SOS1 inhibitors

Abstract

Compounds of Formula I, wherein each variable is defined herein. Also disclosed are pharmaceutical compositions comprising compounds of Formula I, methods of treating cancer using the compounds, and methods of inhibiting SOS1 using the compounds. [Formula 1] JPEG2025538194000112.jpg44170

Description

[Technical Field]

[0001] [Cross-Citation of Related Applications] This application claims priority to U.S. Patent Application No. 63 / 424,310, filed November 10, 2022, the contents and disclosure of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The RAS family of GTPases, including KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey murine sarcoma viral oncogene), are recognized as major oncogenes, occurring in up to 20–30% of human cancers.

[0003] Because RAS proteins have a very high affinity for GDP / GTP, the exchange from the RAS-GDP-bound form (i.e., inactive state) to the RAS-GTP-bound form (i.e., active state) is catalyzed by guanine nucleotide exchange factors (GEFs) such as Son of Sevenless 1 (SOS1), whereas the return to the inactive state (i.e., RAS-GDP-bound form) is catalyzed by GTPase-activating proteins (GAPs). The activated RAS-GTP-bound form interacts with numerous effectors to promote cell growth and differentiation.

[0004] In cancer cells, the RAS signaling pathway is constitutively activated by oncogenic activating mutations in RAS proteins and / or the isoform SOS1, or by inactivating mutations in GAPs, resulting in uncontrolled proliferation and growth of cancer cells. Cancer patients with RAS mutations often present with aggressive, metastatic disease with poor prognosis. Direct inhibition of RAS has proven extremely difficult. Alternative strategies that indirectly target the RAS signaling pathway have also been explored, such as inhibiting the enzymatic activity of GEFs such as SOS1 or their interaction with RAS. These approaches should attenuate the activity of the RAS signaling pathway by preventing the formation of an active RAS-GTP-bound form. Therefore, inhibiting SOS1 activity or its interaction with RAS offers therapeutic benefits. Indeed, certain benzylamino-substituted pyridopyrimidione and quinazoline compounds have been developed as SOS1 inhibitors. See WO2019 / 122129 and Hillig et al., Proc Natl Acad Sci USA, 2019, vol. 116(7), 2551-2560.

[0005] However, there remains a significant unmet need for the development of SOS1 inhibitors for the treatment of cancers and other diseases associated with or regulated by the interaction of KRAS and SOS1, including cancers with genetic alterations (mutations, fusions, translocations, amplifications, and overexpression) of genes encoding ALK, AxL, BCR-ABL, c-Raf, c-Met, EGFR1-4, ErbB2, FGFR1-4, Kras, NRas, HRas, NF1, NTRK, Ret, ROS, and other tumor signaling molecules. Summary of the Invention

[0006] The present invention is based on the unexpected discovery that certain compounds are effective as SOS1 inhibitors and are suitable for the treatment of cancer and other diseases, such as neurofibromatosis, Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC), and hereditary gingival fibromatosis type 1.

[0007] In one embodiment, the present invention relates to compounds of Formula I, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof: [ka] however, A is a C3-C6 cycloalkyl, a 4-10 membered heterocycloalkyl, an aryl, or a 5-10 membered heteroaryl; L is a single bond, -O-, -C(O)-, -C(O)O-, -O-CO-, -C(O)NR'-, -NR'-, -NR'CO-, -NR'SO2-, -SON2NR'-, -S-, -SO-, -S(O)2-, C1-C3 alkylene, C1-C3 haloalkylene, C2-C3 alkenylene, or C2-C3 alkynylene, where R' is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or 6- to 10-membered aryl; M is C5~C 10 cycloalkyl, 5- to 15-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; Q represents the left ring of formula I to which M is fused; R1 is CN, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl; R2 is H, CN, halogen, C1-C3 alkyl, C1-C3 alkoxy, C2-C3 alkynyl, or C3-C6 cycloalkyl; R3 is C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or phenyl; or R2 and R3 together with the carbon atom to which R2 is attached and the nitrogen atom to which R3 is attached form a 4- to 7-membered heterocycloalkyl; R4 is H, C1 to C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkylamides, C2-C 10 Alkylcarbonyl, C1-C 10 Alkylsulfonyl, C1-C 10alkylsulfonamido, C3-C6 cycloalkyl, C3-C6 cycloalkylcarbonyl, C3-C6 cycloalkylamido, 3-10 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl; [ka] is a single or double bond, and Alkyl, alkylene, alkenyl, alkynyl, alkoxy, haloalkylene, alkylamino, alkylamido, alkylcarbonyl, alkylsulfonyl, alkylsulfonamido, alkynylene, cycloalkyl, cycloalkylcarbonyl, cycloalkylamido, heterocycloalkyl, heterocyclyl, phenyl, aryl, and heteroaryl are unsubstituted or substituted with one or more of deuterium, halogen, CN, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C1 -C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR', -C(O)R', -C(O)OR', -O-COR', -C(O)NR'R", -NR'R", -SR', -SOR', -S(O)2R', and -POR'R", where R' and R" are each independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or 6- to 10-membered aryl.

[0008] In another embodiment, the present invention relates to compounds of formula I: [ka] In the formula, A is a C3-C6 cycloalkyl, a 4-10 membered heterocycloalkyl, an aryl (e.g., phenyl), or a 5-10 (e.g., 5-7) membered heteroaryl; L is a single bond, -O-, -C(O)-, -C(O)O-, -O-CO-, -C(O)NR'-, -NR'-, -NR'CO-, -NR'SO2-, -SONR'-, -S-, -SO-, -S(O)2-, C1-C3 alkylene, C1-C3 haloalkylene, C2-C3 alkenyl, or C2-C3 alkynylene, where R' is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or 6- or 10-membered aryl (e.g., phenyl); M is C5~C 10 cycloalkyl, 5-12 (e.g., 5-7) membered heterocycloalkyl, 6- or 10-membered aryl (e.g., phenyl), or 5-10 (e.g., 5-6) membered heteroaryl; Q represents the left ring to which M represented by formula I is fused, R1 is CN, C1-C3 alkyl, ethenyl, or ethynyl; R2 is H, CN, halogen, C1-C3 alkyl, C1-C3 alkoxy, ethenyl, or cyclopropyl; R3 is C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or phenyl; or R2 and R3 together with the carbon atom to which R2 is attached and the nitrogen atom to which R3 is attached form a 4- to 7-membered heterocycloalkyl; R4 is H, C1 to C 10 alkyl, C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; [ka] is a single or double bond, and Alkyl, cycloalkyl, heterocycloalkyl, phenyl, aryl, and heteroaryl are each optionally substituted with one or more deuterium, halogen, CN, oxo, C-C alkyl, C-C cycloalkyl, C-C haloalkyl, C-C alkenyl, C-C alkynyl, -OR', -C(O)R', -C(O)OR', -O-COR', -C(O)NR'R", -NR'R", -SR', -SOR', -S(O)R', or -POR'R", where R' and R" are each independently H, halogen, C-C alkyl, C-C haloalkyl, C-C cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or 6- to 10-membered aryl.

[0009] A subset of compounds of formula I are compounds of formula II. [ka] however, [ka] is a single bond or a double bond, and [ka] is 2 or 3, X is C or N, and Y and Z are each independently C=O, C-Rx, or N-Ry, provided that when X is N, Y is C=O and Z is C-Rx, Rx is H, CN, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, cyclopropyl, 4-6 membered heterocycloalkoxy, or NR'R", and Ry is absent, H, C1-C3 alkyl, or cyclopropyl. The variables A, L, and R1-R4 are as defined above.

[0010] Preferred compounds have any one of the following formulae II-A to II-H, respectively: [ka] In the above formulas II-G and II-H, n is 2, 3, or 4, preferably 2, and Rg1, Rg2, Rg3, Rg4, Rh1, and Rh2 are each independently H, halogen, or methyl. All other variables are as defined above.

[0011] Among the above compounds, [ka] teeth [ka] In another embodiment, [ka] teeth, [ka] is.

[0012] In preferred compounds, L is a single bond, -O-, -C(O)-, -NHC(O)-, -NHS(O)2-, C2-C3 alkenylene, or C2-C3 alkynylene.

[0013] Another subset of compounds of the present invention are compounds of formula III. [ka] Here, Ra1, Ra2, Ra3, Ra4, and Ra5 are each independently H, halogen, amino, CN, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl.

[0014] A further subset of compounds of the invention are compounds of formula IIIa or formula IIIb. [ka]

[0015] A further subset of compounds of the invention are compounds of formula IV, V or VI. [ka] In the above formula IV, m is 0, 1, 2, 3, or 4, preferably 1. All other variables are as defined above.

[0016] In preferred compounds, A is phenyl, 2,3-dihydro-1H-indene, or benzofuran, each unsubstituted or substituted with one or more groups selected from deuterium, halogen, NH, CN, C-C alkyl, C-C alkenyl, C-C haloalkyl, and C-C cycloalkyl.

[0017] In more preferred compounds, A is phenyl substituted with one or more groups selected from halogen (e.g., F, Cl, and Br), NH2, CN, C1-C3 alkyl (e.g., CH3), and C1-C3 haloalkyl (e.g., CF3, CHF2, and CF2CH3).

[0018] Of the compounds listed above, preferred compounds have one or more of the following characteristics: (i) R1 is methyl or ethynyl; (ii) R2 is H, C1-C3 alkyl (e.g., CH3, CD3), or cyclopropyl; (iii) R3 is C1-C4 alkyl (e.g., CH3, CH(CH3)2, CD3), C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl, preferably C1-C4 alkyl (e.g., CH3, CD3) or cyclopropyl; (iv) Rx is H, halogen, C1-C3 alkyl, cyclopropyl, C1-C3 alkoxy, NH2, or C1-C3 alkylamino; (v) Ry is H, C1-C3 alkyl, or cyclopropyl; (vi) A is [ka] [ka] is.

[0019] Preferably, A is [ka] and (vii) L is a single bond, and (viii) R4 is selected from the group consisting of: [ka] [ka]

[0020] Preferably, R4 is selected from the group consisting of: [ka] [ka]

[0021] In preferred compounds of formulas IV, V, and VI, m is 0, 1, or 2, and Rx is H or C1-C 10More preferably, R1 is methyl or ethynyl (most preferably methyl), R2 is H, C1-C3 alkyl (e.g., CH3 and CD3), or cyclopropyl, R3 is C1-C4 alkyl (e.g., CH3 and CD3), C3-C6 cycloalkyl (e.g., cyclopropyl), or 4-6 membered heterocycloalkyl, R4 is H, C1-C6 alkyl (e.g., CH3 and CD3), C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl, and A is [ka] and m is 1 or 2.

[0022] In more preferred compounds of formula IV, R1 is methyl, R2 is H or methyl, R3 is methyl, or R2 and R3 together with the carbon atom to which R2 is attached and the nitrogen atom to which R3 is attached form a 5- or 6-membered heterocycloalkyl, R4 is methyl or cyclopropyl, and m is 1 or 2.

[0023] Another embodiment of the invention relates to a pharmaceutical composition comprising any one of the compounds described above and a pharmaceutically acceptable carrier thereof.

[0024] Also within the scope of the present invention is a method for treating cancer comprising administering to a subject in need thereof an effective amount of any one of the compounds described above, or a pharmaceutical composition comprising such a compound.

[0025] Also included within the scope of the present invention is a method of inhibiting SOS1 by administering to a subject in need thereof an effective amount of any one of the compounds described above, or a pharmaceutical composition containing such a compound.

[0026] Table 1 below lists 113 representative compounds of the present invention. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0027] Preferred compounds include the following: 1, 4, 6, 8, 13, 15, 18, 27, 29, 30, 31, 33, 35, 45, 55, 82, 84, and 92 to 97. More preferably, the compound is any one of compounds 1, 6, 8, 13, 18, 27, 29, 30, 31, and 33, 92, 93, and 96.

[0028] The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine. A particular halogen is fluorine.

[0029] The term "alkyl" refers to alkyl groups containing 1 to 20 carbon atoms (e.g., C 1-10 , C 1-6 , C 1-4 , and C 1-3 ) and a monovalent radical center obtained by removing a hydrogen atom from a carbon atom of a parent alkane. Representative alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl. The term "alkylene" refers to alkyl groups of 1 to 20 carbon atoms (e.g., C 1-10 , C 1-6 , C 1-4 , and C 1-3) and two monovalent radical centers obtained by removing two hydrogen atoms from two of the same or different carbon atoms from a parent alkane. The term "haloalkylene" refers to an alkylene substituted with one or more halogens (fluorine, chlorine, bromine, or iodine).

[0030] The term "haloalkyl" refers to an alkyl substituted with one or more halogens (fluorine, chlorine, bromine, or iodine). Examples include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl (e.g., 1-fluoroethyl and 2-fluoroethyl), difluoroethyl (e.g., 1,1-, 1,2-, and 2,2-difluoroethyl), and trifluoroethyl (e.g., 2,2,2-trifluoroethyl).

[0031] The term "alkoxy" refers to -O-alkyl. Examples are methoxy, ethoxy, propoxy, and isopropoxy. Alkoxy includes haloalkoxy, i.e., alkoxy substituted with one or more halogens, for example, -O-CH2Cl and -O-CHClCH2Cl.

[0032] The term "alkylamino" refers to -NR'-alkyl, where R' is H, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C3-C 10 It is heterocycloalkyl, aryl, or heteroaryl.

[0033] "Alkylamide" refers to -NR'-C(O)-alkyl, where R' is H, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C3-C 10 It is heterocycloalkyl, aryl, or heteroaryl.

[0034] The term "alkylcarbonyl" refers to -C(O)-alkyl.

[0035] The term "alkylsulfonyl" refers to -S(O)2-alkyl.

[0036] The term "alkylsulfonamide" refers to -NR'-S(O)2-alkyl, where R' is H, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C3-C 10 It is heterocycloalkyl, aryl, or heteroaryl.

[0037] The term "cycloalkyl" refers to alkyl groups containing 3 to 12 carbons (e.g., C 3-10 , C 3-8 , C 4-7 , and C 3-6 Cycloalkyl refers to a non-aromatic, saturated or unsaturated, monocyclic, bicyclic, tricyclic, or tetracyclic hydrocarbon group, including cycloalkyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]heptyl, bicyclo[2.2.2]octanyl, and decahydronaphthalene.

[0038] Bicyclic hydrocarbon groups or ring systems include fused bicyclic rings, bridged bicyclic rings, or spiro bicyclic rings. Fused bicyclic structures are composed of two rings (e.g., hydrocarbons or heterohydrocarbons) that share two common atoms (i.e., bridgehead atoms) connected to each other. In bridged bicyclic rings, the two bridgehead atoms are not directly connected, but are separated by at least one atom. Spiro bicyclic rings refer to ring systems in which the two rings share only one common atom.

[0039] The term "cycloalkylamido" refers to -NR'-cycloalkyl, where R' is H, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C3-C 10 It is heterocycloalkyl, aryl, or heteroaryl.

[0040] The term "heterocycloalkyl" refers to a non-aromatic, saturated or unsaturated 3- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 15-membered tricyclic ring system containing one or more heteroatoms (e.g., O, N, P, and S). The term also includes fused, bridged, and spiro ring systems. Examples include aziridinyl, azetidinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydro-2-H-thiopyran-1,1-dioxidyl, piperazinyl, piperidinyl, morpholinyl, imidazolidinyl, azepanyl, dihydrothiadiazolyl, dioxanyl, 2-azaspiro[3.3]heptanyl, quinuclidinyl, pyridinyl-2(1H)-one, 3-azabicyclo[3.1.0]hexanyl, and 3,6-dihydro-2H-pyranyl. , 5-azaspiro[2.4]heptanyl, 3,6-dihydro-2H-pyran, 6-azaspiro[2.5]octanyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 1,2,3,6-tetrahydropyridinyl, 1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazinyl, 2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepinyl, and 8-azabicyclo[3.2.1]octanyl. The term "heterocycloalkoxy" refers to -O-heterocycloalkyl.

[0041] The term "heterocyclyl" refers to a heterocycloalkyl, heteroaryl, benzene-fused heterocycloalkyl or heteroaryl, or a cycloalkyl-fused heterocycloalkyl or heteroaryl. Heterocyclyl includes 3- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 20-membered (e.g., 11- to 15-membered) tricyclic ring systems.

[0042] The term "alkenyl" refers to alkyl groups having 2 to 20 carbon atoms (e.g., C 2-4 , C 2-6 , and C 2-10) and one or more carbon-carbon double bonds. Examples include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, and 2-pentenyl. The term "alkenylene" refers to alkyl groups having 2 to 20 carbon atoms (e.g., C 2-4 , C 2-6 , and C 2-10 ) and one or more carbon-carbon double bonds, a straight or branched, divalent unsaturated aliphatic chain.

[0043] The term "alkynyl" refers to an alkyl group having 2 to 20 carbon atoms (e.g., C 2-4 , C 2-6 , and C 2-10 ) and one or more carbon-carbon triple bonds. Examples include ethynyl, 2-propynyl, 2-butynyl, 3-methylbutynyl, 1-pentynyl. The term "alkynylene" refers to an aliphatic chain having 2 to 20 carbon atoms (e.g., C 2-4 , C 2-6 , and C 2-10 ) and one or more carbon-carbon triple bonds, a straight or branched diunsaturated aliphatic chain.

[0044] The term "aryl" refers to a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system, where each ring can have one or more (e.g., 1 to 10, 1 to 5, or 1 to 3) substituents. Examples include phenyl, biphenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, and indanyl.

[0045] The term "heteroaryl" refers to an aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system containing one or more heteroatoms (e.g., O, N, P, and S). Examples include pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl, pyrazolyl, triazolyl, oxazolyl, thiadiazolyl, tetrazolyl, oxazolyl, isoxazolyl, carbazolyl, furyl, imidazolyl, thienyl, quinolinyl, indolyl, thiazolyl, and benzothiazolyl.

[0046] Alkyl, alkylene, haloalkylene, alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, alkenyl, alkynyl, aryl, and heteroaryl mentioned herein include both substituted and unsubstituted moieties. Examples of substituents include deuterium, halogen (e.g., F, Cl, Br), amino, hydroxy, alkyl and haloalkyl (e.g., methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, and 1,1-difluoro-2-hydroxyethan-1-yl), alkenyl and haloalkenyl (e.g., ethylenyl and 3,3-difluoro-2-methylpropen-3-yl), cycloalkyl (e.g., cyclopropyl and cyclobutyl), cycloheteroalkyl (e.g., tetrahydrofuranyl), —CN, —CONR7R8, —NR7R8, —NR7COR8, —NR7S02R8, —N7COOR8, —COR7, —COOR7, —SR7, —SONR7R8, and —OR9, where R7, R8, and R9 are each independently hydrogen, C 1-6 Alkyl, C 2-4 Alkenyl, and C 2-4 alkynyl, optionally substituted with 1 to 3 halogens, all of which may be further substituted.

[0047] The term "compound" refers to a compound of the present invention and includes salts, solvates, and prodrugs thereof. Pharmaceutically acceptable salts include those described in "Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition" (P.H. Stahl and C.G. Wermuth, eds., Wiley-VCH, New York, 2011). In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. These may serve as intermediates in the purification of the compound or in the preparation of other pharmaceutically acceptable salts, or may be useful in identifying, characterizing, or purifying the compounds of the present invention. A solvate refers to a complex formed between an active compound and a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine. A prodrug refers to a compound that is metabolized to a pharmacologically active drug after administration. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives.

[0048] The compounds of the present invention may contain one or more non-aromatic double bonds or asymmetric centers. They may exist as racemates or racemic mixtures, single R enantiomers, single S enantiomers, individual diastereomers, diastereomeric mixtures, cis isomers, or trans isomers. Such isomeric forms of the compounds are included within the scope of the present invention. They may exist as mixtures or be isolated using chiral synthesis or chiral separation techniques.

[0049] An asterisk (*) in a chemical formula indicates the position at which the group is attached to the corresponding parent compound.

[0050] The invention also features the use of one or more of the aforementioned compounds in the treatment of cancer or in the manufacture of a medicament for treating cancer.

[0051] "Treating" or "treatment" refers to the administration of one or more compounds to a subject with the intent to provide a therapeutic effect, such as slowing, interrupting, preventing, controlling, or halting the progression of an existing disorder and / or its symptoms, but does not necessarily mean complete elimination of all symptoms. An "effective amount" refers to the amount of compound needed to produce a therapeutic effect. As will be recognized by those skilled in the art, effective dosages will vary depending on the type of condition being treated, the route of administration, excipient usage, and the possibility of co-administration with other therapeutic agents.

[0052] The cancer is caused by KRAS mutation, SOS1 oncogenic mutation, or oncogenic mutation / overexpression of receptor tyrosine kinases such as EGFR and FGFR, and is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer, and sarcoma. Preferably, the cancer is pancreatic cancer, non-small cell lung cancer, cholangiocarcinoma, or colorectal cancer.

[0053] The term "subject" refers to animals, such as mammals, including humans. Humans are the preferred subject.

[0054] The compound of the present invention can be administered alone or in the form of a pharmaceutical composition containing pharmaceutically acceptable carrier, diluent or excipient. Such pharmaceutical compositions and their preparation methods are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, A. Adejare, Editor, 23rd Edition., Academic Press, 2020).

[0055] The present invention further features the treatment of a disease defined as a RAS protein family disorder (RASopathy) by inhibiting SOS1 activity, the disease being selected from the group consisting of neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML) (also known as LEOPARD syndrome), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome (also known as NF1-like syndrome), and hereditary gingival fibromatosis.

[0056] To practice the methods of the present invention, compositions or kits containing one or more of the above compounds can be administered alone or simultaneously, in parallel, sequentially, consecutively, alternatingly, or separately with at least one other pharmacologically active substance. Simultaneous administration, also referred to as combined administration, includes administration at substantially the same time. Simultaneous administration includes administration of active agents within the same period, such as on the same day, but not necessarily at the same time. Alternating administration includes administration of one agent within a specific period, e.g., over several days or a week, followed by administration of another agent for a subsequent period, e.g., over several days or a week, and then repeating this pattern for one or more cycles. Sequential or consecutive administration includes administration of one agent using one or more dosages for a first period (e.g., over several days or a week), followed by administration of the other agent using one or more dosages for a second and / or additional period (e.g., over several days or a week). Overlapping schedules may also be employed, including administration of active agents on different days during a treatment period, but not necessarily in a regular order. Variations of these general guidelines may also be employed depending on the agent being administered and the condition of the subject.

[0057] The components of the combination of the present invention are administered (dependently or independently) by methods commonly used by those skilled in the art (e.g., oral, enteral, parenteral, nasal, vaginal, rectal, or topical administration routes) and may be formulated, either alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, excipients, and / or solvents appropriate for each route of administration.

[0058] The term "parenteral" as used herein refers to subcutaneous, intradermal, intravenous, intraperitoneal, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intraspinal, intralesional, or intracranial injection, as well as any suitable infusion technique.

[0059] The composition for oral administration can be any orally acceptable dosage form, including capsules, tablets, emulsions, aqueous suspensions, dispersions, and solutions.For tablets, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also commonly added.For oral administration in capsule form, useful diluents include lactose and dried cornstarch.For oral administration of aqueous suspensions or emulsions, the active ingredient can be suspended or dissolved in an oil phase combined with an emulsifier or suspending agent.If necessary, certain sweeteners, flavors, or colorants can also be added.

[0060] Nasal aerosol or inhalation compositions can be prepared according to techniques well known in the art of pharmaceutical formulation. For example, such compositions can be prepared as a saline solution using benzyl alcohol or other suitable preservatives, absorption enhancers which enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents.

[0061] Compositions containing one or more of the above compounds may also be administered as suppositories for rectal administration.

[0062] A carrier in a pharmaceutical composition must be "acceptable," meaning compatible with (and preferably capable of stabilizing) the active ingredient(s) of the composition and not deleterious to the subject being treated. One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of the active compound(s). Examples include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, D&C Yellow #10, and the like.

[0063] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0064] The present invention is based on the unexpected discovery that compounds of formula I are effective in inhibiting SOS1 activity and treating cancer. [ka] The variables R1-R4, A, L, ring Q, and ring M are as defined above. The compounds of Formula I, and methods for their synthesis and use in treating cancer and / or inhibiting SOS1, are described in detail below.

[0065] Subsets of compounds of Formula I include compounds of Formula II, II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, III, IV, V, and VI, see above.

[0066] In these subsets, ring M is phenyl or a 5- to 15-membered heteroaryl or heterocycloalkyl ring. The number of double bonds in ring M is 1, 2, or 3.

[0067] Compounds of formula I include all cis-trans isomers, enantiomers, diastereomers, and mixtures thereof in any ratio.

[0068] Any compound of the above formula can be prepared by synthetic methods well known in the art. For example, see R. Larock, "Comprehensive Organic Transformations" (3rd edition, John Wiley and Sons 2018); PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis" (4th edition, John Wiley and Sons 2007); L. Fieser and M. Fieser, "Fieser and Fieser's Reagents for Organic Synthesis" (John Wiley and Sons 1994); and L. Paquette, ed., "Encyclopedia of Reagents for Organic Synthesis" (2nd edition, John Wiley and Sons 2009) and subsequent editions.

[0069] The compounds thus prepared can be purified according to conventional methods such as crystallization, distillation / vacuum distillation, silica flash chromatography, and preparative liquid chromatography.

[0070] The efficacy of compounds of the present invention can be initially measured using in vitro homogeneous time-resolved fluorescence (HTRF)-based protein-protein interaction assays, pERK potency assays, or 3D cell proliferation assays, all of which are described below. Selected compounds can be further tested, for example, by administering them to animals, to confirm their efficacy. Based on the results, an appropriate dosage range and route of administration can be determined.

[0071] The compounds of the present invention are preferably formulated as pharmaceutical compositions containing a pharmaceutical carrier, which are then administered to a subject in need thereof to treat cancer by inhibiting SOS1.

[0072] Without further elaboration, it is believed that one skilled in the art can, based on the preceding description, utilize the present invention to its fullest extent. The following examples are not to be construed as limiting in any way the remainder of the disclosure, but merely as illustrative.

[0073] All publications cited herein are incorporated by reference in their entirety.

[0074] Examples illustrating the preparation and evaluation of the effects of the compounds of the present invention will be described below.

[0075] The abbreviations used herein are set out in Table 2 below along with their definitions and are commonly used in the art. [Table 2-1] [Table 2-2]

[0076] General synthesis steps Provided below are exemplary methods for preparing compounds of Formula I, including compounds of Formula II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, III, IV, V, or VI. Methods for preparing these compounds and useful intermediates provide further features of the invention and are described in the steps below.

[0077] Each compound shown below was obtained as the free compound (eg, free base), a salt (eg, formate and trifluoroacetate salts), or any combination thereof.

[0078] In general, compounds of Formulae II-A-II-D and VI can be synthesized by the methods shown in Schemes I-III and Schemes IX-X.

[0079] Compounds of formula II-E and II-F can be synthesized by the methods shown in Schemes VII and VI, respectively.

[0080] Compounds of Formula II-G and II-H can be synthesized by the methods shown in Schemes IV and V, respectively.

[0081] Compounds of formula IV and V can be synthesized by the methods shown in Schemes XII and XI, respectively.

[0082] Compounds of formula VI can be synthesized by the method shown in Scheme VIII.

