especially for paclitaxel, at about 175 mg / m per course of treatment 2 Up to 250 mg / m 2 Doses of docetaxel are approximately 75 mg / m 2 Up to 150 mg / m 2 dosage.

[0628] Camptothecin compounds are advantageously administered at a dosage of 0.1 mg to 400 mg per square meter of body surface area per treatment course. 2 ) is administered at a dose of, for example, 1 mg / m per course of treatment 2 Up to 300 mg / m 2 , especially for irinotecan, at about 100 mg / m per course of treatment 2 Up to 350 mg / m 2 For topotecan, approximately 1 mg / m 2 Up to 2 mg / m 2 dosage.

[0629] The antitumor podophyllotoxin derivative is advantageously administered at a dose of 30 mg to 300 mg per square meter of body surface area (mg / m 2 ) dose, for example, 50 mg / m per course of treatment 2 Up to 250 mg / m 2 , especially for etoposide, at about 35 mg / m per course of treatment 2 Up to 100 mg / m 2 For teniposide, approximately 50 mg / m 2 Up to 250 mg / m 2 dosage.

[0630] The antitumor vinca alkaloids are advantageously administered at a dose of 2 mg to 30 mg per square meter of body surface area (mg / m2 ) dose, especially for vinblastine, about 3 mg / m per course of treatment 2 Up to 12 mg / m 2 For vincristine, approximately 1 mg / m 2 Up to 2 mg / m 2 The dose of vinorelbine is about 10 mg / m per course of treatment. 2 Up to 30 mg / m 2 dosage.

[0631] The antitumor nucleoside derivative is advantageously administered at a dosage of 200 mg to 2500 mg per square meter of body surface area (mg / m 2 ) dose, for example, 700 mg / m per course of treatment 2 Up to 1500 mg / m 2 , especially for 5-FU, 200 mg / m per course of treatment 2 Up to 500 mg / m 2 The dose of gemcitabine is about 800 mg / m per course of treatment. 2 Up to 1200 mg / m 2 For capecitabine, approximately 1000 mg / m2 per course of treatment is recommended. 2 Up to 2500 mg / m 2 dosage.

[0632] Alkylating agents such as nitrogen mustard or nitrosourea are advantageously administered at a dose of 100 mg to 500 mg per square meter of body surface area (mg / m 2 ) is administered at a dose of, for example, 120 mg / m per course of treatment 2 Up to 200 mg / m 2 , especially for cyclophosphamide, at about 100 mg / m per course of treatment 2 Up to 500 mg / m 2 The dosage is about 0.1 mg / kg to 0.2 mg / kg per course of treatment for chlorambucil and about 150 mg / m per course of treatment for carmustine. 2 Up to 200 mg / m 2 For lomustine, approximately 100 mg / m 2 Up to 150 mg / m 2 dosage.

[0633] The antitumor anthracycline derivative is advantageously administered at a dose of 10 mg to 75 mg per square meter of body surface area (mg / m 2 ) dose, for example, 15 mg / m per course of treatment 2 Up to 60 mg / m 2 , especially for doxorubicin, at about 40 mg / m per course of treatment2 Up to 75 mg / m 2 For daunorubicin, approximately 25 mg / m 2 Up to 45 mg / m 2 For idarubicin, approximately 10 mg / m 2 Up to 15 mg / m 2 dosage.

[0634] Antiestrogens are advantageously administered at a dosage of about 1 mg to 100 mg per day, depending on the specific medicament and the condition being treated. Tamoxifen is advantageously administered orally twice a day at a dosage of 5 mg to 50 mg (specifically 10 mg to 20 mg), and the sufficient time for sustained treatment is to achieve and maintain a therapeutic effect. Toremifene is advantageously administered orally once a day at a dosage of about 60 mg, and the sufficient time for sustained treatment is to achieve and maintain a therapeutic effect. Anastrozole is advantageously administered orally once a day at a dosage of about 1 mg. Droloxifene is advantageously administered orally once a day at a dosage of about 20 mg-100 mg. Raloxifene is advantageously administered orally once a day at a dosage of about 60 mg. Exemestane is advantageously administered orally once a day at a dosage of about 25 mg.

[0635] The antibody is advantageously administered at a dose of about 1 mg to 5 mg per square meter of body surface area (mg / m 2 ) or as known in the art (if different). Trastuzumab is advantageously administered at a dose of 1 mg to 5 mg per square meter of body surface area (mg / m 2 ), especially 2mg / m 2 Up to 4 mg / m 2 dosage administration.

[0636] In the case where the compound of formula (I) is used together with one, two, three, four or more other therapeutic agents (specifically one or two, more specifically one) in a combined therapy, the compound can be used simultaneously or sequentially. In the latter case, the two or more compounds will be used within a period of time and in a certain amount and manner, and the time and amount and manner are sufficient to ensure that a favorable effect or a synergistic effect is achieved. When used sequentially, they can be used at closely spaced time intervals (e.g., within the time of 5 minutes to 10 minutes) or at longer time intervals (e.g., 1 hour, 2 hours, 3 hours, 4 hours or longer or even longer time apart in the case of necessity), and the precise dosage regimen is commensurate with the characteristics of one or more therapeutic agents. These dosages can be used, for example, once, twice or more times per course of treatment, and this can be repeated once, for example, every 7 days, 14 days, 21 days or 28 days.

[0637] In one embodiment, there is provided a compound of formula (I) for the preparation of a medicament for therapy, wherein the compound is used in combination with one, two, three or four other therapeutic agents. In another embodiment, there is provided a medicament for the treatment of cancer, comprising a compound of formula (I), wherein the medicament is used in combination with one, two, three or four other therapeutic agents. The present invention further provides the use of a compound of formula (I) in the preparation of a medicament for enhancing or strengthening the response rate of a patient suffering from cancer, wherein the patient is being treated with one, two, three or four other therapeutic agents.

[0638] It should be understood that the specific method and sequence of administration and the corresponding dosage and regimen of each component of the combination depend on the specific other agents and compounds of the present invention being administered, their routes of administration, the specific tumor being treated, and the specific host being treated. The optimal method and sequence of administration, dosage and regimen can be easily determined by those skilled in the art using conventional methods and in view of the information listed herein.

[0639] The weight ratio of the compounds of the present invention and one or more other anticancer agents when given as a combination can be determined by those skilled in the art. The exact dosage and frequency of the ratio and administration depend on the specific compound of the present invention and other anticancer agents used, the specific illness treated, the severity of the illness treated, the age, weight, sex, diet, administration time and general physical condition of a particular patient, the mode of administration, and other drugs that an individual may be taking, as is well known to those skilled in the art. In addition, it is apparent that the effective daily amount can be reduced or increased according to the reaction of the treatment subject and / or according to the evaluation of the clinician who prescribes the compounds of the present invention. The specific weight ratio of the compound of formula (I) of the present invention and another anticancer agent can be 1 / 10 to 10 / 1, more specifically 1 / 5 to 5 / 1, and even more specifically 1 / 3 to 3 / 1.

[0640] The compounds of the invention may also be administered in combination with non-chemotherapeutic treatments, such as radiation therapy, photodynamic therapy, gene therapy; surgery and controlled diet.

[0641] The compounds of the present invention also have therapeutic applications in sensitizing tumor cells to radiotherapy and chemotherapy. Thus, the compounds of the present invention can be used as "radiosensitizers" and / or "chemosensitizers", or can be used in combination with another "radiosensitizer" and / or "chemosensitizer". In one embodiment, the compounds of the present invention are used as chemosensitizers.

[0642] The term "radiosensitizer" is defined as a molecule that is administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to ionizing radiation and / or to facilitate the treatment of a disease treatable by ionizing radiation.

[0643] The term "chemosensitizer" is defined as a molecule that is administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to chemotherapy and / or to facilitate the treatment of a disease treatable with a chemotherapeutic agent.

[0644] In one embodiment, the compounds of the present invention are administered together with a "radiosensitizer" and / or a "chemosensitizer." In one embodiment, the compounds of the present invention are administered together with an "immunosensitizer."

[0645] The term "immunosensitizer" is defined as a molecule that is administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to Pol θ inhibitors.

[0646] Many cancer treatment regimens currently use radiosensitizers in conjunction with X-ray irradiation. Examples of X-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, demethyl misonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives thereof.

[0647] Photodynamic therapy (PDT) of cancer uses visible light as a radioactive agent of a sensitizer. Examples of photodynamic radiosensitizers include, but are not limited to, the following: hematoporphyrin derivatives, photoporphyrins, benzoporphyrin derivatives, tin etioporphyrins, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanines, and therapeutically effective analogs and derivatives thereof.

[0648] The radiosensitizers may be administered in combination with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds of the invention; compounds that promote the incorporation of the radiosensitizer into target cells; compounds that control the flow of therapeutic agents, nutrients and / or oxygen to target cells; chemotherapeutic agents that act on tumors with or without additional radiation; or other therapeutically effective compounds used to treat cancer or other diseases.

[0649] The chemosensitizer may be administered in combination with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds of the invention; compounds that promote the incorporation of the chemosensitizer into target cells; compounds that control the flow of therapeutic agents, nutrients and / or oxygen to target cells; chemotherapeutic agents that act on tumors or other therapeutically effective compounds for the treatment of cancer or other diseases. Calcium antagonists such as verapamil have been found to be useful in combination with anti-tumor agents to establish chemosensitivity in tumor cells that are resistant to established chemotherapeutic agents and to enhance the efficacy of such compounds in drug-sensitive malignancies.

[0650] Examples of immune sensitizers include, but are not limited to, immunomodulators, such as monoclonal antibodies, such as immune checkpoint antibodies [e.g., CTLA-4 blocking antibodies and / or antibodies against PD-1 and PD-L1 and / or PD-L2, such as ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly known as lebronzumab, anti-PD-1), nivolumab (anti-PD-1), BMS-936559 (anti-PD-L1), MPDL320A, AMP-514 or MEDI4736 (anti-PD-L1), or tremelimumab (formerly known as telitumumab, CP-675, 206, anti-CTLA-4); or signal transduction inhibitors; or cytokines (e.g., recombinant interferon); or oncolytic viruses; or immune adjuvants (e.g., BCG).

[0651] The immunosensitizer may be administered in combination with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds of the present invention; compounds that promote the binding of the immunosensitizer to target cells; compounds that control the flow of therapeutic agents, nutrients and / or oxygen to target cells; therapeutic agents that act on tumors or other therapeutically effective compounds for treating cancer or other diseases.

[0652] For combination therapy with another chemotherapeutic agent, the compound of formula (I) and one, two, three, four or more other therapeutic agents can be formulated together, for example, in a dosage form comprising two, three, four or more therapeutic agents, i.e., in a single pharmaceutical composition comprising all the agents. In an alternative embodiment, the individual therapeutic agents can be formulated separately and presented together in the form of a kit, optionally with instructions for their use.

[0653] In one embodiment, a combination of a compound of formula (I) and one or more (e.g., 1 or 2) additional therapeutic agents (e.g., anticancer agents as described above) is provided. In another embodiment, a combination of a Polθ inhibitor as described herein and a PI3K / AKT pathway inhibitor is provided, the PI3K / AKT pathway inhibitor being selected from: apalix, bupalix, copanlis, picolide, ZSTK-474, CUDC-907, GSK-2636771, LY-3023414, ipatacept, ericetate, MK-2206, MK-8156, idelalis, BEZ235 (datolis), BYL719, GDC-0980, GDC-0941, GDC-0032, and GDC-0068.

[0654] In another embodiment, there is provided a combination of a compound of formula (I) and one or more (eg 1 or 2) additional therapeutic agents (eg anti-cancer agents) for use in therapy, eg for the prevention or treatment of cancer.

[0655] In one embodiment, the pharmaceutical composition comprises a compound of formula (I) together with a pharmaceutically acceptable carrier and optionally one or more therapeutic agents.

[0656] In another embodiment, the invention relates to the use of a combination according to the invention for the manufacture of a pharmaceutical composition for inhibiting the growth of tumor cells.

[0657] In another embodiment, the invention relates to a product containing a compound of formula (I) and one or more anticancer agents as a combined preparation for simultaneous, separate or sequential use in the treatment of a patient suffering from cancer. Example

[0658] The invention will now be illustrated, but not limited to, by reference to specific embodiments described in the following examples.

[0659] abbreviation

[0660] aq. water

[0661] BOC tert-Butyloxycarbonyl

[0662] (Boc) 2 O Di-tert-butyl dicarbonate

[0663] dba dibenzylideneacetone

[0664] dppf 1,1′-bis(diphenylphosphino)ferrocene

[0665] DCM Dichloromethane

[0666] DIPEA N,N-Diisopropylethylamine

[0667] DMAP 4-dimethylaminopyridine

[0668] DMF Dimethylformamide

[0669] DMSO Dimethyl sulfoxide

[0670] EEDQ N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline

[0671] EtOH

[0672] EtOAc Ethyl acetate

[0673] h hour

[0674] HPLC High Performance Liquid Chromatography

[0675] MeCN Acetonitrile

[0676] MeOH Methanol

[0677] min

[0678] NMO 4-Methylmorpholine 4-oxide

[0679] NMP N-Methylpyrrolidone

[0680] NMR Nuclear Magnetic Resonance

[0681] PE Petroleum Ether

[0682] rt Room temperature or ambient temperature

[0683] sat. saturated solution

[0684] SCX-2 Propanesulfonic acid (uncapped) functionalized silica column

[0685] SFC Supercritical Fluid Chromatography

[0686] T3P 1-Propanephosphonic anhydride solution

[0687] TBAB Tetrabutylammonium bromide

[0688] TBAF Tetra-n-butylammonium fluoride

[0689] TEA Triethylamine

[0690] TFA Trifluoroacetic acid

[0691] THF Tetrahydrofuran

[0692] TLC Thin layer chromatography

[0693] Typical Preparative HPLC Method

[0694] For purification of samples by HPLC, the following columns are typically used; SunFire C18, Xtimate C18, Phenomenex Gemini, Phenomenex Synergi C18, Phenomenex Luna, Waters Xbridge C18, Boston Prime C18 and Shim-pack C18. Typical mobile phases used are water and MeCN with acidic or basic additives such as formic acid (0.1% v / v) or ammonium hydroxide (0.05% v / v). A typical method starts with 95% water:5% MeCN and gradually decreases the polarity ratio of water and MeCN over a period of 5-12 min with a typical flow rate of 25 mL / min. For mass-directed HPLC, a typical mass spectrometer used is a Waters 3100, which detects masses of 100-700 g / mol.

[0695] Intermediate 1: 2-Chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile

[0696]

[0697] Step a: To a solution of 1,1,1-trifluoropentane-2,4-dione (25 g, 162 mmol) and 2-cyano-acetamide (15 g, 178 mmol) in EtOH (200 mL) was added diethylamine (5.93 g, 81.1 mmol). The mixture was stirred at 70 ° C for 12 h. Upon completion, a white solid precipitated from EtOH. The reaction mixture was filtered, the solid was collected, and further vacuum dried to give 2-hydroxy-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (24.5 g, 121 mmol, crude) as a white solid.

[0698] m / z ES+[M+H] + 203.0; 1 H NMR (400MHz, DMSO-d6) δppm 6.51 (s, 1H), 2.33 (s, 3H).

[0699] Step b: 2-Hydroxy-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (24.5 g, 121 mmol) was carefully added to POCl at rt. 3 (400 mL) and the resulting solution was stirred at 110 °C for 12 h. Upon completion, POCl was carefully removed by distillation. 3The residue was purified by column chromatography (0-20% EtOAc in PE) to give 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile (24.5 g, 111 mmol, 91.6% yield) as a light yellow oil.

[0700] 1 H NMR (400 MHz, CDCl 3 )δppm 7.50 (s, 1H), 2.73 (s, 3H).

[0701] Intermediate 2: (2S, 4S)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)-pyrrolidine-2-carboxylic acid

[0702]

[0703] A mixture of (2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (CAS No. 87691-27-8; 5 g, 21.6 mmol), tert-butylchlorodimethylsilane (3.91 g, 25.9 mmol), imidazole (2.21 g, 32.4 mmol) in DCM (3 mL) was degassed and heated with N 2 Purge 3 times, then the mixture was heated at rt under N 2 Stir for 12 h under atmosphere. 4 Cl aqueous solution (60mL) quenches the reaction mixture, dilutes with water (100mL), extracts with DCM (200mL x 3). The combined organic layer is washed with salt water (100mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated to obtain (2S, 4S)-1-tert-butoxycarbonyl-4-[tert-butyl(dimethyl)silyl]oxy-pyrrolidine-2-carboxylic acid (7.2g, 20.8mmol, 96% yield), which is a yellow-white oil.

[0704] 1 H NMR (400MHz, DMSO-d6) δppm 4.42-4.20 (m, 1H), 4.26-4.07 (m, 1H), 3.64-3.44 (m, 1H), 3.14-2.99 (m, 1H), 2.43-2.3 1 (m, 1H), 1.91-1.76 (m, 1H), 1.40-1.33 (m, 9H), 0.85-0.76 (m, 9H), 0.23-0.16 (m, 6H).

[0705] Intermediate 3: (2S, 4S)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide hydrochloride

[0706] Step a: A solution of intermediate 2 (2 g, 5.79 mmol), N-methyl-3-methyl-aniline (468 mg, 3.86 mmol) and T3P (7.37 g, 11.6 mmol, 50% wt.% DMF solution) in pyridine (20 mL) was stirred at rt for 16 h. Upon completion, the reaction mixture was quenched by adding water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (50 mL x 3), dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (5-25% EtOAc in PE solution) to obtain (2S, 4S)-4-[tert-butyl(dimethyl)silyl]oxy-2-[methyl(m-tolyl)carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (1.23 g, 71% yield) as a yellow oil.

[0707] m / z ES+[M+H] + 449.7

[0708] Step b: (2S,4S)-4-[tert-butyl(dimethyl)silyl]oxy-2-[methyl(m-tolyl)carbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.67 mmol) was dissolved in HCl in 1,4-dioxane (4M, 2 mL) and stirred at rt for 2 h. The solution was evaporated to give (2S,4S)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide (0.9 g, crude, HCl salt) as a yellow solid.

[0709] m / z ES+[M+H] + 235.3

[0710] Intermediate 4: (2S, 4S)-4-(Benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid

[0711]

[0712] To a solution of (2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (30 g, 123 mmol) in THF (400 mL) was added NaH (11.42 g, 285 mmol, 60% dispersion in mineral oil) and benzyl bromide (26.63 g, 155.7 mmol). The mixture was stirred at rt for 16 h. The mixture was slowly poured into water (200 mL), adjusted to pH = 2 by slow addition of HCl (2 M), and then extracted with EtOAc (400 mL x 3). The residue was purified by HPLC. The residue was purified by HPLC. The residue was purified by HPLC. 2 SO 4The combined organic extracts were dried, filtered and evaporated to give a crude product. The crude product was triturated with PE / EtOAc=10 / 1 at rt for 30 min and the solid was collected by filtration. The residual solvent was removed by vacuum drying to give (2S,4S)-4-(benzyloxy)-1-(tert-butoxy-carbonyl)pyrrolidine-2-carboxylic acid (36 g, 112 mmol, 86% yield) as a white solid.

[0713] 1 H NMR (400MHz, DMSO-d6) δppm 7.55-7.25(m, 5H), 4.55-4.40(m, 2H), 4.25-4.10(m, 2H), 3.60-3.50(m, 1H), 2.40-2.30(m, 1H), 2.18-2.08(m, 2H), 1.50-1.26(m, 9H).

[0714] Intermediate 5: (3aS, 4S, 6aS)-2,2-dimethyl-6-oxotetrahydro-4H-[1,3]dioxol[4,5-c]pyrrole-4-carboxylic acid

[0715]

[0716] Step a: To a solution of tert-butyl (S)-(1-(benzyloxy)-3-hydroxypropan-2-yl)carbamate (4.68 g, 16.6 mmol) in DCM (15 mL) was added Dess-Martin reagent (68 g, 50 mL, 24.2 mmol, 15 wt.% in DCM). An exotherm was observed and the temperature increased to 30°C. The mixture was stirred at rt for 1.5 h. The mixture was heated to 40°C by adding saturated NaHCO 3 The reaction was quenched with aqueous solution (100 mL) and stirred vigorously for 1.5 h until the Dess-Martin reagent was completely quenched. The biphasic mixture was filtered through CELITE. The phases were separated and the aqueous phase was extracted into DCM (2 x 50 mL) and washed with Na 2 SO 4 Dry and evaporate. The resulting material was co-evaporated with toluene (25 mL) to give (R)-tert-butyl(1-(benzyloxy)-3-oxopropan-2-yl)carbamate (4.65 g) as a moderately turbid light yellow oil. The crude aldehyde was used in the next step without any further purification.

[0717] 1 H NMR (300 MHz, CDCl 3)δppm 9.61 (s, 1H), 7.51-7.08 (m, 5H), 5.47 (s, 1H), 4.55 (m, 2H), 4.30 (m, 1H), 3.96 (m, 1H), 3.71 (m, 1H), 1.42 (s, 9H).

[0718] Step b: A solution of methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (6.607 g, 20.77 mmol) and 18-crown-6 (21.96 g, 83.08 mmol; dried by coevaporation with toluene and then used) in dry THF (30 mL) was cooled to -78°C and a toluene solution of KHMDS (0.7 M, 4.15 g, 29.7 mL, 20.8 mmol) was added over 10 min. The mixture was stirred at -78°C for 5 min and a solution of (R)-tert-butyl(1-(benzyloxy)-3-oxopropan-2-yl)carbamate (4.65 g, 16.6 mmol) in anhydrous THF (20 mL) was added dropwise over 15 min. The mixture was stirred at -78°C for 2.5 h. Saturated NH 4 Cl aqueous solution (100 mL) was added and the biphasic mixture was warmed to rt. The phases were separated and the aqueous phase was extracted into EtOAc (2 x 50 mL). The combined organic phases were washed with brine and washed with Na 2 SO 4 Drying and evaporation gave 11.6 g of a yellow oil. Purification by column chromatography (0-10% EtOAc in heptane) gave (S,Z)-methyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)pent-2-enoate (3.70 g, 66.3%) as a colorless oil.

[0719] Step c: To a solution of (S,Z)-methyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)pent-2-enoate (3.70 g, 11.0 mmol) in MeOH (25 mL) was added acetyl chloride (8.66 g, 7.87 mL, 110 mmol) dropwise at 0°C. The solution was stirred at rt for 3 h and evaporated. The crude product, methyl (S,Z)-5-(benzyloxy)-4-(chloro-15-ananeyl)pent-2-enoate hydrochloride (3.00 g, 100%), was used as such in the next step.

[0720] Step d. To a solution of (S,Z)-4-amino-5-(benzyloxy)pent-2-enoic acid methyl ester hydrochloride (3.00 g, 11.0 mmol) in DCM (30 mL) was added diphenylmethylamine (1.994 g, 11.00 mmol) at rt. A precipitate formed within 5 min and the mixture was stirred at rt overnight. Saturated NaHCO 3Aqueous solution (30 mL) was added and the phases were separated. The aqueous phase was extracted with DCM (2 x 20 mL). 2 SO 4 The combined organic phases were dried and evaporated to give 4.34 g of a yellow oil. Purification by column chromatography (0-10% EtOAc in heptane) gave (S,Z)-methyl 5-(benzyloxy)-4-((diphenylmethylene)amino)pent-2-enoate (3.30 g, 75.1%) as a colorless oil.

[0721] Step e: To a solution of methyl (S,Z)-5-(benzyloxy)-4-((diphenylmethylene)amino)pent-2-enoate (3.30 g, 8.26 mmol) in a mixture of water (30 mL) and THF (30 mL) was added NMO (2.42 g, 20.7 mmol) followed by a 4% aqueous solution of osmium tetroxide (1.0 g, 1.0 mL, 0.2 mmol) at rt. The mixture was stirred at rt for 24 h. Saturated Na 2 SO 3 The aqueous solution was extracted with EtOAc (2 x 40 mL). The combined organic phases were washed with brine and washed with Na 2 SO 4 The product was dried and concentrated in vacuo to afford 4.12 g of crude material. Purification by chromatography (0-20% EtOAc in heptane) afforded 2.90 g of pure product as a mixture of cis and trans isomers (predominantly cis). Methyl (2S,3S,4R)-5-(benzyloxy)-4-((diphenylmethylene)-amino)-2,3-dihydroxypentanoate (2.90 g, 81.0%) was separated as an equilibrium mixture of acyclic diol and cyclooxazolidine. The ratio of cis to trans isomers was not determined.

[0722] Step f: To a solution of methyl (2S,3S,4R)-5-(benzyloxy)-4-((diphenylmethylene)amino)-2,3-dihydroxypentanoate (2.90 g, 6.69 mmol) and 2,2-dimethoxypropane (12.3 g, 14.65 mL, 118 mmol) in benzene (220 mL) was added pyridinium p-toluenesulfonate (505 mg, 2.01 mmol). The mixture was heated at reflux for 3 h using a Dean-Stark trap. The volatiles were removed in vacuo and the residue was dissolved in EtOAc (75 mL). The residue was washed with saturated NaHCO 3 The solution was washed with aqueous solution (2 x 75 mL) and then with Na 2 SO 4Drying and concentration in vacuo afforded 3.14 g of a light brown oil. The diastereoisomer ratio of the cis and trans isomers was determined by HPLC to be 91.5:8.5. Purification by column chromatography (10-15% EtOAc in heptane) afforded the cis isomer (4S,5S)-methyl 5-((R)-2-(benzyloxy)-1-((diphenyl-methylene)amino)ethyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (2.77 g, 87.4%) as a colorless oil.

[0723] m / z ES+[M+H] + 474.3; 1 H NMR (300 MHz, CDCl 3 )δppm 7.71 (m, 2H), 7.48 (m, 13H), 4.71 (m, 2H), 4.50 (s, 2H), 3.92 (m, 1H), 3.73 (m, 2H), 3.40 (s, 3H), 1.76 (s, 3H), 1.45 (s, 3H).

[0724] Step g: To a solution of (4S,5S)-5-((R)-2-(benzyloxy)-1-((diphenylmethylene)-amino)ethyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid methyl ester (2.77 g, 5.85 mmol) in MeOH (180 mL) was added palladium hydroxide on carbon (277 mg, 0.39 mmol). The mixture was stirred under hydrogen atmosphere (balloon) for 40 h. Pd / C (10 wt%, 100 mg) was added to the mixture and stirring was continued under hydrogen atmosphere for 72 h. The mixture was filtered through CELITE and concentrated in vacuo. Purification by column chromatography (10% MeOH in DCM) gave (3aS,6R,6aS)-6-(hydroxymethyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrol-4-one 8 (0.874 g, 79.8%) as a white solid.

[0725] Step h: To a solution of (3aS,6R,6aS)-6-(hydroxymethyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxol[4,5-c]pyrrole-4-one 8 (875 mg, 4.67 mmol) in a mixture of water (12 mL), MeCN (8 mL) and carbon tetrachloride (8 mL) was added sodium periodate (3.00 g, 14.0 mmol) and ruthenium(III) chloride hydrate (105 mg, 0.467 mmol). The mixture was stirred overnight at rt. EtOAc (50 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with brine (5 mL) and washed with Na2 SO 4 The mixture was dried and concentrated in vacuo to give 250 mg of an off-white solid. The aqueous phase was extracted again with THF (2 x 50 mL). The organic phase was washed with brine (5 mL) and washed with Na 2 SO 4 Dry and add to the EtOAc extracts. A total of 760 mg of off-white solid was isolated. Trituration in DCM gave (3aS,4S,6aS)-2,2-dimethyl-6-oxotetrahydro-4H-[1,3]dioxol[4,5-c]pyrrole-4-carboxylic acid (600 mg, 63.8%) as an off-white solid.

[0726] m / z ES+[M+H] + 202.0; 1 H NMR (300 MHz, D 2 O) δppm 5.07 (dd, J=5.3, 5.3Hz, 1H), 4.79 (d, J=5.3Hz, 1H), 4.53 (d, J=5.3Hz, 1H), 1.31 (s, 3H, 1.30 (s, 3H).

[0727] Example 1

[0728] (S)-1-(3-Cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-phenylpyrrolidine-2-carboxamide

[0729]

[0730] Step a: A mixture of (S)-2-(tert-butoxycarbonyl)pyrrolidine (0.88 g, 5.0 mmol), 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (1.1 g, 5.0 mmol) and DIPEA (2.79 mL, 15.0 mmol) in NMP (10 mL) was heated at 80° C. for 45 min using microwave irradiation. (S)-2-(tert-butoxy-carbonyl)pyrrolidine (0.26 g, 1.5 mmol) was added and the mixture was heated at 80° C. for 30 min using microwave irradiation. The reaction mixture was partitioned between EtOAc (20 mL) and saturated NaHCO 3 The mixture was stirred for 2 hours at 4 ℃ for 10 minutes. The mixture was stirred for 2 hours at 4 ℃ for 3 ...

[0731] m / z ES+[M+H] + 300.38; 1 H NMR (400MHz, DMSO-d6) δppm 7.09 (s, 1H), 4.56 (dd, J=8.1, 5.0Hz, 1H), 3.99-3.84 (m, 2H), 2.42 (s, 3H), 2.25 (dt, J=12.1, 7.7Hz, 1H), 2.02 (p, J=6.7Hz, 2H), 1.96-1.87 (m, 1H), 1.39 (s, 9H).

[0732] Step b: To a solution of (2S)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]-pyrrolidine-2-carboxylic acid tert-butyl ester (700 mg, 1.97 mmol) in DCM (5 mL) was added TFA (2.0 mL, 26 mmol) and the mixture was stirred at rt for 2 h. TFA (4.0 mL, 52 mmol) was added and the mixture was stirred at rt for 3 h. The reaction mixture was evaporated and the residue was treated with toluene and evaporated 3 times to help remove residual TFA. The residue was then treated with IPA, evaporated, treated with MeOH, evaporated, and finally treated with EtOAc and evaporated to give (2S)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]pyrrolidine-2-carboxylic acid (715 mg). The material was used in the next step without further purification.

[0733] m / z ES+[M+H] + 300.39; 1 H NMR (400MHz, DMSO-d6) δppm 12.59 (s, 1H), 7.08 (s, 1H), 4.66 (dd, J=8.3, 4.8Hz, 1H), 3.92 (t, J=6.6Hz, 2H), 2.42 (s, 3H), 2.32-2.23 (m, 1H), 2.07-1.92 (m, 3H).

[0734] Step c: To a solution of (2S)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]pyrrolidine-2-carboxylic acid (70 mg, 0.234 mmol) in EtOAc (2 mL) were added N-methylaniline (0.03 mL, 0.234 mmol), pyridine (0.08 mL, 0.936 mmol) and T3P (0.28 mL, 0.468 mmol, 50 wt.% in EtOAc) and the mixture was stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO 3The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried and evaporated. The crude mixture was purified by mass-directed preparative HPLC to afford the title compound (25 mg, 27%).

[0735] m / z ES+[M+H] + 389.50; 1 H NMR (400MHz, DMSO-d6) δppm 7.58-7.47(m, 4H), 7.45-7.39(m, 1H), 7.06(s, 1H), 4.60-4.48(m, 1H), 3.97- 3.83 (m, 2H), 3.17 (s, 3H), 2.53 (s, 3H), 2.12-2.02 (m, 1H), 1.95-1.80 (m, 3H).