[0083] As shown in Scheme I, amide I-2 is prepared by reacting acid I-1 with ammonium hydroxide in the presence of an amide coupling reagent such as HOBt / EDCI or HATU. The fluorine atom is replaced by RNH, followed by ring closure with a dehydrating agent such as the acyl chloride RCOCl (or triethyl orthoformate when R is H) to give the fused bicyclic intermediate I-4. Alternatively, cyclization can be achieved by treating the resulting acylated I-3 with NaOMe. I-4 is then converted to the thione I-5 using Lawesson's reagent or PSO. The resulting thione is reacted with iodomethane to produce the methylthio-bearing salt I-6, which is then reacted with amine I-7 (prepared according to procedures described in WO2019 / 201848, WO2021 / 074227, WO2022 / 058344, WO201922129, WO2021 / 092115, and WO2020 / 180768) to produce intermediate I-8. Finally, R4 is introduced, and the final product of formula I-9 is obtained using methods shown in Scheme II (including, but not limited to, Suzuki coupling, Buchwald-Hartwig coupling, Stille coupling, Negishi coupling, etc.). As shown in Scheme II, Ar represents the heteroaryl ring system of I-9.

[0084] [ka]

[0085] [ka]

[0086] Alternatively, when R2 is H and R3 is methyl, compounds of formula III-2 can be prepared from III-1 obtained according to the methods described in WO2019 / 201848, WO2021 / 074227, WO2022 / 058344, WO201922129, WO2021 / 092115, WO2020 / 180768, and CN114539245. As shown in Scheme III below, treatment of intermediate III-1 with iodomethane and Cs2CO3 or trimethyloxonium tetrafluoroborate provides the product of formula III-2.

[0087] [ka]

[0088] In the case of Formula II-G, where R2 and R3 are linked via a linker, the synthesis method is as shown in Scheme IV. First, pyridine derivative IV-1 is brominated using NBS to give IV-2. Amination of ester IV-2 gives amide IV-3. Acylation of the amino group on the pyridine ring of IV-3 gives IV-4, which is treated with a base (e.g., t-BuOK) to give IV-5. IV-5 is then reacted with Lawesson's reagent, and the resulting thione IV-6 is treated with MeI to give the iodide salt IV-7. Coupling of IV-7 with amine I-7 gives imine IV-8. Introducing the "R4" substituent gives compound IV-9, an exemplary compound of Formula II-G.

[0089] [ka]

[0090] Scheme V below illustrates the synthesis of compounds of Formula II-H. The pyridine derivative V-1 is reacted with CS2 in the presence of DBU, followed by S-ethylation with iodoethane to give the ethyl thioether V-2. Chloride V-3 is obtained by chlorination of intermediate V-2 with thionyl chloride. Intermediate V-3 is coupled with amine I-7 to give V-4, which is then oxidized with m-CPBA to give sulfone V-5. The resulting sulfone is displaced with 2-((tert-butyldimethylsilyl)oxy)-ethan-1-ol in the presence of NaH, followed by in situ silyl deprotection to give alcohol V-6, which is then converted to chloride V-7 with thionyl chloride. V-7 is converted to tricyclic V-8 using a base such as KCO3. Finally, R4 is introduced into V-8 to produce compound V-9, an exemplary compound of Formula II-H.

[0091] [ka]

[0092] Compounds of Formula II-F are prepared according to Scheme VI, in which pyrido[3,4-d]pyrimidine derivative VI-1 is coupled with amine I-7 (R(CH)ANH) to give VI-2. The methoxy ether of VI-2 is hydrolyzed with HBr in a suitable solvent (e.g., acetic acid) to give VI-3. Treatment of VI-3 with an alkyl halide RyI (e.g., iodomethane) in the presence of a base (e.g., CsCO) gives intermediate VI-4. R4 is introduced and intermediate VI-5 is obtained using methods shown in Scheme II (including, but not limited to, Suzuki coupling, Buchwald-Hartwig coupling, Stille coupling, Negishi coupling, etc.). Treatment of intermediate VI-5 with an alkyl halide (e.g., iodomethane) in the presence of a base (e.g., CsCO) in a suitable solvent (e.g., DMF) gives the product of Formula VI-6.

[0093] [ka]

[0094] Compounds of formula II-E are prepared according to Scheme VII. The 4-hydroxypyrimidine derivative VII-1 is converted to triflate VII-2 using TfO in the presence of a base (e.g., pyridine) in a suitable solvent (e.g., DCM). Displacement of triflate VII-2 with amine I-7 in the presence of a base (e.g., DIEA) and a suitable solvent (e.g., dioxane) gives VII-3. The R group in VII-3 is introduced via, for example, Suzuki coupling, Buchwald-Hartwig coupling, Stille coupling, or Negishi coupling according to Scheme II. Treatment of intermediate VII-3 with an alkyl halide (e.g., iodomethane) in a suitable solvent (e.g., DMF or DMA) gives the product of formula VII-4.

[0095] [ka]

[0096] Compounds of Formula II-C can be prepared according to Scheme VIII, where 2-amino-4,5-dimethoxybenzoic acid VIII-1 is treated with triphosgene to give VIII-2. VIII-2 is alkylated with an alkyl halide (e.g., iodomethane) in the presence of a base (e.g., NaH) in a suitable solvent (e.g., DMF) to give VIII-3. VIII-3 is treated with ammonium hydroxide in a suitable solvent (e.g., THF) to give VIII-4. VIII-4 is converted to the pyrimidone derivative VIII-5 by treatment with RCH(OEt) in the presence of a suitable acid (e.g., acetic acid) in a solvent (e.g., ethanol). VIII-5 is selectively demethylated using L-methionine and methanesulfonic acid to give VIII-6. The hydroxyl in VIII-6 is alkylated with an alkyl tosylate (e.g., (3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate) in the presence of a base (e.g., potassium carbonate) in a suitable solvent (e.g., DMF) to give the ether VIII-7. VIII-7 is converted to the thione VIII-8, which reacts with iodomethane to give the salt VIII-9. The salt VIII-9 is reacted with the amine I-7 to give the final product of formula VIII-10.

[0097] [ka]

[0098] Compounds of formula II-C can be prepared according to Scheme IX, in which intermediate I-8 is coupled with an alkyne derivative in the presence of a base (e.g., TEA) in a suitable solvent (e.g., DMSO) under palladium (e.g., Pd(PPh3)2Cl2) and CuI catalysis to give compounds of formula IX-1. Alternatively, intermediate I-8 is coupled with an alkene boronic acid ester in the presence of a base (e.g., K2CO3) in a suitable solvent (e.g., dioxane and water) under palladium (Pd(dppf)Cl2) catalysis to give compounds of formula IX-2.

[0099] [ka]

[0100] Compounds of Formula II-B are prepared according to Scheme X below. Intermediate I-8 is treated with an alkylsulfonamide (e.g., propane-2-sulfonamide) in a CuI-catalyzed N-heteroarylation coupling reaction with a base (e.g., KCO) and a ligand (N,N'-dimethylethylenediamine) in a suitable solvent (e.g., DMF) to give compounds of Formula X-1. Alternatively, intermediate I-8 can be converted to amide X-2 by nucleophilic substitution followed by coupling with an alkylamide, such as cyclopentanecarboxamide, catalyzed by palladium (e.g., Ruphos and Ruphos Pd G3) in the presence of a base (e.g., CsCO). Intermediate I-8 can then be converted to amide X-3 by a palladium-catalyzed carbonylation reaction in the presence of an amine (e.g., piperidine or piperazine).

[0101] [ka]

[0102] Compounds of Formula V are prepared according to Scheme XI. In the presence of a base (e.g., DIEA) in a suitable solvent (e.g., DMA), the chlorine atom in tert-butyl 2,4-dichloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate XI-1 is replaced with amine I-7 to give intermediate XI-2. Intermediate XI-2 undergoes palladium (Pd / C)-catalyzed dechlorination in the presence of a suitable base (e.g., TEA) in a suitable solvent (e.g., MeOH) to give XI-3 (R = H). Alternatively, 2-chloropyrimidine derivative XI-2 is alkylated with a trialkylboroxine (e.g., trimethylboroxine) in a palladium (e.g., Pd(dppf)Cl)-catalyzed Suzuki coupling in the presence of a base (e.g., KCO) in a suitable solvent (e.g., dioxane and water) to give intermediate XI-3 (R = Me). The Boc group of XI-3 is deprotected using a suitable acid (e.g., HCl in EtOAc) to give XI-4. XI-4 is converted to amide XI-5 using a carboxylic acid derivative RCOOH (e.g., 4-methoxytetrahydro-2H-pyran-4-carboxylic acid) in the presence of a suitable coupling agent (e.g., T3P) and a base (e.g., DIEA) in a suitable solvent (e.g., MeCN) to give amide derivative XI-5. Treatment of intermediate XI-5 with an alkyl halide (e.g., iodomethane) in a suitable solvent (e.g., DMA) gives the product of formula XI-6.

[0103] [ka]

[0104] Compounds of formula IV are prepared according to scheme XII. To synthesize compounds of formula XII-2, starting material XII-1 can be prepared using literature methods (e.g., J. Med. Chem. 2022, 65(23), 15856-15877 and 2022, 65(19), 13158-13171, WO2023001229, WO2023001229, and WO2022135610). Compound XII-1 is treated with MeI in a suitable solvent (e.g., DMF) to produce compounds of formula XII-2.

[0105] [ka] [Example]

[0106] Synthesis of (R,Z)-6-bromo-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-quinazoline-4(1H)-imine [ka]

[0107] Step 1 Synthesis of 6-bromo-1,2-dimethylquinazolin-4(1H)-one To a solution of 5-bromo-2-(methylamino)benzamide (18 g, 78.6 mmol) in EtOH (300 mL) was added 1,1,1-triethoxyethane (216 mL, 1.18 mol) and AcOH (67 mL, 1.18 mol) at 25° C. The mixture was stirred at 120° C. for 12 hours, cooled to room temperature, and filtered. The cake was washed with EtOAc (100 mL) and dried under vacuum to give the title compound (17 g, 67.2 mmol, 85.5% yield) as a gray solid. LCMS m / e: 253, 255 (MH + ).

[0108] Step 2: Synthesis of 6-bromo-1,2-dimethylquinazoline-4(1H)-thione To a solution of 6-bromo-1,2-dimethylquinazolin-4(1H)-one (5 g, 19.8 mmol) in toluene (40 mL) was added Lawesson's reagent (7.99 g, 19.8 mmol). The mixture was stirred at 120 °C for 1 h. The reaction mixture was cooled to room temperature and poured into water (200 mL), followed by extraction with DCM (100 mL × 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 0–10% MeOH in DCM) to give the title compound (3 g, 11.1 mmol, 56.4% yield) as a yellow solid. LCMS m / e: 269, 271 (MH + ).

[0109] Step 3 Synthesis of 6-bromo-1,2-dimethyl-4-(methylthio)quinazolin-1-ium iodide A solution of 6-bromo-1,2-dimethylquinazoline-4(1H)-thione (100 mg, 0.392 mmol) in CHCl (5 mL) was stirred for 3 hours at 25° C. The reaction mixture was concentrated to give the title compound (100 mg, 0.351 mmol, yield: 89.5%) as a yellow solid. LCMS m / e: 284, 286 (M + ).

[0110] Step 4: Synthesis of (R,Z)-6-bromo-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-quinazolin-4(1H)-imine (R)-1-(2-Methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (850 mg, 4.21 mmol) was mixed with 6-bromo-1,2-dimethyl-4-(methylthio)quinazolin-1-ium iodide (1 g, 3.51 mmol) in DMA (5 mL). The reaction mixture was stirred at 25 °C for 2 h, poured into water (100 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (150 mL × 3), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by reverse-phase column chromatography (0–33%, CHCN in HO) to give the title compound (500 mg, 1.14 mmol, 32.5% yield) as a brown solid. LCMS m / e: 438 (MH + ).

[0111] Following similar steps, (R,Z)-3-(1-((6-bromo-1,2-dimethylquinazolin-4(1H)-ylidene)amino)ethyl)-2-methylbenzonitrile was prepared, the structure of which is shown below. LCMS m / e: 395, 397 (MH + ). [ka]

[0112] Synthesis of (R,Z)-6-bromo-2-cyclopropyl-1-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine [ka]

[0113] Step 1 Synthesis of 2-bromo-5-(N-methylcyclopropanecarboxamide)isonicotinamide To a solution of 2-bromo-5-(methylamino)isonicotinamide (2 g, 8.69 mmol) in CHCl (40 mL) was added cyclopropanecarbonyl chloride (2.73 g, 26.1 mmol) and DIEA (3.37 g, 26.1 mmol). The mixture was stirred at 50 °C for 2 h. The resulting mixture was cooled to room temperature, concentrated, basified with saturated NaHCO solution to pH 8, and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel flash column chromatography (gradient, PE to PE: EtOAc = 3:1) to give the title compound (2.21 g, 7.38 mmol, yield: 84.9%) as a white solid. LC-MS m / e: 298.1, 300.1 (MH + ).

[0114] Step 2: Synthesis of 6-bromo-2-cyclopropyl-1-methylpyrido[3,4-d]pyrimidin-4(1H)-one To a solution of 2-bromo-5-(N-methylcyclopropanecarboxamide)isonicotinamide (745 mg, 2.5 mmol) in MeOH (25 mL) was added NaOMe (540 mg, 10 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with brine (20 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel flash column chromatography (gradient, PE to PE: EtOAc = 2:1) to give the title compound (400 mg, 1.43 mmol, yield: 57.2%) as a white solid. LC-MS m / e: 280.1, 282.1 (MH + ).

[0115] Step 3 Synthesis of 6-bromo-2-cyclopropyl-1-methylpyrido[3,4-d]pyrimidine-4(1H)-thione To a solution of 6-bromo-2-cyclopropyl-1-methylpyrido[3,4-d]pyrimidin-4(1H)-one (400 mg, 1.43 mmol) in MeCN (25 mL) was added DIEA (738 mg, 5.72 mmol) and P2S5 (636 mg, 2.86 mmol). The mixture was stirred at 70 °C for 2 h under a N2 atmosphere. The mixture was cooled to room temperature, quenched with saturated NaHCO3 solution (50 mL), and extracted with EtOAc (60 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash column chromatography (gradient, PE to PE: EtOAc = 3:1) to give the title compound (300 mg, 1.01 mmol, yield: 70.6%) as a yellow solid. LC-MS m / e: 296.2, 298.2 (MH + ).

[0116] Step 4 Synthesis of 6-bromo-2-cyclopropyl-1-methyl-4-(methylthio)pyrido[3,4-d]pyrimidin-1-ium iodide A solution of 6-bromo-2-cyclopropyl-1-methylpyrido[3,4-d]pyrimidine-4(1H)-thione (300 mg, 1.01 mmol) in MeI (10 mL) was stirred at room temperature for 1 hour. The mixture was concentrated to give the title compound (300 mg, 0.96 mmol, 96.4% yield) as a brown solid. LC-MS m / e: 310.2, 312.2 (MH + ).

[0117] Step 5: Synthesis of (R,Z)-6-bromo-2-cyclopropyl-1-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine To a solution of 6-bromo-2-cyclopropyl-1-methyl-4-(methylthio)pyrido[3,4-d]pyrimidin-1-ium iodide (300 mg, 0.96 mmol) in DMA (20 mL) was added (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (234.1 mg, 1.15 mmol) and stirred at room temperature for 1 h. The mixture was then poured into water (25 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel flash column chromatography (gradient, DCM to DCM:CHOH = 15:1) to give the title compound (200 mg, 0.43 mmol, 44.8% yield) as a brown solid. LC-MS m / e: 465.3, 467.3 (MH + ).

[0118] Synthesis of (R,Z)-6-chloro-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-pyrido[3,4-d]pyrimidin-4(1H)-imine [ka]

[0119] Step 1. Synthesis of 2-chloro-5-fluoroisonicotinamide At 0°C, EDCI (262 g, 1.37 mol) was added to a solution of 2-chloro-5-fluoroisonicotinic acid (200 g, 1.14 mmol) and HOBt (185 g, 1.37 mmol) in DMF (1800 mL). The mixture was stirred at room temperature for 2 h. At 0°C, NHOH solution (244 g, 25%) was added to the mixture, and the mixture was stirred for an additional 1 h. The resulting mixture was diluted with water (1 L) and extracted with EtOAc (1.6 L × 3). The combined organic layer was washed with brine (1 L), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was triturated with a mixture of PE (150 mL) and DCM (50 mL) to give the title compound (134 g, 766 mmol, yield: 67.4%) as a white solid. LC-MS m / e: 175.3, 177.3 (MH + ).

[0120] Step 2: Synthesis of 2-chloro-5-(methylamino)isonicotinamide In a sealed tube, a mixture of 2-chloro-5-fluoroisonicotinamide (134 g, 766 mmol), methylamine hydrochloride (104 g, 1.54 mol), and DIEA (507 mL, 2.92 mol) in DMSO (900 mL) was stirred at 95 °C overnight. The mixture was cooled to room temperature, diluted with water (400 mL), and then extracted with EtOAc (800 mL × 3). The organic layers were combined, washed with brine (800 mL), dried over anhydrous NaSO, filtered, and concentrated to give the title compound (110 g, 594 mmol, 77.3% yield) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS m / e: 186.1, 188.1 (MH + ).

[0121] Step 3 Synthesis of 6-chloro-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-one A solution of 2-chloro-5-(methylamino)isonicotinamide (72 g, 388 mmol) and acetyl chloride (55.6 mL, 776 mmol) in CHCl (1500 mL) was stirred at 80 °C overnight. The mixture was allowed to cool to room temperature and concentrated. The residue was basified with saturated NaHCO solution (600 mL) and extracted with EtOAc (500 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the title compound (56 g, 267 mmol, yield: 68.7%) as a yellow solid. LC-MS m / e: 210.1, 212.1 (MH + ).

[0122] Step 4 Synthesis of 6-chloro-1,2-dimethylpyrido[3,4-d]pyrimidine-4(1H)-thione A mixture of 6-chloro-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-one (42 g, 200 mmol) and Lawesson's reagent (49 g, 120 mmol) in dichloroethane (500 mL) was stirred at 80 °C overnight. The mixture was allowed to cool to room temperature and concentrated. The residue was diluted with HCl solution (2000 mL, 1 M) and washed with ethyl acetate (800 mL). The aqueous layer was adjusted to pH 7 with NaHCO and extracted with DCM (1000 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the title compound (23 g, 102 mmol, yield: 51%) as a brown solid. The crude product was used directly in the next step without further purification. LC-MS m / e: 226.1, 228.1 (MH + ).

[0123] Step 5 Synthesis of (6-chloro-1-methyl-4-(methylthio)pyrido[3,4-d]pyrimidin-1-ium-2-yl)methane iodide A solution of 6-chloro-1,2-dimethylpyrido[3,4-d]pyrimidine-4(1H)-thione (18 g, 79.6 mmol) in iodomethane (50 mL) was stirred at room temperature for 4 hours. The mixture was concentrated to give the title compound (19.1 g, 79.6 mmol, 100% yield) as a red solid. The crude product was used directly in the next step without further purification. LC-MS m / e: 240.1, 242.1 (M + ).

[0124] Step 6: Synthesis of (R,Z)-6-chloro-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-pyrido[3,4-d]pyrimidin-4(1H)-imine To a solution of (6-chloro-1-methyl-4-(methylthio)pyrido[3,4-d]pyrimidin-1-ium-2-yl)methane iodide (19.1 g, 79.6 mmol) in DMA (100 mL) was added (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (16.2 g, 79 mmol). The mixture was stirred at room temperature for 15 minutes. The resulting mixture was diluted with water (300 mL) and extracted with DCM (500 mL × 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by neutral Al2O3 column chromatography (gradient, PE to PE:DCM:MeOH = 16:3:1) to give the title compound (11.9 g, 30.2 mmol, yield: 38%) as a brown solid. LC-MS m / e: 395.1, 397.1 (MH + ).

[0125] Synthesis of (R,Z)-6-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-imine [ka]

[0126] To a solution of (6-chloro-1-methyl-4-(methylthio)pyrido[3,4-d]pyrimidin-1-ium-2-yl)methanide (2 g, 8.27 mmol) in DMA (15 mL) was added (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (1.88 g, 9.93 mmol) and stirred at room temperature for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with DCM (150 mL × 3). The combined organic layer was washed with brine (100 mL × 3), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by neutral AlO column chromatography (gradient, DCM to DCM:MeOH = 20:1) to give the title compound (1.6 g, 4.2 mmol, yield: 50.8%) as a yellow solid. LC-MS m / e: 381.4 (MH + ).

[0127] Applying the same steps as above, the following intermediates were prepared (Table 3 below, from left to right): (R,Z)-6-chloro-1-isopropyl-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-pyrido[3,4-d]pyrimidin-4(1H)-imine, (R,Z)-3-(1-((6-chloro-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-ylidene)amino)ethyl)-2-methylbenzonitrile, and (R,Z)-6-Chloro-1-cyclopropyl-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-pyrido[3,4-d]pyrimidin-4(1H)-imine [Table 3]

[0128] Synthesis of (R,Z)-6-chloro-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)pyrido[3,4-d]pyrimidin-4(1H)-imine [ka]

[0129] Step 1: Synthesis of (S,E)-2-methyl-N-(2-methyl-3-(trifluoromethyl)benzylidene)propane-2-sulfinamide To a solution of 2-methyl-3-(trifluoromethyl)benzaldehyde (23 g, 122 mmol) and (S)-(−)-2-methyl-2-propanesulfinamide (22.2 g, 183 mmol) in THF (300 mL) was added Ti(OEt) (77 mL, 0.37 mol) at 15 °C under a N atmosphere. The reaction mixture was stirred at 80 °C for 12 h. The mixture was diluted with EtOAc (1 L) and water (50 mL) and then filtered. The organic layer was washed with brine (200 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (32.9 g, 113 mmol, 92% yield) as a white solid. The residue was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 2.68 (d, J = 1.0 Hz, 3H), 1.27 (s, 9H). LC-MS m / e: 292 (MH + ).

[0130] Step 2: Synthesis of (S)-2-methyl-N-((S)-1-(2-methyl-3-(trifluoromethyl)phenyl)-3-(trimethylsilyl)prop-2-yn-1-yl)propane-2-sulfinamide To a solution of (S,E)-2-methyl-N-(2-methyl-3-(trifluoromethyl)benzylidene)propane-2-sulfinamide (5 g, 17.2 mmol) in THF (100 mL) was added a solution of trimethylsilylethynylmagnesium bromide in THF (1 M, 51.5 mL, 51.5 mmol) at -30 °C under a nitrogen atmosphere. The reaction mixture was gradually warmed to 10 °C and stirred for 1 h. After addition of saturated aqueous NH4Cl (10 mL) and brine (50 mL), the mixture was extracted with EtOAc (100 mL × 2). The combined extracts were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography (gradient, PE / EtOAc = 10 / 1 to 5 / 1) to give the title compound (6.3 g, 16.2 mmol, yield: 94%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 7.7 Hz, 1 H), 7.65 (d, J = 7.7 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 6.27 (d, J = 7.6 Hz, 1 H), 5.49 (d, J = 7.6 Hz, 1 H), 2.45 (s, 3 H), 1.11 (s, 9 H), 0.16 (s, 9 H).

[0131] Step 3: Synthesis of (S)-2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)propane-2-sulfinamide A solution of (S)-2-methyl-N-((S)-1-(2-methyl-3-(trifluoromethyl)phenyl)-3-(trimethylsilyl)prop-2-yn-1-yl)propane-2-sulfinamide (6.69 g, 17.2 mmol) in THF (166 mL) and HO (3.4 mL) was added to a solution of 18-crown-6 (5 g, 18.9 mmol) and potassium fluoride (0.443 mL, 18.9 mmol) in THF (61.75 mL) and HO (1.25 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient, EtOAc / PE = 1 / 10 to 1 / 2) to give the title compound (5.3 g, 16.7 mmol, 97% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 7.8 Hz, 1 H), 7.66 (d, J = 7.7 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 1 H), 6.22 (d, J = 7.8 Hz, 1 H), 5.45 (dd, J = 7.7, 2.4 Hz, 1 H), 3.60 (d, J = 2.4 Hz, 1 H), 2.45 (s, 3 H), 1.08 (d, J = 23.6 Hz, 9 H).

[0132] Step 4 Synthesis of (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-amine To a solution of (S)-2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)propane-2-sulfinamide (5.3 g, 16.7 mmol) in EtOAc (40 mL) was slowly added a 2N HCl solution in EtOAc (20.9 mL, 41.8 mmol) in an ice bath and stirred at 10° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with MTBE (30 mL) and stirred at 25° C. for 0.5 h, then filtered. The collected solid was washed with MTBE (20 mL) and dried under reduced pressure to give the hydrochloride salt of the title compound (3.5 g, 16.4 mmol, yield: 98.3%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 3 H), 7.99 (d, J = 7.8 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1 H), 5.65 (d, J = 2.3 Hz, 1 H), 3.96 (d, J = 2.4 Hz, 1 H), 2.50 (s, 3 H).

[0133] Step 4 (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-amine hydrochloride was neutralized to give the corresponding free base by one of the following methods: a) To a solution of the hydrochloride salt in DMA was added solid K2CO3 (2 equivalents). After stirring for 10 minutes, the solution was filtered. The filtrate was collected to give a solution of the free base of the compound. b) The hydrochloride salt was added to saturated aqueous NaHCO3. EA was added to extract the free base. The organic layers were combined, dried over MgSO4, and evaporated to give the compound as the free base.

[0134] Step 5: Synthesis of (R,Z)-6-chloro-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)pyrido[3,4-d]pyrimidin-4(1H)-imine (R)-1-(2-Methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-amine (350 mg, 1.642 mmol) and 6-chloro-1,2-dimethyl-4-(methylthio)-1,2-dihydropyrido[3,4-d]pyrimidine (397 mg, 1.649 mmol) were mixed and stirred in DMA (5 mL) at 25 °C for 2 h. The reaction mixture was poured into ice water (50 mL) and extracted with DCM (50 mL × 4). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified on neutral AlO gel (gradient, PE to PE:DCM:MeOH = 16:3:1) to give the title compound (200 mg, 0.494 mmol, 30.1% yield) as a yellow solid. LCMS m / e: 405.8, 407.8 (MH + ).

[0135] Synthesis of (R,Z)-6-bromo-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)pyrido[2,3-d]pyrimidin-4(1H)-imine [ka]

[0136] Step 1. Synthesis of 5-bromo-2-fluoronicotinamide To a solution of 5-bromo-2-fluoronicotinic acid (35 g, 159 mmol) and HATU (90.7 g, 239 mmol) in DMF (500 mL) was added NH4Cl (25.5 g, 477 mmol) and DIEA (131 mL, 795 mmol), and the mixture was stirred at room temperature overnight. The resulting solution was poured into water (1.5 L) and extracted with EtOAc (1.5 L × 3). The combined organic layer was washed with brine (1.5 L × 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and triturated with a mixture of PE (150 mL) and DCM (50 mL). The solid was collected and dried under reduced pressure to give the title compound (27 g, 123 mmol, 77.5% yield) as a yellow solid. LC-MS m / e: 219, 221 (MH + ).

[0137] Step 2 Synthesis of 5-bromo-2-(methylamino)nicotinamide To a solution of 5-bromo-2-fluoronicotinamide (27 g, 123 mmol) and methylamine hydrochloride (16.7 g, 247 mmol) in DMSO (200 mL), DIEA (61.1 mL, 370 mmol) was added and stirred overnight at 90 °C in a sealed tube. The resulting solution was cooled to room temperature, poured into water (1 L), and extracted with EtOAc (1 L × 3). The combined organic layer was washed with brine (1.5 L × 3), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and then triturated with a mixture of PE (150 mL) and DCM (50 mL). The solid was collected and dried under reduced pressure to give the title compound (27 g, 117 mmol, 95.4% yield) as a yellow solid. LC-MS m / e: 229, 231 (MH + ).

[0138] Step 3 Synthesis of 6-bromo-1,2-dimethylpyrido[2,3-d]pyrimidin-4(1H)-one To a solution of 5-bromo-2-(methylamino)nicotinamide (10 g, 43.5 mmol) in CHCl (50 mL) was added CHCOCl (34.1 g, 435 mmol) and stirred at 70 °C overnight. The reaction mixture was cooled to room temperature, and excess CHCOCl was removed by distillation. The mixture was quenched with saturated NaHCO solution (200 mL) and extracted with DCM / MeOH (10 / 1 in v / v) (100 mL × 3). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound (1.7 g, 6.69 mmol, yield: 15.4%) as a yellow solid. LC-MS m / e: 254, 256 (MH + ).

[0139] Step 4 Synthesis of 6-bromo-1,2-dimethylpyrido[2,3-d]pyrimidine-4(1H)-thione To a solution of 6-bromo-1,2-dimethylpyrido[2,3-d]pyrimidin-4(1H)-one (1.7 g, 6.7 mmol) in toluene (50 mL) was added Lawesson's reagent (1.62 g, 4 mmol). The reaction mixture was stirred at 80 °C overnight. The resulting solution was cooled to room temperature, poured into water (200 mL), and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified on neutral AlO gel (gradient, PE to PE:DCM:MeOH = 16:3:1) to give the title compound (1 g, 3.7 mmol, yield: 55.3%) as a red solid. LC-MS m / e: 270, 272 (MH + ).

[0140] Step 5 Synthesis of (6-bromo-1-methyl-4-(methylthio)pyrido[2,3-d]pyrimidin-1-ium-2-yl)methane iodide A solution of 6-bromo-1,2-dimethylpyrido[2,3-d]pyrimidine-4(1H)-thione (1 g, 3.7 mmol) in CHCl (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude title compound (1 g, 3.49 mmol, 94.4% yield) as a red solid, which was used directly in the next step without further purification. LC-MS m / e: 284, 286 (M + ).

[0141] Step 6. Synthesis of (R,Z)-6-bromo-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)pyrido[2,3-d]pyrimidin-4(1H)-imine To a solution of (6-bromo-1-methyl-4-(methylthio)pyrido[2,3-d]pyrimidin-1-ium-2-yl)methane iodide (1 g, 3.49 mmol) in DMA (5 mL) was added (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (852 mg, 4.19 mmol) and stirred at room temperature for 1 h. The resulting mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified using neutral AlO gel (gradient, DCM to DCM:MeOH = 10:1) to give the title compound (860 mg, 1.96 mmol, 56% yield) as a yellow solid. LC-MS m / e: 441.4, 443.4 (MH + ).

[0142] Synthesis of (R,Z)-6-bromo-1-cyclopropyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine [ka]

[0143] Step 1 Synthesis of 2-bromo-5-(cyclopropylamino)pyridine-4-carboxamide To a solution of 2-bromo-5-fluoropyridine-4-carboxamide (1.9 g, 8.68 mmol) in DMSO (10 mL), cyclopropanamine (1.2 mL, 17.4 mmol) and DIEA (4.5 mL, 26 mmol) were added and stirred at 90 °C in a sealed tube overnight. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL × 3). The organic layers were combined, washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to give the title compound (1.85 g, 7.22 mmol, 83.3% yield) as a yellow solid. LC-MS m / e: 256, 258 (MH + ).

[0144] Step 2: Synthesis of 6-bromo-1-cyclopropylpyrido[3,4-d]pyrimidin-4(1H)-one To 2-bromo-5-(cyclopropylamino)pyridine-4-carboxamide (1.4 g, 5.47 mmol) in EtOH (60 mL) was added triethyl orthoformate (13.7 mL, 82 mmol) and AcOH (4.7 mL, 82 mmol), and the mixture was stirred at 120 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, PE to PE: EtOAc = 3:1) to give the title compound (800 mg, 3 mmol, yield: 55%) as a yellow solid. LC-MS m / e: 266, 268 (MH + ).

[0145] Step 3 Synthesis of 6-bromo-1-cyclopropylpyrido[3,4-d]pyrimidine-4(1H)-thione 6-Bromo-1-cyclopropylpyrido[3,4-d]pyrimidin-4(1H)-one (700 mg, 2.6 mmol) and Lawesson's reagent (851 mg, 2.1 mmol) were mixed in 1,2-dichloroethane (40 mL) and stirred at 80 °C overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in 1 N HCl solution (200 mL) and washed with EtOAc (200 mL). The aqueous layer was then adjusted to approximately pH 7 with NaHCO and extracted with DCM (300 mL × 2). The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was concentrated to give the title compound (400 mg, 1.42 mmol, yield: 53.9%) as a brown solid. LC-MS m / e: 282, 284 (MH + ).

[0146] Step 4. Synthesis of (R,Z)-6-bromo-1-cyclopropyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine A solution of 6-bromo-1-cyclopropylpyrido[3,4-d]pyrimidine-4(1H)-thione (370 mg, 1.3 mmol) in CHCl (4 mL) was stirred at room temperature for 4 hours, followed by the addition of (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-amine (799 mg, 3.9 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated and purified by neutral AlO column chromatography (gradient, PE to PE:DCM:MeOH = 45:5:1) to afford the title compound (500 mg, 1.11 mmol, 84.5% yield) as a brown solid. LC-MS m / e: 451.1, 453.1 (MH + ).

[0147] Examples 1 to 13 Synthesis of (R,Z)-1-(4-(1,2-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-fluoropiperidin-1-yl)ethan-1-one (Compound 1) and (R,Z)-1-(4-(1,2-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (Compound 2) [ka]

[0148] Step 1: Synthesis of (R,Z)-1-(4-(1,2-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (Compound 2) A mixture of (R,Z)-6-chloro-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine (11.9 g, 30.2 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (11.4 g, 45 mmol), Pd(dppf)Cl (1.1 g, 1.5 mmol), and KCO (12.6 g, 90.6 mmol) in dioxane (200 mL) and water (40 mL) was stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with water (200 mL), and extracted with EtOAc (500 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, concentrated, and purified by AlO column chromatography (100% PE to PE:DCM:MeOH=40:4:1) to give the title compound (12 g, 24.8 mmol, yield: 82.7%) as a yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 4.5 Hz, 1H), 8.25 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 6.77 (s, 1H), 5.79(q, J = 6.5 Hz, 1H), 4.23 (s, 1H), 4.18 (s, 1H), 3.74~3.66 (m, 4H), 2.68 (s, 1H), 2.58 (s, 1H), 2.53 (s, 3H), 2.48 (s, 3H), 2.07 (d, J = 15.5 Hz, 3H), 1.44 (d, J = 6.5 Hz, 3H). LC-MS m / e: 484.7 (MH + ).

[0149] Step 2: (R,Z)-1-(4-(1,2-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethan-1-one To a solution of (R,Z)-1-(4-(1,2-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (5.3 g, 10.9 mmol) and Mn(TMHD) (2 g, 3.31 mmol) in isopropanol (180 mL) and DCM (20 mL) was added phenylsilane (1.8 g, 16.7 mmol) under an atmosphere of O at 0 °C and stirred for 4 h. The reaction mixture was quenched with saturated NaSO solution (40 mL), diluted with water (150 mL), and extracted with EtOAc (300 mL × 2). The combined organic layer was dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure and purified by neutral Al2O3 column chromatography (gradient, 100% PE to PE:DCM:MeOH=25:4:1) to give the title compound (2.4 g, 4.8 mmol, yield: 44%) as a yellow solid. LCMS m / e: 502.3 (MH+).

[0150] Step 3: Synthesis of (R,Z)-1-(4-(1,2-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-fluoropiperidin-1-yl)ethan-1-one (Compound 1) To a solution of (R,Z)-1-(4-(1,2-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethan-1-one (1.1 g, 2.2 mmol) in DCM (40 mL) was added DAST (1.5 mL, 11 mmol) at −40° C. and stirred at −20° C. for 3 h. The reaction mixture was quenched with saturated NaHCO solution (40 mL) and extracted with DCM (50 mL × 2). The combined organic layers were dried over NaSO, filtered, concentrated, and purified by preparative HPLC (0% to 40% MeCN in HO containing 0.1% formic acid) to give the formate salt of the title compound (340 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.20 (s, 1H), 8.18 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 5.80~5.73 (m, 1H), 4.43 (d, J = 12.7 Hz, 1H), 3.88 (d, J = 12.1 Hz, 1H), 3.62 (s, 3H), 2.90 (t, J = 12.0 Hz, 2H), 2.50 (s, 3H), 2.45 (s, 3H), 2.34~2.11 (m, 2H), 2.07 (s, 3H), 2.04~1.89 (m, 2H), 1.40 (d, J = 6.3 Hz, 3H).LCMS m / e: 504.3 (MH+).

[0151] (R,Z)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (compound 4), (R,Z)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl- Synthesis of 1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethan-1-one (Compound 5) and (R,Z)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-fluoropiperidin-1-yl)ethan-1-one (Compound 6) [ka]

[0152] Step 1: Synthesis of (R,Z)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (compound 4) To a solution of (R,Z)-6-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-imine (1.5 g, 3.94 mmol) in 1,4-dioxane (50 mL) and HO (10 mL) was added KCO (1.63 g, 11.8 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethan-1-one (1.48 g, 5.91 mmol), and Pd(dppf)Cl (0.58 g, 0.788 mmol), the mixture was stirred at 100 °C for 5 h under a N atmosphere. The reaction mixture was cooled to room temperature, poured into water (20 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous NaSO, then filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, DCM to DCM:MeOH = 10:1) to give the title compound (1.3 g) as a yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 5.5 Hz, 1H), 8.30 (d, J = 7.5 Hz, 1H), 7.94 (t, J = 7.1 Hz, 1H), 7.50 (t, J = 6.9 Hz, 1H), 7.37~7.07 (m, 2H), 6.82 (s, 1H), 5.85 (q, J = 6.6 Hz, 1H), 4.29~4.19 (m, 2H), 3.74 (s, 3H), 3.72~3.65 (m, 2H), 2.74-2.60 (m, 2H), 2.53 (s, 3H), 2.08 (d, J = 15.1 Hz, 3H), 1.50 (d, J = 6.6 Hz, 3H).LC-MS m / e: 470.2 (MH + )

[0153] Step 2: Synthesis of (R,Z)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethan-1-one (compound 5) To a solution of (R,Z)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (300 mg, 0.639 mmol) and Mn(THMD) (193 mg, 0.319 mmol) in i-PrOH (18 mL) and DCM (2 mL) was added PhSiH (0.119 mL, 0.958 mmol) at 0 °C under an atmosphere of O and stirred at 0 °C for 5 h. The reaction mixture was poured into water (20 mL) and extracted with DCM (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by neutral Al2O3 column chromatography (gradient, 100% PE to PE:DCM:MeOH=25:4:1) to give the title compound (150 mg, 0.308 mmol, yield: 48.2%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.44 (s, 1H), 8.23 ​​(s, 1H), 7.91 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 6.9 Hz, 1H), 7.37~7.05 (m, 2H), 5.83 (q, J = 6.6 Hz, 1H), 4.32 (d, J = 11.7 Hz, 1H), 3.75~3.69 (m, 1H), 3.66 (s, 3H), 3.44 (t, J = 13.0 Hz, 1H), 2.93 (t, J = 12.6 Hz, 1H), 2.48 (s, 3H), 2.18~2.08 m, 1H), 2.04 (s, 3H), 2.02~1.93 (m, 1H), 1.63~1.50 (m, 2H), 1.44 (d, J = 6.7 Hz, 3H).LC-MS m / e: 488 (MH + ).

[0154] Step 3: Synthesis of (R,Z)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-fluoropiperidin-1-yl)ethan-1-one (compound 6) To a solution of (R,Z)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethan-1-one (150 mg, 0.308 mmol) in DCM (10 mL) was added DAST (0.203 mL, 1.54 mmol) dropwise at −30° C. and stirred at −30° C. for 1 hour. The reaction was quenched with saturated NaHCO3 solution (20 mL) and extracted with DCM (20 mL × 2). The combined organic layer was dried over Na2SO4, filtered, concentrated, and purified by reverse phase column (SilaSep TM Purification by C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% FA) afforded the title compound (11.1 mg, 0.023 mmol, yield: 7.37%) as a yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.17 (s, 1H), 7.92 (t, J = 6.9 Hz, 1H), 7.46 (d, J = 6.8 Hz, 1H), 7.37~7.05 (m, 2H), 5.79 (d, J = 6.7 Hz, 1H), 4.48~4.39 (m, 1H), 3.93~3.85 (m, 1H), 3.61 (s, 3H), 2.95~2.86 (m, 1H), 2.44 (s, 3H), 2.36~2.12 (m, 2H), 2.08 (s, 3H), 2.03~1.87 (m, 3H), 1.39 (d, J = 6.6 Hz, 3H).LC-MS m / e: 490 (MH + ).

[0155] Examples 3 and 7 to 14 Applying the same synthetic steps as above, compounds 3 and 7-14 of the present invention were prepared.

[0156] Compound 3: 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 5.2 Hz, 1H), 8.31 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 3.5 Hz, 1H), 5.62 (q, J = 6.7 Hz, 1H), 4.28~4.22 (m, 1H), 4.20~4.17 (m, 1H), 3.89 (s, 3H), 3.72~3.65 (m, 2H), 2.74~2.66 (m, 1H), 2.64~2.54 (m, 1H), 2.49 (s, 3H), 2.32~2.23 (m, 1H), 2.08 (d, J = 15.6 Hz, 3H), 1.47 (d, J = 6.6 Hz, 3H), 1.27~1.16 (m, 1H), 1.16~1.08 (m, 1H), 1.06~0.94 (m, 1H), 0.79~0.65 (m, 1H);LC-MS m / e: 510.4 (MH + ).

[0157] Formate of Compound 7: 1 HNMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.21~8.20 (m, 1H), 8.16~8.06 (m, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 6.75 (d, J = '8.4 Hz, 1H), 5.70 (q, J = 6.4 Hz, 1H), 4.20 (d, J = 22.2 Hz, 2H), 3.72~3.62 (m, 5H), 2.72~2.64 (m, 1H), 2.61 (s, 3H), 2.59~2.55 (m, 1H), 2.47 (s, 3H), 2.'07 (d, J = 15.8 Hz, 3H), 1.41 (d, J = 6.3 Hz, 3H);LCMS m / e: 441.6 (MH+).

[0158] Compound 8: 1 HNMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.24 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 5.70 (q, J = 6.4 Hz, 1H), 4.44 (d, J = 12.4 Hz, 1H), 3.88 (d, J = 14.0 Hz, 1H), 3.68 (s, 3H), 3.40 (t, J = 12.9 Hz, 1H), 2.90 (t, J = 12.9 Hz, 1H), 2.62 (s, 3H), 2.51 (s, 3H), 2.37~2.12 (m, 2H), 2.08 (s, 3H), 2.02~1.90 (m, 2H), 1.43 (d, J = 6.5 Hz, 3H); LCMS m / e: 461.2 (MH+).

[0159] Compound 9: 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 6.72 (d, J = 11.4 Hz, 1H), 5.81~5.70 (m, 1H), 4.89~4.73 (m, 1H), 4.20 (d, J = 22.9 Hz, 2H), 3.66 (dd, J = 11.6, 5.9 Hz, 2H), 3.26~3.20 (m, 3H), 2.63 (d, J LCMS m / e: 512 (MH+).

[0160] Compound 10 acid chloride: 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.19 (s, 1H), 8.05 (d, J = 6.3 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 6.78~6.69 (m, 1H), 5.79 (q, J = 6.5 Hz, 1H), 4.20 (d, J = 22.9 Hz, 2H), 3.71~3.64 (m, 3H), 3.25~3.21 (s, 3H), 2.71~2.56 (m, 2H), 2.53 (s, 3H), 2.07 (d, J = 15.9 Hz, 3H), 1.39 (d, J = 6.5 Hz, 3H), 1.30 (d, J = 6.5 Hz, 2H), 1.01~0.89 (m, 2H); LCMS m / e: 510 (MH+).

[0161] Compound 11: 1 HNMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.02 (dd, J = 7.6, 4.5 Hz, 2H), 7.60 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 12.4 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 4.19 (d, J = 22.3 Hz, 2H), 3.74~3.60 (m, 5H), 3.20~3.17 (m, 1H), 2.69~2.59 (m, 2H), 2.53 (s, 3H), 2.47 (s, 3H), 2.06 (d, J = 15.5 Hz, 3H); LCMS m / e: 494.6 (MH+).

[0162] Compound 12: 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.48 (d, J = 5.8 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 6.35 (s, 1H), 5.79 (q, J = 6.5 Hz, 1H), 4.16 (d, J = 17.5 Hz, 2H), 3.70~3.62 (m, 5H), 2.70~2.56 (m, 2H), 2.52 (s, 3H), 2.46 (s, 3H), 2.07 (d, J = 15.7 Hz, 3H), 1.39 (d, J = 6.6 Hz, 3H); LCMS m / e: 484 (MH+).

[0163] Compound 13, Torofluoride acid chloride: 1 H NMR (400 MHz, DMSO-d6) δ 10.76 (d, J = 17.5 Hz, 1H), 9.24 (s, 2H), 7.83 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 6.00~5.86 (m, 1H), 4.56 (d, J = 11.7 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 1H), 3.44 (t, J = 12.3 Hz, 1H), 2.91 (t, J = 13.8 Hz, 1H), 2.77 (s, 3H), 2.61 (s, 3H), 2.52 (s, 1H), 2.25 (ddd, J = 32.6, 23.4, 15.8 Hz, 3H), 2.10 (s, 3H), 1.67 (d, J = 6.9 Hz, 3H); LCMS m / e: 504 (MH+).

[0164] Compound 14: 1HNMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 3.9 Hz, 1H), 8.19 (s, 1H), 8.14~8.09 (m, 2H), 8.02 (d, J = 7.7 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 11.2 Hz, 1H), 5.80 (q, J = 6.5 Hz, 1H), 4.23 (d, J = 2.4 Hz, 1H), 4.17 (d, J = 2.5 Hz, 1H), 3.65 (s, 1H), 3.35~3.31 (m, 1H), 2.67 (s, 1H), 2.58 (s, 1H), 2.47 (s, 3H), 2.07 (d, J = 15.0 Hz, 3H), 1.39 (d, J = 6.6 Hz, 3H), 1.14 (d, J =5.9 Hz, 2H), 1.04 (d, J = 2.9 Hz, 2H);LCMS m / e: 496.2 (MH+).

[0165] Examples 15 to 17 Synthesis of (R,Z)-1-(4-fluoro-4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one hydrochloride (Compound 15) [ka]

[0166] Step 1. Synthesis of (R)-6-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine To a solution of (R)-N-methyl-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (594 mg, 2.34 mmol) in DMF (5 mL) was added DIEA (1.41 mL, 8.51 mmol) at 25 °C. The mixture was stirred at 25 °C for 10 min, and 6-bromo-4-chloropyrido[3,4-d]pyrimidine (520 mg, 2.13 mmol) was added at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was poured into ice water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (60 mL × 3), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (gradient, PE to PE: EtOAc = 2:1) to give the title compound (880 mg, 2.07 mmol, yield: 97.3%) as a pale yellow solid. LC-MS m / e: 427 (MH + ).

[0167] Step 2: Synthesis of (R)-1-(4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one A mixture of (R)-6-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine (140 mg, 0.34 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (103 mg, 0.409 mmol), Pd(dppf)Cl (25 mg, 0.034 mmol), and KCO (118 mg, 0.851 mmol) in dioxane (3 mL) and water (0.4 mL) was stirred at 100 °C under an atmosphere of N for 2.5 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, concentrated, and purified by neutral AlO gel (gradient, PE to PE:DCM:MeOH=40:4:1) to give the title compound (80 mg, 0.176 mmol, yield: 51.6%) as a yellow solid. LC-MS m / e: 455 (MH + ).

[0168] Step 3. Synthesis of (R)-1-(4-hydroxy-4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-amino)pyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one To a solution of (R)-1-(4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-pyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (0.9 g, 1.98 mmol) and Mn(TMHD) (0.36 g, 0.59 mmol) in isopropanol (50 mL) and DCM (10 mL) was added phenylsilane (0.32 g, 2.97 mmol) under an atmosphere of O at 0 °C and stirred at room temperature for 1 h. The mixture was diluted with DCM (100 mL). The organic layer was washed with HO (10 mL) and brine (50 mL), dried over anhydrous NaSO, filtered, concentrated, and purified by silica gel column chromatography (gradient, DCM to DCM:MeOH=15:1) to give the title compound (0.9 g, 1.9 mmol, yield: 96.2%) as a yellow solid. 1H NMR (400 MHz, DMSO- d6) δ 9.11 (d, J = 7.1 Hz, 1H), 9.01 (s, 1H), 8.64 (s, 1H), 8.50 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 5.84~5.71 (m, 1H), 5.52 (s, 1H), 4.34 (d, J = 11.9 Hz, 1H), 3.76 (d, J = 12.8 Hz, 1H), 3.48 (t, J = 12.7 Hz, 1H), 2.99 (t, J = 12.5 Hz, 1H), 2.55 (s, 3H), 2.24~2.12 (m, 1H), 2.06 (d, J = 10.2 Hz, 4H), 1.67 (t, J = 15.0 Hz, 2H), 1.58 (d, J = 6.8 Hz, 3H). LC-MS m / e: 474(MH + ).

[0169] Step 4. Synthesis of (R)-1-(4-fluoro-4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-amino)pyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one To a solution of (R)-1-(4-hydroxy-4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one (0.7 g, 1.48 mmol) in DCM (20 mL) was added DAST (0.36 g, 2.2 mmol) at -40 °C under an atmosphere of N and stirred for 30 min. The reaction mixture was stirred at 0 °C under an atmosphere of N for 2 h and diluted with DCM (100 mL). The reaction was quenched with saturated NaHCO3 solution (20 mL), washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel flash column chromatography (gradient, DCM to DCM:MeOH=30:1) to give the title compound (0.7 g, 1.47 mmol, yield: 99.6%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 6.8 Hz, 1H), 9.05 (s, 1H), 8.61 (s, 1H), 8.54 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 5.76 (d, J = 6.3 Hz, 1H), 4.46 (d, J = 11.9 Hz, 1H), 3.90 (d, J = 13.5 Hz, 1H), 3.45 (d, J = 13.0 Hz, 1H), 2.94 (t, J = 12.7 Hz, 1H), 2.55 (s, 3H), 2.42~2.17 (m, 2H), 2.09 (s, 3H), 2.02 (d, J = 12.1 Hz, 2H), 1.58 (d, J = 6.7 Hz, 3H). LC-MS m / e: 476(MH + ).

[0170] Step 5. Synthesis of (R,Z)-1-(4-fluoro-4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one hydrochloride (Compound 15) To a solution of (R)-1-(4-fluoro-4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one (1 g, 2.1 mmol) in DMF (15 mL) was added Cs2CO3 (2.05 g, 6.3 mmol), and the mixture was stirred at room temperature under a N2 atmosphere for 20 minutes. Iodomethane (0.36 g, 2.52 mmol) was added at 0°C, and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc (100 mL), washed with saturated NH4Cl solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel flash column chromatography (gradient, DCM to DCM:MeOH = 10:1) to give the crude compound, which was dissolved in EtOAc (10 mL) and HCl solution (1 mL, 2 M in EtOAc) at 0 °C. The resulting suspension was filtered. The cake was dried in vacuo to give the title compound (0.58 g, 1.1 mmol, yield: 52.3%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (d, J = 6.4 Hz, 1H), 9.44 (s, 1H), 9.04 (s, 1H), 8.94 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 6.01~5.84 (m, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.07 (s, 3H), 3.93 (d, J = 14.0 Hz, 1H), 3.46 (d, J = 13.2 Hz, 1H), 2.95 (t, J = 12.8 Hz, 1H), 2.55 (s, 3H), 2.39~2.14 (m, 2H), 2.09 (s, 3H), 2.04 (s, 2H), 1.69 (d, J = 6.8 Hz, 3H). LC-MS m / e: 490 (MH + ).

[0171] The above mentioned compounds are applicable to the above-mentioned compounds and the following compounds (compounds 16 and 17) are produced.

[0172] Compound 16: 1 HNMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.16~7.97 (m, 3H), 7.54 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 6.75 (d, J = 9.9 Hz, 1H), 5.80~5.71 (m, 1H), 4.21 (d, J = 22.3 Hz, 2H), 3.72~3.65 (m, 2H), 3.65 (s, 3H), 2.73~2.53 (m, 2H), 2.47 (s, 3H), 2.07 (d, J = 15.7 Hz, 3H), 1.40 (d, J = 6.5 Hz, 3H); LC-MS m / e: 470.4 (MH) + ).

[0173] Compound 17: 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.98 (d, J = 7.8 Hz, 2H), 7.69 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.8 Hz, 2H), 5.81~5.68 (m, 1H), 4.48 (d, J = 11.5 Hz, 1H), 3.87 (d, J = 10.6 Hz, 1H), 3.54 (s, 3H), 3.42~3.36 (m, 1H), 2.91~2.81 (m, 1H), 2.47 (s, 3H), 2.08 (s, 3H), 2.07~1.84 (m, 4H), 1.37 (d, J = 6.4 Hz, 3H); LC-MS m / e: 489.3 (MH + ).

[0174] Examples 18 and 19 Synthesis of (R,Z)-6-(1-(difluoromethyl)cyclopropyl)-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine (Compound 18) [ka]

[0175] Step 1. Synthesis of 1-(4-carbamoyl-5-(methylamino)pyridin-2-yl)cyclopropane-1-carboxylate To a solution of 2-bromo-5-(methylamino)isonicotinamide (5 g, 21.7 mmol), Pd(dba) (1.99 g, 2.17 mmol), and Q-Phos (3.07 g, 4.34 mmol) in THF (50 mL) was added (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (145 mL, 109 mmol, 0.75 M in THF). The mixture was stirred at 25 °C for 2 h, then diluted with water (150 mL) and extracted with EtOAc (200 mL × 2). The combined organic layer was washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, PE to PE: EtOAc = 3:1) to give the title compound (4 g, 16.1 mmol, yield: 74%) as a red solid. LC-MS m / e: 250.3 (MH + ).

[0176] Step 2: Synthesis of 2-(1-(hydroxymethyl)cyclopropyl)-5-(methylamino)isonicotinamide To a solution of 1-(4-carbamoyl-5-(methylamino)pyridin-2-yl)cyclopropane-1-carboxylate methyl (4 g, 16.1 mmol) in DCM (50 mL) was added DIBAL-H (53.7 mL, 80.6 mmol, 1.5 M in hexane) at −50° C. and stirred at −30° C. for 0.5 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, DCM to DCM:MeOH = 10:1) to give the title compound (2.2 g, 9.95 mmol, yield: 61.8%) as a yellow solid. LC-MS m / e: 222.2 (MH + ).