[0736] Example 2

[0737] (S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-isopropyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0738]

[0739] Step a: To a solution of N-isopropyl-3-methyl-aniline (0.164 g, 1.1 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.22 g, 1.0 mmol) and pyridine (0.32 mL, 4.0 mmol) in EtOAc (1 mL) was added T3P (1.19 mL, 2.0 mmol, 50 wt.% in EtOAc) at 0°C and the mixture was stirred for 1 h. The mixture was warmed to rt and stirred for 21 h. Additional T3P (1.19 mL, 2.0 mmol, 50 wt.% in EtOAc) was added and the mixture was stirred for 24 h. The mixture was cooled to 0°C, quenched by addition of aqueous HCl (0.5 M) and extracted with EtOAc. The organic extracts were washed with aqueous HCl (0.5 M) then brine, dried and evaporated to give tert-butyl (2S)-2-[isopropyl(m-tolyl)carbamoyl]pyrrolidine-1-carboxylate (338 mg, 97%) as a gum.

[0740] m / z ES+[M+H] + 347.61; 1H NMR (400MHz, DMSO-d6) δppm 7.43-7.31(m, 1H), 7.30-7.22(m, 1H), 7.12-6.94(m, 2H), 4.74(h, J=6.7Hz, 1H), 4.10-4.00(m, 1H), 3.34-3.29(m, 2H), 2.36(s, 3H), 1.87-1.73(m, 4H), 1.43-1.38(m, 9H), 0.98-0.92(m, 6H).

[0741] Step b: A solution of (2S)-tert-butyl 2-[isopropyl(m-tolyl)carbamoyl]pyrrolidine-1-carboxylate (320 mg, 0.924 mmol) in DCM (8 mL) was treated with TFA (0.07 mL, 0.924 mmol) and stirred for 2 h. The reaction mixture was evaporated, redissolved in MeOH, adsorbed on SCX-2, washed with MeOH and eluted with methanolic ammonia (2 M). The basic fractions were combined and the solvent evaporated to give (2S)-N-isopropyl-N-(m-tolyl)pyrrolidine-2-carboxamide (134 mg, 59%).

[0742] m / z ES+[M+H] + 247.54; 1 H NMR (400MHz, DMSO-d6) δppm 7.40-7.31 (m, 1H), 7.31-7.20 (m, 1H), 7.08-7.00 (m, 2H), 4.79 (hept, J=6.8Hz, 1H), 3.25-3.17 (m, 1H), 3.10- 3.03 (m, 1H), 3.00-2.94 (m, 1H), 2.45-2.39 (m, 1H), 2.38-2.32 (m, 3H), 1.57-1.34 (m, 4H), 1.01-0.88 (m, 6H).

[0743] Step c: A mixture of (2S)-N-isopropyl-N-(m-tolyl)pyrrolidine-2-carboxamide (50 mg, 0.20 mmol), 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (45 mg, 0.20 mmol) and DIPEA (0.11 mL, 0.61 mmol) in NMP (2 mL) was heated at 100 °C for 1 h using microwave irradiation. The reaction mixture was partitioned between EtOAc and saturated NaHCO 3 The aqueous solution was separated. The organic layer was washed with brine (x2), dried and evaporated. The residue was purified by column chromatography (5-30% EtOAc in cyclohexane). The product fractions were combined and evaporated to give the title compound (33 mg, 38%).

[0744] m / z ES+[M+H] + 431.59; 1 H NMR (400MHz, DMSO-d6) δppm7.50-7.42 (m, 1H), 7.42-7.29 (m, 2H), 7.21-7.14 (m, 1H), 7.12-7.04 (m, 1H), 4.78 (hept, J=6.7Hz, 1H) , 4.38-4.28(m, 1H), 3.98-3.86(m, 2H), 2.64-2.57(m, 3H), 2.43(s, 3H), 2.13-2.02(m, 1H), 1.98-1.80(m, 3H), 1.10-0.98(m, 6H).

[0745] Example 3

[0746] (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0747]

[0748] Step a: To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (CAS No. 87691-27-8; 0.75 g, 3.15 mmol) in DCM (15 mL) were added N-methyl-3-methyl-aniline (0.8 mL, 6.292 mmol) and EEDQ (1.57 g, 6.29 mmol) and the mixture was stirred at rt overnight. The reaction mixture was washed with 2M aqueous HCl (2 x 25 mL), the organic layer was dried and evaporated. The resulting residue was dissolved in DCM (6 mL), treated with TFA (3.0 mL, 6.0 mmol) and the mixture was stirred at rt overnight. The reaction mixture was adsorbed on SCX-2, washed with MeOH, eluted with methanolic ammonia (7 M) and the solvent was removed in vacuo. The crude material was purified by flash column chromatography (0-10% methanolic ammonia (7M) in DCM) to afford (2S,4S)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide (0.368 g, 50%).

[0749] 1H NMR (400MHz, DMSO-d6) δppm7.35 (t, J=7.7Hz, 1H), 7.24-6.92 (m, 3H), 4.60 (d, J=4.3Hz, 1H), 4.18-3.91 (m, 1H), 3. 17 (d, J=4.7Hz, 3H), 2.76 (d, J=11.6Hz, 1H), 2.45-2.37 (m, 1H), 2.33 (s, 3H), 1.74-1.55 (m, 1H), 1.51-1.30 (m, 1H).

[0750] Step b: To a solution of (2S,4S)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide (200 mg, 0.854 mmol) in NMP (4 mL) were added intermediate 1 (218 mg, 0.939 mmol) and DIPEA (0.45 mL, 2.56 mmol), and the mixture was stirred at 100 °C for 1 h. The cooled mixture was diluted with EtOAc (20 mL) and washed with saturated NaHCO 3 The aqueous solution (20 mL) was then washed with brine (20 mL), dried and evaporated. The crude material was purified by mass directed preparative HPLC. The product fractions were combined and evaporated. The resulting material was further dried under vacuum for 24 h to afford the title compound (0.290 g, 81%) as a white solid. m / z ES+[M+H] + 419.45; 1 H NMR (400MHz, DMSO-d6) δppm7.41 (t, J=7.7Hz, 1H), 7.34-7.19 (m, 3H), 7.09 (s, 1H), 5.34 (d, J=6.3Hz, 1H), 4.50 (t, J=8.2Hz, 1H), 4.14 (q, J=6.9 Hz, 1H), 4.03 (dd, J=9.7, 6.8Hz, 1H), 3.62 (dd, J=9.7, 7.2Hz, 1H), 3.16 (s, 3H), 2.53 (s, H), 2.37 (s, 3H), 2.23-2.04 (m, 1H), 1.89-1.61 (m, 1H).

[0751] Example 4

[0752] (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-(3,4-difluorophenyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide

[0753]

[0754] Step a: To a solution of intermediate 2 (400 mg, 1.16 mmol) and 3,4-difluoroaniline (299 mg, 2.32 mmol) in pyridine (4 mL) was added T3P (2.22 g, 3.48 mmol, 50% wt.% in DMF) and stirred at rt for 12 h. Upon completion, the reaction mixture was quenched by the addition of water (40 mL) and washed with NH 4 The mixture was diluted with aqueous Cl solution (40 mL) and extracted with EtOAc (80 mL). 4 The organic extract was washed with aqueous Cl solution (80 mL) and then with Na 2 SO 4 Dried and evaporated. The crude residue was purified by column chromatography (10% EtOAc in PE) to give (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-((3,4-difluorophenyl)carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (230 mg, 40% yield) as a yellow oil.

[0755] m / z ES+[M+H] + 457.3

[0756] Step b: To a solution of (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-((3,4-difluoro-phenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (230 mg, 0.50 mmol) in DMF (1 mL) was added NaH (22 mg, 0.55 mmol, 60% dispersion in mineral oil) dropwise at 0°C and the mixture was stirred for 30 min. To the mixture was added iodomethane (86 mg, 0.60 mmol) dropwise at 0°C and stirred for 2 h. The reaction mixture was evaporated to give (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-((3,4-difluorophenyl)(methyl)carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (237 mg, crude) as a yellow oil.

[0757] m / z ES+[M+H] + 471.3

[0758] Step c: To a solution of (2S,4S)-tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-((3,4-difluoro-phenyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (237 mg, crude) in 1,4-dioxane (0.5 mL) was added HCl in 1,4-dioxane (4M, 2 mL). The mixture was stirred at rt for 12 h. Upon completion, the mixture was concentrated in vacuo to give (2S,4S)-N-(3,4-difluoro-phenyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (140 mg, crude) as a yellow solid. m / z ES+[M+H] + 257.2

[0759] Step d: DIPEA (325 mg, 2.52 mmol, 0.44 mL) was added to a solution of (2S, 4S)-N-(3,4-difluorophenyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide (129 mg, crude) and 2-chloro-4,6-dimethylnicotinonitrile (84 mg, 0.53 mmol) in NMP (1 mL). The mixture was stirred at 60 ° C for 12 h. Upon completion, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (20 mL), dried and evaporated. The residue was purified by preparative HPLC to give the title compound (27 mg, 14% yield) as a white solid.

[0760] m / z ES+[M+H] + 387.0; 1 H NMR (400MHz, DMSO-d6) δppm 7.43 (s, 1H), 7.26 (d, J=9.2Hz, 2H), 6.46 (s, 1H), 4.99 (d, J=12.0Hz, 1H), 4.62 (d, J=9.2Hz, 1H), 4.53- 4.44 (m, 1H), 4.33-4.27 (m, 1H), 4.23-4.18 (m, 1H), 3.33 (s, 3H), 2.50-2.30 (m, 6H), 2.17-2.05 (m, 2H).

[0761] Example 5

[0762] (2S,4S)-N-(3-Chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoro-methyl)pyridin-2-yl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide

[0763]

[0764] Step a: A solution of intermediate 4 (0.5 g, 1.56 mmol), 3-chloro-4-fluoro-aniline (226 mg, 1.56 mmol) and T3P (1.49 g, 4.67 mmol, 50 wt.% in EtOAc) in pyridine (10 mL) was stirred at rt for 3 h. The mixture was evaporated, treated with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography (5-25% EtOAc in PE) to give (2S, 4S)-4-benzyloxy-2-[(3-chloro-4-fluoro-phenyl)-carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (0.46 g) as a yellow oil.

[0765] m / z ES+[M+H] + 449.9

[0766] Step b: To a solution of (2S,4S)-4-benzyloxy-2-[(3-chloro-4-fluoro-phenyl)-carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (0.36 g, 0.80 mmol) in DMF (5 mL) was added NaH (48 mg, 1.20 mmol, 60% dispersion in mineral oil) and the mixture was stirred at 0° C. for 30 min. A solution of iodomethane (137 mg, 0.96 mmol) was added dropwise to the mixture at 0° C. and then stirred at rt for 2 h. Upon completion, the reaction mixture was quenched by adding water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated to give (2S,4S)-4-benzyloxy-2-[(3-chloro-4-fluoro-phenyl)-methyl-carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g, crude) as a yellow oil. m / z ES+[M+H] + 463.9

[0767] Step c: A solution of (2S,4S)-4-benzyloxy-2-[(3-chloro-4-fluoro-phenyl)-methyl-carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.54 mmol) in HCl in 1,4-dioxane (4M, 2 mL) was stirred at rt for 2 h. Upon completion, the mixture was evaporated to give (2S,4S)-4-benzyloxy-N-(3-chloro-4-fluoro-phenyl)-N-methyl-pyrrolidine-2-carboxamide (0.25 g, crude, HCl salt) as a yellow oil.

[0768] m / z ES+[M+H] + 363.8

[0769] Step d: A solution of crude (2S, 4S)-4-benzyloxy-N-(3-chloro-4-fluoro-phenyl)-N-methyl-pyrrolidine-2-carboxamide (0.24 g, 0.60 mmol, HCl salt), intermediate 1 (146 mg, 0.66 mmol) and DIPEA (233 mg, 1.80 mmol) in NMP (5 mL) was stirred at 60 ° C for 16 h. The reaction mixture was quenched by adding water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography (5-25% EtOAc in PE) to give (2S,4S)-4-benzyloxy-N-(3-chloro-4-fluoro-phenyl)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]-N-methylpyrrolidine-2-carboxamide (0.11 g, 0.036 mmol) as a yellow solid. m / z ES+[M+H] + 547.9

[0770] Step e: To a solution of (2S,4S)-4-benzyloxy-N-(3-chloro-4-fluoro-phenyl)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]-N-methyl-pyrrolidine-2-carboxamide (0.1 g, 0.18 mmol) in DCM (5 mL) was added BCl at 0 °C. 3 (1 M, 3.66 mL). The mixture was stirred at 0 °C for 20 min. Upon completion, the reaction mixture was quenched by the addition of cold water (10 mL) and washed with saturated NaHCO 3 The aqueous solution was adjusted to pH 8-9. The mixture was extracted into EtOAc (10 mL x 3), the combined organic extracts were washed with saline (10 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC and dried by lyophilization to obtain the title compound (44 mg, 0.095 mmol) as a yellow-white solid.

[0771] m / z ES+[M+H] + 457.8; 1 H NMR (400 MHz, CDCl 3 )δppm 7.61-7.60(m, 1H), 7.31(m, 1H), 7.25-7.23(m, 1H), 6.83(s, 1H), 4.70-4.66(m, 2 H), 4.50 (m, 1H), 4.32-4.25 (m, 2H), 3.33 (s, 3H), 2.55 (s, 3H), 2.17-2.05 (m, 2H).

[0772] Example 6

[0773] (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(4-fluoro-3-methylphenyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide

[0774]

[0775] Step a: A mixture of intermediate 4 (0.5 g, 1.56 mmol, 1 eq), 4-fluoro-3-methyl-aniline (234 mg, 1.87 mmol, 1.2 eq) and T3P (2.98 g, 4.68 mmol, 50 wt.% in EtOAc) in pyridine (2 mL) was stirred at rt for 12 h. The reaction mixture was evaporated and the residue was purified by column chromatography (5-25% EtOAc in PE) to give (2S,4S)-tert-butyl 4-benzyloxy-2-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidine-1-carboxylate (662 mg, 91% yield) as a colorless oil.

[0776] m / z ES+[M+H] + 429.3; 1 H NMR (400MHz, DMSO-d6) δppm 9.78-9.60 (m, 1H), 7.47-7.35 (m, 2H), 7.34-7.21 (m, 5H), 7.13-7.00 (m, 1H), 4.52-4.4 2(m, 2H), 4.32-4.12(m, 2H), 3.64(dd, J=5.9, 11.0Hz, 1H), 3.44-3.35(m, 1H), 2.43(br s, 1H), 2.19 (s, 3H), 2.11-2.00 (m, 1H), 1.49-1.24 (m, 9H)

[0777] Step bc: Perform as described in the synthesis of step cd of Example 5 to obtain (2S,4S)-4-benzyloxy-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]-N-(4-fluoro-3-methyl-phenyl)-N-methyl-pyrrolidine-2-carboxamide. m / z ES+[M+H] + 527.2

[0778] Step d: A mixture of (2S, 4S)-4-benzyloxy-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]-N-(4-fluoro-3-methyl-phenyl)-N-methyl-pyrrolidine-2-carboxamide (150 mg, 0.28 mmol) and Pd / C (30 mg, 10 wt.% loading) in EtOH (10 mL) was stirred at rt in a hydrogen atmosphere (balloon) for 12 h. Upon completion, the reaction mixture was filtered and evaporated. The crude residue was purified by preparative HPLC to give the title compound (58 mg, 47% yield) as a white solid.

[0779] m / z ES+[M+H] + 437.1; 1 H NMR (400MHz, DMSO-d6) δppm 7.45-7.40 (m, 1H), 7.40-7.25 (m, 2H), 7.08 (s, 1H), 5.32 (d, J=6.0Hz, 1H), 4.49 (t, J=8.4Hz, 1H), 4.25-4.10 (m, 1H) , 4.09-3.98(m, 1H), 3.67-3.58(m, 1H), 3.14(s, 3H), 2.53(s, 3H), 2.28(s, 3H), 2.19-2.03(m, 1H), 1.83-1.69(m, 1H)

[0780] The Examples in Table 1 were prepared using methods similar to those described in the syntheses of Examples 4-6.

[0781] Table 1

[0782]

[0783]

[0784]

[0785]

[0786]

[0787] Embodiment 23

[0788] (2S,4R)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0789]

[0790] The title compound was prepared in a manner analogous to Example 3 using (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (CAS No. 13726-69-7) in step a.

[0791] m / z ES+[M+H] + 419.38; 1 H NMR (400MHz, DMSO-d6) δppm 7.42 (t, J=7.7Hz, 1H), 7.36-7.29 (m, 2H), 7.25 (d, J=7.7Hz, 1H), 7.10 (s, 1H), 5.02 (d, J=3.3Hz, 1H), 4.66 (t, J=8.2Hz, 1H), 4.38 (br s, 1H), 4.00 (m, 1H), 3.67 (d, J=10.9Hz, 1H), 3.15 (s, 3H), 2.55 (s, 3H), 2.38 (s, 3H), 1.95 (m, 1H), 1.86 (t, J=10.2Hz, 1H).

[0792] Embodiment 24

[0793] (2S,3R)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0794]

[0795] The title compound was prepared in a manner analogous to Example 3 using (2S,3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (CAS No. 186132-96-7) in step a.

[0796] m / z ES+[M+H] + 419.51; 1 H NMR (400 MHz, CD 3 OD)δppm 7.47-7.36 (m, 3H), 7.32-7.22 (m, 1H), 6.96 (s, 1H), 4.87 (d, J=5.7Hz, 1H), 4.26-4.17 (m, 2H), 4.02-3.88 (m, 1H), 3.28 (s, 3H), 2.58 (s, 3H), 2.43 (s, 3H), 2.12-1.92 (m, 2H).

[0797] Embodiment 25

[0798] (2S,3R)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-3-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0799]

[0800] The title compound was prepared in a manner analogous to Example 3 using (2S,3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (CAS No. 186132-96-7) in step a and 2-chloro-3-cyano-4,6-dimethylpyridine (CAS No. 14237-71-9) in step b.

[0801] m / z ES+[M+H] + 365.47; 1 H NMR (400MHz, DMSO-d6) δppm 7.45-7.28 (m, 3H), 7.18 (d, J=6.8Hz, 1H), 6.56 (s, 1H), 5.34 (d, J=5.6Hz, 1H), 4.69 (d, J=6.3Hz, 1H), 4.17-4.03 ( m, 1H), 4.00-3.87 (m, 1H), 3.82-3.67 (m, 1H), 3.13 (s, 3H), 2.34 (d, J=4.6Hz, 6H), 2.32 (s, 3H), 2.06-1.89 (m, 2H).

[0802] Embodiment 26

[0803] (2S,3S)-1-(3-Cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0804]

[0805] The title compound was prepared in a manner analogous to Example 3 using (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (CAS No. 187039-57-2) in step a.

[0806] m / z ES+[M+H] + 419.47; 1 H NMR (400 MHz, CD 3OD)δppm 7.47-7.34(m, 3H), 7.31-7.25(m, 1H), 6.95(s, 1H), 4.72(s, 1H), 4.44(dt, J=4.2, 1.3Hz, 1H), 4 .23-4.14(m, 2H), 3.28(s, 3H), 2.58(s, 3H), 2.44(s, 3H), 2.37-2.28(m, 1H), 2.11-1.99(m, 1H).

[0807] Embodiment 27

[0808] (2S,4S)-4-Hydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)pyrrolidine-2-carboxamide

[0809]

[0810] The title compound was prepared in a similar manner to Example 3 using 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (CAS No. 22123-14-4) in step b.

[0811] m / z ES+[M+H] + 394.2; 1 H NMR (400 MHz, CDCl 3 )δppm 7.50-7.40(m, 1H), 7.35-7.25(m, 1H), 7.22-7.05(m, 2H), 6.73(s, 1H), 6.5 2(s, 1H), 4.80-4.20(m, 5H), 3.36(s, 3H), 2.96(s, 3H), 2.52-2.25(m, 5H).

[0812] Embodiment 28

[0813] (2S,4S)-4-Hydroxy-1-(4-isopropyl-6-methylpyridin-2-yl)-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0814]

[0815] The title compound was prepared in a similar manner to Example 3 using 2-chloro-4-isopropyl-6-methylpyridine (CAS No. 1427502-12-2) in step b.

[0816] m / z ES+[M+H] + 368.2; 1 H NMR (400 MHz, CD 3OD)δppm 7.50-7.46(m, 1H), 7.34-7.27(m, 3H), 6.81(s, 1H), 6.27(s, 1H), 4.67-4.62(m, 1H), 4.45-4.37(m, 1H), 3.92-3.83(m, 1H), 3.67- 3.59 (m, 1H), 3.31 (m, 3H), 3.02-2.95 (m, 1H), 2.56 (s, 3H), 2.44 (s, 3H), 2.37-2.30 (m, 1H), 2.18-2.10 (m, 1H), 1.33-1.28 (m, 6H).

[0817] Embodiment 29

[0818] (2S,4S)-1-(5-chloro-4,6-dimethylpyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0819]

[0820] The title compound was prepared in a similar manner to Example 3 using 3,6-dichloro-2,4-dimethylpyridine (CAS No. 1639373-35-5) in step b.

[0821] m / z ES+[M+H] + 374.2; 1 H NMR (400 MHz, CDCl 3 )δppm 7.35 (t, J=7.6Hz, 2H), 7.22-7.16 (m, 1H), 6.10 (s, 1H), 5.28 (d, J=12.4Hz, 1H), 4.58-4.55 (m, 1H), 4.44-4.41 (m, 1 H), 3.69-3.66(m, 1H), 3.51-3.47(m, 1H), 3.33(s, 3H), 2.52(s, 3H), 2.42(s, 3H), 2.27(s, 3H), 2.12-2.10(m, 2H).

[0822] Embodiment 30

[0823] (2S,4S)-1-(3-cyano-6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0824]

[0825] Step a: A solution of 2,6-dichloro-4-(trifluoromethyl)pyridine-3-carbonitrile (CAS No. 13600-42-5; 0.5 g, 2.07 mmol) and sodium methoxide (106 mg, 1.97 mmol) in MeOH (2 mL) was stirred at -10 ° C for 2 h. Upon completion, the mixture was filtered and evaporated. The resulting residue was purified by preparative TLC (25% EtOAc in PE) to give 2-chloro-6-methoxy-4-(trifluoromethyl)pyridine-3-carbonitrile (0.1 g, 20% yield) as a yellow solid.

[0826] 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.57 (d, J = 4.0 Hz, 1H), 4.03 (d, J = 3.6 Hz, 3H).

[0827] Step b: intermediate 3 (0.1g, 0.37mmol, HCl salt), 2-chloro-6-methoxy-4-(trifluoromethyl)pyridine-3-carbonitrile (87mg, 0.37mmol) and DIPEA (143mg, 1.11mmol) in NMP (2mL) are stirred at 60 DEG C for 16h. When completed, the reaction mixture is quenched by adding water (10mL), extracted with EtOAc (10mL x 3). The combined organic layer is washed with saline (10mL x3), dried and evaporated. The residue is purified by preparative-HPLC to obtain the title compound (47mg, 29% yield), which is a white solid.

[0828] m / z ES+[M+H] + 435.4; 1 H NMR (400 MHz, CDCl 3 )δppm 7.37-7.33 (m, 1H), 7.22-7.09 (m, 3H), 6.45 (s, 1H), 4.86 (d, J=7.2Hz, 1H), 4 .43-4.18(m, 4H), 4.00(s, 3H), 3.34(s, 3H), 2.41(s, 3H), 2.18-2.05(m, 2H).

[0829] Embodiment 31

[0830] (2S,4S)-1-(3-cyano-6-(ethyl(methyl)amino)-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0831]

[0832] Step a: 2,6-dichloro-4-(trifluoromethyl)pyridine-3-carbonitrile (CAS No. 13600-42-5; 0.5 g, 2.07 mmol), N-methylethylamine (147 mg, 2.49 mmol) and NaHCO 3 The chloro-6-[ethyl (methyl)-amino]-4-(trifluoromethyl)pyridine-3-carbonitrile (0.3g, 49% yield) of 2- was obtained by column chromatography (PE solution of 5-25% EtOAc), which was stirred for 16h at rt.

[0833] m / z ES+[M+H] + 264.0

[0834] Step b: A solution of 2-chloro-6-[ethyl(methyl)amino]-4-(trifluoromethyl)pyridine-3-carbonitrile (60mg, 0.23mmol), intermediate 3 (53mg, 0.23mmol, HCl salt) and DIPEA (88mg, 0.68mmol) in NMP (2mL) was stirred at 60°C for 16h. Upon completion, the reaction mixture was quenched by adding water (10mL) and extracted with EtOAc (10mL x3). The combined organic layer was washed with saline (10mL), dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC to obtain the title compound (23mg, 22% yield) as a yellow solid.

[0835] m / z ES+[M+H] + 462.2; 1 H NMR (400 MHz, CDCl 3 )δppm 7.35-7.31 (m, 1H), 7.19-7.16 (m, 3H), 6.23 (s, 1H), 4.86-4.83 (m, 1H), 4.36-4.32 (m, 1H), 4.24-4.20 (m, 1H), 4.11 -4.08 (m, 1H), 3.75-3.53 (m, 3H), 3.31 (s, 3H), 3.12 (s, 3H), 2.39 (s, 3H), 2.08-1.97 (m, 2H), 1.19 (t, J=3.6Hz, 3H).

[0836] Embodiment 32

[0837] (2S,4S)-1-(3-cyano-6-(dimethylamino)-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0838]

[0839] The title compound was prepared in a similar manner to Example 31 using dimethylamine in step a. m / z ES+[M+H] + 448.2; 1 H NMR (400 MHz, CDCl 3 )δppm 7.33 (t, J=7.6Hz, 1H), 7.22-7.11 (m, 3H), 6.25 (s, 1H), 4.81 (dd, J=8.0, 2.4Hz, 1H), 4.40-4.35 (m, 1 H), 4.26-4.20(m, 1H), 4.15-4.08(m, 1H), 3.31(s, 3H), 3.18(s, 6H), 2.39(s, 3H), 2.10-2.00(m, 2H).

[0840] Embodiment 33

[0841] (2S,4S)-1-(3-cyano-4-isopropyl-6-methylpyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0842]

[0843] Step a: To a solution of (E)-5-methylhex-3-en-2-one (5 g, 44.6 mmol) in EtOH (50 mL) was added 2-cyanoacetamide (4.12 g, 49.0 mmol) and diethylamine (1.63 g, 22.3 mmol). The mixture was stirred at 70 °C for 24 h. Upon completion, the mixture was evaporated and the residue was purified by column chromatography (30% EtOAc in PE) to give 2-hydroxy-4-isopropyl-6-methylnicotinonitrile (3.69 g, 45% yield) as a yellow solid. m / z ES+[M+H]+177.2

[0844] Step b: 2-Hydroxy-4-isopropyl-6-methylnicotinonitrile (3.69 g, 20.9 mmol) was slowly adsorbed on phosphorus oxychloride (61 g, 397 mmol). The mixture was stirred at 100 °C for 3 h. Upon completion, the mixture was slowly poured into ice water (200 mL). The aqueous phase was extracted with EtOAc (200 mL x 3). The residue was purified by evaporation with NaOH. 2 SO 4 The combined organic extracts were dried and evaporated. The residue was purified by column chromatography (2-5% EtOAc in PE) to give 2-chloro-4-isopropyl-6-methylnicotinonitrile (1.13 g, 28% yield) as a light yellow solid.

[0845] m / z ES+[M+H] + 195.1; 1 H NMR (400 MHz, CDCl 3 )δppm 7.10 (s, 1H), 3.40-3.25 (m, 1H), 2.60 (s, 3H), 1.32 (d, J=6.8Hz, 6H).

[0846] Step c: A mixture of 2-chloro-4-isopropyl-6-methylnicotinonitrile (100 mg, 0.51 mmol), intermediate 3 (120 mg, 0.51 mmol, HCl salt), DIPEA (199 mg, 1.54 mmol) in NMP (1 mL) was stirred at 60 ° C for 16 h. Upon completion, EtOAc (10 mL) and water (10 mL) were added to the reaction mixture and then separated. The aqueous phase was extracted with EtOAc (10 mL x 2). The combined organic extracts were dried and evaporated. The residue was purified by preparative HPLC to give the title compound (16.7 mg, 8% yield) as a yellow solid.

[0847] m / z ES+[M+H] + 393.1; 1 H NMR (400MHz, DMSO-d6) δppm 7.42-7.19 (m, 4H), 6.65 (s, 1H), 5.25 (d, J=6.4Hz, 1H), 4.44 (t, J=8.0Hz, 1H), 4.09 (s, 1H), 4.00-3.92 (m, 1H), 3.62 (dd, J=9.6, 7.2Hz, 1H), 3.14(s, 3H), 3.12-3.06(m, 1H), 2.40(s, 3H), 2.36(s, 3H), 2.15-2.05(m, 1H), 1.78-1.68(m, 1H), 1.25-1.15(m, 6H).

[0848] Embodiment 34

[0849] (2S,4S)-1-(3-cyano-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0850]

[0851] Step a: To a solution of 4-(trifluoromethyl)nicotinonitrile (500 mg, 2.91 mmol) in DCM (40 mL) was added H 2 O 2(659 mg, 5.81 mmol, 30% aqueous solution) was then added dropwise with TFA (663 mg, 5.81 mmol) at 0°C. The reaction mixture was heated at 40°C under N 2 Stir for 16 h under atmosphere. When complete, add saturated NH 4 The mixture was quenched with aqueous Cl solution (40 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried and evaporated to give 3-cyano-4-(trifluoromethyl)pyridine 1-oxide (500 mg, crude) as a white solid. m / z ES+[M+H] + 189.2

[0852] Step b: Add POCl 3 3-cyano-4-(trifluoromethyl)pyridine 1-oxide (500mg, 2.66mmol) in (4.08g, 26.6mmol) is stirred at 110 DEG C for 12h.When completed, the mixture is quenched by adding ice water (10mL), extracted with EtOAc (10mL x 3).The combined organic layer is washed with saline (10mL x 3), dried and evaporated.By preparative TLC purification of residue (25% EtOAc PE solution), 2-chloro-4-(trifluoromethyl) nicotinonitrile (100mg, 18% yield, two steps) is obtained as a colorless oil.

[0853] m / z ES+[M+H] + 207.2

[0854] Step c: To a solution of 2-chloro-4-(trifluoromethyl)nicotinonitrile (50 mg, 0.24 mmol) in NMP (1 mL) was added DIPEA (78 mg, 0.61 mmol) and intermediate 3 (55 mg, 0.20 mmol, HCl salt). The reaction mixture was stirred at 80 ° C for 16 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by preparative-HPLC to give the title compound (31 mg, 37% yield) as a brown solid.

[0855] m / z ES+[M+H] + 405.2; 1H NMR (400MHz, DMSO-d6) δppm 8.63 (d, J=4.4Hz, 1H), 7.43-7.19 (m, 4H), 7.14 (d, J=4.8Hz, 1H), 5.35 (d, J=6.0Hz, 1H), 4.51-4.43 (m, 1H), 4.20-4 .10 (m, 1H), 4.09-4.00 (m, 1H), 3.65-3.60 (m, 1H), 3.14 (s, 3H), 2.36 (s, 3H), 2.17-2.08 (m, 1H), 1.83-1.70 (m, 1H).