[0177] Step 3: Synthesis of (1-(1,2-dimethyl-4-oxo-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)cyclopropyl)methyl acetate To a solution of 2-(1-(hydroxymethyl)cyclopropyl)-5-(methylamino)isonicotinamide (2.2 g, 9.95 mmol) in CHCl (50 mL) was added acetyl chloride (3.5 mL, 49.7 mmol) and stirred at 80 °C for 15 h. The reaction mixture was cooled to room temperature, concentrated, basified with saturated NaHCO solution (100 mL), and extracted with DCM (200 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by neutral AlO column chromatography (gradient, PE to PE:DCM:MeOH = 20:3:1) to give the title compound (1.7 g, 5.92 mmol, yield: 59.5%) as a yellow solid. LC-MS m / e: 288.1 (MH + ).

[0178] Step 4: Synthesis of 6-(1-(hydroxymethyl)cyclopropyl)-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-one To a solution of (1-(1,2-dimethyl-4-oxo-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)cyclopropyl)methyl acetate (1.7 g, 5.92 mmol) in MeOH (15 mL) was added K2CO3 (2.12 g, 15.3 mmol) and stirred at 25 °C for 1.5 h. The reaction mixture was adjusted to approximately pH 7 with AcOH, concentrated, and purified by neutral Al2O3 column chromatography (gradient, PE to PE:DCM:MeOH = 16:3:1) to give the title compound (1.3 g, 5.31 mmol, yield: 89.6%) as a yellow solid. LC-MS m / e: 246.1 (MH + ).

[0179] Step 5 Synthesis of 1-(1,2-dimethyl-4-oxo-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)cyclopropane-1-carbaldehyde To a solution of 6-(1-(hydroxymethyl)cyclopropyl)-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-one (1.3 g, 5.31 mmol) in DCM (40 mL) was added Dess-Martin periodinane (4.5 g, 10.62 mmol) at 0 °C and stirred for 2 h at 0 °C. The mixture was purified by neutral Al2O3 column chromatography (gradient, PE to PE:DCM:MeOH = 16:4:1) to give the title compound (600 mg, 2.5 mmol, yield: 46.5%) as a yellow solid. LC-MS m / e: 244.2 (MH + ).

[0180] Step 6: Synthesis of 6-(1-(difluoromethyl)cyclopropyl)-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-one DAST (1.7 mL, 12.3 mmol) was added to a solution of 1-(1,2-dimethyl-4-oxo-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-cyclopropane-1-carbaldehyde (600 mg, 2.5 mmol) in DCM (20 mL) at 0 °C and stirred for 2 h. The mixture was quenched with saturated NaHCO solution (40 mL) and extracted with DCM (50 mL × 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by neutral AlO column chromatography (gradient, PE to PE:DCM:MeOH = 16:4:1) to give the title compound (150 mg, 0.565 mmol, yield: 22.9%) as a yellow solid. LC-MS m / e: 266 (MH + ).

[0181] Step 7 Synthesis of 6-(1-(difluoromethyl)cyclopropyl)-1,2-dimethylpyrido[3,4-d]pyrimidine-4(1H)-thione A mixture of 6-(1-(difluoromethyl)cyclopropyl)-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-one (150 mg, 0.565 mmol) and Lawesson's reagent (228 mg, 0.57 mmol) in dichloroethane (5 mL) was stirred at 85 °C for 3 h. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in 1 N HCl solution (50 mL) and washed with EtOAc (50 mL). The aqueous layer was then adjusted to approximately pH 7 with NaHCO and extracted with DCM (50 mL × 2). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated to give the title compound (100 mg, 0.356 mmol, yield: 62.7%) as a brown solid. The crude product was used directly in the next step without further purification. LC-MS m / e: 282.1 (MH + ).

[0182] Step 8: Synthesis of (R,Z)-6-(1-(difluoromethyl)cyclopropyl)-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine (compound 18) To a solution of 6-(1-(difluoromethyl)cyclopropyl)-1,2-dimethylpyrido[3,4-d]pyrimidine-4(1H)-thione (50 mg, 0.178 mmol) in MeI (2 mL) was added (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (181 mg, 0.892 mmol). The mixture was stirred at room temperature for 10 minutes. The mixture was then concentrated and purified by preparative HPLC to give the title compound (30 mg, 0.067 mmol, 37.6%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.27 (s, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 6.44 (t, J = 55.7 Hz, 1H), 5.81 (q, J = 6.8 Hz, 1H), 3.75 (s, 3H), 2.58~2.52 (m, 6H), 1.50 (s, 3H), 1.34~1.28 (m, 4H). LCMS m / e: 451.2 (MH+).

[0183] Compound 19 was prepared following similar steps as above. 1HNMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.19 (s, 1H), , 7.91 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 6.40 (t, J = 56.1 Hz, 1H), 5.71 (q, J = 6.8 Hz, 1H), 3.69 (s, 3H), 2.62 (s, 3H), 2.50 (s, 3H), 1.44 (d, J = 6.7 Hz, 3H), 1.33~1.33 (m, 4H). LCMS m / e: 408.3 (MH+).

[0184] Example 20 Synthesis of (R,Z)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1-(difluoromethyl)-cyclopropyl)-1-methylpyrido[3,4-d]pyrimidin-4(1H)-imine (Compound 20) [ka]

[0185] Step 1. Synthesis of (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine To a solution of 6-bromo-4-chloropyrido[3,4-d]pyrimidine (1.5 g, 6.14 mmol) in DMF (10 mL) were added DIEA (3.17 g, 24.542 mmol) and (R)-1-(3-(difluoromethyl)-2-fluoro-phenyl)ethan-1-amine (1.28 g, 6.75 mmol). The reaction mixture was stirred at 25 °C for 2 h, then poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL × 3), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (gradient, PE to PE: EtOAc = 1:1) to give the title compound (2.2 g, 5.54 mmol, yield: 90.3%) as a white solid. LC-MS m / e: 397.2, 399.2 (MH + ).

[0186] Step 2: Synthesis of methyl (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-amino)pyrido[3,4-d]pyrimidin-6-yl)cyclopropane-1-carboxylate To a solution of 6-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]pyrido-[3,4-d]pyrimidin-4-amine (1 g, 2.52 mmol) in THF (10 mL) was added Pd(dba) (230 mg, 0.252 mmol), Q-Phos (360 mg, 0.504 mmol), and (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (31.5 mL, 0.75 M in THF). The mixture was stirred at 25 °C for 2 h, poured into saturated NHCl solution (50 mL), and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (gradient, PE to PE: EtOAc = 1:1) to give the title compound (632 mg, 1.52 mmol, yield: 60.3%) as a yellow solid. LC-MS m / e: 417.3 (MH + ).

[0187] Step 3: Synthesis of (R)-(1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclopropyl)methanol To a solution of (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-pyrido[3,4-d]pyrimidin-6-yl)cyclopropane-1-carboxylate (632 mg, 1.52 mmol) in DCM (10 mL) was added DIBAL-H (3 mL, 4.5 mmol, 1.5 M in hexane) at −20° C. and stirred at −20° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (gradient, DCM to DCM:MeOH = 30:1) to give the title compound (300 mg, 0.772 mmol, yield: 50.8%) as a yellow solid. LC-MS m / e: 389.1 (MH + )

[0188] Step 4 Synthesis of (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclopropane-1-carbaldehyde To a solution of (R)-(1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclopropyl)methanol (300 mg, 0.772 mmol) in DCM (10 mL) was added Dess-Martin periodinane (682 mg, 1.54 mmol) at 0 °C. After stirring at 0 °C for 2 h, the reaction mixture was poured into saturated NaHCO3 solution (50 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (gradient, DCM to DCM:MeOH = 30:1) to give the title compound (150 mg, 0.388 mmol, yield: 50.3%) as a yellow solid. LC-MS m / e: 387.1 (MH + ).

[0189] Step 5. Synthesis of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1-(difluoromethyl)cyclopropyl)pyrido[3,4-d]pyrimidin-4-amine To a solution of (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclopropane-1-carbaldehyde in DCM (20 mL) was added DAST (125 mg, 0.777 mmol) at −40° C. under an atmosphere of N. The reaction mixture was stirred at −40° C. for 30 min and then at 0° C. under an atmosphere of N for 2 h. The resulting mixture was diluted with DCM (100 mL) and washed with saturated NaHCO solution (20 mL) and brine (20 mL). The organic layer was dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and purified by silica gel flash column chromatography (gradient, DCM to DCM:MeOH=30:1) to give the title compound (125 mg, 0.306 mmol, yield: 78.5%) as a yellow solid. LC-MS m / e: 409 (MH + ).

[0190] Step 6. Synthesis of (R,Z)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1-(difluoromethyl)cyclopropyl)-1-methylpyrido[3,4-d]pyrimidin-4(1H)-imine (Compound 20) To a solution of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1-(difluoromethyl)cyclopropyl)pyrido[3,4-d]pyrimidin-4-amine (150 mg, 0.37 mmol) in DMF (10 mL) was added Cs2CO3 (362 mg, 1.1 mmol). The mixture was stirred at room temperature under an atmosphere of N2 for 20 min. MeI (62.5 mg, 0.44 mmol) was added at 0 °C and stirred at room temperature for 3 h. The mixture was diluted with EtOAc (50 mL), washed with saturated NH4Cl solution (25 mL) and brine (25 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (SilaSep TMPurification by C18 silica flash cartridge (20% to 95% MeCN in H2O, 0.1% TFA) gave the trifluoroacetate salt of the title compound (58.8 mg) as a yellow solid. 1 H NMR (400 MHz, CD3OD) δ 9.35 (s, 1H), 8.81 (s, 1H), 8.57 (s, 1H), 7.71 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.0 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 6.99 (t, J = 54.7 Hz, 1H), 6.48 (t, J = 56.7 Hz, 1H), 6.07 (q, J = 6.9 Hz, 1H), 4.14 (s, 3H), 1.81 (d, J = 7.0 Hz, 3H), 1.45 (s, 4H). LC-MS m / e: 423.6 (MH + ).

[0191] Example 21 Synthesis of (R,Z)-6-(1-(difluoromethyl)cyclopropyl)-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)imino)-4,6-dihydropyrido[4,3-d]pyrimidin-7(1H)-one (Compound 21) [ka]

[0192] Step 1. Synthesis of 4,6-dichloro-5-(1,3-dioxolan-2-yl)pyrimidine To a solution of 4,6-dichloropyrimidine-5-carbaldehyde (2 g, 11.3 mmol) in toluene (50 mL) was added ethylene glycol (701 mg, 11.3 mmol) and TsOH (389 mg, 2.26 mmol). The mixture was stirred at 120 °C for 2 h, cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (gradient, PE:EtOAc = 10:1 to PE:EtOAc = 5:1) to give the title compound (1.8 g, 8.14 mmol, yield: 72.1%) as a white solid. LCMS m / e:223.4 (MH + ).

[0193] Step 2: Synthesis of dimethyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)pyrimidin-4-yl)malonate To a solution of 4,6-dichloro-5-(1,3-dioxolan-2-yl)pyrimidine (1.8 g, 8.14 mmol) in DMSO (25 mL) was added dimethyl malonate (2.15 g, 16.3 mmol) and CsCO (5.3 g, 16.3 mmol). The reaction mixture was stirred at 80 °C for 2 h, cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (gradient, PE:EtOAc = 5:1 to 3:1) to give the title compound (2 g, 6.31 mmol, yield: 77.6%) as a white solid. LCMS m / e:317.7 (MH + ).

[0194] Step 3 Synthesis of dimethyl (R)-2-(5-(1,3-dioxolan-2-yl)-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)malonate To a solution of dimethyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)pyrimidin-4-yl)malonate (793 mg, 2.51 mmol) in DMSO (15 mL) was added (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-amine (500 mg, 2.09 mmol) and DIEA (809 mg, 6.28 mmol). The mixture was stirred at 100 °C for 2 h, cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (gradient, PE:EtOAc = 5:1 to PE:EtOAc = 2:1) to give the title compound (400 mg, 0.81 mmol, yield: 38.8%) as a white solid. LCMS m / e: 494.4 (MH + ).

[0195] Step 4: Synthesis of methyl (R)-2-(5-(1,3-dioxolan-2-yl)-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)acetate To a solution of dimethyl (R)-2-(5-(1,3-dioxolan-2-yl)-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)malonate (1 g, 2.03 mmol) in DMSO (25 mL) was added LiCl (429 mg, 10.13 mmol). The mixture was stirred at 120 °C for 2 h, cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (gradient, PE:EtOAc = 5:1 to PE:EtOAc = 2:1) to give the title compound (450 mg, 1.03 mmol, yield: 50.9%) as a white solid. LCMS m / e: 436.4 (MH + ).

[0196] Step 5. Synthesis of (R)-2-(5-(1,3-dioxolan-2-yl)-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)acetic acid To a solution of methyl (R)-2-(5-(1,3-dioxolan-2-yl)-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrimidin-4-yl)acetate (450 mg, 1.03 mmol) in t-BuOH (10 mL), a 5 M LiOH solution (0.41 mL) was added and stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (400 mg, 0.95 mmol, yield: 92.2%) as a white solid. LCMS m / e: 422.4 (MH + ).

[0197] Step 6: Synthesis of (R)-2-(5-(1,3-dioxolan-2-yl)-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)-prop-2-yn-1-yl)amino)pyrimidin-4-yl)-N-(1-(difluoromethyl)cyclopropyl)acetamide To a solution of (R)-2-(5-(1,3-dioxolan-2-yl)-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)-prop-2-yn-1-yl)amino)pyrimidin-4-yl)acetic acid (400 mg, 0.95 mmol) in DMF (20 mL) was added 1-(difluoromethyl)cyclopropan-1-amine (204 mg, 1.9 mmol), HATU (722 mg, 1.9 mmol), and DIEA (368 mg, 2.85 mmol). After stirring at room temperature for 0.5 h, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (gradient, PE: EtOAc = 3: 1 to PE: EtOAc = 1: 1) to give the title compound (250 mg, 0.49 mmol, yield: 51.6%) as a white solid. LCMS m / e: 511.5 (MH + ).

[0198] Step 7 Synthesis of (R)-6-(1-(difluoromethyl)cyclopropyl)-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one To a solution of (R)-2-(5-(1,3-dioxolan-2-yl)-6-((1-(2-methyl-3-(trifluoromethyl)phenyl)-prop-2-yn-1-yl)amino)pyrimidin-4-yl)-N-(1-(difluoromethyl)cyclopropyl)acetamide (250 mg, 0.49 mmol) in i-PrOH (25 mL) was added HCl solution (5 M, 2 mL). The reaction mixture was stirred at 100° C. for 2 hours, then cooled to room temperature, basified with saturated NaHCO solution (60 mL), and extracted with EtOAc (60 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated and purified by preparative HPLC to give the title compound (73 mg, 0.16 mmol, yield: 33.2%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 9.22 (s, 1H), 8.26 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 6.45 (s, 1H), 6.23 (t, J = 57.5 Hz, 1H), 3.08 (d, J = 2.4 Hz, 1H), 2.50 (s, 3H), 1.64~1.50 (m, 2H), 1.47~1.35 (m, 2H). LCMS m / e: 449.2 (MH + ).

[0199] Step 8. Synthesis of (R,Z)-6-(1-(difluoromethyl)cyclopropyl)-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)imino)-4,6-dihydropyrido[4,3-d]pyrimidin-7(1H)-one (compound 21) To a solution of (R)-6-(1-(difluoromethyl)cyclopropyl)-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (35 mg, 0.078 mmol) in DMF (5 mL) was added CsCO (51 mg, 0.16 mmol) and CHI (11 mg, 0.078 mmol). The mixture was stirred at 60 °C for 2 h, diluted with water (60 mL), and then extracted with EtOAc (60 mL × 3). The combined organic layer was washed with brine (60 mL), dried over anhydrous NaSO, and then filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to give the title compound (31 mg, 0.067 mmol, yield: 85.9%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.88 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 6.18 (t, J = 56.3 Hz, 1H), 6.01 (s, 1H), 3.35 (s, 3H), 3.22 (d, J = 2.4 Hz, 1H), 2.48 (s, 3H), 1.49~1.37 (m, 2H), 1.37~1.20 (m, 2H). LCMS m / e: 463.2 (MH + ).

[0200] Examples 22 and 23 Synthesis of (R,Z)-1-(4-hydroxy-4-(8-methoxy-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one (Compound 22) and (R,Z)-1-(4-fluoro-4-(8-methoxy-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one (Compound 23) [ka]

[0201] Step 1. Synthesis of 3-amino-6-bromo-2-methoxyisonicotinic acid To a solution of 3-amino-2-methoxyisonicotinic acid (5 g, 27.3 mmol) in DMF (30 mL) was added NBS (5.11 g, 28.7 mmol) in small portions. The mixture was stirred at 20 °C for 1 h, diluted with water (40 mL), and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel flash column chromatography (gradient, PE to PE: EtOAc = 3:1) to give the title compound (4.2 g, 17 mmol, yield: 62.1%) as a brown solid. LC-MS m / e: 247, 249 (MH + ).

[0202] Step 2 Synthesis of 3-amino-6-bromo-2-methoxyisonicotinamide To a solution of 3-amino-6-bromo-2-methoxyisonicotinic acid (4.2 g, 17 mmol) in DMF (20 mL), DIPEA (4.39 g, 34 mmol), NHCl (1.36 g, 25.5 mmol), and HATU (7.75 g, 20.4 mmol) were added and stirred at 20 °C for 1 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel flash column chromatography (gradient, PE to PE: EtOAc = 1:1) to give the title compound (4 g, 16.2 mmol, yield: 95.6%) as a yellow solid. LC-MS m / e: 246, 248 (MH + ).

[0203] Step 3 Synthesis of 6-bromo-8-methoxypyrido[3,4-d]pyrimidin-4-ol To a solution of 3-amino-6-bromo-2-methoxyisonicotinamide (4 g, 16.2 mmol) in EtOH (80 mL), AcOH (13.9 mL, 243 mmol) and CH(OEt) (36 g, 243 mmol) were added and stirred at 120° C. for 3 h. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was triturated with EtOAc (50 mL) to give the title compound (3.4 g, 13.2 mmol, 81.6% yield) as a yellow solid. LC-MS m / e: 256, 258 (MH + ).

[0204] Step 4: Synthesis of (R)-6-bromo-8-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine To a solution of 6-bromo-8-methoxypyrido[3,4-d]pyrimidin-4-ol (3.4 g, 13.2 mmol) in MeCN (30 mL) was added DIPEA (6.85 g, 53.1 mmol) and HCCP (5.08 g, 14.6 mmol). The mixture was stirred at 25 °C for 1 h, and then (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-amine hydrochloride (3.46 g, 14.6 mmol) was added. After stirring at 25 °C for 1 h, the mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL × 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash column chromatography (gradient, DCM to DCM:MeOH=30:1) to give the title compound (4.5 g, 10.1 mmol, yield: 76.8%) as a yellow solid. LC-MS m / e: 441, 443 (MH + ).

[0205] Step 5. Synthesis of (R)-1-(4-hydroxy-4-(8-methoxy-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one To a solution of (R)-6-bromo-8-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine (600 mg, 1.36 mmol) in THF (20 mL) was added n-BuLi (3.39 mL, 5.43 mmol, 1.6 M in hexane) dropwise at −65° C. under an atmosphere of N2 and stirred for 0.5 h. Subsequently, 1-acetylpiperidin-4-one (0.168 mL, 1.36 mmol) was added and stirred at −65° C. for an additional 0.5 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (30 mL × 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient, DCM to DCM:MeOH=20:1) to give the title compound (100 mg, 0.2 mmol, yield: 14.6%) as a yellow solid. LC-MS m / e: 504 (MH + ).

[0206] Step 6. Synthesis of (R)-6-(1-acetyl-4-hydroxypiperidin-4-yl)-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-8(7H)-one A mixture of (R)-1-(4-hydroxy-4-(8-methoxy-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one (100 mg, 0.199 mmol) and 6 N HCl (10 mL, 60 mmol) was stirred at 60 °C for 18 h. The reaction mixture was cooled to 0 °C, adjusted to pH 8 with aqueous NaOH (10%), and extracted with EtOAc (20 mL × 2). The combined organic layer was washed with brine and dried over anhydrous NaSO, then filtered and concentrated to dryness. The residue was dissolved in DCM (1 mL), and EtN (60 mg, 0.596 mmol) and AC0 (0.047 mL, 0.497 mmol) were added. The resulting mixture was stirred at 20°C for 2 hours, diluted with water (10 mL), and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (SilaSep TM Purification by C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% formic acid) afforded the title compound (30 mg, 0.061 mmol, 20.5% yield) as an off-white solid. 1 H NMR (400 MHz, CD3OD) δ 8.42 (d, J = 1.3 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.02 (s, 1H), 5.77 (m, 1H), 4.59~4.49 (m, 1H), 3.89 (m, 1H), 3.60 (m, 1H), 3.10 (m, 1H), 2.57 (s, 3H), 2.15 (d, J = 2.1 Hz, 3H), 2.10~1.99 (m, 2H), 1.92 (m, 2H), 1.61 (d, J = 7.0 Hz, 3H). LC-MS m / e: 490 (MH + ).

[0207] Step 7 Synthesis of (R,Z)-1-(4-hydroxy-4-(8-methoxy-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one (compound 22) To a solution of (R)-6-(1-acetyl-4-hydroxypiperidin-4-yl)-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-8(7H)-one (20 mg, 0.041 mmol) in DMF (0.5 mL) was added CsCO (33 mg, 0.102 mmol). The mixture was stirred at 20 °C for 0.5 h. Then, iodomethane (15 mg, 0.102 mmol) in DMF (0.1 mL) was added dropwise. The resulting mixture was stirred at 20 °C for 2 h, then diluted with water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layer was washed with brine (10 mL × 3), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC (SilaSep TM Purification by C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% formic acid) gave the title compound (10.5 mg, 0.02 mmol, 49.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 5.73 (q, J = 6.5 Hz, 1H), 4.36~4.27 (m, 1H), 3.94 (s, 3H), 3.77 (s, 3H), 3.75~3.68 (m, 1H), 3.46~3.36 (m, 1H), 2.97~2.86 (m, 1H), 2.46 (s, 3H), 2.15 - 2.06 (m, 1H), 2.03 (s, 3H), 2.01 - 1.93 (m, 1H), 1.61~1.48 (m, 2H), 1.38 (d, J = 6.6 Hz, 3H). LC-MS m / e: 518 (MH + ).

[0208] Step 8. Synthesis of (R,Z)-1-(4-fluoro-4-(8-methoxy-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one (compound 23) To a solution of (R,Z)-1-(4-hydroxy-4-(8-methoxy-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one (40 mg, 0.077 mmol) in DCM (1 mL) was added DAST (31 mg, 0.193 mmol) dropwise. The mixture was stirred at 5°C for 0.5 h, diluted with DCM (30 mL), and quenched with saturated NaHCO3 solution (20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (SilaSep TMPurification by C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% NH4HCO3) afforded the title compound (4.7 mg, 0.009 mmol, 11.7% yield) as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ 7.95 (m, 2H), 7.83 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 5.70 (q, J = 6.5 Hz, 1H), 4.46~4.38 (m, 1H), 3.95 (s, 3H), 3.91~3.83 (m, 1H),3.76 (s, 3H), 3.43~3.40 (m,1H), 2.94~2.84 (m, 1H), 2.46 (s, 3H), 2.34~2.09 (m, 2H), 2.07 (s, 3H), 2.03~1.83 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H). LC-MS m / e: 520 (MH + ).

[0209] Example 24 Synthesis of (R,Z)-1-(4-hydroxy-4-(8-methoxy-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-2,2,6,6-tetramethylpiperidin-1-yl)ethan-1-one (Compound 24) [ka]

[0210] Step 1. Synthesis of (R)-1-(4-hydroxy-4-(8-methoxy-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-2,2,6,6-tetramethylpiperidin-1-yl)ethan-1-one To a solution of (R)-6-bromo-8-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)pyrido[3,4-d]pyrimidin-4-amine (500 mg, 1.13 mmol) in THF (20 mL) was added n-BuLi (2.26 mL, 5.66 mmol, 2.5 M in hexane) dropwise at −70° C. and stirred at −70° C. for 0.5 h, followed by the addition of 1-acetyl-2,2,6,6-tetramethylpiperidin-4-one (447 mg, 2.26 mmol). The resulting mixture was stirred at −70° C. for 0.5 h, then quenched with water (10 mL) and extracted with EtOAc (30 mL×2). The combined organic layer was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (gradient, PE to PE: EtOAc = 1:1) and preparative HPLC (SilaSep TM Purification by C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% FA) gave the title compound as a yellow solid (8 mg, 0.014 mmol, yield: 1.26%). 1 H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 5.76 (p, J = 6.8 Hz, 1H), 5.30 (s, 1H), 4.01 (s, 3H), 2.89~2.72 (m, 2H), 2.54 (s, 3H), 2.26~2.20 (m, 2H), 2.11 (s, 3H), 1.68~1.59 (m, 9H), 1.42 (s, 6H). LC-MS m / e: 560 (MH + ).

[0211] Step 2. Synthesis of (R,Z)-1-(4-hydroxy-4-(8-methoxy-1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-2,2,6,6-tetramethylpiperidin-1-yl)ethan-1-one (compound 24) To a solution of (R)-1-(4-hydroxy-4-(8-methoxy-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)-2,2,6,6-tetramethylpiperidin-1-yl)ethan-1-one (25 mg, 0.045 mmol) in DCM (0.6 mL) was added proton sponge (9.6 mg, 0.045 mmol) and trimethyloxonium tetrafluoroborate (6.6 mg, 0.045 mmol). The mixture was stirred at 20 °C for 0.5 h, diluted with water (3 mL), and extracted with DCM (10 mL × 2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (SilaSep TM Purification by C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% FA) gave the formate salt of the title compound (7 mg) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.16 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 5.80 (q, J = 6.6 Hz, 1H), 5.48 (s, 1H), 4.02 (s, 3H), 3.93 (s, 3H), 2.69 (dd, J = 24.9, 15.0 Hz, 2H), 2.51 (s, 3H), 2.17~2.07 (m, 5H), 1.57 (d, J = 1.4 Hz, 6H), 1.51 (d, J = 6.5 Hz, 3H), 1.41 (d, J = 2.6 Hz, 6H). LC-MS m / e: 574 (MH + ).

[0212] Examples 25 to 30 (R,Z)-1-(4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-5,7,8,9-tetrahydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-3-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (Compound 25), (R,Z)-1-(4-hydroxy-4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-5,7,8 Synthesis of (R,Z)-1-(4-fluoro-4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-5,7,8,9-tetrahydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-3-yl)piperidin-1-yl)ethan-1-one (Compound 26) and (R,Z)-1-(4-fluoro-4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-5,7,8,9-tetrahydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-3-yl)piperidin-1-yl)ethan-1-one (Compound 27) [ka]

[0213] Step 1. Synthesis of methyl 5-amino-2-bromoisonicotinate To a solution of methyl 3-aminoisonicotinate (20 g, 132 mmol) in DMF (300 mL) was added NBS (24.6 g, 138 mmol), and the mixture was stirred at 20 °C for 3 hours. The mixture was quenched with water (500 mL) and filtered. The cake was washed with EtOAc (300 mL) and dried under reduced pressure to give the title compound (22 g, 95.2 mmol, 72.4% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.60 (s, 1H), 6.80 (s, 2H), 3.84 (s, 3H).

[0214] Step 2 Synthesis of 5-amino-2-bromoisonicotinamide A mixture of methyl 5-amino-2-bromoisonicotinate (22 g, 95.2 mmol) and NH3 solution (204 mL, 1.43 mol, 7 M in MeOH) was stirred for 18 h at 20 °C. The mixture was concentrated to dryness, and the residue was washed with DCM (100 mL) to give the title compound (14 g, 64.8 mmol, yield: 68.1%) as a yellow solid. LC-MS m / e: 216, 218 (MH + ).

[0215] Step 3 Synthesis of 2-bromo-5-(4-chlorobutanamido)isonicotinamide To a solution of 5-amino-2-bromoisonicotinamide (4.8 g, 22.2 mmol) and EtN (6.18 mL, 44.4 mmol) in THF (100 mL) was added 4-chlorobutanoyl chloride (3.76 mL, 33.3 mmol) at 0 °C and stirred at room temperature overnight. The resulting solution was poured into water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient: DCM to DCM:MeOH = 50:1) to give the title compound (5.5 g, 17.2 mmol, yield: 77.2%) as a yellow solid. LC-MS m / e: 320.6, 322.6 (MH + ).

[0216] Step 4 Synthesis of 3-bromo-8,9-dihydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-5(7H)-one To a solution of 2-bromo-5-(4-chlorobutanamido)isonicotinamide (4.5 g, 14 mmol) in THF (70 mL), potassium tert-butoxide (3.15 g, 28.1 mmol) was slowly added, and the resulting mixture was stirred at room temperature overnight. The resulting reaction mixture was poured into ice water (250 mL) and extracted with EtOAc (250 mL × 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient: DCM to DCM:MeOH = 33:1) to afford the title compound (1.5 g, 5.64 mmol, yield: 40.2%) as an orange solid. LC-MS m / e: 266, 268 (MH + ).

[0217] Step 5 Synthesis of 3-bromo-8,9-dihydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidine-5(7H)-thione To a solution of 3-bromo-8,9-dihydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-5(7H)-one (1.5 g, 5.64 mmol) in toluene (20 mL) was added Lawesson's reagent (2.28 g, 5.64 mmol) and stirred at 110 °C under a N atmosphere for 2 h. The resulting solution was cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (100 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by neutral AlO column chromatography (gradient: PE to PE:DCM = 3:1) to give the title compound (300 mg, 0.513 mmol, yield: 71%) as a red solid. LC-MS m / e: 282, 284 (MH + ).

[0218] Step 6 Synthesis of 3-bromo-5-(methylthio)-8,9-dihydro-7H-pyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-10-um-1-ide A solution of 3-bromo-8,9-dihydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidine-5(7H)-thione (170 mg, 0.602 mmol) in CHCl (10 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (170 mg, 0.57 mmol, 94.6% yield) as a red solid. LC-MS m / e: 296, 298 (MH + ).

[0219] Step 7: Synthesis of (R,Z)-3-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-8,9-dihydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-5(7H)-imine To a solution of 3-bromo-5-(methylthio)-8,9-dihydro-7H-pyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-10-um-1-ide (150 mg, 0.503 mmol) in DMA (5 mL), (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (123 mg, 0.604 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient: DCM to DCM:MeOH = 50:1) to afford the title compound (170 mg, 0.377 mmol, 74.9% yield) as a yellow solid. LC-MS m / e: 451.3, 453.3 (MH + ).

[0220] Step 8. Synthesis of (R,Z)-1-(4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-5,7,8,9-tetrahydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-3-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (compound 25) To a solution of (R,Z)-3-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-8,9-dihydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-5(7H)-imine (90 mg, 0.199 mmol) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethan-1-one (100 mg, 0.398 mmol) in dioxane (4 mL) and HO (2 mL) was added CsCO (195 mg, 0.597 mmol) and Pd(dppf)Cl (146 mg, 0.199 mmol), and the mixture was stirred at 100 °C under a N atmosphere for 2 h. The resulting solution was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by neutral AlO column chromatography (gradient, PE to PE:DCM:MeOH = 16:4:1) to give the crude product, which was purified by preparative HPLC (SilaSep TM Purification by C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% FA) gave the formate salt of the title compound (37.7 mg) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.54 (d, J = 15.3 Hz, 1H), 8.43 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 30.5 Hz, 1H), 5.83 (q, J = 6.6 Hz, 1H), 4.33 (s, 1H), 4.22 (s, 1H), 4.20~4.09 (m, 2H), 3.84 (t, J = 5.6 Hz, 1H), 3.69 (t, J = 5.6 Hz, 1H), 3.11~2.89 (m, 2H), 2.75 (d, J = 27.2 Hz, 2H), 2.57 (s, 3H), 2.41~2.35 (m, 2H), 2.17 (d, J = 12.6 Hz, 3H), 1.62~1.46 (m, 3H). LC-MS m / e: 496 (MH + ).

[0221] Step 9 Synthesis of (R,Z)-1-(4-hydroxy-4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-imino)-5,7,8,9-tetrahydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-3-yl)piperidin-1-yl)ethan-1-one (compound 26) To a solution of (R,Z)-1-(4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-5,7,8,9-tetrahydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-3-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (460 mg, 0.928 mmol) and Mn(dpm) (337 mg, 0.557 mmol) in DCM (18 mL) and i-PrOH (2 mL) was added PhSiH (201 mg, 1.86 mmol) at 0 °C under an atmosphere of O. After stirring at 0 °C for 1.5 h, the reaction mixture was poured into water (100 mL) and extracted with DCM (100 mL × 2). The combined organic layer was washed with brine (100 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by neutral Al2O3 column chromatography (gradient, PE to PE:DCM:MeOH=16:4:1) to give the title compound (320 mg, 0.623 mmol, yield: 67.1%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 9.65 (d, J = 16.6 Hz, 1H), 8.86 (d, J = 4.8 Hz, 1H), 8.10~7.96 (m, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.34~7.27 (m, 1H), 6.02~5.89 (m, 1H), 4.66~4.44 (m, 3H), 3.69 (t, J = 7.9 Hz, 2H), 3.43~3.10 (m, 4H), 2.63 (s, 3H), 2.60~2.54 (m, 2H), 2.26~1.95 (m, 7H), 1.84 (d, J = 7.0 Hz, 3H). LC-MS m / e: 514 (MH + ).

[0222] Step 10: Synthesis of (R,Z)-1-(4-fluoro-4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-imino)-5,7,8,9-tetrahydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-3-yl)piperidin-1-yl)ethan-1-one (compound 27) To a solution of (R,Z)-1-(4-hydroxy-4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-imino)-5,7,8,9-tetrahydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-3-yl)piperidin-1-yl)ethan-1-one (260 mg, 0.506 mmol) in DCM (10 mL) was added DAST (0.334 mL, 2.53 mmol) at −20° C. and stirred under an atmosphere of N for 2 hours. The resulting solution was poured into cold saturated NaHCO solution (50 mL) and extracted with DCM (50 mL × 2). The combined organic layer was washed with brine (50 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to give the title compound (92.7 mg, 0.181 mmol, yield: 35.7%) as a pale yellow solid, which was converted to the formate salt. 1 H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 8.79 (s, 1H), 8.45 (s, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 7.0 Hz, 1H), 7.32~7.28 (m, 1H), 5.93~5.85 (m, 1H), 4.64 (d, J = 12.1 Hz, 1H), 4.56~4.41 (m, 2H), 3.83 (d, J = 13.8 Hz, 1H), 3.56 (t, J = 12.9 Hz, 1H), 3.37~3.11 (m, 2H), 3.03 (t, J = 12.9 Hz, 1H), 2.60 (s, 3H), 2.56~2.47 (m, 2H), 2.34~2.16 (m, 2H), 2.14 (d, J = 1.8 Hz, 3H), 2.11~1.99 (m, 2H), 1.75 (d, J = 6.7 Hz, 3H). LC-MS m / e: 516 (MH + ).

[0223] Following similar steps, the following three compounds (compounds 28-30) were prepared.

[0224] Compound 28: 1H NMR (400 MHz, CDCl3) δ 9.63 (d, J = 8.8 Hz, 1H), 8.84 (d, J = 3.2 Hz, 1H), 8.54 (s, 1H), 7.96 (t, J = 7.0 Hz, 1H), 7.53~7.47 (m, 1H), 7.26~7.22 (m, 1H), 6.89 (t, J = 55.0 Hz, 1H), 6.11~6.08 (m, 1H), 4.62~4.49 (m, 3H), 3.68 (d, J = 6.8 Hz, 2H), 3.42~3.26 (m, 2H), 3.13 (t, J = 12.2 Hz, 1H), 2.62~2.55 (m, 2H), 2.25~1.99 (m, 5H), 1.85 (d, J = 7.2 Hz, 3H), 1.77~1.61 (m, 2H); LC-MS m / e: 500.2 (MH + ).

[0225] Compound 29 acid chloride: 1 H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.65 (s, 1H), 8.44 (s, 1H), 7.96 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 6.8 Hz, 1H), 7.25~7.19 (m, 1H), 6.90 (t, J = 55.1 Hz, 1H), 5.98 (p, J = 6.8 Hz, 1H), 4.66 (d, J = 10.3 Hz, 1H), 4.44~4.23 (m, 2H), 3.83 (d, J = 11.2 Hz, 1H), 3.57 (t, J = 13.1 Hz, 1H), 3.29~3.09 (m, 2H), 3.09~2.99 (m, 1H), 2.60~2.42 (m, 2H), 2.38~2.18 (m, 2H), 2.15 (s, 3H), 2.13~2.07 (m, 1H), 2.06~1.98 (m, 1H), 1.70 (d, J = 6.8 Hz, 3H); LC-MS m / e: 502 (MH + ).

[0226] Compound 30 acid chloride:1 H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.76 (s, 1H), 8.43 (d, J = 3.2 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.33~7.29 (m, 1H), 5.88~5.76 (m, 1H), 4.64 (d, J = 8.4 Hz, 2H), 4.49~4.45 (m, 2H), 3.85~3.81 (m, 1H), 3.59~3.53 (m, 1H), 3.33~3.21 (m, 2H), 3.03 (t, J = 12.8 Hz, 1H), 2.71 (s, 3H), 2.57~2.51 (m, 2H), 2.31~2.18 (m, 1H), 2.15 (d, J = 2.0 Hz, 3H), 2.12~2.01 (m, 2H), 1.72 (d, J = 6.8 Hz, 3H);LC-MS m / e: 473.1 (MH + ).

[0227] Example 31 Synthesis of (R,Z)-3-(1-(difluoromethyl)cyclopropyl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-8,9-dihydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-5(7H)-imine (Compound 31) [ka]

[0228] Step 1 Synthesis of 2-bromo-5-((4-methoxybenzyl)amino)isonicotinamide To a solution of 2-bromo-5-fluoroisonicotinamide (3.2 g, 14.6 mmol) and PMBNH2 (3 g, 21.9 mmol) in DMSO (30 mL) was added DIEA (5.1 mL, 29.3 mmol). The reaction mixture was stirred at 90 °C overnight. The resulting mixture was cooled to room temperature, poured into water (150 mL), and extracted with EtOAc (150 mL × 3). The combined organic layer was washed with brine (150 mL × 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness. The residue was triturated with a mixture of PE (150 mL) and DCM (50 mL). The resulting solid was dried under reduced pressure to give the title compound (3.79 g, 11.32 mmol, yield: 77.5%) as a yellow solid. LC-MS m / e: 336, 338 (MH + ).

[0229] Step 2: Synthesis of 1-(4-carbamoyl-5-((4-methoxybenzyl)amino)pyridin-2-yl)cyclopropane-1-carboxylate To a solution of 2-bromo-5-((4-methoxybenzyl)amino)isonicotinamide (3.2 g, 9.52 mmol), Q-Phos (1.35 g, 1.9 mmol), and Pd(dba) (872 mg, 0.952 mmol) in THF (120 mL) was added (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (102 mL, 76.5 mmol, 0.75 M in THF) at room temperature and stirred for 5 h. The mixture was quenched with water (200 mL) and extracted with EtOAc (400 mL × 2). The combined organic layer was dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (gradient, PE to PE: EtOAc = 2:1) to give the title compound (2 g, 5.63 mmol, yield: 59.2%) as a red solid. LC-MS m / e: 356.0 (MH + ).

[0230] Step 3: Synthesis of 2-(1-(hydroxymethyl)cyclopropyl)-5-((4-methoxybenzyl)amino)-isonicotinamide To a solution of methyl 1-(4-carbamoyl-5-((4-methoxybenzyl)amino)pyridin-2-yl)-cyclopropane-1-carboxylate (2 g, 5.63 mmol) in THF (50 mL) was added DIBAL-H (22.5 mL, 22.5 mmol, 1 M in hexane) at 0 °C. The mixture was stirred at room temperature for 2 h, quenched with water (50 mL), and extracted with EtOAc (100 mL × 2). The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (gradient, DCM to DCM:MeOH = 20:1) to give the title compound (1.3 g, 3.98 mmol, yield: 70.6%) as a brown solid. LC-MS m / e: 328 (MH + ).

[0231] Step 4 Synthesis of 2-(1-formylcyclopropyl)-5-((4-methoxybenzyl)amino)isonicotinamide To a solution of 2-(1-(hydroxymethyl)cyclopropyl)-5-((4-methoxybenzyl)amino)-isonicotinamide (1.3 g, 3.98 mmol) in DCM (50 mL) was added Dess-Martin periodinane (4.22 g, 9.95 mmol) at 0 °C and stirred at room temperature for 2 h. The mixture was quenched with saturated NaHCO3 solution (50 mL), and the aqueous layer was extracted with DCM (50 mL × 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (gradient, DCM to DCM:MeOH = 20:1) to give the title compound (600 mg, 1.85 mmol, yield: 46.4%) as a yellow solid. LC-MS m / e: 326 (MH + ).

[0232] Step 5 Synthesis of 2-(1-(difluoromethyl)cyclopropyl)-5-((4-methoxybenzyl)amino)-isonicotinamide To a solution of 2-(1-formylcyclopropyl)-5-((4-methoxybenzyl)amino)isonicotinamide (600 mg, 1.85 mmol) in DCM (20 mL) was added DAST (1.49 g, 9.25 mmol) at −10° C. and stirred at 0° C. for 2 h. The mixture was quenched with saturated aqueous NaHCO (50 mL) and extracted with DCM (50 mL × 2). The combined organic layer was dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (gradient, DCM to DCM:MeOH = 20:1) to give the title compound (300 mg, 0.865 mmol, yield: 46.7%) as a yellow solid. LC-MS m / e: 348 (MH + ).

[0233] Step 6 Synthesis of 5-amino-2-(1-(difluoromethyl)cyclopropyl)isonicotinamide To a solution of 2-(1-(difluoromethyl)cyclopropyl)-5-((4-methoxybenzyl)amino)-isonicotinamide (300 mg, 0.865 mmol) in DCM (4 mL) was added TFA (2 mL) at 0° C., and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give the crude title compound (196 mg, 0.865 mmol, yield: 100%) as a brown solid. The crude product was used directly in the next step without further purification. LC-MS m / e: 228 (MH + ).

[0234] Step 7 Synthesis of 5-(4-chlorobutanamido)-2-(1-(difluoromethyl)cyclopropyl)-isonicotinamide To a solution of 5-amino-2-(1-(difluoromethyl)cyclopropyl)isonicotinamide (196 mg, 0.865 mmol) and TEA (0.73 mL, 5.3 mmol) in THF (10 mL) was added 4-chlorobutanoyl chloride (0.3 mL, 2.68 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water (50 mL) and extracted with DCM (100 mL × 2). The combined organic layer was dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure and purified by neutral AlO column chromatography (gradient, PE to PE:DCM:MeOH = 40:2:1) to give the title compound (128 mg, 0.388 mmol, yield: 44.8%) as a yellow solid. LC-MS m / e: 332 (MH + ).

[0235] Step 8 Synthesis of 3-(1-(difluoromethyl)cyclopropyl)-8,9-dihydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-5(7H)-one To a solution of 5-(4-chlorobutanamido)-2-(1-(difluoromethyl)cyclopropyl)-isonicotinamide (200 mg, 0.604 mmol) in THF (10 mL) was added potassium tert-butoxide (1.2 mL, 1.2 mmol, 1 M in THF) and stirred at room temperature for 1 h. The mixture was concentrated and purified by neutral Al2O3 column chromatography (gradient, PE to PE:DCM:MeOH = 16:3:1) to give the title compound (70 mg, 0.252 mmol, 41.7% yield) as a yellow solid. LC-MS m / e: 278 (MH + ).

[0236] Step 9 Synthesis of 3-(1-(difluoromethyl)cyclopropyl)-8,9-dihydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidine-5(7H)-thione A solution of 3-(1-(difluoromethyl)cyclopropyl)-8,9-dihydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-5(7H)-one (70 mg, 0.252 mmol) and Lawesson's reagent (102 mg, 0.252 mmol) in toluene (5 mL) was stirred at 80 °C overnight. The reaction was cooled to room temperature and concentrated to dryness. The residue was dissolved in 1 N HCl solution (20 mL) and washed with EtOAc (50 mL). The aqueous layer was then adjusted to approximately pH 7 with NaHCO and extracted with DCM (40 mL × 3). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated to give the title compound (70 mg, 0.239 mmol, 94.5% yield) as a brown solid. LC-MS m / e: 294 (MH + ).

[0237] Step 10: Synthesis of (R,Z)-3-(1-(difluoromethyl)cyclopropyl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-8,9-dihydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-5(7H)-imine (compound 31) To a solution of 3-(1-(difluoromethyl)cyclopropyl)-8,9-dihydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidine-5(7H)-thione (70 mg, 0.239 mmol) in iodomethane (2 mL) was added (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (242 mg, 1.19 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, concentrated, and purified by preparative HPLC to give the title compound (16 mg, 0.035 mmol, 14.5% yield) as a yellow solid. This compound was converted to the formate salt. 1HNMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 6.34 (t, J = 56.0 Hz, 1H), 5.73 (q, J = 6.6 Hz, 1H), 4.08 (m, 2H), 3.00~2.78 (m, 2H), 2.50 (s, 3H), 2.26~2.12 (m, 2H), 1.37 (d, J = 6.6 Hz, 3H), 1.24 (s, 4H). LC-MS m / e: 463 (MH + ).

[0238] Examples 32 to 42 (R,Z)-1-(4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-8,9-dihydro-5H-oxazolo[3,2-a]pyrido[4,3-e]pyrimidin-3-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (compound 32) and Synthesis of (R,Z)-1-(4-fluoro-4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-8,9-dihydro-5H-oxazolo[3,2-a]pyrido[4,3-e]pyrimidin-3-yl)piperidin-1-yl)ethan-1-one (Compound 33) [ka]

[0239] Step 1 Synthesis of 6-bromo-2-mercaptopyrido[3,4-d]pyrimidin-4(1H)-one To a solution of 5-amino-2-bromoisonicotinamide (3 g, 13.89 mmol) in DMF (50 mL) was added CS (5.3 g, 69.4 mmol) and DBU (17.4 g, 69.4 mmol). The mixture was stirred at 60 °C for 12 h. The reaction mixture was cooled to room temperature and purified by reverse-phase column chromatography (gradient, 100% HO to HO:ACN = 60%) to give the title compound (3 g, 11.62 mmol, 83.7% yield) as a brown solid. LCMS m / e: 258.1, 260.1 (MH + ).

[0240] Step 2: Synthesis of 6-bromo-2-(ethylthio)pyrido[3,4-d]pyrimidin-4(1H)-one To a solution of 6-bromo-2-mercaptopyrido[3,4-d]pyrimidin-4(1H)-one (1.5 g, 5.81 mmol) in EtOH (55 mL) was added KOH (2 M, 5.2 mL) and EtI (1.8 g, 11.62 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.5 g, 5.2 mmol, yield: 88.2%) as a white solid. LCMS m / e: 286.1, 288.1 (MH + ).

[0241] Step 3 Synthesis of 6-bromo-4-chloro-2-(ethylthio)pyrido[3,4-d]pyrimidine A mixture of 6-bromo-2-(ethylthio)pyrido[3,4-d]pyrimidin-4(1H)-one (700 mg, 2.45 mmol) and SOCl2 (10 mL) was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature, and excess SOCl2 was removed by distillation. The residue was basified with saturated Na2CO3 solution (100 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (700 mg, 2.3 mmol, yield: 93.9%) as a white solid. LCMS m / e: 304.6, 306.6 (MH + ).

[0242] Step 4. Synthesis of (R)-6-bromo-2-(ethylthio)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-pyrido[3,4-d]pyrimidin-4-amine To a solution of 6-bromo-4-chloro-2-(ethylthio)pyrido[3,4-d]pyrimidine (700 mg, 2.3 mmol) in THF (20 mL) was added (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (467 mg, 2.3 mmol) and EtN (466 mg, 4.6 mmol). The mixture was stirred at room temperature for 0.5 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient, PE to PE:EA = 3:1) to afford the title compound (800 mg, 1.7 mmol, yield: 74.0%) as a white solid. LCMS m / e: 471.3, 473.3 (MH + ).

[0243] Step 5. Synthesis of (R)-6-bromo-2-(ethylsulfonyl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine To a solution of (R)-6-bromo-2-(ethylthio)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)pyrido[3,4-d]pyrimidin-4-amine (800 mg, 1.7 mmol) in DCM (25 mL) was added m-CPBA (1.03 g, 5.95 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with saturated NaHCO3 solution (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient, PE to PE:EA = 2:1) to give the title compound (750 mg, 1.49 mmol, yield: 87.6%) as a white solid. LCMS m / e: 503.4, 505.4 (MH + ).

[0244] Step 6: Synthesis of (R)-2-((6-bromo-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-2-yl)oxy)ethan-1-ol To a solution of (R)-6-bromo-2-(ethylsulfonyl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine (750 mg, 1.49 mmol) in DMF (20 mL) was added NaH (119 mg, 2.98 mmol, 60% suspension in mineral oil) and 2-((tert-butyldimethylsilyl)oxy)-ethan-1-ol (526 mg, 2.98 mmol). The reaction mixture was stirred at 80 °C for 2 h. The resulting mixture was cooled to room temperature, quenched with ice water (60 mL), and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (60 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient, PE to PE:EA=1:1) to give the title compound (500 mg, 1.1 mmol, yield: 71.2%) as a white solid. LCMS m / e: 471.3, 473.1 (MH + ).

[0245] Step 7 Synthesis of (R)-6-bromo-2-(2-chloroethoxy)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine To a solution of (R)-2-((6-bromo-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-2-yl)oxy)ethan-1-ol (500 mg, 1.1 mmol) in CHCl (20 mL) was added SOCl (1.32 g, 11 mmol). The mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the title compound (400 mg, 0.82 mmol, yield: 74.3%) as a colorless oil. LCMS m / e: 489.7, 491.7 (MH + ).

[0246] Step 8: Synthesis of (R,Z)-3-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-8,9-dihydro-5H-oxazolo[3,2-a]pyrido[4,3-e]pyrimidin-5-imine To a solution of (R)-6-bromo-2-(2-chloroethoxy)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine (400 mg, 0.82 mmol) in DMF (20 mL) was added K2CO3 (1.13 g, 8.2 mmol) and stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with water (60 mL), and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient, DCM to DCM:MeOH = 30:1) to give the title compound (300 mg, 0.66 mmol, yield: 80.7%) as a white solid. LCMS m / e: 453.2, 455.2 (MH + ).

[0247] Step 9 Synthesis of (R,Z)-1-(4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-8,9-dihydro-5H-oxazolo[3,2-a]pyrido[4,3-e]pyrimidin-3-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (compound 32) To a solution of (R,Z)-3-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-8,9-dihydro-5H-oxazolo[3,2-a]pyrido[4,3-e]pyrimidin-5-imine (300 mg, 0.66 mmol) in dioxane (25 mL) and water (5 mL) was added 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (166 mg, 0.66 mmol), Pd(dppf)Cl (51 mg, 0.07 mmol), and KCO (268 mg, 1.98 mmol). The reaction mixture was stirred at 120°C for 2 hours, cooled to room temperature, diluted with water (60 mL), and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous NaSO, and then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient, DCM to DCM:MeOH = 15:1) to give the title compound (200 mg, 0.4 mmol, yield: 60.9%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.05 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 6.67 (d, J = 17.5 Hz, 1H), 5.57 (q, J = 6.5 Hz, 1H), 4.73 (t, J = 8.6 Hz, 2H), 4.25 (dd, J = 14.7, 7.9 Hz, 2H), 4.18 (d, J = 19.7 Hz, 2H), 3.70~3.61 (m, 2H), 2.68~2.63 (m, 1H), 2.59~2.52 (m, 1H), 2.47 (s, 3H), 2.07 (d, J = 15.1 Hz, 3H), 1.35 (d, J = 6.5 Hz, 3H). LCMS m / e: 498.6 (MH + ).

[0248] Step 10. Synthesis of (R,Z)-1-(4-hydroxy-4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-imino)-8,9-dihydro-5H-oxazolo[3,2-a]pyrido[4,3-e]pyrimidin-3-yl)piperidin-1-yl)ethan-1-one To a solution of (R,Z)-1-(4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-8,9-dihydro-5H-oxazolo[3,2-a]pyrido[4,3-e]pyrimidin-3-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (200 mg, 0.4 mmol) and Mn(TMHD) (73 mg, 0.12 mmol) in i-PrOH (18 mL) and DCM (2 mL) was added PhSiH (56 mg, 0.52 mmol) at 0 °C under an atmosphere of O. The mixture was stirred at room temperature for 2 h, diluted with water (60 mL), and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with brine (60 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient, DCM to DCM:MeOH=10:1) to give the title compound (150 mg, 0.29 mmol, yield: 72.7%) as a brown solid. LCMS m / e: 516.5 (MH + ).

[0249] Step 11 Synthesis of (R,Z)-1-(4-fluoro-4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-imino)-8,9-dihydro-5H-oxazolo[3,2-a]pyrido[4,3-e]pyrimidin-3-yl)piperidin-1-yl)ethan-1-one (compound 33) To a solution of (R,Z)-1-(4-hydroxy-4-(5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-imino)-8,9-dihydro-5H-oxazolo[3,2-a]pyrido[4,3-e]pyrimidin-3-yl)piperidin-1-yl)ethan-1-one (150 mg, 0.29 mmol) in DCM (10 mL) was added DAST (234 mg, 1.45 mmol) at −20° C. under an atmosphere of N2 and stirred at −20° C. for 2 hours. The reaction mixture was basified with saturated NaHCO3 solution (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to give the title compound (43.3 mg, 0.084 mmol, yield: 28.9%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.13 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 5.56 (dd, J = 12.2, 6.0 Hz, 1H), 4.73 (t, J = 8.0 Hz, 2H), 4.46~4.38 (m, 1H), 4.25 (t, J = 13.9, 7.4 Hz, 2H), 3.91~3.83 (m, 1H), 3.43~3.37 (m, 1H), 2.92~2.86(m, LCMS m / e: 518.6 (MH + ).

[0250] The following compounds 34 to 41 were synthesized using the same steps as above.