[0856] Embodiment 35

[0857] (2S,4S)-1-(4-ethyl-5-methylpyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0858]

[0859] Step a: To potassium trifluoro(vinyl)borate (CAS No. 13682-77-4; 649 mg, 4.84 mmol), 4-bromo-2-chloro-5-methyl-pyridine (CAS No. 867279-13-8; 500 mg, 2.42 mmol), K 2 CO 3 To a solution of (1.67 g, 12.1 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was added Pd(dppf)Cl 2 · DCM (198 mg, 0.24 mmol). 2 The reaction mixture was purged 3 times and then heated at 80 °C under N 2 Stir for 16 h in atmosphere. Upon completion, the reaction mixture was quenched by adding water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried and evaporated. The residue was purified by column chromatography (5-10% EtOAc in PE) to give 2-chloro-5-methyl-4-vinyl-pyridine (0.11 g, 27% yield) as a colorless oil. m / z ES+[M+H]+154.2

[0860] Step b: 2-chloro-5-methyl-4-vinyl-pyridine (55 mg, 0.36 mmol), intermediate 3 (97 mg, 0.36 mmol, HCl salt), Cs 2 CO 3To 4- hydroxy-N- methyl -1- (5- methyl -4- vinyl -2- pyridyl) -N- (m-tolyl) pyrrolidine -2- formamide (0.12 g, 91% yield) was added to the mixture of ...Pd-G2 (350 mg, 1.07 mmol) and RuPhos-Pd-G2 (28 mg, 0.036 mmol) in 1,4- dioxanes (10 mL) and stirred at 80 ° C for 4 h. When completed, the reaction mixture was quenched by adding water (5 mL), extracted with EtOAc (5 mL x 3). The combined organic layer was washed with saline (5 mL x 3), dried over sodium sulfate, and evaporated. The residue was purified by preparative TLC (30% EtOAc PE solution), to obtain (2S, 4S) -4- hydroxy-N- methyl -1- (5- methyl -4- vinyl -2- pyridyl) -N- (m-tolyl) pyrrolidine -2- formamide (0.12 g, 91% yield), as a white solid.

[0861] m / z ES+[M+H]+352.4

[0862] Step c: A suspension of (2S,4S)-4-hydroxy-N-methyl-1-(5-methyl-4-vinyl-2-pyridinyl)-N-(m-tolyl)pyrrolidine-2-carboxamide (0.12 g, 0.34 mmol) and Pd / C (12 mg, 10 wt.% loading) in MeOH (2 mL) was stirred at rt under H 2 Stir under balloon (1 atm) for 3 h. Filter the mixture and evaporate the filtrate to give the title compound (35 mg, 28% yield) as a grey solid.

[0863] m / z ES+[M+H] + 354.2; 1 H NMR (400 MHz, CDCl 3 )δppm 7.86 (s, 1H), 7.34 (t, J = 7.6Hz, 2H), 7.18 (d, J = 7.6Hz, 1H), 6.15 (s, 1H), 5.58 (d, J = 11.6Hz, 1H), 4.52-4.42 (m, 2H), 3.76-3.71 (m, 1H ), 3.51-3.48 (m, 1H), 3.32 (s, 3H), 2.52 (dd, J=15.2, 7.6Hz, 2H), 2.42 (s, 3H), 2.13 (s, 3H), 2.11-2.08 (m, 2H), 1.18 (t, J=7.6Hz, 3H).

[0864] Embodiment 36

[0865] (2S,4S)-1-(3-Cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-4-methoxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0866]

[0867] A suspension of Example 3 (15 mg, 0.036 mmol) in MeCN (1 mL) was slowly treated with silver (I) oxide (25 mg, 0.108 mmol). The reaction mixture was cooled to 0 °C and iodomethane (0.011 mL, 0.179 mmol) was added dropwise. The reaction system was stirred at rt for 18 h. Additional iodomethane batches (3 x 0.022 mL, 0.352 mmol) were added over 5 days. The reaction mixture was diluted with EtOAc (10 mL) and filtered through CELITE. Water (15 mL), saturated NaHCO 3 The filtrate was washed with aqueous solution (15 mL) and brine (15 mL), dried and evaporated. The residue was purified by preparative-HPLC to give the title compound (5.8 mg, 38%). m / z ES+[M+H] + 433.47; 1 H NMR (400MHz, DMSO-d6) δppm 7.41 (t, J=7.7Hz, 1H), 7.36-7.19 (m, 3H), 7.11 (s, 1H), 4.58 (t, J=8.3Hz, 1H), 4.22-4.12 (m, 1H), 3.91 (m, 1 H), 3.63 (m, 1H), 3.25 (s, 3H), 3-14 (s, 3H), 2.54 (s, 3H), 2.37 (s, 3H), 2.31-2.22 (m, 1H), 1.80-1.69 (m, 1H).

[0868] Embodiment 37

[0869] (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-(3,4-difluorophenyl)-N-ethyl-4-fluoropyrrolidine-2-carboxamide

[0870]

[0871] Step a: A solution of N-ethyl-3,4-difluoroaniline (0.07 mL, 0.44 mmol), (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (CAS No. 203866-13-1; 0.25 g, 1.07 mmol) and pyridine (0.35 mL, 4.29 mmol) in EtOAc (1 mL) was treated with T3P (1.28 mL, 2.14 mmol, 50 wt.% in EtOAc) at 0°C. The mixture was stirred at rt for 3 days. The reaction mixture was quenched with 0.5 M aqueous HCl and extracted into EtOAc. The organic extracts were washed with brine, dried and evaporated. The residue was purified by column chromatography (10-50% EtOAc in cycloalkyl) to give (2S,4S)-2-[(3,4-difluorophenyl)-ethyl-carbamoyl]-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (0.170 g, 42%) as a clear gum. m / z ES+[M+H] + 373

[0872] Step b: A solution of (2S,4S)-2-[(3,4-difluorophenyl)-ethyl-carbamoyl]-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (0.17 g, 0.457 mmol) in DCM (5 mL) was treated with TFA (1 mL) and stirred at rt for 3 days. The reaction mixture was evaporated, redissolved in MeOH and loaded onto SCX-2. The column was washed with MeOH and then eluted with methanolic ammonia (7 M). The basic fraction was evaporated to give (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-fluoro-pyrrolidine-2-carboxamide (0.072 g, 58%) as a white solid which was used directly in the next step. m / z ES+[M+H] + 273

[0873] Step c: A solution of (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-fluoro-pyrrolidine-2-carboxamide (50 mg, 0.18 mmol), 2-chloro-4,6-dimethylnicotinonitrile (30 mg, 0.198 mmol) and DIPEA (0.09 mL, 0.54 mmol) in NMP (2 mL) was heated at 90° C. for 2 h and then at 130° C. for 4 h. The reaction mixture was cooled and purified by preparative-HPLC to give the title compound (5.2 mg, 7%) as a light brown solid.

[0874] m / z ES+[M+H] + 403; 1 H NMR (400 MHz, CD 3OD) δppm7.64-7.55 (m, 1H), 7.53-7.37 (m, 2H), 6.61 (s, 1H), 5.29 (d, J=55.3Hz, 1H), 4.88-4.80 (m, 1H), 4.45-4.15 (m, 2H), 4.02-3.89 (m, 1H), 3.60-3.48 (m, 1H), 2.45 (s, 3H), 2.41 (s, 3H), 2.32-2.14 (m, 2H), 1.16 (t, J=7.1Hz, 3H).

[0875] Embodiment 38

[0876] (2S,4S)-4-amino-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0877]

[0878] Step a: A solution of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester hydrochloride (CAS No. 171110-72-8; 1.0 g, 3.46 mmol) and DIPEA (1.81 mL, 10.4 mmol) in DCM (8 mL) was treated with allyl chloroformate (0.44 mL, 4.15 mmol) at 0°C and then stirred at rt for 3 h. The mixture was partitioned between saturated NH 4 The reaction mixture was stirred for 2 h between aqueous Cl and DCM and the layers were separated. The organic layer was washed with brine, dried and evaporated to give (2S,4S)-4-(allyloxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.2 g) which was used without further purification.

[0879] m / z ES+[M+H] + 329.43; 1 H NMR (400MHz, DMSO-d6) δppm 7.46-7.43 (m, 1H), 5.98-5.85 (m, 1H), 5.33-5.24 (m, 1H), 5.22-5.13 (m, 1H), 4.55-4.42 (m, 2H), 4.19 (t, J=8.1Hz, 1H ), 4.11-3.97(m, 1H), 3.71-3.61(m, 4H), 3.11-3.03(m, 1H), 2.50-2.39(m, 1H), 1.86-1.70(m, 1H), 1.43-1.28(m, 9H).

[0880] Step b: 2M NaOH aqueous solution (3.6 mL, 7.25 mmol) was added to (2S,4S)-4-(allyloxycarbonylamino)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.2 g, 3.62 mmol) in MeOH (4 mL) at 0°C, the mixture was warmed to rt and stirred for 4 h. The mixture was evaporated and then partitioned between NaHCO 3 The aqueous solution was stirred for 2 h and then the mixture was stirred for 3 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 3 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 3 h. The mixture was stirred for 2 h.

[0881] m / z ES+[M+H] + 315.43; 1 H NMR (400MHz, DMSO-d6) δppm 12.25 (s, 1H), 7.41 (d, J=7.4Hz, 1H), 5.99-5.81 (m, 1H), 5.34-5.22 (m, 1H), 5.22-5.13 (m, 1H), 4.58-4.42 (m, 2H), 4.08-3.94(m, 2H), 3.74-3.58(m, 1H), 3.09-2.97(m, 1H), 2.49-2.41(m, 1H), 1.83-1.68(m, 1H), 1.43-1.33(m, 9H).

[0882] Step c: A solution of N-ethyl-3-methylaniline (0.17 mL, 1.15 mmol), (2S,4S)-4-(allyloxy-carbonylamino)-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (0.28 g, 0.884 mmol) and pyridine (0.29 mL, 3.54 mmol) in EtOAc (0.9 mL) was treated with T3P (1.04 mL, 1.77 mmol, 50 wt.% in EtOAc) and stirred for 18 h. The mixture was diluted with EtOAc, washed twice with 1 M aqueous HCl, brine, dried and evaporated to give a crude oil (400 mg). The crude product was purified by column chromatography (0-35% EtOAc in cyclohexane) to give (2S,4S)-tert-butyl 4-(allyloxycarbonylamino)-2-[ethyl(m-tolyl)-carbamoyl]pyrrolidine-1-carboxylate (205 mg, 54%).

[0883] m / z ES+[M+H] + 432.24; 1H NMR (400MHz, DMSO-d6) δppm 7.46-7.32 (m, 2H), 7.28-7.19 (m, 1H), 7.16-7.02 (m, 2H), 5.89 (ddt, J=17.3, 10.6, 5.4Hz , 1H), 5.26 (dt, J=17.2, 1.7Hz, 1H), 5.18 (dq, J=10.5, 1.5Hz, 1H), 4.46 (d, J=5.4Hz, 2H), 3 .99-3.90(m, 1H), 3.90-3.81(m, 1H), 3.75-3.63(m, 1H), 3.63-3.52(m, 2H), 3.12-3.00(m , 1H), 2.35 (s, 3H), 2.13-2.03 (m, 1H), 1.75-1.62 (m, 1H), 1.40 (s, 9H), 1.08-0.97 (m, 3H).

[0884] Step d: A solution of (2S,4S)-4-(allyloxycarbonylamino)-2-[ethyl(m-tolyl)-carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (184 mg, 0.426 mmol) in MeOH (4 mL) was treated with 4M HCl in 1,4-dioxane (0.11 mL, 0.44 mmol) and stirred for 2 h. The mixture was evaporated and then loaded onto SCX-2 in MeOH, washed with MeOH and eluted with methanolic ammonia (2 M). The basic fractions were evaporated to give N-[(3S,5S)-5-[ethyl(m-tolyl)carbamoyl]-pyrrolidin-3-yl]carbamic acid allyl ester (99 mg, 70%).

[0885] m / z ES+[M+H] + 332.48; 1H NMR (400MHz, DMSO-d6) δppm 7.36 (t, J=7.7Hz, 1H), 7.27 (d, J=7.0Hz, 1H), 7.22 (d, J=7.7Hz, 1H), 7.10 (s, 1H), 7.06 (d, J=7.9Hz, 1H), 5.90 (ddt, J=17. 4, 10.6, 5.4Hz, 1H), 5.27 (dq, J=17.2, 1.7Hz, 1H), 5.17 (dq, J=10.5, 1.6Hz, 1H), 4.44 (dt, J=5.3, 1.6Hz, 2H), 3.81-3.70 (m , 1H), 3.68 (dq, J=14.7, 7.2Hz, 1H), 3.59 (dq, J=13.9, 7.3Hz, 1H), 3.31 (d, J=9.2Hz, 1H), 2.78 (dd, J=11.3, 4.1Hz, 1H), 2.6 2 (dd, J=11.3, 6.0Hz, 1H), 2.35 (s, 3H), 1.77 (dt, J=13.0, 7.8Hz, 1H), 1.50 (dt, J=12.9, 6.5Hz, 1H), 1.01 (t, J=7.1Hz, 3H).

[0886] Step e: A mixture of allyl N-[(3S,5S)-5-[ethyl(m-tolyl)carbamoyl]pyrrolidin-3-yl]carbamate (97 mg, 0.293 mmol), 2-chloro-4,6-dimethylnicotinonitrile (0.05 g, 0.293 mmol) and DIPEA (0.2 mL, 1.17 mmol) in NMP (1.6 mL) was heated at 130 °C for 3 h. The mixture was partitioned between EtOAc and saturated NaHCO 3 The aqueous solution was stirred for 2 hours and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried and evaporated to give allyl N-[(3S,5S)-1-(3-cyano-4,6-dimethyl-2-pyridinyl)-5-[ethyl(m-tolyl)carbamoyl]pyrrolidin-3-yl]carbamate (70 mg, 52%).

[0887] m / z ES+[M+H] + 462.54; 1H NMR (400MHz, DMSO-d6) δppm 7.55 (d, J=7.3Hz, 1H), 7.41 (t, J=7.7Hz, 1H), 7.38-7.21 (m, 3H), 6.61 (s, 1H), 5.90 (ddt, J=16.2, 10.6, 5.4Hz, 1H), 5.28 (d, J=17.2Hz, 1H), 5.18 (d, J=10.5Hz, 1H), 4.47 (d, J=5.7Hz, 2H), 4.42 (dd, J=9.1, 7.4 Hz, 1H), 4.06-3.94 (m, 2H), 3.77 (dq, J=14.1, 7.1Hz, 1H), 3.70-3.59 (m, 1H), 3.43 (dq, J=14.4, 7.1Hz, 1 H), 2.40 (s, 3H), 2.37 (s, 3H), 2.33 (s, 3H), 2.13-2.02 (m, 1H), 1.81-1.67 (m, 1H), 1.01 (t, J=7.1Hz, 3H)

[0888] Step f: Tetrakis(triphenylphosphine)palladium (0.02 g, 0.015 mmol) was added to N-[(3S,5S)-1-(3-cyano-4,6-dimethyl-2-pyridinyl)-5-[ethyl(m-tolyl)carbamoyl]pyrrolidin-3-yl]-carbamic acid allyl ester (70 mg, 0.152 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.09 g, 0.758 mmol) in DCM (4 mL) and the mixture was stirred for 5 h. The mixture was partitioned between EtOAc and saturated NaHCO 3 The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried and evaporated. The residue was purified by mass-directed preparative HPLC to give the title compound (25 mg, 44%).

[0889] m / z ES+[M+H] + 378.48; 1H NMR (400MHz, DMSO-d6) δppm 7.40 (t, J=7.6Hz, 1H), 7.36-7.19 (m, 3H), 6.57 (s, 1H), 4.37 (t, J=8.3Hz, 1H), 3 .90 (dd, J=9.5, 7.0Hz, 1H), 3.76 (dt, J=14.1, 7.0Hz, 1H), 3.49 (t, J=8.9Hz, 1H), 3.45-3.39(m, 1H), 3.24-3.12(m, 1H), 2.38(s, 3H), 2.37(s, 3H), 2.32(s, 3H), 1. 96 (dt, J=13.0, 6.9Hz, 1H), 1.55 (dt, J=12.1, 9.4Hz, 1H), 1.01 (t, J=7.0Hz, 3H).

[0890] Embodiment 39

[0891] (2R,4R)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-4-(dimethylamino)-N-ethyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0892]

[0893] A solution of Example 38 (20 mg, 0.053 mmol) in THF (1.0 mL) was treated with formaldehyde (37% aqueous solution; 0.11 mL, 1.325 mmol) followed by acetic acid (0.01 mL, 0.175 mmol) and the mixture was stirred for 5 min. Sodium triacetoxyborohydride (20 mg, 0.106 mmol) was added and the mixture was stirred for 2 h. The mixture was partitioned with saturated NaHCO 3 Between aqueous solution and DCM. Separate the layers and extract the aqueous layer with EtOAc. Dry the combined organic layers and evaporate to give the title compound (16 mg, 74%). m / z ES+[M+H] + 406.30; 1H NMR (400 MHz, acetone-d6) δ ppm 7.42 (m, 3H), 7.27 (d, J = 7.4 Hz, 1H), 6.54 (s, 1H), 4.60 (dd, J = 10.4, 7.1 Hz, 1H), 4.13 (dd, J = 9.3, 7.0 Hz, 1H), 3.85 (dq, J = 14.2, 7.1 Hz, 1H), 3.74 (t, J = 9.5 Hz, 1H), 3.51 (dq, J = 14.0, 7.0Hz, 1H), 2.55 (ddt, J=10.9, 9.4, 6.7Hz, 1H), 2.45 (s, 3H), 2.42 (s, 3H), 2.37 ( s, 3H), 2.20 (s, 6H), 2.09-2.08 (m, 1H), 1.74 (q, J=11.0Hz, 1H), 1.07 (t, J=7.1Hz, 3H).

[0894] Embodiment 40

[0895] (2S,4R)-4-amino-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0896]

[0897] The title compound was prepared in a similar manner to Example 38 using (2S,4R)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester hydrochloride (CAS No. 334999-32-5) in step a. m / z ES+[M+H] + 378.49; 1 H NMR (400MHz, DMSO-d6) δppm 7.40 (t, J=7.7Hz, 1H), 7.37-7.25 (m, 2H), 7.23 (d, J=7.6Hz, 1H), 6.56 (s, 1H), 4.54 ( t, J=7.0Hz, 1H), 3.96 (dd, J=10.0, 5.8Hz, 1H), 3.77 (dq, J=14.0, 7.3Hz, 1H), 3.68-3. 59 (m, 1H), 3.46 (dd, J=9.9, 4.0Hz, 1H), 3.44-3.39 (m, 1H), 2.39 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H), 1.88 (dt, J=12.0, 5.9Hz, 1H), 1.63-1.52 (m, 2H), 1.00 (t, J=7.0Hz, 3H).

[0898] Embodiment 41

[0899] (2S,4R)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-4-(dimethylamino)-N-ethyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0900]

[0901] The title compound was prepared in a similar manner to Example 39.

[0902] m / z ES+[M+H] + 406.32; 1 H NMR (400MHz, DMSO-d6) δppm 7.46-7.30 (m, 3H), 7.30-7.18 (m, 1H), 6.59 (s, 1H), 4.52 (dd, J=8.4, 3.3Hz, 1H), 4. 03 (dd, J=9.7, 7.1Hz, 1H), 3.80 (dq, J=14.1, 7.1Hz, 1H), 3.67 (dd, J=9.7, 6.3Hz, 1H) , 3.48-3.36 (m, 1H), 3.01 (p, J=6.8Hz, 1H), 2.39 (s, 3H), 2.36 (s, 3H), 2.33 (s, 3H), 2 .07 (s, 6H), 2.03-1.92 (m, 1H), 1.75 (dt, J=12.6, 8.5Hz, 1H), 1.01 (t, J=7.1Hz, 3H).

[0903] Embodiment 42

[0904] (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-4-morpholino-N-(m-tolyl)pyrrolidine-2-carboxamide

[0905]

[0906] Step a: A solution of N-Boc-(2S,4R)-4-hydroxyproline (2.0 g, 8.48 mmol) and N-ethyl-3-methylaniline (2.44 mL, 16.95 mmol) in DCM (5 mL) was treated with EEDQ (4.23 g, 16.95 mmol) and stirred for 2 h. N-ethyl-3-methylaniline (1.22 mL, 8.48 mmol) and EEDQ (2.12 g, 8.48 mmol) were added and the mixture was stirred for another 2 h. A third batch of N-ethyl-3-methylaniline (1.22 mL, 8.48 mmol) and EEDQ (2.12 g, 8.48 mmol) were added and stirred for another 2 h. A final batch of EEDQ (2.12 g, 8.48 mmol) was added and the mixture was stirred for 16 h. The mixture was diluted with DCM and washed with aqueous HCl, saturated NH 4 The product was washed twice with aqueous Cl solution, water and brine. The organic extract was dried and evaporated to give a yellow oil (7 g). The mixture was purified by column chromatography (0-5% MeOH in DCM) to give (2S, 4R)-2-[ethyl(m-tolyl)carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 51%) as a colorless gum.

[0907] m / z ES+[M+H] + 349.47; 1 H NMR (400MHz, DMSO-d6) δppm 7.46-7.32(m, 1H), 7.29-7.19(m, 1H), 7.17-7.02(m, 2H), 4.89-4.80(m, 1H), 4.07-3.99(m, 1H), 3.76-3.46(m, 2H), 3.37- 3.28 (m, 2H), 3.25-3.20 (m, 1H), 2.36 (s, 3H), 1.89-1.75 (m, 1H), 1.75-1.65 (m, 1H), 1.46-1.35 (m, 9H), 1.07-0.94 (m, 3H).

[0908] Step b: A solution of (2S,4R)-2-[ethyl(m-tolyl)carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.87 mmol) in MeOH (10 mL) was treated with 4M HCl in 1,4-dioxane (0.72 mL, 2.87 mmol). The mixture was stirred for 3 h. The mixture was evaporated and then loaded onto SCX-2 in MeOH, washed with MeOH and eluted with methanolic ammonia (2 M). The basic fraction was evaporated to give (2S,4R)-N-ethyl-4-hydroxy-N-(m-tolyl)-pyrrolidine-2-carboxamide (665 mg, 93%) as a colorless solid.

[0909] m / z ES+[M+H] + 249.36; 1 H NMR (400MHz, DMSO-d6) δppm 7.36 (t, J=7.7Hz, 1H), 7.22 (d, J=7.6Hz, 1H), 7.11 (s, 1H), 7.07 (d, J=7.8Hz, 1H), 4.5 2(d, J=4.0Hz, 1H), 4.15-4.08 (m, 1H), 3.67 (dq, J=14.2, 7.1Hz, 1H), 3.56 (dq, J=14.0, 7.0Hz, 1H), 3.45 (t, J=7.9Hz, 1H), 3.07 (dd, J=11.6, 5.2Hz, 1H), 2.35 (s, 3H), 1.65 (dd d, J=13.0, 8.8, 6.2Hz, 1H), 1.42 (ddd, J=12.9, 7.1, 2.2Hz, 1H), 1.00 (t, J=7.1Hz, 3H).

[0910] Step c: A mixture of (2S,4R)-N-ethyl-4-hydroxy-N-(m-tolyl)pyrrolidine-2-carboxamide (200 mg, 0.805 mmol), 2-chloro-4,6-dimethylnicotinonitrile (134 mg, 0.805 mmol) and DIPEA (1.12 mL, 6.4 mmol) in NMP (1.5 mL) was heated at 110° C. for 4 h. The temperature was increased to 130° C. and the reaction was stirred for 1 h. The mixture was cooled and partitioned between EtOAc and saturated NaHCO 3 The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried and evaporated to give a brown oil (700 mg). The mixture was purified by column chromatography (30-80% EtOAc in cyclohexane) to give (2S,4R)-1-(3-cyano-4,6-dimethyl-2-pyridinyl)-N-ethyl-4-hydroxy-N-(m-tolyl)pyrrolidine-2-carboxamide (245 mg, 80%) as a colorless gum.

[0911] m / z ES+[M+H] + 379.45; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.46-7.20 (m, 4H), 6.59 (s, 1H), 4.97 (d, J=3.3Hz, 1H), 4.54 (t, J=8.1Hz, 1 H), 4.37-4.30 (m, 1H), 3.95 (dd, J=10.6, 4.1Hz, 1H), 3.77 (dq, J=14.1, 7.1H z, 1H), 3.63 (d, J=10.6Hz, 1H), 3.47-3.38 (m, 1H), 2.40 (s, 3H), 2.37 (s, 3H) , 2.33 (s, 3H), 1.91-1.81 (m, 1H), 1.81-1.71 (m, 1H), 1.00 (t, J=7.1Hz, 3H).

[0912] Step d: A solution of oxalyl chloride (0.08 mL, 0.971 mmol) in DCM (2.5 mL) was treated at -78 °C by adding a mixture of DMSO (0.14 mL, 1.94 mmol) in DCM (2 mL) dropwise and stirred for 5 min. The reaction mixture was treated by adding a solution of (2S, 4R)-1-(3-cyano-4,6-dimethyl-2-pyridinyl)-N-ethyl-4-hydroxy-N-(m-tolyl)pyrrolidine-2-carboxamide (245 mg, 0.647 mmol) in DCM (3 mL) dropwise and stirred for 5 min. TEA (0.45 mL, 3.24 mmol) was then added dropwise and the mixture was stirred for 15 min. The mixture was then warmed to rt and stirred for 10 min. Saturated NH 4 Cl aqueous solution and DCM, the layers were separated. The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, dried, and evaporated to give a brown oil (300 mg). The crude product was purified by column chromatography (10-40% EtOAc in cyclohexane) to give (2S)-1-(3-cyano-4,6-dimethyl-2-pyridinyl)-N-ethyl-N-(m-tolyl)-4-oxo-pyrrolidine-2-carboxamide (203 mg, 83%)

[0913] m / z ES+[M+H] + 377.42; 1H NMR (400MHz, DMSO-d6) δppm 7.41 (t, J=7.7Hz, 1H), 7.38-7.28 (m, 2H), 7.25 (d, J=7.6Hz, 1H), 6.73 (s, 1H), 4.94 ( dd, J=9.6, 2.5Hz, 1H), 4.46 (d, J=17.0Hz, 1H), 4.18 (d, J=17.0Hz, 1H), 3.68 (dq, J=1 4.1, 7.1Hz, 1H), 3.50 (dq, J=14.0, 7.1Hz, 1H), 2.76 (dd, J=18.0, 9.6Hz, 1H), 2.63 (d d, J=18.1, 2.5Hz, 1H), 2.42 (s, 3H), 2.37 (s, 3H), 2.36 (s, 3H), 0.99 (t, J=7.1Hz, 3H).

[0914] Step e: Sodium triacetoxyborohydride (180 mg, 0.85 mmol) was added to a mixture of (2S)-1-(3-cyano-4,6-dimethyl-2-pyridinyl)-N-ethyl-N-(m-tolyl)-4-oxo-pyrrolidine-2-carboxamide (80 mg, 0.213 mmol), morpholine (0.04 mL, 0.425 mmol) and acetic acid (0.01 g, 0.213 mmol) in THF (5 mL) and stirred for 16 h. The mixture was partitioned with saturated NaHCO 3 The aqueous solution was partitioned with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were evaporated. The residue was purified by mass-directed preparative HPLC to give the title compound (47 mg, 49%).

[0915] m / z ES+[M+H] + 448.57; 1 H NMR (400 MHz, CD 3OD)δppm 7.57-7.11 (m, 4H), 6.57 (s, 1H), 4.57 (dd, J=10.6, 6.8Hz, 1H), 4.16 (dd, J=9.4, 7.3Hz, 1H), 3 .89 (dq, J=13.6, 7.1Hz, 1H), 3.82 (t, J=9.5Hz, 1H), 3.76-3.62 (m, 4H), 3.53 (dq, J=14.2, 7.2 Hz, 1H), 2.73 (ddt, J=11.0, 9.5, 6.9Hz, 1H) 2.61-2.51 (m, 2H), 2.49-2.43 (m, 5H), 2.41 (s, 3H ), 2.38 (s, 3H), 2.18 (dt, J=12.6, 6.6Hz, 1H), 1.78 (q, J=11.2Hz, 1H), 1.12 (t, J=7.1Hz, 3H).

[0916] The examples in Table 2 were prepared by methods similar to those described for the synthesis of Example 42.

[0917]

[0918]

[0919]

[0920] Embodiment 48

[0921] (2R,4R)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-4-(methyl(pyrrolidin-3-yl)amino)-N-(m-tolyl)pyrrolidine-2-carboxamide

[0922]

[0923] Step a: A solution of (2S)-1-(3-cyano-4,6-dimethyl-2-pyridinyl)-N-ethyl-N-(m-tolyl)-4-oxo-pyrrolidine-2-carboxamide (60 mg, 0.159 mmol), 1-Boc-3-methylamino-pyrrolidine (0.02 mL, 0.32 mmol) and acetic acid (0.01 mL, 0.161 mmol) in THF (3.7 mL) was treated with sodium triacetoxyborohydride (0.07 g, 0.32 mmol) and the mixture was stirred for 18 h. Additional sodium triacetoxyborohydride (0.07 g, 0.32 mmol) was added and the mixture was stirred for an additional 6 h. The mixture was partitioned between saturated NaHCO 3The layers were separated between aqueous solution and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were evaporated. The residue was purified by mass directed preparative HPLC and the fractions evaporated to give a clear gum (45 mg).

[0924] Step b: A solution of the crude intermediate in MeOH (2 mL) was treated with 4M HCl in 1,4-dioxane (1.85 mL, 7.4 mmol) and stirred for 2 h. The reaction was evaporated and then loaded onto SCX-2 in MeOH, washed with MeOH and eluted with methanolic ammonia (2 M). The basic fractions were evaporated to give the title compound (33 mg, 45%).

[0925] m / z ES+[M+H] + 461.59; 1 H NMR (400MHz, DMSO-d6) δppm 7.41 (t, J=7.7Hz, 1H), 7.38-7.25 (m, 2H), 7.24 (d, J=7.6Hz, 1H), 6.59 (s, 1H), 4.46-4.34 ( m, 1H), 3.88 (t, J=8.3Hz, 1H), 3.77 (dq, J=14.0, 7.0Hz, 1H), 3.70-3.58 (m, 1H), 3.47-3.38 (m, 2H), 3.12-3.03 (m, 2H), 2.86-2.68 (m, 3H), 2.39 (s, 3H), 2.37 (s, 3H), 2.33 (s, 3H), 2.1 3(s, 3H), 1.98-1.87(m, 1H), 1.76-1.61(m, 2H), 1.56-1.47(m, 1H), 1.00(t, J=7.1Hz, 3H).

[0926] The examples in Table 3 were prepared by methods similar to those described for the synthesis of Example 48.