[0251] Compound 34: 11H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.02 (t, J = 9.3 Hz, 2H), 7.60 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 6.67 (d, J = 18.7 Hz, 1H), 5.47 (q, J = 6.5 Hz, 1H), 4.73 (t, J = 8.7 Hz, 2H), 4.25 (t, J = 14.7, 7.7 Hz, 2H), 4.18 (d, J = 20.0 Hz, 2H), 3.69~3.60 (m, 2H), 2.69~2.58 (m, 2H), 2.57 (s, 3H), 2.07 (d, J = 15.1 Hz, 3H), 1.34 (d, J = 6.6 Hz, 3H); LCMS m / e: 455.2 (MH + ).

[0252] Compound 35: 1 1H NMR(400MHz, DMSO-d6) δ 8.53 (s, 1H), 8.14 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 5.47 (q, J = 11.7, 5.3 Hz, 1H), 4.75 (t, J = 8.5 Hz, 2H), 4.42 (dd, J = 16.5, 7.6 Hz, 1H), 4.30~4.20 (m, 2H), 3.86 (dd, J = 14.2, 6.3 Hz, 1H), 3.45~3.35 (m, 1H), 2.91~2.87 (m, 1H), 2.56 (s, 3H), 2.31~2.26 (m, 1H), 2.19~2.14 (m, 1H), 2.07 (s, 3H), 1.99~1.94 (m, 2H), 1.35 (d, J = 6.1 Hz, 3H); LCMS m / e: 475.2 (MH + ).

[0253] Compound 36: 1HNMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.87~7.78 (m, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 6.54 (s, 1H), 5.94~5.78 (m, 1H), 4.33~4.28 (m, 2H), 3.89 (t, J = 5.3 Hz, 2H), 3.78 (s, 3H), 2.64~2.60 (m, 2H), 2.59 (s, 3H), 2.53 (s, 3H), 1.58 (d, J = 6.6 Hz, 3H); LCMS m / e: 442 (MH + ).

[0254] Compound 37: 1 HNMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.81~7.72 (m, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 6.40 (s, 1H), 5.90~5.80 (m, 1H), 4.19 (d, J = 18.8 Hz, 2H), 3.74 (s, 3H), 3.72~3.68 (m, 2H), 2.71~2.69 (m, 1H), 2.65~2.59 (m, 1H), 2.57 (s, 3H), 2.54 (s, 3H), 2.11 (d, J = 16.4 Hz, 3H), 1.55 (d, J = 6.0 Hz, 3H); LCMS m / e: 483.3 (MH + ).

[0255] Compound 38: 1HNMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.94-7.90 (m, 2H), 7.71~7.60 (m, 2H), 7.38 (t, J = 7.7 Hz, 1H), 6.45 (s, 1H), 5.75 (q, J = 6.7 Hz, 1H), 4.29 (d, J = 2.5 Hz, 2H), 3.88 (t, J = 5.4 Hz, 2H), 3.68 (s, 3H), 2.65 (s, 3H), 2.56~2.51 (m, 5H), 1.48 (d, J = 6.5 Hz, 3H);LCMS m / e: 399.3 (MH + ).

[0256] Compound 39: 1 HNMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.12 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 6.81 (s, 1H), 5.78 (q, J = 6.7 Hz, 1H), 4.30 (d, J = 2.4 Hz, 2H), 3.86 (t, J = 5.5 Hz, 2H), 3.65 (s, 3H), 2.57 (s, 2H), 2.52 (s, 3H), 2.47 (s, 3H), 1.42 (d, J = 6.6 Hz, 3H);LCMS m / e: 443.2 (MH + ).

[0257] Compound 40: 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.08 (s, 1H), 7.97 (d, J = 7.3 Hz, 1H), 7.59 (d, J = 6.8 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 6.58 (s, 1H), 5.72~5.64 (m, 1H), 3.60 (s, 3H), 2.86~2.74 (m, 4H), 2.60 (s, 3H), 2.43 (s, 3H), 2.27~2.13 (m, 2H), 1.37 (d, J = 6.6 Hz, 3H);LCMS m / e: 434.4 (MH + ).

[0258] Compound 41: 1 HNMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.08 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 6.80 (s, 1H), 5.69 (q, J = 6.4 Hz, 1H), 4.32~4.28 m, 2H), 3.85 (t, J = 5.5 Hz, 2H), 3.64 (s, 3H), 2.61 (s, 3H), 2.59~2.53 (m, 2H), 2.46 (s, 3H), 1.39 (d, J = 6.6 Hz, 3H); LCMS m / e: 400 (MH + ).

[0259] Example 42 Synthesis of (R,Z)-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrido[3,4-d]pyrimidin-4(1H)-imine (Compound 42) [ka]

[0260] Step 1: Synthesis of tert-butyl (R,Z)-4-(1,2-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of (R,Z)-6-chloro-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine (300 mg, 0.76 mmol) in 1,4-dioxane (10 mL) and HO (2 mL) was added KCO (315 mg, 2.28 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (282 mg, 0.912 mmol), and Pd(dppf)Cl (56 mg, 0.076 mmol), and the mixture was stirred at 100 °C under an atmosphere of N for 5 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, DCM to DCM:MeOH = 10:1) to give the title compound (300 mg, 0.554 mmol, yield: 72.9%) as a yellow solid. LC-MS m / e: 542 (MH + )

[0261] Step 2: Synthesis of (R,Z)-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[3,4-d]pyrimidin-4(1H)-imine hydrochloride To a solution of tert-butyl (R,Z)-4-(1,2-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (300 mg, 0.554 mmol) in 10 mL of EtOAc, HCl solution (5 mL, 4 M in EtOAc) was added and stirred at room temperature for 0.5 hours. The resulting mixture was concentrated to give the title compound (200 mg, 0.419 mmol, yield: 75.7%) as a pale yellow solid. LC-MS m / e: 442 (MH + )

[0262] Step 3: Synthesis of (R,Z)-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrido[3,4-d]pyrimidin-4(1H)-imine (Compound 42) To a solution of (R,Z)-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[3,4-d]pyrimidin-4(1H)-imine hydrochloride (70 mg, 0.147 mmol) and EtN (0.088 mL, 0.634 mmol) in DCM (5 mL) was added MsCl (0.025 mL, 0.317 mmol) at 0 °C and stirred at 0 °C for 2 h. The reaction mixture was poured into ice water (10 mL) and extracted with DCM (20 mL × 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (25 mg, 0.048 mmol, yield: 30.4%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.14 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 6.78 (s, 1H), 5.78 (q, J = 6.5 Hz, 1H), 3.95 (d, J = 2.7 Hz, 2H), 3.64 (s, 3H), 3.42 (t, J = 4.0 Hz, 2H), 2.95 (s, 3H), 2.73 (s, 2H), 2.52 (s, 3H), 2.46 (s, 3H), 1.41 (d, J = 6.6 Hz, 3H). LC-MS m / e: 520 (MH + ).

[0263] Example 43 Synthesis of (R,Z)-4-(1,2-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxamide (Compound 43) [ka]

[0264] To a solution of (R,Z)-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[3,4-d]pyrimidin-4(1H)-imine hydrochloride (100 mg, 0.21 mmol) in THF (5 mL) and 1 N HCl (2 mL) was added KOCN (85 mg, 1.05 mmol) and stirred at 25 °C for 12 h. The reaction mixture was basified with saturated NaHCO solution (40 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (21 mg, 0.043 mmol, yield: 20.5%) as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.27 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 6.80 (s, 1H), 6.04 (s, 2H), 5.80 (q, J = 6.6 Hz, 1H), 4.07 (d, J = 2.6 Hz, 2H), 3.70 (s, 3H), 3.56~3.56 (m, 2H), 2.60 (s, 2H), 2.54 (s, 3H), 2.50 (d, J = 1.7 Hz, 3H), 1.47 (d, J = 6.7 Hz, 3H). LC-MS m / e: 485 (MH + ).

[0265] Examples 44 and 45 1-((R)-4-((Z)-1,2-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-6-methyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one and 1-((R)-4-((Z)-1,2-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-2-methyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (compound 44), and Synthesis of 1-((2R)-4-((Z)-1,2-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-fluoro-2-methylpiperidin-1-yl)ethan-1-one (Compound 45) [ka]

[0266] Step 1. Synthesis of tert-butyl (R)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-pyridine-1(2H)-carboxylate and tert-butyl (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of tert-butyl (R)-2-methyl-4-oxopiperidine-1-carboxylate (1 g, 4.68 mmol) in THF (20 mL) was added LiHMDS (4.7 mL, 6.09 mmol, 1.3 M in THF) dropwise at −65° C. under an atmosphere of N2, stirred for 0.5 h, and N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.39 g, 6.09 mmol) was added portionwise at −65° C. The reaction mixture was stirred at room temperature for 18 h, diluted with water (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient, PE to PE: EtOAc = 20:1) to give the title compound (0.75 g, 2.17 mmol, yield: 46.3%) as a yellow oil. LCMS m / e: 346 (MH + ).

[0267] Step 2: Synthesis of tert-butyl (R)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl (R)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate To a mixture of tert-butyl (R)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (0.75 g, 2.17 mmol) in dioxane (20 mL) was added bis(pinacolato)diboron (0.61 g, 2.38 mmol), KOAc (0.64 g, 6.51 mmol), and Pd(dppf)Cl (160 mg, 0.217 mmol). The mixture was stirred under an atmosphere of N at 100 °C for 1 h, cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient, PE to PE: EtOAc = 20:1) to give the title compound (0.65 g, 2.01 mmol, yield: 92.5%) as a yellow oil. LCMS m / e: 324 (MH + ).

[0268] Step 3: Synthesis of (R)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride and (R)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride To a mixture of tert-butyl (R)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl (R)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (325 mg, 1 mmol) in 10 mL of EtOAc was added dropwise HCl (2.5 mL, 10 mmol, 4N in EtOAc). The mixture was stirred at room temperature for 1 hour and evaporated to give the crude title compound (250 mg, 0.963 mmol, 95.7% yield) as a yellow solid. LCMS m / e: 224 (MH + ).

[0269] Step 4 Synthesis of (R)-1-(6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one and (R)-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one To a mixture of (R)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride, (R)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (250 mg, 0.963 mmol), and EtN (291 mg, 2.88 mmol) in DCM (5 mL) was added AcCl (75 mg, 0.963 mmol) dropwise at 0° C. and stirred for 1 h. The resulting mixture was diluted with water (10 mL) and extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (190 mg, 0.717 mmol, yield: 74.4%) as a yellow solid. LCMS m / e: 266 (MH + ).

[0270] Step 5. Synthesis of 1-((R)-4-((Z)-1,2-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-6-methyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one and 1-((R)-4-((Z)-1,2-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-2-methyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (Compound 44) (R)-1-(6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one and (R)-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (174 mg, 0.659 mmol) To a mixture of (R,Z)-6-chloro-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4(1H)-imine (200 mg, 0.507 mmol) and Pd(dppf)Cl (37 mg, 0.051 mmol) in dioxane (5 mL) and water (0.5 mL) was added KCO (210 mg, 1.52 mmol). The mixture was stirred at 100 °C under N for 2 h, cooled to room temperature, and concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient, DCM to DCM:MeOH = 10:1) and reverse-phase chromatography (SilaSep TM Purification of a C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% formic acid) afforded the title mixture (110 mg, 0.221 mmol, 43.6% yield) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.17~8.06 (m, 1H), 7.91~7.95 (m, 1H), 7.52 (d, J = 7.8 Hz,1H), 7.36 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 21.8 Hz, 1H), 5.84~5.73 (m, 1H), 5.02~4.56 (m, 1H), 4.47~3.92 (m, 1H), 3.64 (s, 3H), 3.59~3.47 (m, 1H), 3.22 (s, 3H), 2.64~2.80 (m, 2H), 2.46 (s, 3H), 2.14~2.01 (m, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.36~1.11 (m, 3H). LCMS m / e: 498 (MH + ).

[0271] Step 6. Synthesis of 1-((2R)-4-((Z)-1,2-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-hydroxy-2-methylpiperidin-1-yl)ethan-1-one A solution of Mn(TMHD)3 (103 mg, 0.171 mmol) was treated with 1-((R)-4-((Z)-1,2-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-6-methyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one and 1-((R)-4-((Z)-1,2-dimethyl-4- To a solution of (((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-2-methyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (170 mg, 0.342 mmol) in DCM (3 mL) and i-PrOH (8 mL) was added PhSiH (55 mg, 0.512 mmol) dropwise at 0 °C under an atmosphere of O. The mixture was stirred at 0 °C for 1 h, diluted with water (10 mL), and extracted with DCM (20 mL × 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by neutral Al2O3 column chromatography (gradient, 100% PE to PE:DCM:MeOH=25:4:1) to give the title compound (50 mg, 0.097 mmol, yield: 28.3%) as a yellow solid. LCMS m / e: 516 (MH + ).

[0272] Step 7. Synthesis of 1-((2R)-4-((Z)-1,2-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-fluoro-2-methylpiperidin-1-yl)ethan-1-one (Compound 45) To a solution of 1-((2R)-4-((Z)-1,2-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-hydroxy-2-methylpiperidin-1-yl)ethan-1-one (50 mg, 0.097 mmol) in DCM (3 mL) was added DAST (62 mg, 0.38 mmol) dropwise at -30 °C and stirred at 0 °C for 1 h. The reaction was quenched with saturated NaHCO solution (20 mL) and extracted with DCM (20 mL × 2). The combined organic layer was dried over NaSO, filtered, concentrated, and purified using a reverse-phase column (SilaSep TM Purification by C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% TFA) gave the trifluoroacetate salt of the title compound (9 mg). 1 HNMR (400 MHz, DMSO-d6) δ 10.88 (d, J = 6.1 Hz, 1H), 9.50 (s, 1H), 8.85 (s, 1H), 7.82 (d, J = 7.8 Hz,1H), 7.63 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 5.92 (p, J = 7.3 Hz, 1H), 4.98~4.90 (m, 0.5H),4.56~4.49 (m, 0.5H), 4.34~4.38 (m, 0.5H), 4.02 (s, 3H), 3.83~3.86 (m, 0.5H), 3.58~3.49 (m, 1H), 3.05(t, J = 13.3 Hz, 0.5H), 2.77 (s, 3H), 2.60 (s, 3H), 2.16~2.40 (m, 1.5H), 2.10 (d, J = 2.6 Hz, 3H), 2.06~1.89 (m, 2H), 1.68 (d, J = 6.9 Hz, 3H), 1.36 (dd, J = 50.2, 6.9 Hz, 3H). LCMS m / e: 518 (MH + ).

[0273] Example 46 Synthesis of 1-(4-((Z)-1,2-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-fluoro-2,2-dimethylpiperidin-1-yl)ethan-1-one (Compound 46) [ka]

[0274] Step 1. Synthesis of tert-butyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of tert-butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate (2 g, 8.8 mmol) in THF (50 mL) was added LiHMDS (1.3 M, 13.5 mL) at -50 °C. After stirring at -50 °C for 0.5 h, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (3.8 g, 10.56 mmol) was added and stirred at room temperature for 2 h. The resulting mixture was quenched with saturated NH4Cl solution (40 mL), diluted with water (40 mL), and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient, PE to PE: EtOAc = 20:1) to give the title compound (2 g, 5.56 mmol, yield: 63.2%) as a colorless oil. LCMS m / e: 360.3 (MH + ).

[0275] Step 2: Synthesis of tert-butyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of tert-butyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-pyridine-1(2H)-carboxylate (2 g, 5.56 mmol) in dioxane (50 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.8 g, 11.1 mmol), Pd(dppf)Cl (410 mg, 0.56 mmol), and KOAc (1.6 g, 16.7 mmol). The mixture was stirred at 120 °C under an atmosphere of N for 2 h, cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient, PE to PE: EtOAc = 10:1) to give the title compound (400 mg, 1.19 mmol, yield: 21.3%) as a colorless oil. LCMS m / e: 338.3 (MH + ).

[0276] Step 3: Synthesis of 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine To a solution of tert-butyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg, 1.19 mmol) in EtOAc (5 mL) was added HCl solution (5 mL, 4 M in EtOAc). The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated to dryness, basified with saturated NaHCO3 solution (40 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient, PE to PE: EtOAc = 2:1) to give the title compound (250 mg, 1.05 mmol, yield: 88.2%) as a white solid. LCMS m / e: 238.3 (MH + ).

[0277] Step 4: Synthesis of 1-(6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one To a solution of 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (250 mg, 1.05 mmol) and EtN (319 mg, 3.15 mmol) in DCM (20 mL) was added AcCl (82 mg, 1.05 mmol). The mixture was stirred at room temperature for 2 h, diluted with water (20 mL), and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (80 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient, PE to PE: EtOAc = 5:1) to give the title compound (150 mg, 0.54 mmol, 51.2% yield) as a white solid. LCMS m / e: 280.2 (MH + ).

[0278] Step 5. Synthesis of (R,Z)-1-(4-(1,2-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-6,6-dimethyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one To a solution of 1-(6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (150 mg, 0.54 mmol) in dioxane (20 mL) and water (5 mL) was added (R,Z)-6-bromo-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine (285 mg, 0.65 mmol), Pd(dppf)Cl (37 mg, 0.05 mmol), and KCO (224 mg, 1.62 mmol). The mixture was stirred at 120 °C under an atmosphere of N for 2 h. The mixture was cooled to room temperature, diluted with water (60 mL), and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous NaSO, and then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (gradient, DCM to DCM:MeOH = 15:1) to give the title compound (80 mg, 0.16 mmol, yield: 29.0%) as a brown solid. LCMS m / e: 512.6 (MH + ).

[0279] Step 6 Synthesis of 1-(-4-((Z)-1,2-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-hydroxy-2,2-dimethylpiperidin-1-yl)ethan-1-one. To a solution of (R,Z)-1-(4-(1,2-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-6,6-dimethyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (80 mg, 0.16 mmol) and Mn(TMHD) (29 mg, 0.048 mmol) in i-PrOH (9 mL) and DCM (1 mL) was added PhSiH (23 mg, 0.21 mmol) at 0 °C under an atmosphere of O. The mixture was stirred at room temperature for 2 h, diluted with water (60 mL), and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with brine (60 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by neutral Al2O3 column chromatography (gradient, 100% PE to PE:DCM:MeOH=25:4:1) to give the title compound (60 mg, 0.11 mmol, yield: 70.8%) as a brown solid. LCMS m / e: 530.6 (MH + ).

[0280] Step 7: Synthesis of 1-(4-((Z)-1,2-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-fluoro-2,2-dimethylpiperidin-1-yl)ethan-1-one (compound 46) To a solution of 1-(4-((Z)-1,2-dimethyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-hydroxy-2,2-dimethylpiperidin-1-yl)ethan-1-one (60 mg, 0.11 mmol) in DCM (15 mL) was added DAST (89 mg, 0.55 mmol) at −20° C. and stirred for 2 hours. The mixture was made basic with saturated NaHCO solution (50 mL), and the aqueous layer was extracted with DCM (60 mL × 3). The combined organic layer was washed with brine (60 mL), dried over anhydrous NaSO, and then filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to give the title compound (22 mg, 0.04 mmol, yield: 37.6%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.13 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 5.76 (q, 1H), 3.68~3.62 (m, 1H), 3.59 (s, 3H), 3.55~3.51 (m, 1H), 2.53 (s, 3H), 2.43 (s, 3H), 2.41~2.18 (m, 2H), 2.17~2.08 (m, 1H), 2.06 (s, 3H), 1.98~1.88 (m, 1H), 1.50 (t, J = 4.9 Hz, 6H), 1.38 (d, J = 6.6 Hz, 3H) LCMS m / e: 532.4 (MH + ).

[0281] Example 47 Synthesis of (R,Z)-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(3-(trifluoromethyl)imidazo[1,5-a]pyridin-7-yl)pyrido[3,4-d]pyrimidin-4(1H)-imine (Compound 47) [ka]

[0282] Step 1: Synthesis of 7-bromo-3-(trifluoromethyl)imidazo[1,5-a]pyridine To a solution of (4-bromopyridin-2-yl)methanamine (600 mg, 3.2 mmol) in THF (12 mL) and TEA (811 mg, 8.02 mmol) was added TFAA (1.55 g, 7.37 mmol) dropwise at 0° C. and stirred at room temperature for 18 h. The mixture was diluted with MeOH (7 mL) and purified by silica gel flash chromatography (gradient, PE to PE: EtOAc = 10:1) to give the title compound (700 mg, 2.64 mmol, 82.3% yield) as a yellow solid. LCMS m / e: 265, 267 (MH + ).

[0283] Step 2: Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-imidazo[1,5-a]pyridine To a solution of 7-bromo-3-(trifluoromethyl)imidazo[1,5-a]pyridine (350 mg, 1.321 mmol) and bis(pinacolato)diboron (352 mg, 1.38 mmol) in dioxane (6 mL) was added KOAc (388 mg, 3.962 mmol) and Pd(dppf)Cl (96 mg, 0.132 mmol). The mixture was stirred at 100 °C for 1 h under a N atmosphere, cooled to room temperature, and concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient, PE to PE: EtOAc = 10:1) to give the title compound (400 mg, 1.28 mmol, 97.0% yield) as a yellow solid. LCMS m / e: 313 (MH + ).

[0284] Step 3: Synthesis of (R,Z)-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(3-(trifluoromethyl)imidazo[1,5-a]pyridin-7-yl)pyrido[3,4-d]pyrimidin-4(1H)-imine (Compound 47) To a solution of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-imidazo[1,5-a]pyridine (100 mg, 0.32 mmol) and (R,Z)-6-chloro-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine (126 mg, 0.32 mmol) in dioxane (4 mL) and water (0.4 mL) was added Na2CO3 (101 mg, 0.961 mmol) and Pd(dppf)Cl2 (23 mg, 0.032 mmol). The mixture was stirred at 100 °C under an atmosphere of N2 for 1 h, cooled to room temperature, and concentrated to dryness. The residue was purified by reverse-phase chromatography (SilaSep TM Purification by C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% formic acid) afforded the title compound (10 mg, 0.018 mmol, 5.7% yield) as a pale yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 8.51 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.76 (dd, J = 7.6, 1.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 5.81 (q, J = 6.6 Hz, 1H), 3.63 (s, 3H), 2.53 (s, 3H), 2.43 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H). LCMS m / e: 545 (MH + ).

[0285] Examples 48 to 53 Synthesis of (R,Z)-6-(4,4-difluoropiperidin-1-yl)-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine (Compound 48) [ka]

[0286] A mixture of (R,Z)-6-chloro-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine (124 mg, 1.024 mmol), RuPhos (32 mg, 0.068 mmol), RuPhos Pd G3 (50 mg, 0.068 mmol), and CsCO3 (333 mg, 1.02 mmol) in dioxane (15 mL) was stirred at 100 °C under an atmosphere of N2 overnight. The mixture was allowed to cool to room temperature, diluted with water (20 mL), and then extracted with EtOAc (30 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative HPLC to give the title compound (7.2 mg, 0.015 mmol, yield: 4.40%) as a yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.8 Hz, 1H), 5.78 (q, J = 6.7 Hz, 1H), 3.77~3.68 (m, 4H), 3.62 (s, 3H), 2.52 (s,3H), 2.44 (s, 3H), 2.10~2.01 (m, 4H), 1.43 (d, J = 6.6 Hz, 3H). LC-MS m / e: 480.3 (MH + ).

[0287] Applying the same steps as above, the following compounds (compounds 49-53) were prepared.

[0288] Compound 49: 1HNMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.61~7.52 (m, 2H), 7.38 (t, J = 7.7 Hz, 1H), 5.81 (q, J = 6.6 Hz, 1H), 3.71 (s, 3H), 3.64~3.55 (m, 8H), 2.55 (s, 3H), 2.50 (s, 3H), 2.07 (s, 3H), 1.51 (d, J = 5.0 Hz, 3H); LC-MS m / e: 487.3 (MH + ).

[0289] Compound 50: 1 HNMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.14 (s, 1H), 5.80 (q, J = 6.9 Hz, 1H), 3.68 (s, 3H), 3.64 (t, J = 6.8Hz, 2H), 3.39 (s, 2H), 2.54 (s, 3H), 2.51 (s, 3H), 1.95 (t, J = 6.7 Hz, 2H), 1.48 (d, J = 6.6 Hz, 3H), 0.71~0.61 (m, 4H); LC-MS m / e: 456.3 (MH + ).

[0290] Compound 51: 1 HNMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.36 (t, J = 7.9 Hz, 1H), 5.78 (q, J = 6.7 Hz, 1H), 3.67~3.60 (m, 7H), 2.53 (s, 3H), 2.45 (s, 3H), 1.48~1.39 (m, 7H), 0.37 (s, 4H); LC-MS m / e: 470.3 (MH +).

[0291] Compound 52: 1 HNMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.7 Hz, 2H), 7.37 (t, J = 7.9 Hz, 1H), 5.80 (q, J = 6.6 Hz, 1H), 4.17 (d, J = 12.4 Hz, 1H), 4.06 (d, J = 13.0 Hz, 1H), 4.01~3.95 (m, 1H), 3.69 (s, 3H), 3.60 (dd, J = 11.6, 8.8 Hz, 2H), 2.94~2.86 (m, 1H), 2.54 (s, 3H), 2.50 (s, 3H), 2.52~2.50 (m, 1H), 1.49 (d, J = 6.7 Hz, 3H), 1.20 (d, J = 6.2 Hz, 3H); LC-MS m / e: 460.6 (MH + ).

[0292] Compound 53 acid acid: 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 5.84 (q, J = 6.3 Hz, 1H), 3.81 (s, 3H), 3.64 (s, 4H), 3.41 (s, 2H), 3.34 (s, 2H), 2.58 (s, 6H), 2.07 (s, 3H), 1.55 (d, J = 6.6 Hz, 3H); LC-MS m / e: 487 (MH + ).

[0293] Examples 54~79 (R,Z)-3-(1-((1,2-ジメチル-6-モルホリノピリド[3,4-d]ピリミジSynthesis of ン-4(1H)-イリデン)アミノ)エチル)-2-メチルベンゾニトリル (Compound 54) [ka]

[0294] To a solution of (R,Z)-3-(1-((6-chloro-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-ylidene)amino)ethyl)-2-methylbenzonitrile (150 mg, 0.426 mmol) and morpholine (74 mg, 0.852 mmol) in toluene (10 mL) was added t-BuONa (123 mg, 1.28 mmol), BINAP (53 mg, 0.085 mmol), and Pd(OAc) (19 mg, 0.085 mmol) at 25 °C. The mixture was stirred at 100 °C under an atmosphere of N for 2 h, after which the reaction mixture was cooled to room temperature, poured into ice water (20 mL), and extracted with DCM (50 mL × 3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated and purified by preparative HPLC to give the title compound (74.6 mg, 0.185 mmol, yield: 43.5%) as a yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.32 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.52 (s, 1H), 7.37 (t, J = 7.7 Hz, 1H), 5.72 (q, J = 6.6 Hz, 1H), 3.77~3.72 (m, 4H), 3.68 (s, 3H), 3.55~3.46 (m, 4H), 2.63 (s, 3H), 2.50 (s, 3H), 1.46 (d, J = 6.7Hz, 3H). LCMS m / e: 403.4 (MH + ).

[0295] Applying the same steps as above, the following compounds 55-79 were prepared.

[0296] Compound 55: 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.36 (t, J = 7.8 Hz, 1H), 5.84~5.75 (m, 1H), 3.78~3.73 (m, 4H), 3.64 (s, 3H), 3.52~3.47 (m, 4H), 2.53 (s, 3H), 2.46 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H); LCMS m / e: 446.2 (MH + ).

[0297] Compound 56 acid acid: 1 HNMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.30 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.37 (t, J = 7.7 Hz, 1H), 5.71 (q, J = 6.8 Hz, 1H), 3.67 (s, 3H), 3.63~3.57 (m, 8H), 3.56~3.51 (m, 3H), 2.63 (s, 3H), 2.06 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H);LCMS m / e: 444.3 (MH + ).

[0298] Compound 57 acid acid: 1HNMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.33 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.21 (s, 1H), 5.73 (q, J = 6.5 Hz, 1H), 3.71 (s, 3H), 3.50~3.42 (m, 4H), 2.64 (s, 3H), 2.52 (s, 3H), 2.03~1.94 (s, 4H), 1.49 (d, J = 6.7 Hz, 3H);LCMS m / e: 387.2 (MH + ).

[0299] Compound 58: 1 HNMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.48 (s, 1H), 7.37 (t, J = 7.8 Hz, 1H), 5.70 (q, J = 6.7 Hz, 1H), 4.02~3.93 (m, 2H), 3.66 (s, 3H), 3.25~3.20 (m, 3H), 2.63 (s, 3H), 2.48 (s, 3H), 1.93 (dd, J = 10.1, 3.4 Hz, 2H), 1.45 (d, J = 6.7 Hz, 5H);LCMS m / e: 434.5 (MH + ).

[0300] Compound 59 acid chloride: 1HNMR (400 MHz, DMSO-d6) δ 8.72~8.66 (m, 1H), 8.34~8.28 (m, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.66~7.56 (m, 2H), 7.37 (t, J = 7.7 Hz, 1H), 5.74~5.68 (m, 1H), 3.75 (s, 4H), 3.69~3.66 (m, 3H), 2.63(s, 3H), 2.50 (s, 3H), 2.12~2.00 (m, 4H), 1.49~1.43 (m, 3H); LCMS m / e: 437.4 (MH + ).

[0301] Compound 60 acid chloride: 1 HNMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.35 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.52 (s, 1H), 7.37 (t, J = 7.7 Hz, 2H), 5.71 (q, J = 6.2 Hz, 1H), 3.68 (s, 3H), 3.66~3.62 (m, 4H), 2.63 (s, 3H), 2.50 (s, 3H), 1.50~1.39 (m, 6H), 0.37 (s, 4H);LCMS m / e: 427.3 (MH + ).

[0302] Compound 61 acid chloride: 1HNMR(400 MHz, DMSO-d6) δ 8.73~8.66 (m, 1H), 8.31~8.26 (m, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.56~7.47 (m, 1H), 7.37 (t, J = 7.7 Hz, 1H), 5.72 (q, J = 5.7 Hz, 1H), 4.17(d, J = 12.6 Hz, 1H), 4.06 (d, J = 11.1 Hz, 1H), 4.00~3.94 (m, 1H), 3.71~3.68 (m, 3H), 3.62~3.59 (m, 2H), 2.89 (t, J = 12.0 Hz, 1H), 2.63 (s, 3H), 2.56 (t, J = 11.0 Hz, 1H), 2.51 (s, 3H), 1.50~1.45(m, 3H), 1.20 (d, J = 6.2 Hz, 3H);LCMS m / e: 417.3 (MH + ).

[0303] Compound 62: 1 HNMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.23 (s, 1H), 5.79 (q, J = 6.7 Hz, 1H), 3.91 (t, J = 13.2 Hz, 2H), 3.70 (t, J = 7.3 Hz, 2H), 3.64 (s, 3H), 2.64~2.55 (m, 2H), 2.53 (s, 3H), 2.46 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H);LCMS m / e: 466 (MH + ).

[0304] Compound 63 acid chloride: 11H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.23 (brs, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.77 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 5.85 (q, J = 6.8 Hz, 1H), 3.85 (s, 3H), 3.64 (t, 4H), 2.76~2.71 (m, 1H), 2.61 (s, 3H), 2.60 (t, 3H), 2.58 (s, 4H), 1.62 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.5 Hz, 6H); LCMS m / e: 487.3 (MH + ).

[0305] Compound 64: 1 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.93 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 6.9 Hz, 1H), 7.42 (s, 1H), 7.36 (t, J = 7.7 Hz, 1H), 5.70 (q, J = 6.6 Hz, 1H), 3.63 (s, 3H), 3.58~3.54 (m, 4H), 2.62 (s, 3H), 2.46 (s, 3H), 1.65~1.54 (m, 6H), 1.43 (d, J = 6.7 Hz, 3H); LCMS m / e: 401.4 (MH + ).

[0306] Compound 65: 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.90 (d, J = 7.3 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.02 (s, 1H), 5.70 (q, J = 6.7 Hz, 1H), 3.63~3.60 (m, 4H), 3.36 (s, 3H), 2.61 (s, 3H), 2.44 (s, 3H), 1.93 (t, J = 6.8 Hz, 2H), 1.41 (d, J = 6.7 Hz, 3H), 069~0.61 (m, 4H);LCMS m / e: 413.3 (MH + ).

[0307] Compound 66 acid chloride: 1 H NMR (400 MHz, DMSO-d6) δ 8.64~8.58 (m, 1H), 8.30 (dd, J = 7.5, 3.7 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 9.4 Hz, 1H), 7.18 (dd, J = 14.6, 4.3 Hz, 1H), 5.70 (q, J = 6.3 Hz, 1H), 3.91 (t, J = 13.2 Hz, 2H), 3.69 (t, J = 7.2 Hz, 2H), 3.64 (s, 3H), 2.62 (s, 3H), 2.60~2.53 (m, 2H), 2.47 (s, 3H), 1.42 (s, 3H); LCMS m / e: 423.2 (MH + ).

[0308] Compound 67 acid acid: 1HNMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.37 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.53 (s, 1H), 7.37 (t, J = 7.8 Hz, 1H), 5.71 (q, J = 6.7 Hz, 1H), 3.93~3.87 (m, 2H), 3.69 (s, 3H), 3.45~3.32 (m, 2H), 3.11 (m, 1H), 2.64 (s, 3H), 2.53~2.50 (m, 3H), 1.64~1.41 (m, 7H), 1.16 (s, 3H);LCMS m / e: 431.3 (MH + ).

[0309] Compound 68: 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.45 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 5.77 (q, J = 6.3 Hz, 1H), 4.36 (s, 1H), 4.25 (s, 1H), 4.10~4.05 (m, 1H), 3.98~3.92 (m, 1H), 3.83~3.81 (m, 1H), 3.79~3.75 (m, 1H), 3.61 (s, 3H), 2.51 (s, 3H), 2.45 (s, 3H), 2.07 (d, J = 5.6 Hz, 3H), 1.38 (d, J = 6.6 Hz, 3H); LCMS m / e: 501.2 (MH + ).

[0310] Compound 69 acid chloride: 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.30 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.17~7.11 (m, 1H), 5.73~5.66 (m, 1H), 5.64~5.43 (m, 1H), 4.41~4.31 (m, 2H), 4.13~4.03 (m, 2H), 3.64 (s, 3H), 2.62 (s, 3H), 2.47 (s, 3H), 1.44 (d, J = 6.7 Hz, 3H);LCMS m / e: 391.3 (MH + ).

[0311] Compound 70: 1 H NMR (400 MHz, CD3OD) δ 9.03 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.49~7.43 (m, 1H), 7.37 (t, J = 7.8 Hz, 1H), 5.74~5.65 (m, 1H), 4.53 (t, J = 12.0 Hz, 4H), 3.99 (s, 3H), 3.31 (d, 3H), 2.73 (s, 3H), 1.71 (d, J = 7.0 Hz, 3H); LCMS m / e: 409.2 (MH + ).

[0312] Compound 71: 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 6.91 (s, 1H), 5.70~5.62 (m, 1H), 3.97 (t, J = 6.9 Hz, 4H), 3.54 (s, 3H), 2.60 (s, 3H), 2.39 (s, 3H), 2.37~2.29 (m, 2H), 1.37 (d, J = 6.3 Hz, 3H);LCMS m / e: 373.3 (MH + ).

[0313] Compound 72, Torofluoride acid chloride: 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.05 (s, 1H), 7.98 (d, J = 7.0 Hz, 1H), 7.69 (d, J = 7.7 Hz, 2H), 7.42 (t, J = 7.8 Hz, 1H), 5.82 (p, J = 6.6 Hz, 1H), 3.91 (s, 3H), 3.84 (dd, J = 15.0, 10.9 Hz, 2H), 3.51 (t, J = 9.0 Hz, 2H), 2.68 (d, J = 7.6 Hz, 6H), 1.83~1.75 (m, 2H), 1.69 (d, J = 7.0 Hz, 3H), 0.86~0.76 (m, 1H), 0.20 (dd, J = 8.3, 4.2 Hz, 1H); LCMS m / e: 399 (MH + ).

[0314] Compound 73 acid chloride: 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.32 (d, J = 5.9 Hz, 1H), 7.91 (d, J = 6.3 Hz, 1H), 7.76~7.55 (m, 1H), 7.37 (dd, J = 13.4, 7.2 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 5.81~5.64 (m, 1H), 3.91 (s, 2H), 3.86 (s, 2H), 3.72 (s, 1H), 3.67 (s, 3H), 2.63 (d, J = 3.5 Hz, 3H), 2.55 (s, 3H), 1.47 (d, J = 2.7 Hz, 6H);LCMS m / e: 403 (MH + ).

[0315] Compound 74: 1 H NMR (400 MHz, CD3OD) δ 9.04 (d, J = 4.8 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 4.5 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 5.98~5.85 (m, 1H), 4.60~4.49 (m, 1H), 4.10~4.02 (m, 2H), 4.00 (d, J = 2.5 Hz, 3H), 3.86 (d, J = 11.5 Hz, 1H), 3.79~3.74 (m, 1H), 3.68~3.56 (m, 1H), 3.38~3.33 (m, 1H), 3.31 (s, 3H), 2.73 (s, 3H), 1.71 (d, J = 7.0 Hz, 3H), 1.29 (d, J = 6.7 Hz, 3H); LCMS m / e: 417.4 (MH + ).

[0316] Compound 75 acid chloride: 1HNMR(400 MHz, CD3OD) δ 9.05 (s, 1H), 8.49 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.52 (s, 1H), 7.37 (t, J = 7.8 Hz, 1H), 5.91 (q, J = 6.9 Hz, 1H), 4.56 (d, J = 4.0 Hz, 1H), 4.06 (dd, J = 11.1, 3.9 Hz, 2H), 4.01 (s, 3H), 3.86 (d, J = 11.5 Hz, 1H), 3.77 (dd, J = 11.5, 3.0 Hz, 1H), 3.63 (td, J = 11.9, 3.0 Hz, 1H), 3.36 (dd, J = 12.9, 4.0 Hz, 1H), 2.74 (s, 6H), 1.72 (d, J = 7.0 Hz, 3H), 1.29 (d, J = 6.7 Hz, 3H); LCMS m / e: 417 (MH + ).

[0317] Compound 76 acid chloride: 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.29 (d, J = 9.1 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 16.4 Hz, 1H), 5.72 (q, J = 6.7 Hz, 1H), 4.37 (dt, J = 6.1, 5.1 Hz, 1H), 4.27~4.22 (m, 2H), 3.86~3.82 (m, 2H), 3.70 (s, 3H), 2.63 (s, 3H), 2.51 (s, 3H), 2.50 (s, 3H), 1.49 (d, J = 3.9 Hz, 3H); LCMS m / e: 403 (MH + ).

[0318] Compound 77 acid chloride: 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.41~8.32 (m, 1H), 8.30 (s, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 5.84 (q, J = 6.8 Hz, 1H), 4.36~4.18 (m, 2H), 3.88~3.78 (m, 4H), 3.76~3.63 (m, 4H), 3.19~2.99 (m, 2H), 2.60 (s, 3H), 2.43 (dd, J = 15.2, 8.2 Hz, 2H), 1.71 (d, J = 6.8 Hz, 3H).LC-MS m / e: (MH + );LCMS m / e: 458 (MH + ).

[0319] Compound 78 acid chloride: 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.35 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 5.79 (q, J = 6.7 Hz, 1H), 5.02~4.82 (m, 1H), 3.75 (s, 4H), 3.53 (s, 4H), 2.56 (d, J = 6.8 Hz, 6H), 1.59 (t, J = 7.4 Hz, 6H), 1.48 (d, J = 6.6 Hz, 3H);LCMS m / e: 476 (MH + ).

[0320] Compound 79: 1H NMR (400 MHz, CD3OD) δ 9.22 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.35 (t, J = 7.8 Hz, 1H), 5.97 (q, J = 6.8 Hz, 1H), 3.89~3.77 (m, 4H), 3.73~3.64 (m, 4H), 3.31 (s, 3H), 2.80~2.74 (m, 1H), 2.62 (s, 3H), 1.69 (d, J = 6.8 Hz, 3H), 1.49 (d, J = 7.0 Hz, 2H), 1.13 (s, 2H); LCMS m / e: 472 (MH + ).

[0321] Example 80 Synthesis of (R,Z)-6-(3-(difluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine (Compound 80) [ka]

[0322] Step 1. Synthesis of ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxylate To a solution of ethyl imidazo[1,2-a]pyrazine-3-carboxylate (5 g, 26.2 mmol) in MeOH (300 mL) was added Pd / C (1 g, 10% and 55% wet) under a H balloon at 25 °C. After stirring for 16 h, the reaction mixture was filtered and cooled to 100 °C. (R) The mixture was filtered through a pad, and the filtrate was concentrated to give the title compound (5 g, 25.6 mmol, yield: 97.9%) as a white solid. LC-MS m / e: 196.2 (MH + ).

[0323] Step 2: Synthesis of 7-(tert-butyl) 3-ethyl 5,6-dihydroimidazo[1,2-a]pyrazine-3,7(8H)-dicarboxylate To a solution of ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxylate (2.4 g, 12.3 mmol) and di-tert-butyl dicarbonate (3.16 mL, 14.5 mmol) in DCM (50 mL) was added EtN (3.76 mL, 27.1 mmol) at 25 °C and stirred for 3 h. The reaction mixture was poured into ice-water (20 mL), and the aqueous layer was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel flash column chromatography (gradient, PE to PE: EtOAc = 3:1) to give the title compound (3 g, 10.2 mmol, yield: 82.6%) as a yellow solid. LCMS m / e: 296.2 (MH+).

[0324] Step 3: Synthesis of tert-butyl 3-(hydroxymethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate To a solution of 2-methylpropan-2-yl 3-(ethoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carboxylate (2.4 g, 8.13 mmol) in THF (50 mL) was added LiAlH (0.46 g, 12.1 mmol) at −78° C. The mixture was stirred at −40° C. for 2 hours, and then THF (20 mL) was added, followed by the dropwise addition of water (3 mL), 15% aqueous NaOH (3 mL), and water (9 mL). Anhydrous MgSO was added. The mixture was stirred at room temperature for 0.5 hours. The resulting mixture was filtered through a Celite® pad and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to give the title compound (1.5 g, 5.92 mmol, 72.9% yield) as a white solid. LCMS m / e: 254.3 (MH+).

[0325] Step 4. Synthesis of tert-butyl 3-formyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate To a solution of tert-butyl 3-(hydroxymethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (1 g, 3.95 mmol) in DCM (20 mL) was added Dess-Martin periodinane (1.67 g, 3.95 mmol) at 0 °C and stirred at 25 °C for 12 h. The reaction mixture was poured into a mixture of saturated NaSO solution (50 mL) and saturated NaHCO solution (50 mL) and stirred for 0.5 h. The aqueous layer was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel flash column chromatography (gradient, PE to PE: EtOAc = 1:1) to give the title compound (600 mg, 2.39 mmol, 60.5% yield) as a yellow solid. LCMS m / e: 252.26 (MH+).

[0326] Step 5: Synthesis of tert-butyl 3-(difluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate To a solution of tert-butyl 3-formyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (200 mg, 0.732 mmol) in DCM (5 mL) was added DAST (1 mL, 7.96 mmol) at 0 °C and stirred at 0 °C for 4 h. The reaction mixture was made basic with cold saturated NaHCO3 solution (20 mL), and the aqueous layer was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash column chromatography (gradient, PE to PE: EtOAc = 3:1) to give the title compound (150 mg, 0.549 mmol, 69% yield) as a yellow oil. LCMS m / e: 274.3 (MH+).

[0327] Step 6 Synthesis of 3-(difluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine To a solution of tert-butyl 3-(difluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (150 mg, 0.55 mmol) in DCM (5 mL) was added TFA (1 mL) at 0 °C and stirred at room temperature for 12 h. The reaction mixture was concentrated to dryness. The residue was diluted with DCM (20 mL) and adjusted to pH 8 with saturated NaHCO3 solution (20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash column (gradient, DCM to DCM:MeOH = 20:1) to give the title compound (70 mg, 0.404 mmol, yield: 73.6%) as a yellow oil. LCMS m / e: 174.3 (MH+).

[0328] Step 7: Synthesis of (R,Z)-6-(3-(difluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine (compound 80) To a solution of (R,Z)-6-chloro-1,2-dimethyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)-ethyl)pyrido[3,4-d]pyrimidin-4(1H)-imine (100 mg, 0.25 mmol) and 3-(difluoromethyl)-5,6,7,8-tetrahydroimidazo[3,2-a]pyrazine (53 mg, 0.304 mmol) in toluene (10 mL) was added t-BuONa (73 mg, 0.76 mmol), BINAP (32 mg, 0.051 mmol), and Pd(OAc) (12 mg, 0.05 mmol) at 25 °C. The mixture was stirred at 100 °C for 2 h under a N atmosphere. The reaction mixture was cooled to room temperature, poured into water (20 mL), and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to give the formate salt of the target compound (15 mg) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.34 (s, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.64 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.33~7.05 (m, 2H), 5.80 (q, J = 6.7 Hz, 1H), 4.81 (s, 2H), 4.17 (dd, J = 13.7, 4.2 Hz, 4H), 3.66 (s, 3H), 2.54 (s, 3H), 2.47 (s, 3H), 1.47 (d, J = 6.7 Hz, 3H). LCMS m / e: 532.2 (MH + ).

[0329] Example 81 Synthesis of (R,Z)-6-(1-acetyl-4-hydroxypiperidin-4-yl)-1,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,7-dihydropyrido[3,4-d]pyrimidin-8(4H)-one (Compound 81) [ka]

[0330] Step 1. Synthesis of 3-amino-6-bromo-2-methoxyisonicotinic acid To a solution of 3-amino-2-methoxyisonicotinic acid (5 g, 27.3 mmol) in DMF (30 mL) was added NBS (5.11 g, 28.7 mmol) in portions, and the mixture was stirred at 20 °C for 1 h, diluted with water (40 mL), and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel flash column chromatography (gradient, PE to PE: EtOAc = 3:1) to give the title compound (4.2 g, 17 mmol, yield: 62.1%) as a brown solid. LC-MS m / e: 247, 249 (MH + ).

[0331] Step 2 Synthesis of 3-amino-6-bromo-2-methoxyisonicotinamide To a solution of 3-amino-6-bromo-2-methoxyisonicotinic acid (4.2 g, 17 mmol) in DMF (20 mL), DIPEA (4.39 g, 34 mmol), NHCl (1.36 g, 25.5 mmol), and HATU (7.75 g, 20.4 mmol) were added and stirred at 20 °C for 1 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel flash column chromatography (gradient, PE to PE: EtOAc = 1:1) to give the title compound (4 g, 16.2 mmol, yield: 95.6%) as a yellow solid. LC-MS m / e: 246, 248 (MH + ).

[0332] Step 3 Synthesis of 6-bromo-8-methoxypyrido[3,4-d]pyrimidin-4-ol To a solution of 3-amino-6-bromo-2-methoxyisonicotinamide (4 g, 16.2 mmol) in EtOH (80 mL), AcOH (13.9 mL, 243 mmol) and CH(OEt) (36 g, 243 mmol) were added and stirred at 120° C. for 3 h. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was triturated with EtOAc (50 mL) to give the title compound (3.4 g, 13.2 mmol, 81.6% yield) as a yellow solid. LC-MS m / e: 256, 258 (MH + ).

[0333] Step 4: Synthesis of (R)-6-bromo-8-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine To a solution of 6-bromo-8-methoxypyrido[3,4-d]pyrimidin-4-ol (3.4 g, 13.2 mmol) in MeCN (30 mL) was added DIPEA (6.85 g, 53.1 mmol) and HCCP (5.08 g, 14.6 mmol). After stirring at 25 °C for 1 h, (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-amine hydrochloride (3.46 g, 14.6 mmol) was added. After stirring at 25 °C for 1 h, the mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL × 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash column chromatography (gradient, DCM to DCM:MeOH=30:1) to give the title compound (4.5 g, 10.1 mmol, yield: 76.8%) as a yellow solid. LC-MS m / e: 441, 443 (MH + ).

[0334] Step 5. Synthesis of (R)-6-bromo-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-pyrido[3,4-d]pyrimidin-8(7H)-one A suspension of (R)-6-bromo-8-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine (1.2 g, 2.72 mmol) in HBr (10 mL, 48% aqueous solution) was stirred at 100° C. for 2 hours. The mixture was allowed to cool to room temperature, and the pH was adjusted to approximately 7 with the addition of 20% NaOH at 10° C. The resulting solid was collected by filtration and dried under reduced pressure to give the title compound (600 mg, 1.4 mmol, yield: 51.6%) as a yellow solid. LC-MS m / e: 427, 429 (MH + ).

[0335] Step 6. Synthesis of (R)-6-bromo-7-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-amino)pyrido[3,4-d]pyrimidin-8(7H)-one To a solution of (R)-6-bromo-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-amino)pyrido[3,4-d]pyrimidin-8(7H)-one (600 mg, 1.4 mmol) in DMF (5 mL) was added CsCO (686 mg, 2.1 mmol) and stirred at 20 °C for 0.5 h. MeI (199 mg, 1.4 mmol) was added at 0 °C, and the mixture was stirred at 20 °C for 1 h. The resulting mixture was poured into ice water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layer was washed with brine (50 mL × 2) and dried over anhydrous NaSO, then filtered and concentrated to dryness. The residue was purified by silica gel chromatography (gradient, DCM to DCM:MeOH = 10:1) to give the title compound (250 mg, 0.567 mmol, yield: 40.3%) as a yellow solid. LC-MS m / e: 441, 443 (MH + ).

[0336] Step 7 Synthesis of (R)-6-(1-acetyl-4-hydroxypiperidin-4-yl)-7-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-8(7H)-one To a solution of (R)-6-bromo-7-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-amino)pyrido[3,4-d]pyrimidin-8(7H)-one (230 mg, 0.521 mmol) in THF (10 mL) was added n-BuLi (1.04 mL, 2.6 mmol, 2.5 M in hexane) dropwise at −70° C. and stirred for 0.5 h, followed by the addition of 1-acetylpiperidin-4-one (154 mg, 0.782 mmol). The resulting mixture was stirred at −70° C. for 0.5 h, then quenched with water (10 mL) and extracted with EtOAc (30 mL × 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (gradient, DCM to DCM:MeOH=10:1) to give the title compound (50 mg, 0.099 mmol, yield: 19.0%) as a yellow solid. LC-MS m / e: 504 (MH + ).

[0337] Step 8. Synthesis of (R,Z)-6-(1-acetyl-4-hydroxypiperidin-4-yl)-1,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,7-dihydropyrido[3,4-d]pyrimidin-8(4H)-one (compound 81) To a solution of (R)-6-(1-acetyl-4-hydroxypiperidin-4-yl)-7-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-8(7H)-one (50 mg, 0.099 mmol) in DCM (5 mL), proton sponge (21 mg, 0.099 mmol) and trimethyloxonium tetrafluoroborate (15 mg, 0.1 mmol) were added and stirred at 20 °C for 0.5 h. The resulting mixture was quenched with water (5 mL) and extracted with DCM (10 mL × 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (SilaSep TM Purification by C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% FA) gave the title compound (13 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 6.99 (s, 1H), 5.82 (s, 1H), 5.67 (q, J = 6.8 Hz, 1H), 4.32 (d, J = 12.8 Hz, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 3.74 (s, 1H), 3.47 (d, J = 3.1 Hz, 1H), 2.98 (t, J = 13.1 Hz, 1H), 2.47 (s, 3H), 2.18~2.06 (m, 2H), 2.04 (s, 3H), 1.97~1.74 (m, 2H), 1.43~1.35 (m, 3H). LCMS m / e: 518 (MH + ).

[0338] Example 82 Synthesis of (R,Z)-6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,7-dihydropyrido[3,4-d]pyrimidin-8(4H)-one (Compound 82) [ka]

[0339] Step 1. Synthesis of (R)-6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-8(7H)-one To a solution of (R)-6-bromo-7-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-8(7H)-one (300 mg, 0.680 mmol) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (256 mg, 1.02 mmol) in dioxane (10 mL) and water (2 mL) was added NaCO (216 mg, 2.04 mmol) and Pd(dppf)Cl (49 mg, 0.068 mmol) and the mixture was stirred at 100 °C under an atmosphere of N for 18 h. After cooling, the solution was purified by silica gel flash chromatography (gradient, DCM to DCM:MeOH=10:1) to give the title compound (250 mg, 0.515 mmol, yield: 75.7%) as a light brown solid. LCMS m / e: 486 (MH + ).

[0340] Step 2 Synthesis of (R,Z)-6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1,7-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-1,7-dihydropyrido[3,4-d]pyrimidin-8(4H)-one (compound 82). To a solution of (R)-6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-8(7H)-one (150 mg, 0.309 mmol) in DMF (2 mL) was added CsCO (151 mg, 0.463 mmol). The mixture was stirred at room temperature for 30 minutes, and then iodomethane (65 mg, 0.463 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature for 30 minutes, poured into water (15 mL), and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (15 mL × 2), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by reverse-phase chromatography (SilaSep TMPurification by C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% formic acid) gave the formate salt of the title compound (80 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.15 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 6.85 (s, 1H), 6.03 (s, 1H), 5.72 (q, J = 6.8 Hz, 1H), 4.20~4.12 (m, 2H), 3.98 (s, 3H), 3.73~3.64 (m, 2H), 3.40 (s, 3H), 2.49 (s, 3H), 2.45~2.37 (m, 1H), 2.35~2.29 (m, 1H), 2.08 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H).LCMS m / e: 500 (MH + ).

[0341] Example 83 Synthesis of (R,Z)-6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1,8-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-4,8-dihydropyrido[2,3-d]pyrimidin-7(1H)-one (Compound 83). [ka]

[0342] Step 1 Synthesis of 6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl trifluoromethanesulfonate. To a solution of 6-bromo-4-hydroxy-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-7-one (1 g, 3.91 mmol) in DCM (40 mL) was added pyridine (0.032 mL, 0.391 mmol) and TfO (3.3 g, 11.8 mmol) at 0 °C and stirred at room temperature under a N atmosphere for 3 h. The resulting mixture was partitioned between water (10 mL) and EtOAc (50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give the title compound (595 mg, 1.53 mmol, 39.3% yield) as a yellow solid. LC-MS m / e: 388, 390 (MH + ).