[0927]

[0928]

[0929] Embodiment 52

[0930] (2R,4R)-4-((1-acetylpyrrolidin-3-yl)(methyl)amino)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0931]

[0932] A solution of Example 48 (16.0 mg, 0.035 mmol) in DCM (1 mL) was treated with acetic anhydride (0.01 mL, 0.104 mmol) and TEA (0.05 mL, 0.347 mmol) and stirred at rt for 1 h. The mixture was partitioned with saturated NaHCO 3 The layers were separated and then washed with saturated NaHCO 3 The organic layer was washed with aqueous solution and brine, dried and evaporated. The crude product was purified by column chromatography (0-10% MeOH in DCM). The product fractions were combined and evaporated. The material was dissolved in DCM, washed with 1M NaOH aqueous solution and brine, dried and evaporated. The product was further dried in vacuo to give the title compound (11.1 mg, 63%).

[0933] m / z ES+[M+H] + 503.64; 1 H NMR (400MHz, DMSO-d6) δppm 7.46-7.18(m, 4H), 6.60(s, 1H), 4.42(dt, J=9.3, 5.7Hz, 1H), 3.96-3.82(m, 1H), 3 .81-3.71(m, 1H), 3.68-3.55(m, 2H), 3.51(dd, J=10.6, 7.6Hz, 1H), 3.48-3.36(m, 2H), 3.24-3.03(m, 3H), 2.39(s, 3H), 2.37(s, 3H), 2.33(s, 3H), 2.21-2.15(m, 3H) , 2.07-1.90 (m, 2H), 1.91-1.88 (m, 3H), 1.84-1.58 (m, 2H), 1.00 (t, J=7.0Hz, 3H).

[0934] Embodiment 53

[0935] (2S,3R,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0936] Embodiment 54

[0937] (2S,3S,4R)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide

[0938]

[0939]

[0940] Step a: A solution of N-methyl-3-methylaniline (1.58 mL, 12.6 mmol), (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (CAS No. 51154-06-4; 2.5 g, 11.5 mmol) and pyridine (3.7 mL, 46 mmol) in EtOAc (12 mL) was treated with T3P (13.7 mL, 23.0 mmol, 50 wt.% in EtOAc) at 0°C and stirred at rt for 3 h. T3P (6.8 mL, 11.5 mmol, 50 wt.% in EtOAc) was added and the mixture was stirred for 1 h. The mixture was diluted with EtOAc, washed twice with 1 M HCl solution, once with brine, dried and evaporated to give a brown oil (4.1 g). The mixture was purified by column chromatography (10-50% EtOAc in cyclohexane) to give (2S)-tert-butyl 2-[methyl(m-tolyl)carbamoyl]-2,5-dihydropyrrole-1-carboxylate (3.64 g, 100%).

[0941] m / z ES+[M+H] + 317.48; 1 H NMR (400MHz, DMSO-d6) δppm 7.44-7.35(m, 1H), 7.31-7.15(m, 3H), 6.04-5.88(m, 1H), 5.70-5.60(m, 1H), 4.87- 4.71 (m, 1H), 4.08-3.93 (m, 2H), 3.23-3.07 (m, 3H), 2.35 (s, 3H), 1.46-1.34 (m, 9H).

[0942] Step b: A solution of (2S)-tert-butyl 2-[methyl(m-tolyl)carbamoyl]-2,5-dihydropyrrole-1-carboxylate (3.64 g, 11.5 mmol) in MeOH (15 mL) was treated with 4M HCl in 1,4-dioxane (15 mL, 60 mmol) and stirred for 1 h. The reaction mixture was evaporated to give (2S)-N-methyl-N-(m-tolyl)-2,5-dihydro-1H-pyrrole-2-carboxamide hydrochloride (3.1 g) as a light yellow hygroscopic solid which was used without further purification.

[0943] m / z ES+[M+H] + 217.37; 1H NMR (400MHz, DMSO-d6) δppm 10.73 (s, 1H), 8.86 (s, 1H), 7.43 (t, J=7.7Hz, 1H), 7.39-7.25 (m, 3H), 6.00 (dq, J=6.4, 2.1Hz, 1H), 5.51 (dq , J=6.6, 2.3Hz, 1H), 4.86 (s, 1H), 4.06 (d, J=15.9Hz, 1H), 3.90 (d, J=14.9Hz, 1H), 3.23 (s, 3H), 2.37 (s, 3H).

[0944] Step c: (2S)-N-methyl-N-(m-tolyl)-2,5-dihydro-1H-pyrrole-2-carboxamide hydrochloride (1.0 g, 3.957 mmol), Intermediate 1 (0.87 g, 3.957 mmol) and DIPEA (2.76 mL, 15.8 mmol) in NMP (4 mL) were heated at 100 °C for 2 h. The mixture was partitioned between EtOAc and saturated NaHCO 3 The layers were separated, the aqueous layer was extracted with EtOAc, and the combined organic layers were washed twice with brine, dried, and evaporated. The mixture was purified by column chromatography (10-50% EtOAc in cyclohexane) to give (2S)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]-N-methyl-N-(m-tolyl)-2,5-dihydro-pyrrole-2-carboxamide (1.284 g, 81%) as a light yellow solid.

[0945] m / z ES+[M+H] + 401.45; 1 H NMR (400MHz, DMSO-d6) δppm 7.41 (t, J=7.6Hz, 1H), 7.38-7.32 (m, 2H), 7.25 (d, J=7.5Hz, 1H), 7.10 (s, 1H), 6.16-6.08 (m, 1H), 5.90-5.78 (m, 1H), 5.45-5.29 (m, 1H), 4.74-4.57 (m, 2H), 3.15 (s, 3H), 2.54 (s, 3H), 2.37 (s, 3H).

[0946] Step d: A mixture of (2S)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]-N-methyl-N-(m-tolyl)-2,5-dihydropyrrole-2-carboxamide (0.60 g, 1.50 mmol), citric acid monohydrate (0.24 g, 1.124 mmol) and NMO (0.23 g, 1.99 mmol) in MeCN (6.8 mL) and water (1.7 mL) was treated with potassium osmate (VI) dihydrate (6 mg, 0.015 mmol) and stirred for 18 h. The mixture was evaporated and purified by column chromatography (30-70% EtOAc in cyclohexane) to give (2S,3R,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-3,4-dihydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide (450 mg, 69%) as the major product.

[0947] Example 53 m / z ES+[M+H] + 435.45; 1 H NMR (400MHz, DMSO-d6) δppm7.46-7.35(m, 3H), 7.25-7.14(m, 1H), 7.08(s, 1H), 5.21(d, J=5.6Hz, 2H), 4.52(d , J=2.9Hz, 1H), 4.32-4.26 (m, 1H), 4.16-4.06 (m, 2H), 3.66 (dd, J=10.0, 6.2Hz, 1H), 3.17 (s, 3H), 2.36 (s, 3H).

[0948] Fractions containing a small amount of product were further purified by preparative-HPLC to give (2S,3S,4R)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide (21 mg, 3%).

[0949] Example 54 m / z ES+[M+H] + 435.45; 1 H NMR (400MHz, DMSO-d6) δppm7.44-7.37(m, 1H), 7.36-7.27(m, 2H), 7.26-7.20(m, 1H), 7.08(s, 1H), 5.38-5.27(m, 1H), 5.26-5.15(m, 1H), 4.75-4.66(m, 1H), 3.98-3.82(m, 2H), 3.82-3.69(m, 2H), 3.19-3.11(m, 3H), 2.36(s, 3H)

[0950] The examples in Table 4 were prepared by methods similar to those described for the synthesis of Example 54:

[0951]

[0952] Embodiment 58

[0953] (S)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxo-N-(m-tolyl)oxazolidine-4-carboxamide

[0954]

[0955] Step a: To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropionic acid (800 mg, 3.90 mmol) in IPA (10 mL) was added DIPEA (1.01 g, 7.80 mmol, 1.36 mL) at 0°C. After 30 min, T3P (4.96 g, 7.80 mmol, 50 wt.% in DMF) and N-methyl-3-methyl-aniline (472 mg, 3.90 mmol) were added at 0°C. The reaction mixture was stirred at rt for 12 h. The reaction mixture was evaporated, the resulting residue was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried and evaporated. The residue was purified by column chromatography (50% EtOAc in PE) to give tert-butyl (S)-(3-hydroxy-1-(methyl(m-tolyl)amino)-1-oxopropan-2-yl)carbamate (456 mg, 87% yield) as a yellow oil. m / z ES+[M+H] + 309.4

[0956] Step b: To a solution of (S)-tert-butyl (3-hydroxy-1-(methyl(m-tolyl)amino)-1-oxopropyl-2-yl)carbamate (456 mg, 1.48 mmol) in 1,4-dioxane (4 mL) was added 4M HCl in 1,4-dioxane (4 mL). The mixture was stirred at rt for 2 h. Upon completion, the mixture was evaporated to give (S)-2-amino-3-hydroxy-N-methyl-N-(m-tolyl)propionamide (450 mg, crude) as a yellow solid.

[0957] Step c: (S)-2-amino-3-hydroxy-N-methyl-N-(m-tolyl)propionamide (450 mg, 2.16 mmol), KHCO 3 (238 mg, 2.38 mmol) and K 2 CO 3The mixture of (328mg, 2.38mmol) in water (5mL) is cooled to 0 ℃.Then carbonate bis(trichloromethyl) ester (321mg, 1.08mmol) in toluene (5mL) is added to the mixture and stirred for 2h at 0 ℃.When completed, the mixture is separated and the aqueous phase is extracted with EtOAc (30mL). The combined organic layer is washed with saline (30mL), dried and evaporated. By column chromatography residue (PE solution of 30%EtOAc), (S)-N-methyl-2-oxo-N-(m-tolyl)oxazolidine-4-methane amide (140mg, 28% yield) is obtained, which is a yellow oil.

[0958] m / z ES+[M+H] + 235.1

[0959] Step d: To (S)-N-methyl-2-oxo-N-(m-tolyl)oxazolidine-4-carboxamide (60 mg, 0.26 mmol), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (65 mg, 0.33 mmol), Pd 2 (dba) 3 To a solution of Cs(23 mg, 0.026 mmol) and Xantphos (22 mg, 0.038 mmol) in 1,4-dioxane (3 mL) was added 2 CO 3 (167 mg, 0.52 mmol). 2 The mixture was degassed 3 times and stirred at 120 ° C for 2h. When completed, the mixture was diluted with water (10mL) and extracted into EtOAc (20mL x 2). The combined organic layer was washed with saline (20mL), dried and evaporated. The residue was purified by preparative-HPLC to obtain the title compound (45mg, 43% yield) as a yellow solid.

[0960] m / z ES+[M+H] + 394.1; 1 H NMR (400MHz, DMSO-d6) δppm 8.14 (s, 1H), 7.50-7.40 (m, 2H), 7.36-7.25 (m, 3H), 4.97 (dd, J=9.2, 3.2Hz, 1H), 4.57 (dd, J=8.4, 3.6Hz, 1H), 4.35 (t, J=9.2Hz, 1H), 3.20 (s, 3H), 2.59 (s, 3H), 2.39 (s, 3H).

[0961] Embodiment 59

[0962] (S)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxo-N-(m-tolyl)pyrrolidine-2-carboxamide

[0963]

[0964] Step a: To a solution of (2S)-1-benzyloxycarbonyl-5-oxo-pyrrolidine-2-carboxylic acid (CAS No. 32159-21-0; 200 mg, 0.76 mmol) and N-methyl-3-methyl-aniline (119 mg, 0.99 mmol) in pyridine (8 mL) was added T3P (1.45 g, 2.28 mmol, 50 wt.% in EtOAc). The mixture was stirred at rt for 12 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (30 mL x 2), dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (0-10% EtOAc in PE) to give (2S)-2-[methyl(m-tolyl)-carbamoyl]-5-oxo-pyrrolidine-1-carboxylic acid benzyl ester (210 mg, 75% yield) as a white solid.

[0965] 1 H NMR (400 MHz, CDCl 3 )δppm 7.48-7.34(m, 5H), 7.27-7.21(m, 1H), 7.19-7.13(m, 1H), 6.84-6.75(m, 2H), 5.38-5.15(m, 2H), 4.57(dd , J=3.6, 8.8Hz, 1H), 3.24 (s, 3H), 2.83-2.72 (m, 1H), 2.45-2.36 (m, 1H), 2.32 (s, 3H), 2.02-1.89 (m, 2H).

[0966] Step b: In N 2 To a solution of (2S)-2-[methyl(m-tolyl)carbamoyl]-5-oxo-pyrrolidine-1-carboxylic acid benzyl ester (190 mg, 0.52 mmol) in THF (15 mL) was added Pd / C (20 mg, 10 wt.% loading) under atmospheric pressure. The suspension was degassed in vacuo and heated with H 2 The mixture was purged several times under H 2 Stirred at rt for 1 h under atmosphere (15 psi).The reaction mixture was filtered and concentrated in vacuo to give (2S)-N-methyl-N-(m-tolyl)-5-oxo-pyrrolidine-2-carboxamide (120 mg, 99.6% yield) as a colorless oil.

[0967] Step c: To a solution of (2S)-N-methyl-N-(m-tolyl)-5-oxo-pyrrolidine-2-carboxamide (80 mg, 0.34 mmol) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (74 mg, 0.38 mmol) in 1,4-dioxane (8 mL) was added Pd 2 (dba) 3 (31.5 mg, 0.034 mmol), Xantphos (39.9 mg, 0.069 mmol) and Cs 2 CO 3 (337 mg, 1.03 mmol). The mixture was heated at 100 °C under N 2 Atmosphere is stirred for 2h.The reaction mixture is diluted with water (20mL), extracted with EtOAc (15mL x3).The organic extracts combined are washed with salt water (20mL x2), dried over sodium sulfate, filtered, and evaporated.Through column chromatography crude residue (0-20% EtOAc PE solution), then purified by preparation-HPLC, title compound (121mg, 88% yield) is obtained, which is a white solid.

[0968] m / z ES+[M+H] + 392.0; 1 H NMR (400MHz, DMSO-d6) δppm8.42 (s, 1H), 7.47-7.42 (m, 1H), 7.40 (s, 2H), 7.38-7.34 (m, 1H), 7.29-7.24 (m, 1H), 4.91 (d d, J=3.2, 8.8Hz, 1H), 3.18 (s, 3H), 2.71-2.63 (m, 1H), 2.60 (s, 3H), 2.49-2.46 (m, 1H), 2.39 (s, 3H), 2.14-1.99 (m, 2H).

[0969] Embodiment 60

[0970] (S)-N-(5-fluoro-6-methylpyridin-2-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[0971]

[0972]

[0973] Steps a, b: To a solution of (S)-1-((benzyloxy)carbonyl)-5-oxopyrrolidine-2-carboxylic acid (CAS No. 32159-21-0; 2.00 g, 7.60 mmol) in DCM (40 mL) and DMF (2 mL) was added oxalyl chloride (1.45 g, 11.4 mmol). The mixture was stirred at 0°C for 30 min. The reaction mixture was evaporated to give the acid chloride intermediate (2.3 g, crude) as a brown solid. A solution of the crude acid chloride (0.20 g, 1.59 mmol) in DCM (6 mL) was treated with TEA (0.48 g, 4.76 mmol), followed by the stepwise addition of 5-fluoro-6-methylpyridin-2-amine (0.67 g, 2.38 mmol). The resulting mixture was stirred at 0°C for 30 min. Upon completion, the reaction mixture was evaporated to give a residue which was purified by column chromatography (25% EtOAc in PE) to give (S)-benzyl 2-((5-fluoro-6-methylpyridin-2-yl)carbamoyl)-5-oxopyrrolidine-1-carboxylate (400 mg, 66% yield) as a yellow solid. m / z ES+[M+H] + 372.2

[0974] Step c: NaH (24 mg, 0.59 mmol, 60% mineral oil dispersion) was added to a solution of (S)-2-((5-fluoro-6-methylpyridin-2-yl)formamyl)-5-oxo-pyrrolidine-1-carboxylic acid benzyl ester (200 mg, 0.54 mmol) in DMF (2 mL) at 0 ° C, and the mixture was stirred for 30 min at 0 ° C. Iodomethane (92 mg, 0.65 mmol) was dropped into the mixture at 0 ° C, and then stirred for 2 h at rt. Upon completion, the mixture was quenched with water (5 mL) and evaporated. The crude residue was purified by column chromatography (50% EtOAc in PE solution) to obtain (S)-2-((5-fluoro-6-methylpyridin-2-yl) (methyl)formamyl)-5-oxo-pyrrolidine-1-carboxylic acid benzyl ester (105 mg, 46% yield) as a white solid. m / z ES+[M+H] + 385.4

[0975] Step d: To a solution of (S)-benzyl 2-((5-fluoro-6-methylpyridin-2-yl)(methyl)carbamoyl)-5-oxopyrrolidine-1-carboxylate (105 mg, 0.27 mmol) in THF (2 mL) was added Pd-coated activated carbon (5 mg, 10 wt.% loading). 2 The mixture was purged 3 times and stirred at rt for 4 h (15 psi H 2). Upon completion, the mixture was filtered through CELITE. The filter cake was washed with 20 mL of EtOAc. The combined organic layers were evaporated to give a residue which was purified by column chromatography (3% MeOH in EtOAc) to give (S)-N-(5-fluoro-6-methylpyridin-2-yl)-N-methyl-5-oxopyrrolidine-2-carboxamide (54 mg, 78% yield) as a white solid. m / z ES+[M+H] + 252.1

[0976] Step e: To (S)-N-(5-fluoro-6-methylpyridin-2-yl)-N-methyl-5-oxopyrrolidine-2-carboxamide (44 mg, 0.18 mmol), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (44 mg, 0.23 mmol), Xantphos (15.2 mg, 0.026 mmol) and Cs 2 CO 3 (114 mg, 0.35 mmol) was added to a solution of Pd in ​​1,4-dioxane (5 mL). 2 (dba) 3 (16 mg, 0.018 mmol). 2 The mixture was degassed 3 times and stirred at 100 ° C for 2h. When completed, the mixture was diluted with water (20mL) and extracted with EtOAc (40mL x 3). The combined organic extracts were washed with saline (20mL x 2), dried and evaporated. The crude product was purified by preparative-HPLC to obtain the title compound (27mg, 14% yield) as a white solid.

[0977] m / z ES+[M+H] + 411.0; 1 H NMR (400 MHz, CDCl 3 )δppm 8.56 (s, 1H), 7.56-7.40 (m, 1H), 7.31-7.25 (m, 1H), 7.06 (s, 1H), 5.29-4.84 (m, 1H), 3.40 (br s, 3H), 3.05-2.90 (m, 1H), 2.70-2.60 (m, 1H), 2.55 (d, J=2.8Hz, 3H), 2.48 (s, 3H), 2.47-2.40 (m, 1H), 2.39-2.25 (m, 1H).

[0978] Embodiment 61

[0979] (2S,4S)-4-amino-N-(3-chloro-4-fluorophenyl)-N-ethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[0980]

[0981] Step a: To (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (CAS No. 171110-72-8; 7.50 g, 26.7 mmol, HCl salt) and Na 2 CO 3 Benzyl chloroformate (5.01 g, 29.4 mmol) (8.49 g, 80.1 mmol) was added to a solution of 1,4-dioxane (120 mL) and water (60 mL). The reaction mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was evaporated, the residue was diluted with water (80 mL) and extracted with EtOAc (200 mL). The organic layer was dried over sodium sulfate and evaporated. By column chromatography residue (25% EtOAc in PE solution), (2S, 4S)-4-(((benzyloxy) carbonyl) amino) pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (10.0 g, 99% yield) was obtained as a colorless oil.

[0982] 1 H NMR (400 MHz, CDCl 3 )δppm 7.41-7.27(m, 5H), 5.85-5.70(m, 1H), 5.10(s, 2H), 4.50-4.20(m, 2H), 3.93-3.73(m, 3H), 3. 71-3.61 (m, 1H), 3.60-3.40 (m, 1H), 2.60-2.35 (m, 1H), 2.03-1.88 (m, 1H), 1.52-1.35 (m, 9H).

[0983] Step b: Add NaIO 4 (17.0 g, 79.3 mmol) was added to a solution of RuO 2 ·H 2 O (2.0 g, 13.2 mmol). Then a solution of (2S,4S)-4-(((benzyloxy)carbonyl)-amino)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (10.0 g, 26.4 mmol) in EtOAc (100 mL) was added. The reaction mixture was heated at rt under N 2 Stir for 12 h in a 5% CO atmosphere. When complete, filter the reaction mixture. 2 S 2 O 3The filtrate was washed with water (50 mL), dried and evaporated. The residue was purified by column chromatography (20% EtOAc in PE) to give 1-tert-butyl 2-methyl (2S,4S)-4-(((benzyloxy)carbonyl)amino)-5-oxopyrrolidine-1,2-dicarboxylate (850 mg, 8% yield) as a yellow solid.

[0984] 1 H NMR (400 MHz, CDCl 3 )δppm 7.41-7.30 (m, 5H), 5.13 (s, 2H), 4.53-4.37 (m, 2H), 3.81 (s, 3H), 3.01-2.84 (m, 1H), 1.89-1.77 (m, 1H), 1.51 (s, 9H).

[0985] Step c: A solution of (2S,4S)-4-(((benzyloxy)carbonyl)amino)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.8 g, 2.0 mmol) in HCl in 1,4-dioxane (4M, 24 mL) was stirred at rt for 30 min. The reaction mixture was evaporated to give (2S,4S)-4-(((benzyloxy)-carbonyl)amino)-5-oxopyrrolidine-2-carboxylic acid methyl ester (0.59 g, crude) as a yellow solid. m / z ES+[M+H] + 293.0

[0986] Step d: A mixture of (2S,4S)-4-(((benzyloxy)carbonyl)amino)-5-oxopyrrolidine-2-carboxylic acid methyl ester (0.59 g, 2.0 mmol) and LiOH monohydrate (254 mg, 6.1 mmol) in MeOH (10 mL) was stirred at rt for 1 h. Upon completion, the reaction mixture was adjusted to pH 4-5 by slowly adding 0.5 M HCl aqueous solution. The resulting solid was collected by filtration. The filtrate was washed with brine (30 mL) and extracted with EtOAc (30 mL). The residue was purified by column chromatography (HPLC) and purified by column chromatography (HPLC). The residue was purified by column chromatography (HPLC) and eluted with 5% ethyl acetate (50 mL). The residue was purified by column chromatography (HPLC) and eluted with 5% ethyl acetate (50 mL). The residue was purified by column chromatography (HPLC) and eluted with 5% ethyl acetate (50 mL). 2 SO 4 The organic layer was dried and evaporated. The resulting residue was combined with the filtered solid to give (2S,4S)-4-(((benzyloxy)carbonyl)amino)-5-oxopyrrolidine-2-carboxylic acid (0.5 g, 89% yield) as a brown solid.

[0987] m / z ES+[M+H] + 279.1; 1H NMR (400MHz, DMSO-d6) δppm 12.85(s, 1H), 8.14(s, 1H), 7.52(d, J=8.8Hz, 1H), 7.39-7.31(m, 5H), 5.03(s, 2 H), 4.26-4.14(m, 1H), 4.12-4.00(m, 1H), 2.63-2.54(m, 1H), 1.87-1.74(m, 1H).

[0988] Step e: to (2S, 4S)-4-(((benzyloxy) carbonyl) amino)-5-oxopyrrolidine-2-carboxylic acid (490mg, 1.8mmol) and 3-chloro-N-ethyl-4-fluoroaniline (611mg, 3.2mmol) in pyridine (20mL) solution, add T3P (3.36g, 5.3mmol, 50wt.% EtOAc solution). The reaction mixture was stirred at rt for 12h. When completed, the reaction mixture was concentrated in vacuo. The residue obtained was diluted with water (50mL) and extracted with EtOAc (50mL). The organic layer was dried and evaporated. The residue was purified by preparation-HPLC to obtain ((3S, 5S)-5-((3-chloro-4-fluorophenyl) (ethyl) formamyl)-2-oxopyrrolidine-3-yl) benzyl carbamate (200mg, 26% yield), which was a white solid.

[0989] m / z ES+[M+H] + 434.0; 1 H NMR (400 MHz, CDCl 3 )δppm 7.40-7.28 (m, 6H), 7.09 (d, J=8.0Hz, 1H), 6.84 (s, 1H), 5.84 (d, J=6.8Hz, 1H), 5.15-4.96 (m, 2H), 4.35-4.21 (m, 1H), 4 .15-3.95 (m, 1H), 3.86-3.71 (m, 1H), 3.69-3.52 (m, 1H), 2.49-2.32 (m, 1H), 1.98-1.92 (m, 1H), 1.10 (t, J=7.2Hz, 3H).

[0990] Step f: Benzyl ((3S,5S)-5-((3-chloro-4-fluorophenyl)(ethyl)carbamoyl)-2-oxopyrrolidin-3-yl)carbamate (200 mg, 0.46 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)-pyridine (144 mg, 0.60 mmol), Pd 2 (dba) 3 (42 mg, 0.046 mmol), Xantphos (40 mg, 0.069 mmol) and Cs2 CO 3 A mixture of (300 mg, 0.92 mmol) in 1,4-dioxane (10 mL) was heated at 120 °C under N 2 Stir for 2 h in atmosphere. Upon completion, the reaction mixture was evaporated and the residue was purified by column chromatography (50% EtOAc in PE) to give benzyl ((3S,5S)-5-((3-chloro-4-fluorophenyl)(ethyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidin-3-yl)carbamate (200 mg, 73% yield) as a yellow oil. m / z ES+[M+H] + 593.1

[0991] Step g: A solution of benzyl ((3S,5S)-5-((3-chloro-4-fluorophenyl)(ethyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxopyrrolidin-3-yl)carbamate (200 mg, 0.34 mmol) in HBr (7.45 g, 30.4 mmol, 33 wt.% in acetic acid) was stirred at rt for 1 h. Upon completion, the reaction mixture was poured into saturated NaHCO 3 The aqueous solution (100 mL) was extracted with EtOAc (100 mL). The organic layer was dried and evaporated. The residue was purified by preparative HPLC to give the title compound (60 mg, 39% yield) as a yellow solid.

[0992] m / z ES+[M+H] + 458.9; 1 H NMR (400 MHz, CD 3 OD)δppm 8.55 (s, 1H), 7.85 (d, J=3.6Hz, 1H), 7.58 (s, 1H), 7.51-7.43 (m, 1H), 7.29 (s, 1H), 4.94 (d, J=8.4Hz, 1H), 3.9 7-3.80 (m, 2H), 3.67-3.56 (m, 1H), 2.67 (s, 3H), 2.54-2.43 (m, 1H), 1.87-1.72 (m, 1H), 1.15 (t, J=7.2Hz, 3H).

[0993] Embodiment 62

[0994] (2S,4S)-4-Acetylamino-N-(3-chloro-4-fluorophenyl)-N-ethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[0995]

[0996] To a solution of Example 61 (10 mg, 0.022 mmol) and TEA (4 mg, 0.044 mmol) in DCM (1 mL) was added acetyl chloride (3 mg, 0.033 mmol). The reaction mixture was stirred at rt for 1 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue obtained by preparative HPLC purification was dried by lyophilization to give the title compound (6.6 mg, 56% yield) as a yellow solid.

[0997] m / z ES+[M+H] + 501.0; 1 H NMR (400 MHz, CD 3 OD)δppm 8.52 (s, 1H), 7.85 (d, J = 4.8Hz, 1H), 7.58 (s, 1H), 7.51-7.43 (m, 1H), 7.31 (s, 1H), 4.98 (d, J = 8.8Hz, 1H), 4.80-4.70 (m, 1H), 3 .97-3.80 (m, 1H), 3.67-3.56 (m, 1H), 2.67 (s, 3H), 2.54-2.43 (m, 1H), 2.10-2.00 (m, 1H), 1.99 (s, 3H), 1.15 (t, J=7.2Hz, 3H).

[0998] Embodiment 63

[0999] (2S,4S)-N-(3-Chloro-4-fluorophenyl)-N-ethyl-1-(6-methyl-4-(trifluoro-methyl)pyridin-2-yl)-4-morpholino-5-oxopyrrolidine-2-carboxamide

[1000]

[1001] Example 61 (15 mg, 0.033 mmol), 1-bromo-2-(2-bromoethoxy)ethane (15 mg, 0.065 mmol), NaI (5 mg, 0.033 mmol) and K 2 CO 3 A solution of (23 mg, 0.16 mmol) in MeCN (2 mL) was stirred at 80 °C for 3 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC and dried by lyophilization to give the title compound (7.4 mg, 43% yield) as a white solid.

[1002] m / z ES+[M+H] + 529.0; 1 H NMR (400 MHz, CD 3OD)δppm 8.54 (s, 1H), 7.86 (d, J=4.4Hz, 1H), 7.59 (s, 1H), 7.51-7.44 (m, 1H), 7.30 (s, 1H), 4.99-4.92 (m, 1H), 3.97-3.84 (m, 2H), 3.77-3.67 (m, 4 H), 3.66-3.55 (m, 1H), 2.93-2.83 (m, 2H), 2.67 (s, 3H), 2.64-2.52 (m, 2H), 2.34-2.24 (m, 1H), 2.20-2.10 (m, 1H), 1.15 (t, J=7.2Hz, 3H).

[1003] Embodiment 64

[1004] (2S,4S)-N-(3-Chloro-4-fluorophenyl)-N-ethyl-4-hydroxy-1-(4-methyl-6-(trifluoromethyl)-pyrimidin-2-yl)pyrrolidine-2-carboxamide

[1005]

[1006] The title compound was prepared in a similar manner to Example 2 using Intermediate 2 in step a and 2-chloro-4-methyl-6-trifluoromethylpyrimidine (CAS No. 241164-09-0) in step c.

[1007] m / z ES+[M+H] + 447.1; 1 H NMR (400MHz, DMSO-d6) δppm7.58 (s, 1H), 7.45-7.38 (m, 1H), 7.36 (s, 1H), 6.92 (s, 1H), 4.29 (s, 1H), 4.20-4.10 (m, 1H), 3.80 (s, 1H), 3.71 (qd, J=7.2, 14.0Hz, 1H), 3.53-3.42 (m, 2H), 3.35-3.30 (m, 1H), 2.36 (s, 3H), 2.28-2.09 (m, 1H), 1.84-1.75 (m, 1H), 0.98 (t, J=6.8Hz, 3H).

[1008] Embodiment 65

[1009] (2S,3S,4S)-N-(3-chloro-4-fluorophenyl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[1010]

[1011] Step a: A mixture of intermediate 5 (100 mg, 0.45 mmol), 3-chloro-4-fluoro-N-methyl-aniline (CAS No. 77898-24-9; 159 mg, 0.99 mmol), T3P (3.16 g, 4.97 mmol, 50% wt.% DMF solution) in pyridine (5 mL) was degassed and heated to 40 ℃ for 2 h. 2 The mixture was purged 3 times and then stirred at rt for 12 h. The reaction mixture was stirred at 60 °C for another 3 h. The reaction mixture was evaporated and the crude residue was purified by reverse phase column chromatography to give (3aS, 4S, 6aS)-N-(3-chloro-4-fluorophenyl)-N, 2, 2-trimethyl-6-oxotetrahydro-3aH-[1, 3] dioxol[4, 5-c] pyrrole-4-carboxamide (100 mg, 59% yield) as a yellow solid.

[1012] 1 H NMR (400 MHz, CD 3 OD)δppm 7.65 (d, J=5.2Hz, 1H), 7.43-7.38 (m, 2H), 4.48 (d, J=6.0Hz, 1H), 4.41 (d, J=5.2Hz, 1H), 4.06-4.04 (m, 1H), 3.66 (s, 3H), 1.40 (s, 3H), 1.32 (s, 3H).

[1013] Step b: (3aS, 4S, 6aS)-N-(3-chloro-4-fluorophenyl)-N, 2, 2-trimethyl-6-oxo-tetrahydro-3aH-[1, 3] dioxol[4, 5-c] pyrrole-4-carboxamide (80 mg, 0.23 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (84 mg, 0.35 mmol), Xantphos (27 mg, 0.047 mmol), Pd 2 (dba) 3 (21 mg, 0.023 mmol) and Cs 2 CO 3 A mixture of (152 mg, 0.47 mmol) in 1,4-dioxane (4 mL) was degassed and heated with N 2 Purge 3 times and then stir for 2 h at 120° C. The reaction mixture was evaporated and the crude residue was purified by column chromatography (20% EtOAc in PE) to give (3aS,4S,6aS)-N-(3-chloro-4-fluorophenyl)-N,2,2-trimethyl-5-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6-oxotetrahydro-3aH-[1,3]dioxol[4,5-c]pyrrole-4-carboxamide (60 mg, 46% yield) as a yellow oil.

[1014] 1 H NMR (400 MHz, CD 3 OD)δppm 8.47 (s, 1H), 7.77 (d, J=6.4Hz, 1H), 7.60-7.58 (m, 1H), 7.52-7.47 (m, 1H), 7.32 (s, 1H), 5.20 (d, J=6.8Hz , 1H), 4.80 (d, J=6.8Hz, 1H), 4.54 (d, J=6.8Hz, 1H), 3.25 (s, 3H), 2.64 (s, 3H), 1.47 (s, 3H), 1.41 (s, 3H).

[1015] Step c: A solution of (3aS,4S,6aS)-N-(3-chloro-4-fluorophenyl)-N,2,2-trimethyl-5-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6-oxotetrahydro-3aH-[1,3]dioxol[4,5-c]pyrrole-4-carboxamide (60 mg, 0.1 mmol) in HCl in 1,4-dioxane (4 M, 2 mL) was stirred at rt for 6 h and then at 60° C. for 2 h. The reaction mixture was evaporated and the crude residue was purified by reverse phase column to give the title compound (32 mg, 56% yield) as a yellow solid.

[1016] m / z ES+[M+H] + 462.0; 1 H NMR (400 MHz, CD 3 OD)δppm 8.41(s, 1H), 7.83(dd, J=6.4Hz, 2.0Hz, 1H), 7.64-7.61(m, 1H), 7.49-7.44(m, 1H) , 7.29 (s, 1H), 5.12 (d, J=5.2Hz, 1H), 4.26-4.19 (m, 2H), 3.27 (s, 3H), 2.64 (s, 3H).

[1017] The examples in Table 5 were prepared by methods similar to those described for the synthesis of Example 65.

[1018]

[1019]

[1020] Embodiment 69

[1021] (3aS,4S,6aS)-N-(3-Chloro-2,4-difluorophenyl)-N,2,2-trimethyl-5-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-6-oxotetrahydro-4H-[1,3]dioxol[4,5-c]pyrrole-4-carboxamide

[1022] Step a: To a solution of (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (3 g, 14.1 mmol), 3-chloro-2,4-difluoro-aniline (2.99 g, 18.3 mmol) in pyridine (50 mL) was added T3P (44.8 g, 70.4 mmol, 50 wt.% in EtOAc) and the mixture was stirred at rt for 12 h. Upon completion, the mixture was heated to 40 ℃ with NH 4 The reaction mixture was quenched with aqueous Cl solution (60 mL), diluted with water (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (30 mL x 3) and washed with Na 2 SO 4 Dry and evaporate. The residue was purified by column chromatography (20-30% EtOAc in PE) to give (S)-tert-butyl 2-((3-chloro-2,4-difluorophenyl)carbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4.8 g, 91% yield) as a colorless solid. m / z ES+[M+H-Boc] + 259.0

[1023] Step b: To a solution of (S)-tert-butyl 2-((3-chloro-2,4-difluorophenyl)carbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4.8 g, 13.4 mmol) in MeCN (5 mL), water (5 mL) and tert-butanol (5 mL) was added OsO 4 (340 mg, 1.34 mmol) and NMO (1.88 g, 16.05 mmol). The mixture was stirred at rt for 12 h. Upon completion, Na 2 S 2 O 3 The reaction mixture was quenched with aqueous solution (20 mL), filtered and concentrated. The residue was purified by preparative-HPLC to give the minor isomer (2S,3S,4R)-2-((3-chloro-2,4-difluorophenyl)carbamoyl)-3,4-dihydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (720 mg, 13% yield) as a yellow solid, which was used in the next step; m / z ES+[M+Na] + 415.1

[1024] Step c: To a solution of (2S,3S,4R)-2-((3-chloro-2,4-difluorophenyl)carbamoyl)-3,4-dihydroxypyrrolidine-1-carboxylic acid tert-butyl ester (720 mg, 1.83 mmol) and 2,2-dimethoxypropane (9.55 g, 91.7 mmol) in acetone (30 mL) was added pyridinium p-toluenesulfonate (553 mg, 2.20 mmol). The mixture was stirred at 60 ° C for 3 h. Upon completion, the reaction mixture was filtered and concentrated. The residue was diluted with water (60 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried and evaporated. The residue was purified by column chromatography (20-30% EtOAc in PE) to give (3aS,4S,6aR)-4-((3-chloro-2,4-difluorophenyl)carbamoyl)-2,2-dimethyl-dihydro-3aH-[1,3]dioxol[4,5-c]pyrrole-5(4H)-carboxylic acid tert-butyl ester (630 mg, 79% yield) as a solid.

[1025] Step d: A solution of tert-butyl (3aS,4S,6aR)-4-((3-chloro-2,4-difluorophenyl)carbamoyl)-2,2-dimethyldihydro-3aH-[1,3]dioxol[4,5-c]pyrrole-5(4H)-carboxylate (620 mg, 1.43 mmol) in DMF (20 mL) was treated with NaH (86 mg, 2.15 mmol, 60% in mineral oil) and the mixture was stirred for 2 h. 2 Degas 3 times. The mixture was heated at 0 °C under N 2 Stir for 30 min under atmosphere. Slowly add iodomethane (610 mg, 4.30 mmol) and stir the mixture at 0°C for 1.5 h. When complete, add NH 4 The reaction mixture was quenched with CI aqueous solution (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried and evaporated. The residue was purified by column chromatography (0-50% EtOAc in PE solution) to give (3aS, 4S, 6aR)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2,2-dimethyldihydro-3aH-[1,3]dioxol[4,5-c]pyrrole-5(4H)-tert-butyl carboxylate (630 mg, 98% yield) as a white solid. m / z ES+[M+H-Boc] + 347.2

[1026] Step e: Use N 2 Ruthenium(IV) dioxide hydrate (20 mg, 0.14 mmol) and NaIO 4A mixture of (862 mg, 4.03 mmol) in water (20 mL) was degassed 3 times and then heated at rt under N 2 Stir for 15min in atmosphere.Add (3aS, 4S, 6aR) -4- ((3- chloro-2,4- difluorophenyl) (methyl) formamyl) -2,2- dimethyldihydro -3aH- [1,3] dioxol [4,5-c] pyrrole -5 (4H) - tert-butyl formate (600mg, 1.34mmol) in EtOAc (20mL), the mixture is stirred at rt for 12h.When finished, the reaction mixture is quenched with water (30mL), extracted with EtOAc (50mL x 3).The organic layer is washed with salt water (50mL x 3), dried and evaporated. The residue was purified by prep-HPLC to give tert-butyl (3aS,4S,6aS)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2,2-dimethyl-6-oxodihydro-3aH-[1,3]dioxol[4,5-c]pyrrole-5(4H)-carboxylate (100 mg, 16% yield) as a yellow solid.

[1027] Step f: To a solution of (3aS,4S,6aS)-4-((3-chloro-2,4-difluorophenyl)(methyl)-carbamoyl)-2,2-dimethyl-6-oxodihydro-3aH-[1,3]dioxol[4,5-c]pyrrole-5(4H)-carboxylic acid tert-butyl ester (100 mg, 0.22 mmol) in DCM (10 mL) was added ZnBr 2 (245 mg, 1.08 mmol), and the mixture was stirred at rt for 12 h. Upon completion, the mixture was treated with saturated NaHCO 3 The reaction mixture was quenched with aqueous solution (20 mL), diluted with water (20 mL), extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3) and washed with Na 2 SO 4 Drying and evaporation gave (3aS,4S,6aS)-N-(3-chloro-2,4-difluorophenyl)-N,2,2-trimethyl-6-oxo-tetrahydro-3aH-[1,3]dioxol[4,5-c]pyrrole-4-carboxamide (70 mg, 89% yield) as a yellow solid which was used directly in the next step.

[1028] Step g: Use N 2(3aS,4S,6aS)-N-(3-chloro-2,4-difluorophenyl)-N,2,2-trimethyl-6-oxo-tetrahydro-3aH-[1,3]dioxol[4,5-c]pyrrole-4-carboxamide (70 mg, 0.20 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (60 mg, 0.25 mmol), Pd 2 (dba) 3 (18 mg, 0.019 mmol), Xantphos (22 mg, 0.039 mmol) and Cs 2 CO 3 A mixture of (190 mg, 0.58 mmol) in dioxane (3 mL) was degassed 3 times and then stirred at 100 °C for 2 h. Upon completion, the reaction mixture was filtered and concentrated. The resulting residue was purified by preparative-HPLC to give the title compound (60 mg, 60% yield) as a yellow solid.

[1029] m / z ES+[M+H] + 520.1; 1 H NMR (400MHz, DMSO-d6) δppm 8.40-8.25(m, 1H), 7.85-7.54(m, 2H), 7.51-7.44(m, 1H), 5.13-4.97(m, 1H), 4.84-4.74(m , 1H), 4.51-4.40(m, 1H), 3.12(s, 3H), 2.63(s, 3H), 1.40-1.35(m, 3H), 1.34-1.22(m, 3H).

[1030] Embodiment 70

[1031] (2S,3S,4S)-N-(3-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[1032]

[1033] To a solution of (3aS,4S,6aS)-N-(3-chloro-2,4-difluorophenyl)-N,2,2-trimethyl-5-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6-oxotetrahydro-3aH-[1,3]dioxol[4,5-c]pyrrole-4-carboxamide (60 mg, 0.12 mmol) in MeCN (5 mL) was added Amberlyst -15 (200 mg) was added and the mixture was stirred at 80°C for 12 h. Upon completion, the reaction mixture was filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (13 mg, 23% yield) as a white solid.

[1034] m / z ES+[M+H] + 480.0; 1 H NMR (400MHz, DMSO-d6) δppm 8.26-8.15(m, 1H), 7.77-7.63(m, 1H), 7.60-7.50(m, 1H), 7.46-7.34(m, 1H), 4.8 9-4.47 (m, 1H), 4.30-4.20 (m, 1H), 4.02-3.91 (m, 1H), 3.11 (s, 3H), 2.60 (s, 3H).

[1035] Embodiment 71

[1036] (2S,3R,4R)-N-(3-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[1037]

[1038] The title compound was prepared in a manner analogous to Example 70 using the major isomer isolated in step b of Synthesis Example 69, (2S,3R,4S)-2-((3-chloro-2,4-difluorophenyl)carbamoyl)-3,4-dihydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester.

[1039] m / z ES+[M+H] + 480.0; 1 H NMR (400 MHz, CD 3 OD)δppm 8.59-8.54(m, 1H), 7.92-7.68(m, 1H), 7.45-7.18(m, 2H), 4.94and 4.87(s x2, 1H), 4.60-4.54(m, 1H), 4.52and 4.27 (dx2, J=5.2Hz, 1H), 3.30 and 3.29 (s x2, 3H), 2.67 and 2.56 (s x2, 3H).

[1040] Embodiment 72

[1041] (2S,3R,4R)-N-(3-chloro-4-fluorophenyl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[1042]

[1043] The title compound was prepared in a similar manner to Example 71 using 3-chloro-4-fluoroaniline (CAS No. 367-21-5).

[1044] m / z ES+[M+H] + 462.1; 1 H NMR (400 MHz, CD 3 OD)δppm 8.58 (s, 1H), 7.91 (dd, J=6.4, 2.4Hz, 1H), 7.70-7.63 (m, 1H), 7.50 (t, J=8.8Hz, 1H), 7.31 (s , 1H), 4.96 (s, 1H), 4.55 (d, J=5.2Hz, 1H), 4.46 (d, J=5.2Hz, 1H), 3.32 (s, 3H), 2.67 (s, 3H).

[1045] Embodiment 73

[1046] (2S,3S,4S)-N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[1047]

[1048] The title compound was prepared in a similar manner to Example 70 using 5-chloro-2,4-difluoroaniline (CAS No. 348-65-2).

[1049] m / z ES+[M+H] + 480.2; 1 H NMR (400 MHz, CD 3 OD)δppm 8.44-8.35(m, 1H), 8.11-7.84(m, 1H), 7.57-7.45(m, 1H), 7.35-7.17(m, 1H), 5.19and 5.03(d x2, J=5.4Hz, 1H), 4.28 (dd, J=6.8Hz, 1H), 4.24-4.16 (m, 1H), 3.26-3.21 (m, 3H), 2.67 and 2.53 (s x2, 3H).

[1050] Embodiment 74

[1051] (2S,4S)-N-(3-Chloro-4-fluorophenyl)-4-hydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[1052]

[1053]

[1054] Step a: To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)-pyrrolidine-2-carboxylic acid (2.0 g, 5.79 mmol) and 3-chloro-4-fluoro-N-methylaniline (1.39 g, 8.68 mmol) in pyridine (21.8 g, 275 mmol) was added T3P (11.1 g, 17.4 mmol, 50 wt.% in EtOAc). The mixture was stirred at rt for 12 h. Upon completion, the mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3) and washed with Na2SO4 (10 mL x 3). 2 SO 4 The residue was dried and evaporated. The residue was purified by column chromatography (5-25% EtOAc in PE) to give (2S,4S)-4-((tert-butyl-dimethylsilyl)oxy)-2-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (900 mg, 32% yield) as a colorless oil.

[1055] Step b: At rt at N 2 NaIO 4 (1.19 g, 5.54 mmol) was added to a solution of RuCl in water (10 mL). 3The mixture was stirred for 15 min and then treated with a solution of (2S, 4S)-tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (900 mg, 1.85 mmol) in EtOAc (10 mL) and the mixture was stirred for another 3 h. Upon completion, the mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried and evaporated. The residue was purified by column chromatography (20-30% EtOAc in PE) to give tert-butyl (3S,5S)-3-((tert-butyl-dimethylsilyl)oxy)-5-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)-2-oxopyrrolidine-1-carboxylate (250 mg, 26% yield) as a yellow solid.

[1056] Step c: A mixture of (3S,5S)-tert-butyl 3-((tert-butyldimethylsilyl)oxy)-5-((3-chloro-4-fluoro-phenyl)(methyl)carbamoyl)-2-oxopyrrolidine-1-carboxylate (200 mg, 0.40 mmol) in HCl / dioxane (4M, 2.5 mL) was stirred at rt for 30 min. Upon completion, the mixture was concentrated to give (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-hydroxy-N-methyl-5-oxo-pyrrolidine-2-carboxamide (120 mg, crude) as a yellow oil which was used in the next step without further purification.

[1057] Step d: To a solution of (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-hydroxy-N-methyl-5-oxo-pyrrolidine-2-carboxamide (100 mg, 0.35 mmol) in DCM (1 mL) was added dihydropyran (59 mg, 0.70 mmol) and p-toluenesulfonic acid (6 mg, 0.035 mmol). The mixture was stirred at rt for 1 h. Upon completion, the mixture was concentrated and purified by column chromatography (50% EtOAc in PE) to give (2S,4S)-N-(3-chloro-4-fluorophenyl)-N-methyl-5-oxo-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-2-carboxamide (60 mg, 46% yield, two steps) as a yellow solid.

[1058] Step e: To a solution of (2S,4S)-N-(3-chloro-4-fluorophenyl)-N-methyl-5-oxo-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-2-carboxamide (60 mg, 0.16 mmol) in dioxane (1 mL) were added 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (58 mg, 0.24 mmol), Pd(dba) and 2 (9.3 mg, 0.016 mmol), Xantphos (14 mg, 0.024 mmol) and Cs 2 CO 3 (158 mg, 0.49 mmol). 2 The mixture is degassed 3 times, then stirred at 120 DEG C for 2h.When completing, the mixture is cooled, quenched with water (2mL), extracted with EtOAc (2mL x 3).The organic layer merged is washed with saline (2mL x 3), dried, and evaporated.By preparation-TLC purification of residue (PE solution of 25%EtOAc), (2S, 4S)-N-(3-chloro-4-fluoro-phenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl) pyridin-2-yl)-5-oxo-4-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) pyrrolidine-2-carboxamide (60mg, 32% yield) is obtained, it is yellow solid.

[1059] Step f: To a solution of (2S,4S)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxo-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-2-carboxamide (60 mg, 0.11 mmol) in EtOH (1 mL) was added p-toluenesulfonic acid (19 mg, 0.11 mmol). The mixture was stirred at 50 °C for 1 h. Upon completion, the mixture was concentrated and purified by preparative-HPLC to give the title compound (11 mg, 19% yield) as a yellow solid.

[1060] m / z ES+[M+H] + 446.0; 1 H NMR (400MHz, DMSO-d6) δppm 8.35 (s, 1H), 7.89 (d, J=7.2Hz, 1H), 7.63 (d, J=7.2Hz, 2H), 7.44 (s, 1H), 5.93 (s, 1H), 4.66 (t, J=8 .0Hz, 1H), 4.32 (t, J=9.2Hz, 1H), 3.16 (s, 3H), 2.62 (s, 3H), 2.42-2.36 (m, 1H), 1.73-1.67 (m, 1H).

[1061] Embodiment 75

[1062] (2S,4S)-N-(3-Chloro-4-fluorophenyl)-N-ethyl-4-hydroxy-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[1063]

[1064] The title compound was prepared in a manner similar to Example 74.

[1065] m / z ES+[M+H] + 460.1; 1 H NMR (400 MHz, CD 3 OD)δppm 8.49 (s, 1H), 7.84 (s, 1H), 7.65-7.60 (m, 1H), 7.50-7.45 (m, 1H), 7.31 (s, 1H), 4.79-4.75 (m, 1H), 4.36 (t, J=9.2Hz, 1 H), 3.97-3.85 (m, 1H), 3.60-3.52 (m, 1H), 2.67 (s, 3H), 2.55-2.49 (m, 1H), 1.88-1.78 (m, 1H), 1.15 (t, J=7.2Hz, 3H).

[1066] Embodiment 76

[1067] (2S,4R)-4-((Benzyloxy)methyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[1068]

[1069] Step a: To a solution of dimethyl (2S)-2-(tert-butoxycarbonylamino)pentanedioate (5 g, 18.1 mmol) in THF (50 mL) was added LiHMDS (1 M, 36.3 mL) dropwise at -78°C. The mixture was heated at -78°C under N 2 Stir for 30 min in an atmosphere. Chloromethoxymethylbenzene (5.69 g, 36.3 mmol) was added dropwise and the mixture was stirred at -78 °C for 3 h. Upon completion, saturated NH 4The Cl aqueous solution (50mL) quenches the reaction mixture, dilutes with water (50mL), extracts with EtOAc (50mL x 3). Wash the organic layer merged with salt solution (50mL x 2), dry, evaporate. By column chromatography residue (PE solution of 5-30%EtOAc), obtain (2R, 4S)-2-(benzyloxy-methyl)-4-(tert-butoxycarbonylamino) dimethyl glutarate (4.2g, 58% yield), be colorless oil.

[1070] Step b: A solution of (2R,4S)-2-(benzyloxymethyl)-4-(tert-butoxycarbonylamino)-pentanedioic acid dimethyl ester (2.20 g, 5.56 mmol) in TFA (20 mL) and DCM (20 mL) was stirred at rt for 1 h. Upon completion, the reaction was concentrated and washed with saturated NaHCO 3 The reaction mixture was stirred for 2 h at 4 ℃ for 1 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried and evaporated. The residue was diluted with toluene (20 mL) and heated at 120 ° C for 12 h. Upon completion, the reaction was concentrated and purified by column chromatography (0-25% EtOAc in PE) to give (2S, 4R)-4-(benzyloxymethyl)-5-oxo-pyrrolidine-2-carboxylic acid methyl ester (400 mg, 37% yield) as a colorless oil. m / z ES+[M+H] + 264.0

[1071] Steps: To a solution of (2S, 4R)-4-(benzyloxymethyl)-5-oxo-pyrrolidine-2-carboxylic acid methyl ester (400 mg, 1.52 mmol) in MeOH (4 mL) and water (0.5 mL) was added LiOH monohydrate (191 mg, 4.56 mmol). The mixture was stirred at rt for 5 h. Upon completion, the reaction mixture was concentrated. The residue was diluted with water (10 mL), adjusted to pH 2 with 2M HCl, and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and washed with Na 2 SO 4 Drying and evaporation gave (2S,4R)-4-(benzyloxymethyl)-5-oxo-pyrrolidine-2-carboxylic acid (300 mg, 98% yield) as a colorless oil.

[1072] m / z ES+[M+H] + 250.1

[1073] Step d: To a solution of (2S,4R)-4-(benzyloxymethyl)-5-oxo-pyrrolidine-2-carboxylic acid (620 mg, 2.49 mmol) and 3-chloro-4-fluoro-N-methyl-aniline (476 mg, 2.98 mmol) in pyridine (10 mL) was added T3P (4.75 g, 7.46 mmol, 50 wt.% in EtOAc). The mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was concentrated. The mixture was washed with saturated NH 4 The residue was diluted with aqueous Cl solution (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried and evaporated. The residue was purified by column chromatography (0-20% EtOAc in PE) to give (2S, 4R)-4-(benzyloxymethyl)-N-(3-chloro-4-fluoro-phenyl)-N-methyl-5-oxo-pyrrolidine-2-carboxamide (680 mg, 70% yield) as a colorless oil. m / z ES+[M+H] + 391.0

[1074] Step e: Use N 2 (2S,4R)-4-(benzyloxymethyl)-N-(3-chloro-4-fluoro-phenyl)-N-methyl-5-oxo-pyrrolidine-2-carboxamide (200 mg, 0.51 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)-pyridine (147 mg, 0.61 mmol), Pd 2 (dba) 3 (47 mg, 0.051 mmol), Xantphos (59 mg, 0.10 mmol) and Cs 2 CO 3 A mixture of (333 mg, 1.02 mmol) in dioxane (10 mL) was degassed 3 times and then stirred for 1 h at 80° C. Upon completion, the reaction was concentrated and purified by column chromatography (20-50% EtOAc in PE) to give the title compound (180 mg, 61% yield) as a colorless oil.

[1075] m / z ES+[M+H] + 550.1; 1H NMR (400MHz, DMSO-d6) δppm 8.34 (s, 1H), 7.94-7.85 (m, 1H), 7.63 (d, J=7.2Hz, 2H), 7.43 (s, 1H), 7.40-7.30 (m, 5H), 4.88-4.74 (m, 1H), 4.52 (s, 2H), 3.74-3.63 (m, 3H), 3.17 (s, 3H), 3.05-2.94 (m, 1H), 2.62 (s, 3H), 2.29-2.16 (m, 1H), 2.00-1.90 (m, 1H).

[1076] Embodiment 77

[1077] (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[1078]

[1079] To a solution of Example 76 (160 mg, 0.28 mmol) in DCM (16 mL) was added dropwise BCl 3 (1M, 5.59 mL). The mixture was stirred at 0°C for 5 min. Upon completion, the reaction mixture was quenched with ice water (5 mL) at 0°C and adjusted to pH 9 with 5% NaOH solution. The aqueous layer was extracted into DCM (10 mL x 3) and washed with Na 2 SO 4 Dry and evaporate. The residue was purified by prep-HPLC to give the title compound (80 mg, 61% yield) as a white solid.

[1080] m / z ES+[M+H] + 460.0; 1 H NMR (400MHz, DMSO-d6) δppm 8.35(s, 1H), 7.87(dd, J=2.0, 6.8Hz, 1H), 7.67-7.54(m, 2H), 7.41(s, 1H), 4.89-4.74(m, 2H), 3.64( d, J=4.8Hz, 2H), 3.17 (s, 3H), 2.86-2.73 (m, 1H), 2.61 (s, 3H), 2.20-2.10 (m, 1H), 2.05-1.90 (m, 1H).

[1081] Embodiment 78

[1082] (2R,4S)-N-(3-chloro-4-fluorophenyl)-4-((dimethylamino)methyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[1083]

[1084] Step a: (2S,4R)-4-(benzyloxymethyl)-N-(3-chloro-4-fluoro-phenyl)-N-methyl-5-oxo-pyrrolidine-2-carboxamide (300 mg, 0.77 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)-pyridine (184 mg, 0.77 mmol), Pd 2 (dba) 3 (70 mg, 0.077 mmol), Cs 2 CO 3 To 4- (2S)-N-(3-chloro-4-fluoro-phenyl)-N-methyl-4-methylene-1-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-5-oxopyrrolidine-2-carboxamide (70mg, 17% yield) was added to the mixture of 4-nitropropene (2S)-1-nitropropene (2S)-1-nitropropene (2S)-2-nitropropene (7S)-1-nitropropene (2S)-2-nitropropene (2 ...2-nitropropene (2S)-2-nitropropene (2S)-2-nitropropene (2S)-2-nitropropene (2S)-2-nitropropene (2S)-2-nitropropene (2S)-2-nitropropene (

[1085] Step b: To a solution of (2S)-N-(3-chloro-4-fluoro-phenyl)-N-methyl-4-methylene-1-[6-methyl-4-(trifluoromethyl)-2-pyridinyl]-5-oxo-pyrrolidine-2-carboxamide (50 mg, 0.11 mmol) in MeOH (10 mL) was added TEA (115 mg, 1.13 mmol) and dimethylamine (92 mg, 1.13 mmol, HCl salt). The mixture was stirred at 60 ° C for 3 h. Upon completion, the reaction system was concentrated. The residue was purified by preparative-HPLC to give the title compound as the minor isomer (19 mg, 34% yield) as a white solid.

[1086] m / z ES+[M+H] + 487.1; 1 H NMR (400 MHz, CD 3OD)δppm 8.48(s, 1H), 7.89-7.82(m, 1H), 7.64-7.56(m, 1H), 7.50-7.42(m, 1H), 7.29(s, 1H), 5.00-4.93(m, 1H), 3.27( s, 3H), 2.98-2.88 (m, 1H), 2.76-2.69 (m, 2H), 2.66 (s, 3H), 2.38-2.32 (m, 1H), 2.29 (s, 6H), 2.00-1.89 (m, 1H).

[1087] Embodiment 79

[1088] (2R,4R)-N-(3-chloro-4-fluorophenyl)-4-((dimethylamino)methyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[1089]

[1090] The title compound was prepared according to Example 78 and the major isomer was isolated in the final step.

[1091] m / z ES+[M+H] + 487.2; 1 H NMR (400 MHz, CD 3 OD)δppm 8.52(s, 1H), 7.89-7.84(m, 1H), 7.65-7.57(m, 1H), 7.50-7.43(m, 1H), 7.27(s, 1H), 5.06-4.99(m, 1H), 3.29(s, 3H), 3.16 -3.03 (m, 1H), 2.81 (dd, J=4.0, 12.4Hz, 1H), 2.65 (s, 3H), 2.54-2.39 (m, 2H), 2.28 (s, 6H), 1.95 (td, J=10.4, 13.2Hz, 1H).

[1092] Embodiment 80

[1093] (2S,3R)-N-(3-Chloro-4-fluorophenyl)-3-hydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

[1094]

[1095] Step a: DMF (1.9 mL) was added to (2S, 3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (1.85 g, 8.0 mmol), imidazole (2.23 g, 32.8 mmol) and tert-butyl-dimethylsilyl chloride (2.53 g, 16.8 mmol), and the mixture was stirred for 18 h. The mixture was diluted with water, extracted with cyclohexane (x2), and washed with saturated NaHCO 3 The combined organic layers were washed with aqueous solution, dried and evaporated to give 1-(tert-butyl)-2-(tert-butyldimethylsilyl)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (3.55 g, 96%).

[1096] 1 H NMR (400 MHz, CDCl 3 )δppm 4.52-4.35(m, 1H), 4.23-4.05(m, 1H), 3.63-3.44(m, 1H), 3.30-3.15(m, 1H), 2.02-1.89(m, 2H), 1.35-1.32 (m, 9H), 0.89-0.82 (m, 9H), 0.80-0.77 (m, 9H), 0.23-0.14 (m, 6H), 0.02--0.02 (m, 6H).

[1097] Step b: To (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-(tert-butyldimethylsilyl) ester (308 mg, 0.67 mmol) in DCM (3 mL) was added DMF (0.01 mL, 0.129 mmol) and the mixture was cooled to 0°C. Oxalyl chloride (0.07 mL, 0.804 mmol) was added and the effervescence subsided within 5 min. More DMF (0.01 mL, 0.129 mmol) was added and the mixture was warmed to rt and stirred for 10 min. The mixture was diluted with THF (5 mL) and evaporated. The residue was dissolved in THF (5 mL) and evaporated a second time to give (7R,7aS)-7-((tert-butyldimethylsilyl)oxy)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazole-1,3-dione (176 mg, 97%) as a colorless waxy solid.

[1098] 1 H NMR (400 MHz, CDCl 3)δppm 4.47 (td, J=2.9, 1.2Hz, 1H), 4.20 (d, J=2.8Hz, 1H), 3.77 (td, J=10.4, 7.9Hz, 1H), 3.35 (ddd, J=10.9, 8.4, 2.7Hz, 1H), 2.10-1.99 (m, 2H), 0.76 (s, 9H), 0.01 (d, J=4.3Hz, 6H). 13 C NMR (101 MHz, CDCl 3 )δppm 166.00, 156.30, 71.14, 70.76, 44.90, 36.44, 25.36, 17.69, -4.75, -5.34.

[1099] Step c: To 3-chloro-4-fluoro-N-methyl-aniline (770 mg, 4.82 mmol) in DMF (2 mL) was added 4M HCl in dioxane (0.6 mL, 2.40 mmol) and the mixture was stirred for 5 min. The mixture was added to a solution of (7R,7aS)-7-((tert-butyldimethylsilyl)oxy)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazole-1,3-dione (483 mg, 1.78 mmol) in DMF (2 mL) and stirred at 100 °C for 20 h. The mixture was evaporated to give a crude oil which was suspended in DCM (10 mL) and treated with DIPEA (1.24 mL, 7.12 mmol). (Boc) was added 2 In the mixture of 4-nitro-1-nitropropene (2S, 3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-[(3-chloro-4-fluoro-phenyl)-methyl-carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (60mg, 7%) was obtained.

[1100] m / z ES+[M+H] + 487.2; 1 H NMR (400 MHz, CDCl 3)δppm 7.49-7.03(m, 3H), 4.48-4.37(m, 1H), 4.34-4.15(m, 1H), 3.63-3.51(m, 1H), 3.41-3.23(m, 1H), 3.2 0-3.16(m, 3H), 2.29-2.03(m, 1H), 1.94-1.79(m, 1H), 1.36(s, 9H), 0.84(s, 9H), 0.07--0.02(m, 6H)

[1101] Step d: Ruthenium (III) chloride hydrate (5.1 mg, 0.025 mmol) and sodium metaperiodate (32 mg, 0.148 mmol) were added to (2S, 3R)-3-[tert-butyl (dimethyl) silyl] oxy-2-[(3-chloro-4-fluoro-phenyl)-methyl-carbamoyl] pyrrolidine-1-carboxylic acid tert-butyl ester (60 mg, 0.123 mmol) in EtOAc (4 mL) and water (4 mL) to give a dark brown / grey mixture. After 5 min, the mixture turned light brown, stirred for 1 h, and then returned to its original color. Sodium metaperiodate (0.07 g, 0.308 mmol) was added and the mixture was stirred for 17 h. The mixture was evaporated and the residue was distributed between EtOAc and water. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layers were dried and evaporated to give a brown oil. The mixture was purified by column chromatography (0-30% EtOAc in cyclohexane) to give (2S,3R)-3-[tert-butyl-(dimethyl)silyl]oxy-2-[(3-chloro-4-fluoro-phenyl)-methyl-carbamoyl]-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (80 mg) as a brown oil which was used directly in the next step.

[1102] m / z ES+[M+H] + 501.2; 1 H NMR (400 MHz, CDCl 3 )δppm 7.43 (dd, J=6.6, 2.6Hz, 1H), 7.28 (dq, J=6.4, 2.1, 1.6Hz, 1H), 7.05-7.00 (m, 1H), 4.64 (d, J=7.8Hz, 1H), 4.29 (dt, J=9.6, 7.9Hz, 1H), 3.17 (s, 3H), 2.84 (dd, J=16.3, 9.5Hz, 1H), 2.45 (dd, J=16.4, 7.9Hz, 1H), 1.38 (s, 9H), 0.81-0.79 (m, 9H), -0.00 (s, 3H), -0.04 (s, 3H).

[1103] Step e: 4M HCl in dioxane (2.0 mL, 8.0 mmol) was added to (2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-[(3-chloro-4-fluoro-phenyl)-methyl-carbamoyl]-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (80 mg, 0.16 mmol). The mixture was stirred for 30 min and evaporated to give (2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-N-(3-chloro-4-fluoro-phenyl)-N-methyl-5-oxo-pyrrolidine-2-carboxamide HCl salt (62 mg, 89%) which was used directly in the next step.

[1104] m / z ES+[M+H] + 401.1; 1 H NMR (400 MHz, CDCl 3 )δppm 7.25 (s, 1H), 7.19 (t, J=7.8Hz, 1H), 7.08 (d, J=7.5Hz, 1H), 4.34-4.12 (m, 2H), 3.13 (s, 3H), 2.4 8 (dd, J=16-3, 5.6Hz, 1H), 2-34-2.26 (m, 1H), 0.77 (d, J=4.5Hz, 9H), 0.00 (s, 3H), -0.03 (s, 3H).

[1105] Step f: Cs 2 CO 3 A mixture of D, Xantphos (0.01 g, 0.026 mmol) and (2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-N-(3-chloro-4-fluoro-phenyl)-N-methyl-5-oxo-pyrrolidine-2-carboxamide HCl salt (56 mg, 0.128 mmol) in 1,4-dioxane (2 mL) was evacuated and heated with N 2 Back-charge 3 times. Add Pd 2 (dba) 3 A mixture of 4-(trifluoromethyl)pyridine (0.01 g, 0.013 mmol) and 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (44 mg, 0.183 mmol) in 1,4-dioxane (2 mL) (degassed in the same manner as above) was heated under reflux for 2 h. The mixture was evaporated and the crude residue was purified by column chromatography (0-20% EtOAc in cyclohexane) to give the desired product with a small amount of impurities. The other fractions from the column were evaporated, containing a small amount of the desired product. Each fraction was treated with TBAF (1 M in THF; 1 mL) and stirred for 2 h. The two mixtures were combined and washed with saturated NH 4 HCO 3The organic layer was dried, evaporated and the residue was purified by prep-HPLC to give the title compound (1.2 mg, 2%).

[1106] m / z ES+[M+H] + 446.1; 1 H NMR (400 MHz, CDCl 3 )δppm 8.52 (s, 1H), 7.81-7.74 (m, 1H), 7.53-7.50 (m, 1H), 7.34-7.29 (m, 1H), 7.13 (s, 1H), 5.22 (d, J = 7.6 Hz, 1H), 4.47 (m, 1H), 3.35 (s, 3H), 2.94 (dd, J = 7.3, 5.1 Hz, 1H), 2.62 (s, 3H), 2.41 (d, J = 8.7 Hz, 1H). An aromatic peak was replaced by CHCl 3 masking.

[1107] Embodiment 81

[1108] (2S,3R)-N-(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-hydroxy-N-methylpyrrolidine-2-carboxamide

[1109]

[1110] Step a: To 3-chloro-4-fluoro-N-methyl-aniline (237 mg, 1.483 mmol) in NMP (1.0 mL) was added 4M HCl in dioxane (0.19 mL, 0.742 mmol) and the mixture was stirred for 5 min. The suspension was transferred to a flask containing (7R,7aS)-7-[tert-butyl(dimethyl)silyl]oxy-5,6,7,7a-tetrahydropyrrolo[1,2-c]oxazole-1,3-dione (161 mg, 0.593 mmol) in NMP (0.5 mL) and the mixture was stirred at 80° C. for 20 h and then evaporated. The mixture was purified by column chromatography (0-7% MeOH in DCM). The product fractions were combined and the solvent removed in vacuo to give (2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-N-(3-chloro-4-fluoro-phenyl)-N-methyl-pyrrolidine-2-carboxamide (21 mg, 9%).

[1111] m / z ES+[M+H] + 387.1

[1112] Step b: A mixture of 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (10 mg, 0.065 mmol), (2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-N-(3-chloro-4-fluoro-phenyl)-N-methyl-pyrrolidine-2-carboxamide (21 mg, 0.054 mmol) and DIPEA (0.04 mL, 0.217 mmol) in NMP (0.5 mL) was heated to 90° C. for 2.5 h. The mixture was treated with TBAF (0.22 mL, 0.217 mmol, 1 M in THF) and stirred for 3 h. The mixture was evaporated and purified by preparative-HPLC to give the title compound (15 mg, 60%).

[1113] m / z ES+[M+H] + 456.8; 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (d, J = 6.7 Hz, 1H), 7.57 (d, J = 6.6 Hz, 2H), 7.07 (s, 1H), 5.54 (d, J = 5.2 Hz, 1H), 4.72 (d, J = 6.2 Hz, 1H), 4.21-4.12 (m, 1H), 4.02-3.92 (m, 1H), 3.88-3.77 (m, 1H), 3.15 (s, 3H), 2.00 (d, J = 6.5 Hz, 2H), one methyl signal is hidden under the DMSO peak.

[1114] Embodiment 82

[1115] (2S,3R)-N-(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-ethyl-3-hydroxypyrrolidine-2-carboxamide

[1116]

[1117] The title compound was prepared in a manner similar to Example 81.

[1118] m / z ES+[M+H] + 471.3; 1H NMR (400MHz, DMSO-d6) δppm 7.77-7.71 (m, 1H), 7.63-7.51 (m, 2H), 7.07 (s, 1H), 5.45 (d, J=5.5Hz, 1H), 4.64 (d, J=5.9Hz, 1H), 4.13-4.03 (m, 1H), 4.02-3.88 (m, 1H), 3.87-3.72 (m, 2H), 2.45-2.39 (m, 3H), 2.02-1.90 (m, 2H), 0.99 (t, J=7.1Hz, 3H).

[1119] Embodiment 83

[1120] (S)-N-(3-Chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide

[1121]

[1122] Step a: To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (300 mg, 1.46 mmol) and 3-chloro-4-fluoro-N-methyl-aniline (303 mg, 1.90 mmol) in IPA (3 mL) was added DIPEA (378 mg, 2.92 mmol) and T3P (1.86 g, 2.92 mmol, 50 wt.% in EtOAc) and the mixture was stirred at rt for 16 h. Upon completion, the mixture was concentrated and purified by column chromatography (25-100% EtOAc in PE) to give tert-butyl (S)-(1-((3-chloro-4-fluorophenyl)(methyl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate (220 mg, 43% yield) as a yellow oil.

[1123] Step b: A mixture of (S)-tert-butyl (1-((3-chloro-4-fluorophenyl)(methyl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate (220 mg, 0.63 mmol) in HCl / dioxane (4M, 2 mL) was stirred at rt for 1 h. Upon completion, the mixture was evaporated to give (S)-2-amino-N-(3-chloro-4-fluorophenyl)-3-hydroxy-N-methylpropanamide (200 mg, crude) as a brown oil which was used in the next step without further purification.

[1124] Step c: To a solution of (S)-2-amino-N-(3-chloro-4-fluorophenyl)-3-hydroxy-N-methyl-propionamide (100 mg, 0.41 mmol) in water (1 mL) was added K 2 CO 3(62 mg, 0.45 mmol) and KHCO 3 (45 mg, 0.45 mmol). The mixture was stirred at rt for 30 min. A solution of triphosgene (60 mg, 0.20 mmol) in toluene (1 mL) was added at 0 °C and the mixture was stirred at 0 °C for 2 h. Upon completion, the mixture was quenched with water (1 mL) and extracted with EtOAc (1 mL x 3). The combined organic layers were washed with brine (2 mL x 3) and washed with Na 2 SO 4 Dried and evaporated. The residue was purified by preparative-TLC (25% EtOAc in PE) to give (S)-N-(3-chloro-4-fluoro-phenyl)-N-methyl-2-oxooxazolidine-4-carboxamide (30 mg, 27% yield) as a white solid in two steps.

[1125] Step d: To a solution of (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxooxazolidine-4-carboxamide (30 mg, 0.11 mmol) in dioxane (1 mL) were added 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (32 mg, 0.13 mmol), Pd(dba) 2 (6.3 mg, 0.011 mmol), Xantphos (9.5 mg, 0.017 mmol) and Cs 2 CO 3 (108 mg, 0.33 mmol). The mixture was heated at 120 °C under N 2 In the mixture of 4-nitro-1-yl pyridine-2 ...

[1126] m / z ES+[M+H] + 432.0; 1 H NMR (400MHz, DMSO-d6) δppm 8.14 (s, 1H), 7.85 (dd, J=2.4, 6.4Hz, 1H), 7.68-7.60 (m, 1H), 7.56 (m, 1H), 7.42 (s, 1H), 5.01 (dd , J=3.2, 8.8Hz, 1H), 4.60 (dd, J=3.2, 8.8Hz, 1H), 4.35 (t, J=8.8Hz, 1H), 3.20 (s, 3H), 2.60 (s, 3H)

[1127] Embodiment 84

[1128] (S)-N-(4-chloro-3-methylphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide

[1129]

[1130] Step a: MeOH (250 mL) was added to sodium methoxide (19.0 g, 353 mmol) in portions. When the temperature cooled to rt, 4-chloro-3-methyl-aniline (5.0 g, 35 mmol) and formaldehyde (1.27 g, 42 mmol) were added and the mixture was stirred at rt for 8 h. NaBH 4 (2.7 g, 71 mmol), the mixture was stirred at rt for 12 h. Upon completion, the reaction was diluted with water (15 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL x 3) and washed with Na 2 SO 4 Dry and evaporate. The residue was purified by column chromatography (100% PE) to give 4-chloro-N,3-dimethylaniline (3 g, 53% yield) as a yellow liquid.

[1131] m / z ES+[M+H] + 156.1; 1 H NMR (400 MHz, CDCl 3 )δppm 7.13 (d, J=8.4Hz, 1H), 6.48 (d, J=2.8Hz, 1H), 6.40 (dd, J=2.8, 8.4Hz, 1H), 2.82 (s, 3H), 2.37-2.27 (m, 3H).

[1132] Step b: T3P (2.9g, 4.6mmol, 50wt.% DMF solution), 4-chloro-N, 3-dimethylaniline (261mg, 1.7mmol) and (4S)-2-oxo-oxazolidine-4-formic acid (200mg, 1.5mmol) solution in pyridine (2mL) were stirred at rt for 20h. When completed, the reaction mixture was concentrated in vacuo, diluted with water (15mL), extracted with EtOAc (30mL x3). The combined organic layer was washed with salt water (10mL x3), dried, and evaporated. By column chromatography residue (PE solution of 10-50%EtOAc), (4S)-N-(4-chloro-3-methyl-phenyl)-N-methyl-2-oxo-oxazolidine-4-methane amide (200mg, 49% yield) was obtained as an oil.

[1133] m / z ES+[M+H] + 269.0; 1H NMR (400 MHz, CDCl 3 )δppm 7.37 (d, J=8.4Hz, 1H), 7.05 (d, J=2.4Hz, 1H), 6.93 (dd, J=2.4, 8.4Hz, 1H), 6.13 (br s, 1H), 4.35 (dd, J=6.0, 9.2Hz, 1H), 4.27 (dd, J=6.0, 8.4Hz, 1H), 4.06-3.95 (m, 1H), 3.22 (s, 3H), 2.34 (s, 3H).

[1134] Step c: Use N 2 (4S)-N-(4-chloro-3-methyl-phenyl)-N-methyl-2-oxo-oxazolidine-4-carboxamide (100 mg, 0.37 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (134 mg, 0.56 mmol), Xantphos (43 mg, 0.074 mmol), Pd 2 (dba) 3 (34 mg, 0.037 mmol) and Cs 2 CO 3 The mixture of (243mg, 0.74mmol) in dioxane (2mL) is degassed 3 times, then stirred at 80 ℃ for 1h.When completed, the reaction mixture is diluted with water (15mL), extracted with EtOAc (30mLx 3).The combined organic layer is washed with saline (10mL x 3), dried, and evaporated.By preparative-TLC purification of residue (25%EtOAc PE solution), title compound (123mg, 75% yield) is obtained, which is a yellow-white solid.

[1135] m / z ES+[M+H] + 428.1; 1 H NMR (400 MHz, CD 3 OD)δppm 8.26 (s, 1H), 7.57 (d, J=8.4Hz, 1H), 7.49 (s, 1H), 7.35 (d, J=7.6Hz, 1H), 7.27 (s, 1H), 5.18 (dd, J =4.4, 9.2Hz, 1H), 4.53-4.44(m, 1H), 4.43-4.36(m, 1H), 3.31(s, 3H), 2.64(s, 3H), 2.47(s, 3H).

[1136] Embodiment 85

[1137] (S)-N-(3-Chloro-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide

[1138]

[1139]

[1140] Step a: A solution of 3-chloro-2,4-difluoroaniline (623 mg, 3.81 mmol), (S)-2-oxoxazolidine-4-carboxylic acid (0.5 g, 3.81 mmol) and T3P (6.06 g, 11.43 mmol, 50 wt.% in EtOAc) in pyridine (10 mL) was stirred at 60 ° C for 2 h. Upon completion, the mixture was evaporated. The resulting residue was purified by column chromatography (20-100% EtOAc in PE) to give (S)-N-(3-chloro-2,4-difluorophenyl)-2-oxoxazolidine-4-carboxamide (0.75 g, 71% yield) as a white solid.

[1141] Step b: NaH (35mg, 0.87mmol, 60% mineral oil dispersion) was added to a solution of (S)-N-(3-chloro-2,4-difluorophenyl)-2-oxo-oxazolidine-4-carboxamide (0.2g, 0.72mmol) in DMF (5mL) at 0°C. The mixture was stirred for 30min at 0°C. Iodomethane (123mg, 0.87mmol) was added and the mixture was stirred for 2h at rt. Upon completion, the reaction system was quenched with water (10mL) and extracted with EtOAc (20mL x 3). The combined organic layer was washed with saline (10mL x 3), dried and evaporated. The residue was purified by preparative-HPLC to obtain (S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-oxazolidine-4-carboxamide (100mg, 48% yield) as a colorless oil.

[1142] Step c: (S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxooxazolidine-4-carboxamide (100 mg, 0.34 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (83 mg, 0.34 mmol), Xantphos (40 mg, 0.069 mmol), Cs 2 CO 3 (336 mg, 1.03 mmol) and Pd(dba) 2 A solution of (20 mg, 0.034 mmol) in dioxane (2 mL) was stirred at 100° C. for 1 h. Upon completion, the reaction mixture was evaporated and the residue was purified by prep-TLC (35% EtOAc in PE) to give the title compound (35 mg, 62% yield) as a white solid.

[1143] m / z ES+[M+H] + 450.2; 1 H NMR (400MHz, DMSO-d6) δ = 8.15 (s, 1H), 7.64-7.35 (m, 3H), 5.90-5.00 (m, 1H), 4.85-4.25 (m, 2H), 3.54-3.20 (m, 3H), 2.62-2.52 (m, 3H).

[1144] The examples in Table 6 were prepared using methods similar to those described in the syntheses of Examples 83-85.

[1145]

[1146]

[1147]

[1148]

[1149]

[1150]

[1151]

[1152] Embodiment 105

[1153] (S)-N-(3-Hydroxy-4-methylphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide

[1154]

[1155] To a solution of Example 92 (100 mg, 0.24 mmol) in DCM (3 mL) was added BBr at -60 °C 3 (592 mg, 2.36 mmol). The reaction mixture was slowly warmed to 0°C and stirred at 0°C for 1 h. Upon completion, the mixture was quenched with ice water (3 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3) and washed with Na 2 SO 4 Dry and evaporate. The residue was purified by prep-HPLC to give the title compound (51 mg, 53% yield) as a white solid.

[1156] m / z ES+[M+H] + 410.0; 1H NMR (400MHz, DMSO-d6) δppm 9.83 (s, 1H), 8.12 (s, 1H), 7.39 (s, 1H), 7.20 (d, J=8.0Hz, 1H), 6.86-6.74 (m, 2H), 4.99 (dd, J=3.6, 8 .8Hz, 1H), 4.52 (dd, J=3.6, 8.8Hz, 1H), 4.36 (t, J=8.8Hz, 1H), 3.15 (s, 3H), 2.58 (s, 3H), 2.14 (s, 3H)

[1157] Embodiment 106

[1158] (S)-N-(4-Fluoro-3-hydroxyphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide

[1159]

[1160] The title compound was prepared in a similar manner to Example 105 using Example 90 as starting material. m / z ES+[M+H] + 414.0; 1 H NMR (400 MHz, CD 3 OD)δppm 8.24 (s, 1H), 7.24 (s, 1H), 7.19 (dd, J=10.8, 8.4Hz, 1H), 7.08-6.99 (m, 1H), 6.92-6. 82 (m, 1H), 5.20 (dd, J=9.2, 4.4Hz, 1H), 4.50-4.35 (m, 2H), 3.27 (s, 3H), 2.62 (s, 3H).

[1161] Embodiment 107

[1162] (S)-N-(2,4-difluoro-3-vinylphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide

[1163]

[1164] Example 85 (30 mg, 0.067 mmol), potassium trifluoro(vinyl)borate (27 mg, 0.20 mmol) and K 2 CO 3 XPhos-Pd-G2 (5.3 mg, 0.0067 mmol) (28 mg, 0.20 mmol) was added to a solution of dioxane (4 mL) and water (1 mL). 2The mixture was purged 3 times and stirred at 80 ° C for 2h. When completed, the reaction mixture was quenched with water (10mL), extracted with EtOAc (10mL x 3). The combined organic layer was washed with saline (10mL x 3), dried and evaporated. The residue was purified by preparative-TLC (25% EtOAc PE solution), title compound (6.9mg, 23% yield) was obtained as a white solid.

[1165] m / z ES+[M+H] + 442.3; 1 H NMR (400 MHz, CD 3 OD)δppm 8.28-8.26 (m, 1H), 7.77-7.36 (m, 1H), 7.30-7.14 (m, 2H), 6.87-6.73 (m, 1H), 6.18-6.10 (m, 1H), 5.78-5.7 4(m, 1H), 5.22-5.12(m, 1H), 4.58-4.45(m, 1H), 4.44-4.33(m, 1H), 3.31-3.29(m, 3H), 2.64-2.55(m, 3H).

[1166] Embodiment 108

[1167] (S)-N-(3-ethyl-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide

[1168]

[1169] To a solution of Example 107 (20 mg, 0.045 mmol) in MeOH (2 mL) was added Pd / C (2 mg, 10% loading on activated carbon). 2 The mixture was purged 3 times and then heated at rt under H 2 Stir under atmosphere (15 psi) for 30 min. Upon completion, the mixture was filtered, evaporated and purified by prep-HPLC to give the title compound (3 mg, 14% yield) as an off-white solid.

[1170] m / z ES+[M+H] + 444.2; 1 H NMR (400 MHz, CD 3OD)δppm 8.30-8.28(m, 1H), 7.70-7.05(m, 3H), 5.19-5.10(m, 1H), 4.58-4.44(m, 1H), 4.43-4.3 3(m, 1H), 3.30-3.25(m, 3H), 2.86-2.80(m, 2H), 2.64-2.57(m, 3H), 1.30-1.25(m, 3H).

[1171] Embodiment 109

[1172] (S)-N-(4-Fluoro-3-vinylphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide

[1173]

[1174] Use N 2 Example 93 (70 mg, 0.15 mmol), potassium trifluoro(vinyl)-borate (30 mg, 0.2 mmol), Pd(dppf)Cl 2 (11 mg, 0.015 mmol) and Na 2 CO 3 The mixture of (47mg, 0.44mmol) in dioxane (0.4mL) and water (0.1mL) is degassed 3 times, then stirred at 100 ℃ for 1h.When finished, the reaction mixture is diluted with water (10mL), extracted with EtOAc (30mL x 3).The combined organic layer is washed with saline (8mL x 3), dried, and evaporated.By preparation-TLC purification of residue (50%EtOAc PE solution), then by preparation-HPLC purification, title compound (57mg, 92% yield) is obtained, which is a white solid.

[1175] m / z ES+[M+H] + 424.1; 1 H NMR (400 MHz, CD 3 OD)δppm 8.25 (s, 1H), 7.94-7.71 (m, 1H), 7.55-7.39 (m, 1H), 7.33-7.24 (m, 2H), 6.91 (dd, J=11.2, 17.6Hz, 1H), 5.97 (d, J=17.6Hz, 1H) , 5.52 (d, J=11.2Hz, 1H), 5.16 (dd, J=4.0, 9.6Hz, 1H), 4.54-4.46 (m, 1H), 4.42-4.33 (m, 1H), 3.30-3.29 (m, 3H), 2.62 (s, 3H).

[1176] Embodiment 110

[1177] (S)-N-(3-ethyl-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxo-oxazolidine-4-carboxamide

[1178]

[1179] A solution of Example 109 (50 mg, 0.12 mmol) and Pd / C (5 mg, 10% loading on activated carbon) in MeOH (5 mL) was stirred at rt under H 2 Stir under atmosphere (15 psi) for 2 h. Upon completion, the reaction mixture was filtered and concentrated to give a residue which was purified by prep-HPLC to give the title compound (22 mg, 42% yield) as an off-white solid.

[1180] m / z ES+[M+H] + 426.0; 1 H NMR (400 MHz, CD 3 OD)δppm 8.27(s,1H),7.46(br s,1H),7.37(br s, 1H), 7.29-7.22 (m, 2H), 5.16 (dd, J=4.4, 9.2Hz, 1H), 4.50 (dd, J=4.4, 9.2Hz, 1H), 4 .42-4.32 (m, 1H), 3.31 (s, 3H), 2.81-2.73 (m, 2H), 2.65 (s, 3H), 1.30 (t, J=7.6Hz, 3H).

[1181] Embodiment 111

[1182] (S)-N-(2-Fluoro-4-vinylphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide

[1183]

[1184] The title compound was prepared in a similar manner to Example 109 using Example 94 as starting material. m / z ES+[M+H] + 424.0; 1 H NMR (400 MHz, CD 3OD)δppm 8.29-8.19(m, 1H), 7.75-7.45(m, 2H), 7.41-7.17(m, 2H), 6.84-6.73(m, 1H), 5.96-5.86(m, 1H), 5.45-5.3 9 (m, 1H), 5.23-5.09 (m, 1H), 4.57-4.48 (m, 1H), 4.47-4.38 (m, 1H), 3.30-3.24 (m, 3H), 2.65-2.51 (m, 3H).

[1185] Embodiment 112

[1186] (S)-N-(4-ethyl-2-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide

[1187]

[1188] The title compound was prepared in a similar manner to Example 108 using Example 111 as starting material. m / z ES+[M+H] + 426.1; 1 H NMR (400 MHz, DMSO-d 6 )δppm 8.14 (s, 1H), 7.69-7.15 (m, 4H), 5.14-4.95 (m, 1H), 4.70-4.45 (m, 1H), 4.38-4.20 (m, 1H), 3.18 and 3.14 (s x2, 3H), 2.75-2.65 (m, 2H), 1.28-1.20 (m, 3H). The additional 3H portion was masked by DMSO.

[1189] Embodiment 113

[1190] (S)-3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxooxazolidine-4-carboxamide

[1191]

[1192] The title compound was prepared in a manner analogous to Example 83 using 2,6-dichloro-4-(trifluoromethyl)pyridine (CAS No. 39890-98-7) in step d.

[1193] m / z ES+[M+H] + 452.0; 1 H NMR (400 MHz, DMSO-d 6)δppm 8.27 (s, 1H), 7.86 (dd, J=2.4, 6.4Hz, 1H), 7.78 (s, 1H), 7.68-7.61 (m, 1H), 7.61-7.54 (m, 1H) , 4.98 (dd, J=3.2, 8.8Hz, 1H), 4.63 (dd, J=3.2, 8.8Hz, 1H), 4.36 (t, J=8.8Hz, 1H), 3.20 (s, 3H)

[1194] Embodiment 114

[1195] (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-6-vinylpyridin-2-yl)oxazolidine-4-carboxamide

[1196]

[1197] Example 113 (90 mg, 0.20 mmol), potassium vinyl trifluoroborate (27 mg, 0.20 mmol) and Na 2 CO 3 (63 mg, 0.60 mmol) was added to a solution of Pd(dppf)Cl in dioxane (0.8 mL) and water (0.2 mL). 2 ·CH 2 Cl 2 (16 mg, 0.020 mmol). The mixture was heated at 60 °C under N 2 Stir for 2 h in air. When completed, add NH 4 The reaction mixture was quenched with Cl (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2) and washed with Na 2 SO 4 Dried and evaporated. The residue was purified by preparative-TLC (35% EtOAc in PE) to give the title compound (50 mg, 50% yield) as a white solid.

[1198] m / z ES+[M+H] + 444.1; 1 H NMR (400 MHz, CDCl 3)δppm 8.41 (s, 1H), 7.45 (d, J=4.8Hz, 1H), 7.35-7.29 (m, 2H), 7.26-7.20 (m, 1H), 6.80 (dd, J=10.8, 17.2Hz, 1H), 6 .15 (d, J=17.2Hz, 1H), 5.67 (d, J=10.8Hz, 1H), 5.22 (dd, J=5.2, 9.2Hz, 1H), 4.37-4.27 (m, 2H), 3.31 (s, 3H).

[1199] Embodiment 115

[1200] (S)-N-(3-Chloro-4-fluorophenyl)-3-(6-ethyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-2-oxooxazolidine-4-carboxamide

[1201]

[1202] In N 2 To a solution of Example 114 (50 mg, 0.099 mmol) in MeOH (0.5 mL) was added PtO 2 (4.50 mg, 0.020 mmol). The suspension was degassed in vacuo and heated to 400 °C. 2 The mixture was purged 3 times under H 2 Stir under atmosphere (15 psi) at 30° C. for 15 min. Upon completion, the reaction mixture was filtered, evaporated and the residue was purified by prep-HPLC to give the title compound (8 mg, 17% yield) as a yellow solid.

[1203] m / z ES+[M+H] + 446.1; 1 H NMR (400 MHz, CD 3 OD)δppm 8.27 (s, 1H), 7.75-7.72 (m, 1H), 7.49-7.44 (m, 2H), 7.26 (s, 1H), 5.19 (dd, J=4.0, 9.6Hz, 1H ), 4.51-4.47(m, 1H), 4.42-4.36(m, 1H), 3.29(s, 3H), 2.93-2.88(m, 2H), 1.36-1.32(m, 3H).

[1204] Embodiment 116

[1205] (S)-3-(4-bromo-6-methylpyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxooxazolidine-4-carboxamide

[1206] The title compound was prepared in a similar manner to Example 83 using 2,4-dibromo-6-methylpyridine (CAS No. 79055-52-0) in step d.

[1207] m / z ES+[M+H] + 443.9; 1 H NMR (400 MHz, CDCl 3 )δppm 8.28 (s, 1H), 7.60-7.55 (m, 1H), 7.32-7.26 (m, 2H), 7.08 (s, 1H), 5.15-5.08 (m, 1H), 4.31-4.25 (m, 2H), 3.30 (s, 3H), 2.49 (s, 3H)

[1208] Embodiment 117

[1209] (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(prop-1-en-2-yl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide

[1210]

[1211] Example 116 (20 mg, 0.045 mmol), potassium trifluoro(prop-1-en-2-yl)borate (13.4 mg, 0.090 mmol) and Na 2 CO 3 To a solution of (14.4 mg, 0.14 mmol) in dioxane (0.4 mL) and water (0.1 mL) was added Pd(dppf)Cl 2 ·CH 2 Cl 2 (3.7 mg, 0.0045 mmol). The mixture was heated at 60 °C under N 2 Stir in atmosphere for 45 min. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (4 mL x 2) and washed with Na 2 SO 4 Drying, evaporation and purification by prep-HPLC gave the title compound (11 mg, 61% yield) as a white solid.

[1212] m / z ES+[M+H] + 404.1; 1 H NMR (400 MHz, CDCl 3)δppm 8.10(s, 1H), 7.68-7.56(m, 1H), 7.34-7.27(m, 2H), 6.95(s, 1H), 5.55(s, 1H), 5.29-5.10 (m, 2H), 4.32-4.20 (m, 2H), 3.31 (s, 3H), 2.52 (s, 3H), 2.13 (s, 3H).

[1213] Embodiment 118

[1214] (S)-N-(3-Chloro-4-fluorophenyl)-3-(4-isopropyl-6-methylpyridin-2-yl)-N-methyl-2-oxooxazolidine-4-carboxamide

[1215]

[1216] In N 2 To a solution of Example 117 (100 mg, 0.25 mmol) in MeOH (2 mL) was added PtO 2 (5.6 mg, 0.025 mmol). The suspension was degassed in vacuo and heated to 400 °C. 2 The mixture was purged 3 times under H 2 Stir under atmosphere (15 psi) at rt for 1 h. Upon completion, the reaction mixture was filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (28 mg, 56% yield) as a white solid.

[1217] m / z ES+[M+H] + 406.1; 1 H NMR (400 MHz, CDCl 3 )δppm 7.91(s, 1H), 7.72-7.58(m, 1H), 7.35-7.28(m, 2H), 6.76(s, 1H), 5.18-5.10(m, 1H), 4 .36-4.16 (m, 2H), 3.31 (s, 3H), 2.95-2.80 (m, 1H), 2.50 (s, 3H), 1.24 (d, J=7.2Hz, 6H).

[1218] Embodiment 119

[1219] (S)-N-(3-Chloro-4-fluorophenyl)-3-(4-ethyl-6-methylpyridin-2-yl)-N-methyl-2-oxooxazolidine-4-carboxamide

[1220]

[1221] Step a: 4-bromo-2-chloro-6-methylpyridine (500 mg, 2.42 mmol), potassium vinyl trifluoroborate (973 mg, 7.27 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (198 mg, 0.24 mmol) and Na 2 CO 3 A mixture of (770 mg, 7.27 mmol) in dioxane (4 mL) and water (1 mL) was heated at 60 °C under N 2 Stir under atmosphere for 1 h. Upon completion, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL x 3). 2 SO 4 The combined organic layers were dried and evaporated. The residue was purified by prep-HPLC to give 2-chloro-6-methyl-4-vinylpyridine (200 mg, 51% yield) as a yellow oil.

[1222] m / z ES+[M+H] + 154.1; 1 H NMR (400 MHz, CDCl 3 )δppm 7.14 (s, 1H), 7.05 (s, 1H), 6.59 (dd, J=10.8, 17.6Hz, 1H), 5.96 (d, J=17.6Hz, 1H), 5.52 (d, J=10.8Hz, 1H), 2.53 (s, 3H).

[1223] Step b: In N 2 To a solution of 2-chloro-6-methyl-4-vinylpyridine (70 mg, 0.43 mmol) in MeOH (1 mL) was added PtO 2 (49 mg, 0.22 mmol). The suspension was degassed in vacuo and heated to 400 °C. 2 The mixture was purged 3 times under H 2 Stir at 30°C for 15 min under atmosphere (15 psi). Upon completion, the mixture was filtered and concentrated to give 2-chloro-4-ethyl-6-methylpyridine (50 mg, crude) as a colorless oil, which was used in the next step without further purification. m / z ES+[M+H] + 156.1

[1224] Step c: 2-Chloro-4-ethyl-6-methyl-pyridine (40 mg, 0.18 mmol), (4S)-N-(3-chloro-4-fluoro-phenyl)-N-methyl-2-oxo-oxazolidine-4-carboxamide (72 mg, 0.26 mmol), Xantphos (22 mg, 0.039 mmol) and Cs 2 CO 3 (251 mg, 0.77 mmol) was added to a solution of Pd(dba) in dioxane (1 mL) 2 (15 mg, 0.026 mmol). 2 The mixture was purged 3 times and then stirred at 100 °C for 1 h. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (4 mL x 2) and washed with Na 2 SO 4 Dried and evaporated. The residue was purified by prep-HPLC to give the title compound (HCl salt, 10.4 mg, 13% yield) as a yellow solid.

[1225] m / z ES+[M+H] + 392.1; 1 H NMR (400 MHz, CDCl 3 )δppm 7.91(s, 1H), 7.65(s, 1H), 7.50-7.30(m, 2H), 6.81(s, 1H), 5.55-5.45(m, 1H), 4.30 -4.20 (m, 2H), 3.31 (s, 3H), 2.70-2.60 (m, 2H), 2.56 (s, 3H), 1.26 (t, J=7.6Hz, 3H).

[1226] Embodiment 120

[1227] (S)-3-(6-chloro-4-(difluoromethoxy)pyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxooxazolidine-4-carboxamide

[1228]

[1229] Step a: Water (5mL) and NaOH (1.22g, 30.5mmol) were added to a solution of 2,6-dichloropyridine-4-ol (1g, 6.1mmol) in dioxane (10mL) at rt. Chlorodifluoromethane (1.05g, 12.2mmol) was bubbled into the mixture for 5h at 55°C. Upon completion, EtOAc (50mL) and water (50mL) were added to the cooled reaction mixture and separated. The aqueous phase was extracted with EtOAc (50mLx2). The combined organic phases were dried and evaporated. The residue was purified by column chromatography (10-25% EtOAc in PE solution) to give 2,6-dichloro-4-(difluoromethoxy)pyridine (630mg, 48% yield) as an oil. m / z ES+[M+H] + 214.0

[1230] Step b: 2,6-dichloro-4-(difluoromethoxy)pyridine (118 mg, 0.55 mmol), (4S)-N-(3-chloro-4-fluoro-phenyl)-N-methyl-2-oxo-oxazolidine-4-carboxamide (100 mg, 0.37 mmol), Pd 2 (dba) 3 (33 mg, 0.037 mmol), Xantphos (42 mg, 0.073 mmol) and Cs 2 CO 3 A mixture of (239 mg, 0.73 mmol) in dioxane (2.5 mL) was degassed and heated with N 2 Purge 3 times, then stir at 80°C for 2 h. Upon completion, concentrate the reaction. The residue was purified by column chromatography (10-35% EtOAc in PE) to give the title compound (120 mg, 73% yield) as a white solid.

[1231] m / z ES+[M+H] + 449.7; 1 H NMR (400 MHz, DMSO-d 6 )δppm 7.86 (dd, J=2.2, 6.4Hz, 1H), 7.76 (d, J=1.6Hz, 1H), 7.70-7.35 (m, 3H), 7.21 (d, J=1.6Hz, 1H ), 4.94 (dd, J=3.6, 9.2Hz, 1H), 4.56 (dd, J=3.6, 9.2Hz, 1H), 4.39-4.27 (m, 1H), 3.19 (s, 3H)

[1232] Embodiment 121

[1233] (S)-N-(3-chloro-4-fluorophenyl)-3-(4-(difluoromethoxy)-6-methylpyridin-2-yl)-N-methyl-2-oxooxazolidine-4-carboxamide

[1234]

[1235] Example 120 (50 mg, 0.11 mmol), MeB(OH) 2 (10mg, 0.17mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (9.1 mg, 0.011 mmol), K 2 CO 3 A mixture of (31 mg, 0.22 mmol) in water (0.25 mL) and dioxane (2 mL) was degassed and heated with N 2 Purge 3 times, then stir at 80°C for 12 h. Upon completion, concentrate the reaction. Purify the residue by column chromatography (20-30% EtOAc in PE) and then by prep-HPLC to give the title compound (24 mg, 51% yield) as a white solid.

[1236] m / z ES+[M+H] + 430.0; 1 H NMR (400 MHz, CD 3 OD)δppm 7.80-7.70(m, 2H), 7.55-7.40(m, 2H), 7.25-6.85(m, 1H), 6.76(s, 1H), 5.17- 5.08 (m, 1H), 4.47-4.40 (m, 1H), 4.39-4.32 (m, 1H), 3.29 (s, 3H), 2.53 (s, 3H).

[1237] Embodiment 122

[1238] (S)-3-(4-(tert-butyl)-6-chloropyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxooxazolidine-4-carboxamide

[1239]

[1240] Step a: To a solution of 4-tert-butyl-2-chloro-pyridine (200 mg, 1.18 mmol) in DCM (10 mL) was added m-CPBA (1.02 g, 5.89 mmol) in portions. The mixture was stirred at rt for 12 h. Upon completion, EtOAc (100 mL) was added and the mixture was washed with saturated NaHCO 3The mixture was washed with aqueous solution (100 ml x 3). The combined aqueous phase was extracted with EtOAc (50 mL x 2). 2 SO 4 The combined organic phases were dried and evaporated. The residue was purified by column chromatography (10-50% EtOAc in PE) to give 4-tert-butyl-2-chloro-1-oxido-pyridin-1-ium (150 mg, 69% yield) as a yellow solid. m / z ES+[M+H] + 186.1

[1241] Step b: 4-tert-butyl-2-chloro-1-oxido-pyridin-1-ium (150 mg, 0.81 mmol) and POCl 3 In 4- tert-butyl-2-yl-4- chloro-pyridine (150 mg, 91% yield) was added to 4- tert-butyl-2-yl-4- chloro-pyridine (200 mg, 100% yield) in 4- tert-butyl-2-yl-4- chloro-pyridine (200 mg, 100% yield) solution.The mixture of (3.3 g, 21.5 mmol) was stirred at 110 ° C for 5 h.When completed, the reaction mixture was quenched by slowly adding water (100 mL), then extracted with EtOAc (100 mL x 3).The combined organic layers were washed with saline (100 mL x 3), dried, and evaporated to give 4- tert-butyl-2,6- dichloro-pyridine (150 mg, 91% yield) as a brown solid.

[1242] Step c: (4S)-N-(3-chloro-4-fluoro-phenyl)-N-methyl-2-oxo-oxazolidine-4-carboxamide (60 mg, 0.22 mmol), 4-tert-butyl-2,6-dichloro-pyridine (67 mg, 0.33 mmol), Pd 2 (dba) 3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.044 mmol) and Cs 2 CO 3 A solution of (143 mg, 0.44 mmol) in dioxane (1 mL) was degassed and heated with N 2 Purge 3 times, then stir at 80°C for 1 h. Upon completion, concentrate the reaction. The resulting residue was purified by column chromatography (10-35% EtOAc in PE) and then by prep-HPLC to give the title compound (30 mg, 31% yield) as a white solid.

[1243] m / z ES+[M+H] + 439.9; 1 H NMR (400 MHz, DMSO-d 6)δppm 8.06 (d, J=1.2Hz, 1H), 7.89 (dd, J=2.4, 6.8Hz, 1H), 7.67-7.57 (m, 2H), 7.30 (d, J=1.2Hz, 1H), 4.93 (dd, J=3.2, 9.2Hz, 1H), 4.52 (dd, J=3.2, 9.2Hz, 1H), 4.35-4.28 (m, 1H), 3.19 (s, 3H), 1.28 (s, 9H).

[1244] Embodiment 123

[1245] (S)-3-(4-(tert-Butyl)-6-methylpyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxooxazolidine-4-carboxamide

[1246]

[1247] (4S)-3-(4-tert-butyl-6-chloro-2-pyridinyl)-N-(3-chloro-4-fluoro-phenyl)-N-methyl-2-oxo-oxazolidine-4-carboxamide (50 mg, 0.11 mmol), MeB(OH) 2 (10mg, 0.17mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (9.3 mg, 0.011 mmol), K 2 CO 3 A mixture of (31 mg, 0.23 mmol) in water (0.25 mL) and dioxane (2 mL) was degassed and heated with N 2 Purge 3 times, then stir at 80°C for 12 h. Upon completion, concentrate the reaction. Purify the resulting residue by column chromatography (20-30% EtOAc in PE) and then by preparative-HPLC to give the title compound (8 mg, 16% yield) as a white solid.

[1248] m / z ES+[M+H] + 420.2; 1 H NMR (400 MHz, CD 3 OD)δppm 8.01(s, 1H), 7.88-7.77(m, 1H), 7.59-7.50(m, 1H), 7.49-7.41(m, 1H), 7.04(s, 1H), 5.20-5.10 (m, 1H), 4.48-4.31 (m, 2H), 3.30 (s, 3H), 2.56-2.53 (m, 3H), 1.33 (s, 9H).

[1249] Embodiment 124

[1250] (4S)-N-(3-Chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide

[1251]

[1252] Step a: 4-bromo-2-chloro-6-methyl-pyridine (1 g, 4.84 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.48 g, 5.81 mmol), Pd(dppf)Cl 2 A mixture of 1,4-dioxane (354 mg, 0.48 mmol) and potassium acetate (951 mg, 9.69 mmol) in dioxane (10 mL) was heated at 60 °C under N 2 Atmosphere is stirred for 2h.When complete, the reaction mixture is concentrated in vacuo.The residue obtained by column chromatography (10% EtOAc in PE solution) is purified to obtain 2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.1 g, 90% yield) as a white solid.

[1253] 1 H NMR (400 MHz, CDCl 3 )δppm 7.48 (s, 1H), 7.41 (s, 1H), 2.54 (s, 3H), 1.35 (s, 12H).

[1254] Step b: 2-Chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.1 g, 4.34 mmol), 2-bromo-3,3,3-trifluoro-prop-1-ene (7.59 g, 43.4 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (354 mg, 0.43 mmol) and Cs 2 CO 3 A mixture of (2.83 g, 8.68 mmol) in dioxane (15 mL) and water (3 mL) was heated at 80 °C under N 2 Stir in atmosphere for 12h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (1% EtOAc in PE) to give 2-chloro-6-methyl-4-[1-(trifluoromethyl)-vinyl]pyridine (0.8 g, 83% yield) as a yellow oil.

[1255] 1 H-NMR (400 MHz, CDCl 3 )δppm 7.22 (s, 1H), 7.14 (s, 1H), 6.14 (d, J = 0.8Hz, 1H), 5.97 (d, J = 1.6Hz, 1H), 2.58 (s, 3H).

[1256] Step c: 2-chloro-6-methyl-4-[1-(trifluoromethyl)vinyl]pyridine (0.1 g, 0.45 mmol), PtO 2 A mixture of (10.3 mg, 0.045 mmol) in MeOH (5 mL) was heated at rt under H 2 (15 Psi) atmosphere for 5 min. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give 2-chloro-6-methyl-4-(2,2,2-trifluoro-1-methyl-ethyl)pyridine (0.1 g, 99% yield) as a yellow oil, which was used in the next step without further purification.

[1257] Step d: (4S)-N-(3-chloro-4-fluoro-phenyl)-N-methyl-2-oxo-oxazolidine-4-carboxamide (0.1 g, 0.37 mmol), 2-chloro-6-methyl-4-(2,2,2-trifluoro-1-methyl-ethyl)pyridine (100 mg, 0.45 mmol), Xantphos (32 mg, 0.055 mmol), Pd 2 (dba) 3 (33 mg, 0.037 mmol) and Cs 2 CO 3 A mixture of (239 mg, 0.73 mmol) in dioxane (1 mL) was heated at 100 °C under N 2 Stir for 2 h under atmosphere. Upon completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative-HPLC and then by preparative-TLC (50% EtOAc in PE) to give the title compound (14 mg, 8% yield) as an off-white solid.

[1258] m / z ES+[M+H] + 460.1; 1 H NMR (400 MHz, CD 3OD)δppm 8.01 (d, J=2.8Hz, 1H), 7.80 (d, J=4.8Hz, 1H), 7.55-7.48 (m, 1H), 7.44 (t, J=8.8Hz, 1H), 7.00 (s, 1H), 5.19-5.06 ( m, 1H), 4.45-4.39 (m, 1H), 4.39-4.32 (m, 1H), 3.69-3.56 (m, 1H), 3.28 (s, 3H), 2.55 (s, 3H), 1.48 (d, J=7.2Hz, 3H).

[1259] Embodiment 125

[1260] (S)-N-(3-chloro-4-fluorophenyl)-3-(4-(1,1-difluoroethyl)-6-methylpyridin-2-yl)-N-ethyl-2-oxooxazolidine-4-carboxamide

[1261]

[1262] Step a: at 0°C under N 2 In atmosphere, to 2-chloro-6-methyl-pyridine-4-formic acid (2.5g, 14.6mmol) in THF (10mL) solution, methylmagnesium iodide (33.5mmol, 3M) is added dropwise, then stirred at 0 ℃ for 12h.When completing, the reaction mixture is diluted with water (100mL), extracted with EtOAc (50mL x 3).The organic layer merged is washed with salt water (50mL), dried, evaporated.By column chromatography residue (PE solution of 5-20%EtOAc), 1-(2-chloro-6-methyl-4-pyridyl) ethyl ketone (2.0g, 79% yield) is obtained, which is a red oil.

[1263] m / z ES+[M+H] + 169.9; 1 H NMR (400 MHz, CDCl 3 )δppm 7.49 (s, 1H), 7.43 (s, 1H), 2.55 (s, 3H), 2.53 (s, 3H).

[1264] Step b: A mixture of 1-(2-chloro-6-methyl-4-pyridinyl)ethanone (300 mg, 1.8 mmol) and DAST (2.9 g, 17.7 mmol) in EtOH (0.05 mL) and DCM (2.34 mL) was degassed and heated to 40 ℃ for 1 hr. 2 The mixture was purged 3 times and then stirred at rt for 12 h. Upon completion, the mixture wa...

Claims

1. Compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein: W represents = C (R 4 )-or=N-; R 1 , R 2 , R 3 and R 4 independently represent hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, halogen, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, cyano or -NR x R y ; X represents -C(H)(R 6 )-、-N(R 14 )-or-O-; R 5 Represents hydrogen, -CH2-R z or oxo, so that when X represents -N(R 14 )- or -O-, R 5 represents oxygen generation; R 6 Represents hydrogen, -OR 15a , cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl alcohol, C 3-8 Cycloalkyl, halogen, -NR v R w 、-CH2-NR v R w , -Z-phenyl or heterocyclic, wherein the phenyl or heterocyclic can be optionally substituted by one or more oxo, hydroxyl, C 1-6 Alkyl alcohol, -COC 1-6 Alkyl or -COOC 1-6 Alkyl group substitution; Z represents -CH2-O-CH2-; R 7 Represents hydrogen, -CH2-R z OR 15b , so that when X represents -N(H)- or -O-, R 7 represents hydrogen; R 8 Represents C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 3-8 Cycloalkyl; Y represents -C(R 9 )=or-N=; R 9 , R 10 , R 11 , R 12 and R 13 independently represent hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, hydroxyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, halogen or halogenated C 1-6 Alkyl, or the R 9 , R 10 , R 11 , R 12 and R 13 Two adjacent groups of the group may be linked to form a 5-7 membered saturated or unsaturated ring, which optionally contains one or more heteroatoms selected from O, N or S; R 14 Represents hydrogen, C 1-6 Alkyl, C 1-6 Alkyl alcohol or -SO2-C 1-6 alkyl; R 15a and R 15b independently represents hydrogen, or R 15a and R 15b are connected together to form a 5-7 membered saturated ring system, which may be optionally replaced by one or more C 1-6 Alkyl substitution; R v , R w , R x and R y independently represent hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, -COC 1-6 wherein the alkyl group may be optionally substituted with one or more hydroxyl, amino or sulfone groups, and the heterocyclyl ring may be optionally substituted with one or more oxo, hydroxyl, C 1-6 Alkyl alcohol or -COC 1-6 Alkyl substituted; and R z Represents C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or C 1-6 Alkanol; The heterocyclyl group refers to a monocyclic or bicyclic non-aromatic, partially saturated or fully saturated ring system containing 3 to 12 ring members, and each ring contains up to 5 heteroatoms selected from nitrogen, oxygen and sulfur.

2. The compound defined in claim 1, which is of formula (I) a Compounds Where R 1 , R 2 , R 3 , R 4 , R 5 ,X,R 7 , R 8 , R 9 , R 10 , R 11 and R 12 As defined in claim 1; or formula (I) b Compounds: Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 As defined in claim 1.

3. A compound as defined in claim 1 or claim 2, wherein: R 6 -COC in the phenyl or heterocyclic optional substituent 1-6 Alkyl is -COMe, -COOC 1-6 The alkyl group is -COOtBu.

4. A compound as defined in claim 1 or claim 2, wherein W represents =C(R 4 )-; or =N-; or =C(H)-, =C(CN)- or =N-; or =C(H)- or =C(CN)-.

5. A compound as defined in claim 1 or claim 2, wherein R 1 express: hydrogen; C 1-6 alkyl; C 2-6 alkenyl; C 1-6 Alkoxy; halogen; or -NR x R y .

6. A compound as defined in claim 5, wherein R 1 express: hydrogen; Methyl or ethyl; Vinyl; Methoxy; Chlorine; or -N(Me)2 or -N(Me)(Et).

7. A compound as defined in claim 1 or claim 2, wherein R 2 Represents: hydrogen; halogen; or C 1-6 alkyl.

8. The compound as defined in claim 7, wherein R 2 represents: hydrogen; chlorine; or methyl.

9. A compound as defined in claim 1 or claim 2, wherein R 3 express: C 1-6 alkyl; C 2-6 alkenyl; halogen; Halogenated C 1-6 Alkyl; or Halogenated C 1-6 Alkoxy.

10. The compound as defined in claim 9, wherein R 3 express: methyl, ethyl or isopropyl; -C(=CH2)(Me); bromine; trifluoromethyl or -C(H)(Me)-CF3; or Difluoromethoxy.

11. A compound as defined in claim 1 or claim 2, wherein R 4 It means: hydrogen; or cyano.

12. A compound as defined in claim 1 or claim 2, wherein: R x and R y Represents C 1-6 Alkyl; or R x and R y Both represent C 1-6 Alkyl; or R x and R y Both represent methyl or one represents methyl and the other represents ethyl.

13. A compound as defined in claim 12, wherein: R x and R y represents a methyl or ethyl group; or R x and R y all represent methyl or ethyl; or R x and R y Both represent methyl or one represents methyl and the other represents ethyl.

14. A compound as defined in claim 1 or claim 2, wherein W represents =C(R 4 )-,and; R 1 Represents C 1-6 Alkyl, R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 Alkyl, and R 4 represents a cyano group; or R 1 Represents C 1-6 Alkyl, R 2 Represents hydrogen, R 3 Represents C 1-6 Alkyl, and R 4 represents a cyano group; or R 1 Represents C 1-6 Alkyl, R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 Alkyl, and R 4 represents hydrogen; or R 1 Represents C 1-6 Alkyl, R 2 Represents hydrogen, R 3 Represents C 1-6 Alkyl, and R 4 represents hydrogen; or R 1 Represents C 1-6 Alkyl, R 2 Represents halogen, R 3 Represents C 1-6 Alkyl, and R 4 represents hydrogen; or R1 Represents C 1-6 Alkoxy, R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 Alkyl, and R 4 represents a cyano group; or R 1 Indicates -NR x R y , R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 Alkyl, and R 4 represents a cyano group; or R 1 Represents hydrogen, R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 Alkyl, and R 4 represents a cyano group; or R 1 Represents hydrogen, R 2 Represents C 1-6 Alkyl, R 3 Represents C 1-6 Alkyl, and R 4 represents hydrogen; or R 1 Represents halogen, R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 Alkyl, and R 4 represents hydrogen; or R 1 Represents halogen, R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 Alkoxy, and R 4 represents hydrogen; or R 1 Represents C 2-6 Alkenyl, R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 Alkyl, and R 4 represents hydrogen; or R 1 Represents C 1-6 Alkyl, R 2 Represents hydrogen, R 3 Represents halogenated C 1-6 Alkoxy, and R 4 represents hydrogen; or R 1 Represents C 1-6 Alkyl, R 2 Represents hydrogen, R 3 Represents C2-6 alkenyl, and R 4 represents hydrogen; or R 1 Represents C 1-6 Alkyl, R 2 Represents hydrogen, R 3 represents a halogen, and R 4 Represents hydrogen.

15. A compound as defined in claim 14, wherein W represents =C(R 4 )-,and; R 1 Represents methyl, R 2 Represents hydrogen, R 3 represents trifluoromethyl, and R 4 represents a cyano group; or R 1 Represents methyl, R 2 Represents hydrogen, R 3 represents methyl or isopropyl, and R 4 represents a cyano group; or R 1 Represents methyl or ethyl, R 2 Represents hydrogen, R 3 represents trifluoromethyl or -CH(Me)-CF3, and R 4 represents hydrogen; or R 1 Represents methyl, R 2 Represents hydrogen, R 3 represents isopropyl, and R 4 represents hydrogen; or R 1 Represents methyl, R 2 Represents chlorine, R 3 represents a methyl group, and R 4 represents hydrogen; or R 1 Represents methoxy, R 2 Represents hydrogen, R 3 represents trifluoromethyl, and R 4 represents a cyano group; or R 1 represents -N(Me)2 or -N(Me)(Et), R 2 Represents hydrogen, R 3 represents trifluoromethyl, and R 4 represents a cyano group; or R 1 Represents hydrogen, R 2 Represents hydrogen, R 3 represents trifluoromethyl, and R 4 represents a cyano group; or R 1 Represents hydrogen, R 2Represents methyl, R 3 represents ethyl, and R 4 represents hydrogen; or R 1 Represents chlorine, R 2 Represents hydrogen, R 3 represents trifluoromethyl, and R 4 represents hydrogen; or R 1 Represents chlorine, R 2 Represents hydrogen, R 3 represents a difluoromethoxy group, and R 4 represents hydrogen; or R 1 Indicates vinyl, R 2 Represents hydrogen, R 3 represents trifluoromethyl, and R 4 represents hydrogen; or R 1 Represents methyl, R 2 Represents hydrogen, R 3 represents a difluoromethoxy group, and R 4 represents hydrogen; or R 1 Represents methyl, R 2 Represents hydrogen, R 3 represents -C(Me)(=CH2), and R 4 represents hydrogen; or R 1 Represents methyl, R 2 Represents hydrogen, R 3 represents bromine, and R 4 Represents hydrogen.

16. A compound as defined in claim 1 or claim 2, wherein W represents =N-, and: R 1 Represents C 1-6 Alkyl, R 2 represents hydrogen, and R 3 Represents halogenated C 1-6 alkyl.

17. A compound as defined in claim 16, wherein W represents =N-, and R 1 Represents methyl, R 2 represents hydrogen, and R 3 represents trifluoromethyl.

18. A compound as defined in claim 1 or claim 2, wherein X represents -C(H)(R 6 )-or-O-.

19. A compound as defined in claim 18, wherein X represents -C(H)(R 6 )-.

20. A compound as defined in claim 1 or claim 2, wherein R5 Means: hydrogen; or oxo.

21. A compound as defined in claim 1 or claim 2, wherein R 6 express: hydrogen; -OR 15a ; halogen; C 1-6 Alkanol; C 1-6 Alkoxy; -NR v R w ; -CH2-NR v R w ; -Z-phenyl; or Optionally, one or more hydroxyl groups or C 1-6 A heterocyclic group substituted with an alkanol group.

22. A compound as defined in claim 21, wherein R 6 express: hydrogen; Hydroxyl; fluorine; CH2OH; Methoxy; -NH2, -NMe2, -N(H)(Me), -N(H)(COMe), -N(H)((CH2)2OH), -N(H)((CH2)2SO2Me), N(Me)((CH2)2SO2Me), -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), -N(H)(azetidinyl), -N(H)(oxetanyl), -N(Me)(oxetanyl), -N(H)(cyclopentyl), -N(Me)(cyclopentyl), -N(H)(tetrahydropyranyl), -N(Me)(tetrahydropyranyl, or -N(H)((CH2)2NH2), wherein the pyrrolidinyl, tetrahydropyranyl or cyclopentyl ring can be optionally substituted with one or more oxo, hydroxy, -COC 1-6 Alkyl or -COOC 1-6 Alkyl group substitution; -CH2-N(Me)2; -CH2-O-CH2-phenyl; or Azetidinyl, pyrrolidinyl, morpholinyl or piperazinyl optionally substituted with one or more hydroxyl or CH2OH groups.

23. A compound as defined in claim 22, wherein as R 6 The optional substituents on the pyrrolidinyl, tetrahydropyranyl or cyclopentyl ring in1-6 Alkyl is -COMe, -COOC 1-6 The alkyl group is -COOtBu.

24. A compound as defined in claim 1 or claim 2, wherein R 7 Means: Hydrogen; or -OR 15b .

25. The compound as defined in claim 24, wherein R 7 Means: hydrogen; or hydroxyl.

26. A compound as defined in claim 1 or claim 2, wherein X represents -C(H)(R 6 )-,and; R 5 , R 6 and R 7 each represents hydrogen; or R 5 and R 7 Both represent hydrogen, and R 6 Indicates -OR 15a ;or R 5 and R 6 Both represent hydrogen, and R 7 Indicates -OR 15b ;or R 5 and R 7 Both represent hydrogen, and R 6 represents a halogen; or R 5 and R 7 Both represent hydrogen, and R 6 Represents C 1-6 Alkoxy; or R 5 and R 7 Both represent hydrogen, and R 6 Indicates -NR v R w ;or R 5 and R 7 Both represent hydrogen, and R 6 represents a heterocyclic group; or R 5 Represents hydrogen, R 6 Indicates -OR 15a , and R 7 Indicates -OR 15b ;or R 5 represents oxo, and R 6 and R 7 all represent hydrogen; or R 5 Represents oxo, R 6Indicates -NR v R w , and R 7 represents hydrogen; or R 5 Represents oxo, R 6 represents a heterocyclic group, and R 7 represents hydrogen; or R 5 Represents oxo, R 6 Indicates -OR 15a , and R 7 Indicates -OR 15b ;or R 5 Represents oxo, R 6 Indicates -OR 15a , and R 7 represents hydrogen; or R 5 Represents oxo, R 6 represents -Z-phenyl, and R 7 represents hydrogen; or R 5 Represents oxo, R 6 Represents C 1-6 Alkanol, and R 7 represents hydrogen; or R 5 Represents oxo, R 6 represents hydrogen, and R 7 Indicates -OR 15b ;or R 5 Represents oxo, R 6 Represents -CH2-NR v R w , and R 7 represents hydrogen; or R 5 Represents oxo, R 6 Indicates -OR 15a and R 7 Indicates -OR 15b , where R 15a and R 15b are connected together to form a 5-7 membered saturated ring system, which may be optionally replaced by one or more C 1-6 Alkyl substitution.

27. A compound as defined in claim 26, wherein X represents -C(H)(R 6 )-,and; R 5 , R 6 and R 7 each represents hydrogen; or R 5 and R 7Both represent hydrogen, and R 6 represents a hydroxyl group; or R 5 and R 6 Both represent hydrogen, and R 7 represents a hydroxyl group; or R 5 and R 7 Both represent hydrogen, and R 6 represents fluorine; or R 5 and R 7 Both represent hydrogen, and R 6 represents a methoxy group; or R 5 and R 7 Both represent hydrogen, and R 6 represents -NH2, -NMe2, -N(H)(Me), -N(H)((CH2)2OH), -N(H)((CH2)2SO2Me), N(Me)((CH2)2SO2Me), -N(H)(pyrrolidinyl), -N(Me)(pyrrolidinyl), -N(H)(azetidinyl), -N(H)(oxetanyl), -N(Me)(oxetanyl), -N(H)(cyclopentyl), -N(Me)(cyclopentyl), -N(H)(tetrahydropyranyl), -N(Me)(tetrahydropyranyl or -N(H)((CH2)2NH2), wherein the pyrrolidinyl, tetrahydropyranyl or cyclopentyl ring may be optionally substituted with one or more oxo, hydroxy, -COC 1-6 Alkyl or -COOC 1-6 Alkyl group substitution; or R 5 and R 7 Both represent hydrogen, and R 6 represents an azetidinyl, pyrrolidinyl, morpholinyl or piperazinyl group, which is optionally substituted by one or more hydroxyl groups or C 1-6 Alkanol group substitution; or R 5 Represents hydrogen, R 6 represents a hydroxyl group, and R 7 represents a hydroxyl group; or R 5 represents oxo, and R 6 and R 7 all represent hydrogen; or R 5 Represents oxo, R 6 represents -NH2 or -N(H)(COMe), and R 7 represents hydrogen; or R 5 Represents oxo, R 6 represents a morpholinyl group, and R 7 represents hydrogen; or R 5 Represents oxo, R 6 represents a hydroxyl group, and R 7 represents a hydroxyl group; or R 5 Represents oxo, R 6 represents a hydroxyl group, and R 7 represents hydrogen; or R 5 Represents oxo, R 6 represents -CH2-O-CH2-phenyl, and R 7 represents hydrogen; or R 5 Represents oxo, R 6 represents CH2OH, and R 7 represents hydrogen; or R 5 Represents oxo, R 6 represents hydrogen, and R 7 represents a hydroxyl group; or R 5 Represents oxo, R 6 represents -CH2-N(Me)2, and R 7 represents hydrogen; or R 5 Represents oxo, R 6 Indicates -OR 15a and R 7 Indicates -OR 15b , where R 15a and R 15b Together they form a 5-membered saturated ring system, which may be substituted by two methyl groups.

28. The compound as defined in claim 27, wherein as R 6 The optional substituents on the pyrrolidinyl, tetrahydropyranyl or cyclopentyl ring in 1-6 Alkyl is -COMe, -COOC 1-6 Alkyl is -COOtBu; or As R 6 The optional substituent C on the azetidinyl, pyrrolidinyl, morpholinyl or piperazinyl 1-6 The alkanol group is CH2OH; or R 5 Represents oxo, R 6 Indicates -OR 15a and R 7 Indicates -OR 15b , where R 15a and R 15b Together they form a dioxolanyl group, which may be substituted by two methyl groups.

29. A compound as defined in claim 1 or claim 2, wherein X represents -O-, and R 5 represents oxo, and R 7 Represents hydrogen.

30. A compound as defined in claim 1 or claim 2, wherein X represents -N(R 14 )-,and; R 5 represents oxo, and R 7 and R 14 all represent hydrogen; or R 5 Represents oxo, R 7 represents hydrogen, and R 14 Represents C 1-6 Alkanol; or R 5 Represents oxo, R 7 represents hydrogen, and R 14 Represents -SO2-C 1-6 alkyl.

31. A compound as defined in claim 30, wherein X represents -N(R 14 )-,and; R 5 represents oxo, and R 7 and R 14 all represent hydrogen; or R 5 Represents oxo, R 7 represents hydrogen, and R 14 represents -CH2-CH(OH)Me; or R 5 Represents oxo, R 7 represents hydrogen, and R 14 It represents -SO2-Me.

32. A compound as defined in claim 1 or claim 2, wherein: R v and R w Represents hydrogen, C 1-6 Alkyl, -COC 1-6 Alkyl, C 3-8 Cycloalkyl or heterocyclyl, wherein the alkyl group may be optionally substituted with one or more hydroxyl, amino or sulfone groups, and the heterocyclyl ring may be optionally substituted with one or more oxo or -COC 1-6 Alkyl group substitution; or R v and R w Both represent hydrogen or C 1-6 Alkyl, or one represents hydrogen and the other represents C 1-6 Alkyl, or a hydrogen or C 1-6 Alkyl and the other represents -COC 1-6 Alkyl, C 3-8 Cycloalkyl or heterocyclyl, wherein the alkyl group may be optionally substituted with one or more hydroxyl, amino or sulfone groups, and the heterocyclyl ring may be optionally substituted with one or more oxo or -COC 1-6 Alkyl group substitution.

33. A compound as defined in claim 32, wherein: R v and R w represents hydrogen, methyl, -COMe, cyclopentyl or oxetanyl, azetidinyl, tetrahydropyranyl or pyrrolidinyl, wherein the alkyl group may be optionally substituted with one or more (CH2)2OH, (CH2)2NH2 or (CH2)2SO2Me groups, and the heterocyclyl ring may be optionally substituted with one or more oxo or -COMe groups; or R v and R w Both represent hydrogen or methyl, or one represents hydrogen and the other represents methyl, or one represents hydrogen or methyl and the other represents -COMe, cyclopentyl or azetidinyl, tetrahydropyranyl or pyrrolidinyl, wherein the alkyl may be optionally substituted with one or more (CH2)2OH, (CH2)2NH2 or (CH2)2SO2Me groups, and the heterocyclyl ring may be optionally substituted with one or more oxo or -COMe groups.

34. A compound as defined in claim 1 or claim 2, wherein R 8 Represents C 1-6 Alkyl or C 3-8 Cycloalkyl.

35. The compound as defined in claim 34, wherein R 8 Represents C 1-6 alkyl.

36. The compound as defined in claim 35, wherein R 8 It represents CH3, CD3, ethyl or isopropyl.

37. The compound as defined in claim 36, wherein R 8 It represents CH3 or ethyl.

38. The compound as defined in claim 34, wherein R 8 It represents cyclopropyl.

39. A compound as defined in claim 1 or claim 2, wherein Y represents -C(R 9 )=.

40. A compound as defined in claim 1 or claim 2, wherein R 9 Represents: hydrogen; halogen; or C 1-6 Alkoxy.

41. The compound defined in claim 40, wherein R 9 represents: hydrogen; fluorine; or methoxy.

42. A compound as defined in claim 1 or claim 2, wherein R 10 express: hydrogen; halogen; C 1-6 alkyl; C 2-6 alkenyl; Hydroxyl; C 1-6 Alkoxy; or R 10 and R 11 The rings are connected to form a 5-7 membered saturated or unsaturated ring, which optionally contains one or more heteroatoms selected from O, N or S.

43. The compound defined in claim 42, wherein R 10 express: hydrogen; Fluorine, bromine or chlorine; Methyl or ethyl; Vinyl; Hydroxyl; Methoxy; or R 10 and R 11 Connected to form a pyrroline or tetrahydropyranyl ring.

44. A compound as defined in claim 1 or claim 2, wherein R 11 express: hydrogen; halogen; C 1-6 alkyl; C 2-6 alkenyl; Halogenated C 1-6 Alkyl; or R 11 and R 10 The rings are connected to form a 5-7 membered saturated or unsaturated ring, which optionally contains one or more heteroatoms selected from O, N or S.

45. The compound defined in claim 44, wherein R 11 express: hydrogen; Fluorine, bromine or chlorine; Methyl or ethyl; Vinyl; trifluoromethyl; or R 11 and R 10 Connected to form a pyrroline or tetrahydropyranyl ring.

46. ​​A compound as defined in claim 1 or claim 2, wherein R 12 express: hydrogen; halogen; C 1-6 alkyl; Halogenated C 1-6 Alkyl; or C 1-6 Alkoxy.

47. The compound defined in claim 46, wherein R 12 express: hydrogen; Fluorine or chlorine; methyl; fluoromethyl, difluoromethyl or trifluoromethyl; or Methoxy.

48. A compound as defined in claim 1 or claim 2, wherein R 13 Means: hydrogen; or halogen.

49. The compound as defined in claim 48, wherein R 13 Means: hydrogen; or fluorine.

50. A compound as defined in claim 1 or claim 2, wherein Y represents -C(R 9 )=, and: R 9 , R 10 , R 11 , R 12 and R 13 represents hydrogen; or R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12Represents C 1-6 Alkyl; or R 9 , R 10 and R 13 Each of represents hydrogen, and R 11 and R 12 all represent halogen; or R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents a halogen, and R 12 Represents C 1-6 Alkyl; or R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents a halogen, and R 12 Represents halogenated C 1-6 Alkyl; or R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12 Represents halogenated C 1-6 Alkyl; or R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12 represents a halogen; or R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents a halogen, and R 12 Represents C 1-6 Alkoxy; or R 9 , R 11 and R 13 Each of represents hydrogen, and R 10 and R 12 all represent halogen; or R 9 , R 10 and R 13 Each of R represents hydrogen, 11 Represents halogenated C 1-6 Alkyl, and R 12 represents a halogen; or R 9 , R 11 , R 12 and R 13Each of represents hydrogen, and R 10 Represents C 1-6 alkyl; R 9 , R 11 , R 12 and R 13 Each of represents hydrogen, and R 10 represents halogen; R 9 , R 12 and R 13 Each of represents hydrogen, and R 10 and R 11 All represent halogen; R 9 , R 10 and R 13 Each of R represents hydrogen, 11 Represents C 1-6 Alkyl, and R 12 represents halogen; R 9 , R 12 and R 13 Each of R represents hydrogen, 10 Represents C 1-6 Alkyl, and R 11 represents halogen; R 9 , R 12 and R 13 Each of R represents hydrogen, 10 Represents C 1-6 Alkoxy, and R 11 represents halogen; R 9 , R 12 and R 13 Each of R represents hydrogen, 10 Represents C 1-6 Alkoxy, and R 11 Represents C 1-6 alkyl; R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents a halogen, and R 11 Represents C 1-6 alkyl; R 12 and R 13 Both represent hydrogen, R 9 and R 11 Both represent halogen, and R 10 Represents C 1-6 alkyl; R 10 , R12 and R 13 Each of represents hydrogen, and R 9 and R 11 Both represent halogens; R 9 and R 12 Both represent hydrogen, and R 10 , R 11 and R 13 Each of represents a halogen; R 11 , R 12 and R 13 Each of represents hydrogen, and R 9 and R 10 Both represent halogens; R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents a hydroxyl group, and R 11 represents halogen; R 9 , R 12 and R 13 Each of R represents hydrogen, 10 Represents C 2-6 alkenyl, and R 11 Indicates halogen R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents a hydroxyl group, and R 11 Represents C 1-6 alkyl; R 10 , R 11 and R 13 Each of represents hydrogen, and R 9 and R 12 Both represent halogens; R 10 and R 13 Both represent hydrogen, R 11 and R 12 Both represent halogen, and R 9 Represents C 1-6 Alkoxy; R 12 and R 13 Both represent hydrogen, and R 9 , R 10 and R 11 Each of represents a halogen; R 12 and R 13 Both represent hydrogen, R9 and R 11 Both represent halogen, and R 10 Represents C 2-6 alkenyl; R 9 , R 12 and R 13 Each of represents hydrogen, and R 10 and R 11 connected to form a pyrroline or tetrahydropyranyl ring; or R 10 and R 13 Both represent hydrogen, and R 9 , R 11 and R 12 Each of represents a halogen.

51. A compound as defined in claim 50, wherein Y represents -C(R 9 )=, and: R 9 , R 10 , R 11 , R 12 and R 13 represents hydrogen; or R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12 represents a methyl group; or R 9 , R 10 and R 13 Each of represents hydrogen, and R 11 and R 12 all represent fluorine or chlorine; or R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents fluorine, and R 12 represents a methyl group; or R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents fluorine, and R 12 represents a fluoromethyl group or a trifluoromethyl group; or R 9 , R 10 , R 11 and R 13 Each of represents hydrogen, and R 12 represents fluoromethyl or difluoromethyl; or R 9 , R 10, R 11 and R 13 Each of represents hydrogen, and R 12 represents chlorine; or R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents fluorine, and R 12 represents a methoxy group; or R 9 , R 11 and R 13 Each of represents hydrogen, and R 10 and R 12 all represent fluorine or chlorine; or R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents trifluoromethyl, and R 12 represents fluorine; or R 9 , R 11 , R 12 and R 13 Each of represents hydrogen, and R 10 represents a methyl group; R 9 , R 11 , R 12 and R 13 Each of represents hydrogen, and R 10 represents chlorine; R 9 , R 12 and R 13 Each of represents hydrogen, and R 10 and R 11 All represent fluorine, bromine or chlorine; R 9 , R 10 and R 13 Each of R represents hydrogen, 11 represents a methyl group, and R 12 represents chlorine; R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents a methyl group or an ethyl group, and R 11 represents chlorine or fluorine; R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents a methoxy group, and R 11 represents fluorine; R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents a methoxy group, and R 11 represents a methyl group; R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents chlorine, and R 11 represents a methyl group; R 12 and R 13 Both represent hydrogen, R 9 and R 11 Both represent fluorine, and R 10 represents a methyl or ethyl group; R 10 , R 12 and R 13 Each of represents hydrogen, and R 9 and R 11 Both represent chlorine, bromine, or fluorine; R 9 and R 12 Both represent hydrogen, and R 10 , R 11 and R 13 Each of represents chlorine or fluorine; R 11 , R 12 and R 13 Each of represents hydrogen, and R 9 and R 10 Both represent chlorine or fluorine; R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents a hydroxyl group, and R 11 represents fluorine; R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents vinyl, and R 11 represents fluorine; R 9 , R 12 and R 13 Each of R represents hydrogen, 10 represents a hydroxyl group, and R 11 represents a methyl group; R 10 , R 11 and R 13 Each of represents hydrogen, and R9 and R 12 Both represent fluorine or chlorine; R 10 and R 13 Both represent hydrogen, R 11 and R 12 Both represent fluorine or chlorine, and R 9 represents methoxy; R 12 and R 13 Both represent hydrogen, and R 9 , R 10 and R 11 Each of represents fluorine or chlorine; R 12 and R 13 Both represent hydrogen, R 9 and R 11 Both represent fluorine, and R 10 It means vinyl; R 9 , R 12 and R 13 Each of represents hydrogen, and R 10 and R 11 connected to form a pyrroline or tetrahydropyranyl ring; or R 10 and R 13 Both represent hydrogen, and R 9 , R 11 and R 12 Each of represents chlorine or fluorine.

52. A compound as defined in claim 1 or claim 2, wherein Y represents -N=, and: R 11 and R 13 Both represent hydrogen, R 10 Represents C 1-6 Alkyl, and R 12 Represents halogenated C 1-6 Alkyl; or R 10 and R 11 connected to form a pyrroline ring, and R 12 and R 13 All represent hydrogen.

53. A compound as defined in claim 52, wherein Y represents -N=, and: R 11 and R 13 Both represent hydrogen, R 10 represents a methyl group, and R 12 represents trifluoromethyl.

54. The compound as defined in claim 1, wherein the compound is (S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-phenylpyrrolidine-2-carboxamide; (S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-isopropyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-(3,4-difluorophenyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide; (2S,4S)-N-(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoro-methyl)pyridin-2-yl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(4-fluoro-3-methylphenyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-4-hydroxy-N-methyl-N-phenylpyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-phenylpyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-(3-(fluoromethyl)phenyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-(3-(difluoromethyl)phenyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide; (2S,4S)-N-(3-chlorophenyl)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-(4-fluoro-3-(fluoromethyl)phenyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(4-fluoro-3-(fluoromethyl)-phenyl)-4-hydroxy-N-methyl-pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(4-fluoro-3-methoxyphenyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(3,5-difluorophenyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide; (2S,4S)-N-(4-chloro-3-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(3-fluoro-4-(trifluoromethyl)-phenyl)-4-hydroxy-N-methyl-pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-(2,4,5-trifluorophenyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-4-hydroxy-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-ethyl-4-hydroxy-N-(m-tolyl)-pyrrolidine-2-carboxamide; (2S,4R)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,3R)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,3R)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-3-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,3S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-4-hydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-4-Hydroxy-1-(4-isopropyl-6-methylpyridin-2-yl)-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(5-chloro-4,6-dimethylpyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-(ethyl(methyl)amino)-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-(dimethylamino)-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-4-isopropyl-6-methylpyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-4-(trifluoromethyl)pyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(4-ethyl-5-methylpyridin-2-yl)-4-hydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-4-methoxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-(3,4-difluorophenyl)-N-ethyl-4-fluoropyrrolidine-2-carboxamide; (2S,4S)-4-amino-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2R,4R)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-4-(dimethylamino)-N-ethyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4R)-4-amino-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-4-(dimethylamino)-N-ethyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-4-morpholino-N-(m-tolyl)pyrrolidine-2-carboxamide; (2R,4R)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-4-(methylamino)-N-(m-tolyl)-pyrrolidine-2-carboxamide; (2R,4R)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-4-((2-hydroxyethyl)amino)-N-(m-tolyl)pyrrolidine-2-carboxamide; (2R,4R)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-4-((2-(methylsulfonyl)ethyl)-amino)-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-4-(methyl(2-(methylsulfonyl)-ethyl)amino)-N-(m-tolyl)-pyrrolidine-2-carboxamide; (2R,4R)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-4-((2-oxopyrrolidin-3-yl)amino)-N-(m-tolyl)pyrrolidine-2-carboxamide; (2R,4R)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-4-(methyl(pyrrolidin-3-yl)amino)-N-(m-tolyl)pyrrolidine-2-carboxamide; (2R,4R)-4-((2-aminoethyl)amino)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2R,4R)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-4-(piperazin-1-yl)-N-(m-tolyl)-pyrrolidine-2-carboxamide; (2S,4S)-4-(azetidin-3-ylamino)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2R,4R)-4-((1-acetylpyrrolidin-3-yl)(methyl)amino)-1-(3-cyano-4,6-dimethylpyridin-2-yl)-N-ethyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,3R,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,3S,4R)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroxy-N-methyl-N-(m-tolyl)pyrrolidine-2-carboxamide; (2S,3S,4R)-1-(3-cyano-4,6-dimethyl-pyridin-2-yl)-3,4-dihydroxy-N-methyl-N-(m-tolyl)-pyrrolidine-2-carboxamide; (2S,3S,4R)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(3,4-difluorophenyl)-N-ethyl-3,4-dihydroxypyrrolidine-2-carboxamide; (2S,3S,4R)-N-(3-chloro-4-fluoro-phenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-ethyl-3,4-dihydroxypyrrolidine-2-carboxamide; (S)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxo-N-(m-tolyl)oxazolidine-4-carboxamide; (S)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxo-N-(m-tolyl)pyrrolidine-2-carboxamide; (S)-N-(5-fluoro-6-methylpyridin-2-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,4S)-4-amino-N-(3-chloro-4-fluorophenyl)-N-ethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,4S)-4-Acetylamino-N-(3-chloro-4-fluorophenyl)-N-ethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,4S)-N-(3-chloro-4-fluorophenyl)-N-ethyl-1-(6-methyl-4-(trifluoro-methyl)pyridin-2-yl)-4-morpholino-5-oxopyrrolidine-2-carboxamide; (2S,4S)-N-(3-chloro-4-fluorophenyl)-N-ethyl-4-hydroxy-1-(4-methyl-6-(trifluoromethyl)-pyrimidin-2-yl)pyrrolidine-2-carboxamide; (2S,3S,4S)-N-(3-chloro-4-fluorophenyl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3S,4S)-N-(3-chloro-4-fluoro-phenyl)-N-ethyl-3,4-dihydroxy-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3S,4S)-N-(4-fluoro-3-methyl-phenyl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3S,4S)-N-(3-chloro-5-fluoro-phenyl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (3aS,4S,6aS)-N-(3-chloro-2,4-difluorophenyl)-N,2,2-trimethyl-5-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-6-oxotetrahydro-4H-[1,3]dioxol[4,5-c]pyrrole-4-carboxamide; (2S,3S,4S)-N-(3-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3R,4R)-N-(3-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3R,4R)-N-(3-chloro-4-fluorophenyl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3S,4S)-N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,4S)-N-(3-chloro-4-fluorophenyl)-4-hydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,4S)-N-(3-chloro-4-fluorophenyl)-N-ethyl-4-hydroxy-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,4R)-4-((Benzyloxy)methyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,4R)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2R,4S)-N-(3-chloro-4-fluorophenyl)-4-((dimethylamino)methyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2R,4R)-N-(3-chloro-4-fluorophenyl)-4-((dimethylamino)methyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3R)-N-(3-chloro-4-fluorophenyl)-3-hydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3R)-N-(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-hydroxy-N-methylpyrrolidine-2-carboxamide; (2S,3R)-N-(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-ethyl-3-hydroxypyrrolidine-2-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(4-chloro-3-methylphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(4-Fluoro-3-methyl-phenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-chlorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-Chloro-4-methyl-phenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3,4-dichlorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(4-Fluoro-3-methoxy-phenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(4-chloro-3-methoxy-phenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-Methoxy-4-methyl-phenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-bromo-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(4-bromo-2-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-chloro-2-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(5-chloro-2-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(4-chloro-2-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(5-Chloro-2,4-difluoro-phenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(5-chloro-4-fluoro-2-methoxyphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(2,4-difluoro-3-methyl-phenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(4-chloro-2,3-difluoro-phenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(1,3-Dihydro-isobenzofuran-5-yl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-N-ethyl-3-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-N-isopropyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-hydroxy-4-methylphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(4-fluoro-3-hydroxyphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(2,4-difluoro-3-vinylphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-ethyl-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(4-fluoro-3-vinylphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-ethyl-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxo-oxazolidine-4-carboxamide; (S)-N-(2-fluoro-4-vinylphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(4-ethyl-2-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxooxazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-6-vinylpyridin-2-yl)oxazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-3-(6-ethyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-2-oxooxazolidine-4-carboxamide; (S)-3-(4-bromo-6-methylpyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxooxazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(prop-1-en-2-yl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-3-(4-isopropyl-6-methylpyridin-2-yl)-N-methyl-2-oxooxazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-3-(4-ethyl-6-methylpyridin-2-yl)-N-methyl-2-oxooxazolidine-4-carboxamide; (S)-3-(6-chloro-4-(difluoromethoxy)pyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxooxazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-3-(4-(difluoromethoxy)-6-methylpyridin-2-yl)-N-methyl-2-oxooxazolidine-4-carboxamide; (S)-3-(4-(tert-butyl)-6-chloropyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxooxazolidine-4-carboxamide; (S)-3-(4-(tert-butyl)-6-methylpyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-oxooxazolidine-4-carboxamide; (4S)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-3-(4-(1,1-difluoroethyl)-6-methylpyridin-2-yl)-N-ethyl-2-oxooxazolidine-4-carboxamide; (S)-N-(1H-indol-6-yl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxo-N-(1H-pyrrolo[2,3-b]pyridin-6-yl)oxazolidine-4-carboxamide; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-(2-(hydroxymethyl)-morpholino)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide; (3S,5S)-N-(3,4-difluorophenyl)-N-ethyl-3-hydroxy-1'-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-[1,3'-bipyridine]-5'-carboxamide; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-(3-hydroxyazetidin-1-yl)-1-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)pyrrolidine-2-carboxamide; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-(((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)amino)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-(((1R,2R)-2-hydroxy-cyclopentyl)amino)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-pyrrolidine-2-carboxamide; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-(((1S,2R)-2-hydroxy-cyclopentyl)amino)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-pyrrolidine-2-carboxamide; rac-(3R,4R)-3-(((3S,5S)-5-((3,4-difluorophenyl)-(ethyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-pyrrolidin-3-yl)amino)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester; (3S,4R)-3-(((3S,5S)-5-((3,4-difluorophenyl)(ethyl)-carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-pyrrolidin-3-yl)amino)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-4-((5-oxopyrrolidin-3-yl)amino)-pyrrolidine-2-carboxamide; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-4-(oxetan-3-ylamino)pyrrolidine-2-carboxamide; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)(methyl)amino)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-(((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)(methyl)amino)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-(((1R,2R)-2-hydroxycyclopentyl)-(methyl)amino)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-(((1S,2R)-2-hydroxycyclopentyl)-(methyl)amino)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide; rac-(3R,4R)-tert-butyl 3-(((3S,5S)-5-((3,4-difluorophenyl)(ethyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)amino)-4-hydroxypyrrolidine-1-carboxylate; tert-Butyl (3S,4R)-3-(((3S,5S)-5-((3,4-difluorophenyl)(ethyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)amino)-4-hydroxypyrrolidine-1-carboxylate; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-(methyl(5-oxopyrrolidin-3-yl)amino)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide; (2S,4S)-N-(3,4-difluorophenyl)-N-ethyl-4-(methyl(oxetan-3-yl)amino)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide; (2S,4S)-N-(3-chlorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-ethyl-4-(2-(hydroxymethyl)-morpholino)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-N-(3,4-dichlorophenyl)-N-ethyl-4-(2-(hydroxymethyl)-morpholino)-pyrrolidine-2-carboxamide; (2S,4S)-N-(3-chloro-4-methylphenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-N-ethyl-4-(2-(hydroxymethyl)morpholino)pyrrolidine-2-carboxamide; (2S,4S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-N-ethyl-N-(4-fluoro-3-methylphenyl)-4-(2-(hydroxymethyl)morpholino)pyrrolidine-2-carboxamide; (2S,4S)-N-(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-4-(2-(hydroxy-methyl)morpholino)-N-methylpyrrolidine-2-carboxamide; (2S,4S)-N-(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-N-ethyl-4-((S)-3-(hydroxymethyl)morpholino)pyrrolidine-2-carboxamide; (2S,4S)-N-(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-N-ethyl-4-((R)-3-(hydroxymethyl)morpholino)pyrrolidine-2-carboxamide; (2S,4S)-N-(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-N-ethyl-4-((S)-2-(hydroxymethyl)morpholino)pyrrolidine-2-carboxamide; (2S,4S)-N-(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-N-ethyl-4-((R)-2-(hydroxymethyl)morpholino)pyrrolidine-2-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-N-ethyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(methylsulfonyl)-2-oxoimidazolidine-4-carboxamide; (4S)-N-(3-chloro-4-fluorophenyl)-1-(2-hydroxypropyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-N-cyclopropyl-3-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (2S,3S,4S)-N-(3-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-d3)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3S,4S)-N-(3-chloro-4-fluorophenyl)-3,4-dihydroxy-N-(methyl-d3)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3S,4S)-N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-d3)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3S,4S)-N-(4-chloro-2-fluorophenyl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3S,4S)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxo-N-(1H-pyrrolo[2,3-b]pyridin-6-yl)pyrrolidine-2-carboxamide; (2S,3S,4S)-3,4-dihydroxy-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3S,4S)-3,4-dihydroxy-N-methyl-N-(1-methyl-1H-indazol-6-yl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3S,4S)-3,4-dihydroxy-N-methyl-N-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (2S,3S,4S)-N-(5-fluoro-6-methylpyridin-2-yl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide; (S)-N-(2,4-dichlorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(4-bromo-3-chlorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(3-chloro-4-cyclopropylphenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(1H-indazol-6-yl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(6-aminopyridin-2-yl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(6-(methylamino)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-(6-(dimethylamino)pyridin-2-yl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxooxazolidine-4-carboxamide; (S)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxo-N-(quinolin-7-yl)oxazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-N-isopropyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(2-(methylsulfonyl)ethyl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-1-(2-(N,N-dimethylsulfamoyl)ethyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-1-(2-(dimethylamino)ethyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-1-(3-(dimethylamino)propyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-1-(2-amino-2-oxoethyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluoro-phenyl)-1-((3-(hydroxymethyl)-oxetan-3-yl)methyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(2-(methylsulfonylamino)ethyl)-2-oxoimidazolidine-4-carboxamide; (S)-1-(azetidin-3-ylmethyl)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-((1-methylazetidin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-1-(3-(dimethylamino)-3-oxopropyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(3-(methylamino)-3-oxopropyl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxo-1-(2-(piperazin-1-yl)ethyl)imidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(2-morpholinoethyl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(2-morpholinoethyl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-1-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-1-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-1-(2-(azetidin-1-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-1-(2-(azetidin-1-yl)ethyl)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-1-(2-(3-hydroxyazetidin-1-yl)ethyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (4S)-N-(3-Chloro-2,4-difluoro-phenyl)-1-(2-(2-(hydroxymethyl)-azetidin-1-yl)-ethyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-1-(2-(4-acetylpiperazin-1-yl)ethyl)-N-(3-chloro-2,4-difluoro-phenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-1-(2-((S)-3-fluoropyrrolidin-1-yl)ethyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-1-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (4S)-N-(3-Chloro-2,4-difluoro-phenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(2-(3-(N-methylacetylamino)-pyrrolidin-1-yl)ethyl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-1-(2-(1,1-dioxythiomorpholino)-ethyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-1-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-1-(2-(4-methyl-3-oxopiperazin-1-yl)ethyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-1-(2-(4-cyanopiperidin-1-yl)ethyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (4S)-N-(3-chloro-2,4-difluorophenyl)-1-(3-(dimethylamino)-2-hydroxypropyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (4S)-N-(3-chloro-2,4-difluorophenyl)-1-(3-((R)-3-fluoropyrrolidin-1-yl)-2-hydroxy-propyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (4S)-N-(3-chloro-2,4-difluorophenyl)-1-(3-(3,3-difluoropyrrolidin-1-yl)-2-hydroxy-propyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (4S)-N-(3-chloro-2,4-difluorophenyl)-1-(2-hydroxy-3-morpholinopropyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (4S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(morpholin-2-ylmethyl)-2-oxoimidazolidine-4-carboxamide; (4S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-((4-methylmorpholin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxo-1-(3-(piperazin-1-yl)propyl)imidazolidine-4-carboxamide; (S)-1-(3-(4-acetylpiperazin-1-yl)propyl)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (4S)-N-(3-chloro-2,4-difluorophenyl)-1-((3-hydroxypyrrolidin-3-yl)methyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (4S)-N-(3-chloro-2,4-difluorophenyl)-1-((3-hydroxy-1-methylpyrrolidin-3-yl)methyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-2,4-difluorophenyl)-1-((3-hydroxyazetidin-3-yl)methyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-4-fluorophenyl)-1-((3-hydroxyazetidin-3-yl)methyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (4S)-N-(3-chloro-2,4-difluorophenyl)-1-(2,3-dihydroxypropyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-2-(4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidin-1-yl)ethyl sulfamic acid; (4S)-N-(3-chloro-4-fluorophenyl)-N-cyclopropyl-1-(2,3-dihydroxypropyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (4S)-N-(3-chloro-4-fluorophenyl)-1-(3,4-dihydroxybutyl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxo-N-(1H-pyrrolo[2,3-b]pyridin-6-yl)imidazolidine-4-carboxamide; (S)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-methyl-N-(1-methyl-1H-indazol-6-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(3-methylfuro[3,2-b]pyridin-5-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxo-N-(thieno[3,2-b]pyridin-5-yl)imidazolidine-4-carboxamide; (S)-N-methyl-N-(3-methyl-1H-indazol-6-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-6-yl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (S)-N-(3-chloro-1H-pyrrolo[2,3-b]pyridin-6-yl)-N-methyl-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide; (2S,5R)-N-(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N,5-dimethylpyrrolidine-2-carboxamide; (2S,5S)-N-(3-chloro-4-fluorophenyl)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N,5-dimethylpyrrolidine-2-carboxamide; (S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)pyrrolidine-2-carboxamide; (S)-N-(4-chloro-1-methyl-pyrrolo[2,3-b]pyridin-6-yl)-1-[3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridinyl]-N-methyl-pyrrolidine-2-carboxamide; or (S)-1-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)pyrrolidine-2-carboxamide, free base or a pharmaceutically acceptable salt thereof.

55. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 54.

56. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 54 in combination with one or more therapeutic agents.

57. Use of a compound as defined in any one of claims 1 to 54 in the preparation of a medicament for the prevention or treatment of cancer.

58. A process for preparing a compound of formula (I) as defined in claim 1, comprising: (a) making a compound of formula (II): Where R 1 , R 2 , R 3 , W, R 5 , X and R 7 As defined in claim 1, reacting with a compound of formula (III): Where R 8 , Y, R 10 , R 11 , R 12 and R 13 As defined in claim 1; (b) making a compound of formula (IV): Where R 5 ,X,R 7 , R 8 ,Y,R 10 , R 11 , R 12 and R 13 As defined in claim 1, reacting with a compound of formula (V): Where R 1 , R 2 , R 3 and W as defined in claim 1, and L 1 represents a suitable leaving group; (c) deprotecting a protected derivative of a compound of formula (I); (d) interconverting a compound of formula (I) or a protected derivative thereof into another compound of formula (I) or a protected derivative thereof; and (e) optionally forming a pharmaceutically acceptable salt of a compound of formula (I).

59. The method defined in claim 58, wherein L of formula (V) 1 represents a halogen atom.

60. The method as defined in claim 58, wherein L of formula (V) 1 Represents chlorine.

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