[0343] Step 2 Synthesis of (R)-6-bromo-8-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl trifluoromethanesulfonate (595 mg, 1.53 mmol) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (312 mg, 1.53 mmol) in dioxane (5 mL) was added DIEA (1.27 mL, 7.67 mmol), and the mixture was stirred at 100 °C under an atmosphere of N for 2 h. The resulting mixture was allowed to cool to room temperature and concentrated to dryness. The residue was partitioned between water (10 mL) and EtOAc (30 mL). The organic layer was dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel flash chromatography (gradient, PE to PE: EtOAc = 10:1) to give the title compound (503 mg, 1.18 mmol, yield: 76.8%) as a yellow solid. LC-MS m / e: 441, 443 (MH + ).

[0344] Step 3. Synthesis of (R)-6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-8-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one To a solution of (R)-6-bromo-8-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (400 mg, 0.936 mmol), Pd(dppf)Cl (67 mg, 0.091 mmol), and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethan-1-one (342 mg, 1.36 mmol) in dioxane (15 mL) and HO (3 mL) was added NaCO (289 mg, 2.73 mmol), and the mixture was stirred at 100 °C under an atmosphere of N for 3 h. The resulting mixture was cooled to room temperature and purified by silica gel flash chromatography (gradient, DCM to DCM:MeOH=10:1) to give the title compound (422 mg, 0.869 mmol, yield: 92.8%) as a yellow solid. LC-MS m / e: 486 (MH + ).

[0345] Step 4 Synthesis of (R,Z)-6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1,8-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imino)-4,8-dihydropyrido[2,3-d]pyrimidin-7(1H)-one. A mixture of (R)-6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-8-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.412 mmol) and CsCO (201 mg, 0.618 mmol) in DMA (1 mL) was stirred at 15 °C under an atmosphere of N for 10 min, and then CHCl (88 mg, 0.618 mmol) was added at 0 °C. The mixture was stirred at 15 °C for 12 h and filtered. The filtrate was purified by preparative HPLC (SilaSepTM Purification by C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% formic acid) afforded the title compound (24.6 mg, 0.049 mmol, 12.0% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 3.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 6.49 (d, J = 19.2 Hz, 1H), 6.16 (q, J = 6.4 Hz, 1H), 4.05 (d, J = 23.6 Hz, 2H), 3.61 (s, 3H), 3.58~3.46 (m, 2H), 2.94 (s, 3H), 2.50~2.23 (m, 2H), 2.20 (s, 3H), 2.00 (d, J = 11.6 Hz, 3H), 1.61 (d, J = 6.8 Hz, 3H).LC-MS m / e: 500 (MH + ).

[0346] Example 84 Synthesis of (Z)-7-methoxy-1,2-dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazoline-4(1H)-imine (Compound 84). [ka]

[0347] Step 1 Synthesis of 6,7-dimethoxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione. To a solution of 2-amino-4,5-dimethoxybenzoic acid (10 g, 50.7 mmol) in THF (100 mL) was slowly added triphosgene (4.51 g, 15.2 mmol) at 0° C. and stirred at room temperature for 0.5 hours. The solvent was removed under reduced pressure, and petroleum ether (200 mL) was added and sonicated. The precipitated solid was filtered off with suction. The cake was collected and dried in vacuo to give the title compound (10 g, 44.8 mmol, 88.4% yield) as a gray solid. LC-MS m / e: 224.1 (MH + ).

[0348] Step 2: Synthesis of 6,7-dimethoxy-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione To a solution of 6,7-dimethoxy-2,4-dihydro-1H-benzo[2,1-d][1,3]oxazine-2,4-dione (5 g, 22.4 mmol) in DMF (50 mL) was added NaH (1.16 g, 29.0 mmol, 60% suspension in mineral oil) at 0 °C under an atmosphere of N2. The mixture was stirred at room temperature for 30 min. After cooling to 0 °C, MeI (2.1 mL, 33.6 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was diluted with ice water (300 mL), and the residue was filtered and rinsed with water (20 mL) and ethyl ether (20 mL). The cake was collected and dried in vacuo to give the title compound (4 g, 16.9 mmol, yield: 75.3%) as a yellow solid. LC-MS m / e: 238.01 (MH + ).

[0349] Step 3 Synthesis of 4,5-dimethoxy-2-(methylamino)benzamide. To a solution of 6,7-dimethoxy-1-methyl-2,4-dihydro-1H-benzo[2,1-d][1,3]oxazine-2,4-dione (4 g, 16.9 mmol) in THF (60 mL) was added NH4OH solution (30 mL, 30% in water) at 0 °C, and the mixture was stirred at 0 °C for 30 minutes, followed by stirring at room temperature for 30 minutes. THF was distilled under vacuum, and the remaining suspension was neutralized with HCl solution (2 M). The product was isolated by filtration. The cake was collected and dried under vacuum to give the title compound (3.5 g, 16.6 mmol, yield: 98.7%) as a yellow solid. LC-MS m / e: 211.1 (MH + ).

[0350] Step 4 Synthesis of 6,7-dimethoxy-1,2-dimethylquinazolin-4(1H)-one. To a solution of 4,5-dimethoxy-2-(methylamino)benzene-1-carboxamide (3.6 g, 17.1 mmol) in EtOH (75 mL) was added 1,1,1-triethoxyethane (47.1 mL, 257 mmol) and AcOH (14.7 mL, 257 mmol) at 25° C. The mixture was stirred in a sealed tube at 120° C. for 12 hours, and the reaction mixture was cooled to room temperature and filtered. The cake was washed with EtOAc (100 mL) and dried under vacuum to give the title compound (3 g, 12.8 mmol, yield: 74.8%) as a gray solid. LC-MS m / e: 235.1 (MH + ).

[0351] Step 5 Synthesis of 6-hydroxy-7-methoxy-1,2-dimethylquinazolin-4(1H)-one. To a solution of 6,7-dimethoxy-1,2-dimethylquinazolin-4(1H)-one (1 g, 4.27 mmol) in MSA (15 mL) was added L-methionine (0.96 g, 6.40 mmol) at 25°C. The mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature and adjusted to pH 5-6 with 40% aqueous sodium hydroxide solution under ice-water bath cooling. The solid precipitated was filtered, washed with water (30 mL x 2), and dried under reduced pressure to give the title compound (900 mg, 4.09 mmol, yield: 95.7%) as a gray solid. LC-MS m / e: 221.10 (MH +).

[0352] Step 6 Synthesis of (S)-7-methoxy-1,2-dimethyl-6-((tetrahydrofuran-3-yl)oxy)quinazolin-4(1H)-one To a solution of 6-hydroxy-7-methoxy-1,2-dimethylquinazolin-4(1H)-one (200 mg, 0.908 mmol) and (3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (220 mg, 0.908 mmol) in DMF (10 mL) was added K2CO3 (377 mg, 2.72 mmol) at 25 °C. The mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness. The residue was purified by reverse-phase column (C18, gradient, 0-30% CH3CN in HO) to give the title compound (100 mg, 0.344 mmol, yield: 37.9%) as a yellow solid. LC-MS m / e: 291.3 (MH + ).

[0353] Step 7 Synthesis of (S)-7-methoxy-1,2-dimethyl-6-((tetrahydrofuran-3-yl)oxy)quinazoline-4(1H)-thione. To a solution of (S)-7-methoxy-1,2-dimethyl-6-((tetrahydrofuran-3-yl)oxy)quinazolin-4(1H)-one (100 mg, 0.344 mmol) in dichloroethane (10 mL) was added Lawesson's reagent (84 mg, 0.207 mmol) at 25 °C. The mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by flash column (silica gel, gradient, 0-10% MeOH in DCM) to give the title compound (44 mg, 0.144 mmol, yield: 41.7%) as a yellow solid. LC-MS m / e: 307.2 (MH + ).

[0354] Step 8 Synthesis of (S)-7-methoxy-1,2-dimethyl-4-(methylthio)-6-((tetrahydrofuran-3-yl)oxy)quinazolin-1-ium iodide. A solution of (S)-7-methoxy-1,2-dimethyl-6-((tetrahydrofuran-3-yl)oxy)quinazoline-4(1H)-thione (44 mg, 0.144 mmol) in MeI (2 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated to give the title compound (44 mg, 0.136 mmol, yield: 95%) as a red solid, which was used directly without further purification. LC-MS m / e: 322.4 (MH + ).

[0355] Step 9 Synthesis of (Z)-7-methoxy-1,2-dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4(1H)-imine (Compound 84). To a solution of (S)-7-methoxy-1,2-dimethyl-4-(methylthio)-6-((tetrahydrofuran-3-yl)oxy)quinazolin-1-ium iodide (44 mg, 0.136 mmol) in DMA (2 mL), (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-amine (31 mg, 0.150 mmol) was added and stirred at 25° C. for 1 hour. The reaction mixture was purified by preparative HPLC to give the formate salt of the title compound (20 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.30 (d, J = 24.6 Hz, 1H), 7.92 (t, J = 8.5 Hz, 1H), 7.56 (d, J = 7.4 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.33~7.22 (m, 1H), 5.89~5.79 (m, 1H), 5.49~5.25 (m, 1H), 4.05~3.98 (m, 3H), 3.90~3.77 (m, 7H), 2.67 (s, 3H), 2.61 (s, 3H), 2.42~2.30 (m, 1H), 2.04~1.94 (m, 1H), 1.63 (d, J = 6.7 Hz, 3H).LC-MS m / e: 476.3 (MH + ).

[0356] Example 85 Synthesis of (R,Z)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)prop-2-yn-1-amine (Compound 85) [ka]

[0357] Step 1 Synthesis of tert-butyl (R,Z)-(3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)prop-2-yn-1-yl)carbamate. To a solution of (R,Z)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-imine (300 mg, 0.705 mmol) and tert-butyl prop-2-yn-1-ylcarbamate (219 mg, 1.410 mmol) in DMSO (5 mL) and EtN (5 mL) was added CuI (27 mg, 0.141 mmol) and Pd(PPh)Cl (99 mg, 0.141 mmol), and the mixture was stirred at 50 °C under an atmosphere of N for 16 h. The resulting solution was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL × 2). The combined organic layer was washed with saturated brine (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by aluminum oxide (gradient, PE to PE:DCM:MeOH=50:4:1) to give the title compound (240 mg, 0.480 mmol, yield: 68.1%) as a pale yellow solid. LC-MS m / e: 500 (MH + ).

[0358] Step 2: Synthesis of (R,Z)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)prop-2-yn-1-amine To a solution of tert-butyl (R,Z)-(3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)prop-2-yn-1-yl)carbamate (240 mg, 0.48 mmol) in DCM (10 mL) was added TFA (2 mL) at 0 °C and stirred at room temperature for 1 h. The resulting solution was quenched with saturated NaHCO solution (40 mL) and extracted with DCM (20 mL × 2). The combined organic layer was dried over anhydrous NaSO, filtered, concentrated, and purified by aluminum oxide column (gradient, DCM to DCM:MeOH = 20:1) to give the title compound (160 mg, 0.401 mmol, yield: 83.5%) as a brown solid. LC-MS m / e: 400 (MH + ).

[0359] Step 3: Synthesis of (R,Z)-N-(3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)prop-2-yn-1-yl)acetamide (Compound 85) To a solution of (R,Z)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)prop-2-yn-1-amine (60 mg, 0.150 mmol) in DCM (20 mL) was added EtN (0.021 mL, 0.150 mmol) at 0 °C, followed by acetyl chloride (0.011 mL, 0.15 mmol). The mixture was stirred at 0 °C for 0.5 h. The resulting solution was poured into water (10 mL) and extracted with DCM (10 mL × 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous NaSO, and then filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to give the formate salt of the title compound (35 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.44 (t, J = 4.8 Hz, 1H), 8.19 (s, 1H), 8.05 (d, J = 3.8 Hz, 1H), 7.93 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.0 Hz, 1H), 7.35~7.04 (m, 2H), 5.77 (q, J = 6.6 Hz, 1H), 4.15 (d, J = 5.4 Hz, 2H), 3.61 (s, 3H), 2.45 (s, 3H), 1.87 (s, 3H), 1.38 (d, J = 6.6 Hz, 3H). 19 F NMR (377 MHz, DMSO) δ -112.76 (dd, J = 13.4, 3.9 Hz), -125.65 (s).LC-MS m / e: 442 (MH + ).

[0360] Synthesis of (R,Z)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-N-isopropylprop-2-yn-1-amine (Compound 86) [ka]

[0361] A solution of (R,Z)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)prop-2-yn-1-amine (90 mg, 0.225 mmol) and propan-2-one (1.5 mL, 20 mmol) in THF (15 mL) was stirred at room temperature for 5 minutes, followed by the addition of NaBH(OAc) (96 mg, 0.451 mmol) and stirring for 0.5 hours. The resulting solution was directly purified by preparative HPLC to afford the title compound (5.6 mg, 0.013 mmol, 5.6% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.91 (t, J = 7.0 Hz, 1H), 7.48 (t, J = 6.8 Hz, 1H), 7.33 (t, J = 9.8 Hz, 1H), 7.14 (t, J = 54.4 Hz, 1H), 5.77 (q, J = 6.4 Hz, 1H), 3.73 (s, 2H), 3.64 (s, 3H), 3.07 (s, 1H), 2.47 (s, 3H), 1.40 (d, J = 6.6 Hz, 3H), 1.06 (d, J = 6.0 Hz, 6H).LC-MS m / e: 442 (MH + ).

[0362] Synthesis of (R,Z)-N-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)propane-2-sulfonamide (Compound 87) [ka]

[0363] To a solution of (R,Z)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-imine (50 mg, 0.12 mmol) and propane-2-sulfonamide (21.7 mg, 0.18 mmol) in DMF (5 mL) was added CuI (22.4 mg, 0.12 mmol), KCO (49 mg, 0.35 mmol), and 2,5-diazahexane (21 mg, 0.24 mmol) at 25 °C. The reaction mixture was stirred at 120 °C under a N atmosphere for 3 h. The resulting mixture was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to give the formate salt of the title compound (1.2 mg) as a pale yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.18 (s, 1H), 7.89 (t, J = 7.2 Hz, 1H), 7.64 (s, 1H), 7.47 (t, J = 7.1 Hz, 1H), 7.36~7.30 (m, 1H), 7.19 (t, J = 43.7 Hz, 1H), 5.76 (q, J = 6.7 Hz, 1H), 3.73 (dd, J = 13.6, 6.7 Hz, 1H), 3.60 (s, 3H), 2.43 (s, 3H), 1.39 (d, J = 6.6 Hz, 3H), 1.28 (d, J = 5.8 Hz, 6H).LCMS m / e: 468.5 (MH + ).

[0364] Synthesis of (R,Z)-N-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)cyclopentanecarboxamide (Compound 88) [ka]

[0365] To a solution of (R,Z)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-imine (100 mg, 0.235 mmol) and cyclopentanecarboxamide (80 mg, 0.705 mmol) in dioxane (20 mL), RuPhos (44 mg, 0.094 mmol), CsCO (191 mg, 0.588 mmol), and RuPhos Pd G (39 mg, 0.047 mmol) were added and stirred at 100 °C under an atmosphere of N for 16 h. The resulting solution was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (20 mL × 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to give the formate salt of the title compound (35 mg) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.75 (s, 1H), 8.64 (s, 1H), 8.19 (s, 1H), 7.87 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 6.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 46.6 Hz, 1H), 5.82 (q, J = 6.4 Hz, 1H), 3.63 (s, 3H), 2.95 (dd, J = 15.4, 7.8 Hz, 1H), 2.45 (s, 3H), 1.93~1.82 (m, 2H), 1.78~1.64 (m, 4H), 1.61~1.50 (m, 2H), 1.41 (d, J = 6.6 Hz, 3H).LC-MS m / e: 458 (MH + ).

[0366] Synthesis of (R,Z)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidine-6-carbonyl)piperazin-1-yl)ethan-1-one (Compound 89) [ka]

[0367] To a solution of (R,Z)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-imine (100 mg, 0.24 mmol) and 1-(piperazin-1-yl)ethan-1-one (150.7 mg, 1.18 mmol) in DMF (5 mL) was added TEA (0.16 mL, 1.18 mmol) and Pd(dppf)Cl (34.4 mg, 0.05 mmol) at 25 °C. The reaction mixture was stirred at 100 °C under an atmosphere of CO for 12 h. The reaction mixture was cooled to room temperature, poured into ice water (30 mL), and extracted with DCM (30 mL × 3). The combined organic layer was washed with brine (30 mL × 3), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to give the formate salt of the title compound (6.1 mg) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 4.0 Hz, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 7.94 (t, J = 6.0 Hz, 1H), 7.48 (t, J =6.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 46.0 Hz, 1H), 5.80 (q, J = 8.0 Hz, 1H), 3.74~3.62 (m, 5H), 3.59~3.46 (m, 6H), 2.49 (s, 3H), 2.04 (d, J = 20.0 Hz, 3H), 1.41 (d, J = 4.0 Hz, 3H).LCMS m / e: 501.2 (MH+).

[0368] Synthesis of (R,Z)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-methoxytetrahydro-2H-pyran-4-yl)methanone (Compound 90). [ka]

[0369] Step 1 Synthesis of tert-butyl (R)-2-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate. To a solution of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (780 mg, 3.46 mmol) in DMA (3 mL) and DIPEA (1.11 g, 8.64 mmol) was added tert-butyl 2,4-dichloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (1.20 g, 4.15 mmol). The mixture was stirred at 20 °C for 2 h, then poured into ice water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient, PE to PE: EtOAc = 3:1) to give the title compound (1.30 g, 2.94 mmol, yield: 84.9%) as a yellow solid. LCMS m / e: 443, 445(MH + ).

[0370] Step 2 Synthesis of tert-butyl (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate. To a solution of tert-butyl (R)-2-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)-ethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (1.2 g, 2.71 mmol) in MeOH (50 mL), EtN (5.0 mL, 36 mmol) and Pd / C (1 g, 2.71 mmol, 10%, containing 55% water) were added and stirred at 30 °C under a H balloon for 2 h. The resulting mixture was filtered through a Celite pad and washed with MeOH (50 mL). The filtrate was concentrated to give the title compound (800 mg, 1.96 mmol, yield: 72.3%) as a yellow solid. LCMS m / e: 409 (MH + ).

[0371] Step 3 Synthesis of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine hydrochloride. A solution of tert-butyl (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (0.8 g, 1.96 mmol) in HCl (50 mL, 100 mmol, 2 M in EtOAc) was stirred at room temperature for 2 hours and concentrated to give the title compound (0.5 g, 1.45 mmol, yield: 74.0%) as a yellow solid. LCMS m / e: 309(MH + ).

[0372] Step 4 Synthesis of (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-methoxytetrahydro-2H-pyran-4-yl)methanone. To a solution of (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine hydrochloride (500 mg, 1.45 mmol) and 4-methoxytetrahydro-2H-pyran-4-carboxylic acid (464 mg, 2.9 mmol) in MeCN (10 mL) and DIPEA (1.12 g, 8.7 mmol) was added T3P (1.85 g, 2.9 mmol, 50% in EtOAc) dropwise at 0 °C. The mixture was stirred at room temperature for 1 h and diluted with saturated NaHCO3. Extraction with EtOAc (20 mL × 2) was performed. The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient, PE to PE: EtOAc = 1:9) to give the title compound (400 mg, 0.888 mmol, yield: 61.2%) as a yellow solid. LCMS m / e: 451 (MH + ).

[0373] Step 5 Synthesis of (R,Z)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-methoxytetrahydro-2H-pyran-4-yl)methanone (Compound 90). To a solution of (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-methoxytetrahydro-2H-pyran-4-yl)methanone (80 mg, 0.178 mmol) in DMF (1 mL) was added iodomethane (50 mg, 0.355 mmol). The mixture was stirred at room temperature for 18 hours, poured into ice water (10 mL), and extracted with EtOAc (20 mL × 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by reverse phase chromatography (SilaSep TM Purification by C18 silica flash cartridge (0% to 40% MeCN in H2O containing 0.1% formic acid) afforded the title compound (20.0 mg, 0.043 mmol, yield: 24.3%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 12.4 Hz, 1H), 7.76 (dd, J = 18.4, 7.6 Hz, 1H), 7.55 (t, J = 6.8 Hz, 1H), 7.37~7.09 (m, 2H), 5.70 (q, J = 6.8 Hz, 1H), 5.15 (s, 1H), 5.05 (d, J = 7.6 Hz, 1H), 4.90 (d, J = 8.4 Hz, 1H), 4.76 (d, J = 12.4 Hz, 1H), 3.78 (d, J = 5.6 Hz, 3H), 3.74~3.57 (m, 4H), 3.19 (d, J = 6.4 Hz, 3H), 2.02~1.83 (m, 4H), 1.58 (d, J = 6.8 Hz, 3H).LCMS m / e: 465 (MH + ).

[0374] Synthesis of (R,Z)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-d]pyrimidine-6-carbonyl)-4-fluoropiperidin-1-yl)ethan-1-one (Compound 91). [ka]

[0375] Step 1 Synthesis of tert-butyl (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate. To a solution of tert-butyl (R)-2-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (600 mg, 1.36 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.94 mL, 6.77 mmol, 3 M in THF) in dioxane (10 mL) and water (2 mL) was added KCO (562 mg, 4 mmol) and Pd(dppf)Cl (99 mg, 0.135 mmol). The mixture was stirred at 100 °C under an atmosphere of N for 2 h. The resulting mixture was cooled to room temperature, concentrated, and purified by silica gel flash chromatography (gradient, PE to PE: EtOAc = 4:1) to give the title compound (350 mg, 0.829 mmol, yield: 61.2%) as a yellow solid. LCMS m / e: 423 (MH + ).

[0376] Step 2 Synthesis of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine hydrochloride. A solution of tert-butyl (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (350 mg, 0.829 mmol) in HCl (10 mL, 40.0 mmol, 4 M in dioxane) was stirred at room temperature for 2 hours and concentrated to give the title compound (290 mg, 0.808 mmol, 97.6% yield) as a yellow solid. LCMS m / e: 323 (MH + ).

[0377] Step 3 Synthesis of tert-butyl (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6-carbonyl)-4-fluoropiperidine-1-carboxylate. To a solution of (R)-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine hydrochloride (290 mg, 0.836 mmol) and 1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid (414 mg, 1.67 mmol) in ACN (10 mL) was added DIEA (648 mg, 5.02 mmol) and T3P (532 mg, 1.67 mmol, 50% in EtOAc). The mixture was stirred under an atmosphere of N2 at room temperature for 1 h, then diluted with saturated NaHCO3 (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient, PE to PE: EtOAc = 1:9) to give the title compound (380 mg, 0.689 mmol, yield: 76.6%) as a yellow solid. LCMS m / e: 552 (MH + ).

[0378] Step 4 Synthesis of (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-fluoropiperidin-4-yl)methanone. A solution of tert-butyl (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6-carbonyl)-4-fluoropiperidine-1-carboxylate (380 mg, 0.689 mmol) in HCl (10 mL, 2 M in EtOAc) was stirred at room temperature for 1 hour and then concentrated to give the title compound (310 mg, 0.687 mmol, 99.7% yield) as a white solid. LCMS m / e: 452 (MH + ).

[0379] Step 5 Synthesis of (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6-carbonyl)-4-fluoropiperidin-1-yl)ethan-1-one. To a solution of (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-fluoropiperidin-4-yl)methanone (310 mg, 0.687 mmol) in DCM (8 mL) was added DIPEA (444 mg, 3.43 mmol) and AcO (140 mg, 1.37 mmol). The mixture was stirred at room temperature under an atmosphere of N for 2 h, then diluted with ice-water (10 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with saturated NaHCO solution (20 mL), brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient, DCM to DCM:MeOH=5:1) to give the title compound (230 mg, 0.466 mmol, yield: 67.9%) as a white solid. LCMS m / e: 494 (MH + ).

[0380] Step 6 Synthesis of (R,Z)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-d]pyrimidine-6-carbonyl)-4-fluoropiperidin-1-yl)ethan-1-one TFA salt (Compound 91). To a solution of (R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6-carbonyl)-4-fluoropiperidin-1-yl)ethan-1-one (90 mg, 0.182 mmol) in DMF (1.5 mL) was added iodomethane (310 mg, 2.18 mmol) and stirred at room temperature under an atmosphere of N for 18 hours. At room temperature, the mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated NaHCO solution (20 mL), brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to give the TFA salt of the title compound (14 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (t, J = 7.2 Hz, 1H), 7.71~7.67 (m, 1H), 7.59~7.52 (m, 1H), 7.37~7.10 (m, 2H), 5.75~5.65 (m, 1H), 5.22 (s, 1H), 5.03 (s, 1H), 4.91 (d, J = 8.0 Hz, 1H), 4.70 (s, 1H), 4.34 (d, J = 12.0 Hz, 1H), 3.87~3.77 (m, 1H), 3.69 (d, J = 7.2 Hz, 3H), 3.30 (t, J = 12.4 Hz, 1H), 2.91~2.77 (m, 1H), 2.62 (d, J = 2.4 Hz, 3H), 2.21~1.87 (m, 7H), 1.59 (dd, J = 6.4, 4.4 Hz, 3H).LCMS m / e: 508 (MH + ).

[0381] Synthesis of 1-((R,Z)-11-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-8-methyl-1,2,4a,5,8,11-hexahydropyrazino[1',2':4,5][1,4]oxazino[3,2-g]quinazolin-3(4H)-yl)ethan-1-one (Compound 92). [ka]

[0382] Step 1: Synthesis of tert-butyl (R)-4-(2-fluoro-5-(methoxycarbonyl)-4-nitrophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate To a solution of methyl 4,5-difluoro-2-nitrobenzoate (10 g, 46 mmol) in DMF (100 mL) was added tert-butyl (R)-3-(hydroxymethyl)piperazine-1-carboxylate (12 g, 55.3 mmol) and DIEA (23.8 g, 184 mmol). The mixture was stirred at 90 °C under a N atmosphere for 15 h. The reaction mixture was cooled to room temperature, poured into water (200 mL), and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, PE to PE: EtOAc = 3:1) to give the title compound (7 g, 16.9 mmol, yield: 36.8%) as a yellow solid. LC-MS m / e: 414 (MH + ).

[0383] Step 2 Synthesis of 3-(tert-butyl) 9-methyl (R)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3,9(4H)-dicarboxylate. To a solution of tert-butyl (R)-4-(2-fluoro-5-(methoxycarbonyl)-4-nitrophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate (7 g, 16.9 mmol) in DMF (100 mL) was added NaH (0.68 g, 17.09 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (200 mL) and extracted with EtOAc (300 mL × 3). The combined organic layer was washed with brine (200 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, PE to PE: EtOAc = 3:1) to give the title compound (6 g, 15.3 mmol, yield: 90.1%) as a yellow solid. LC-MS m / e: 394 (MH + ).

[0384] Step 3 Synthesis of (R)-3-(tert-butoxycarbonyl)-8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-9-carboxylic acid. To a solution of 3-(tert-butyl) 9-methyl (R)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino-[1,2-d][1,4]oxazine-3,9(4H)-dicarboxylate (4 g, 10.2 mmol) in EtOH (10 mL), THF (10 mL), and HO (10 mL) was added LiOH monohydrate (4.27 g, 102 mmol). The mixture was stirred at 35 °C for 4 h. The reaction mixture was cooled to room temperature, acidified with HCl solution (1 M in water) to pH 4.0, and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to give the title compound (3.5 g, 9.23 mmol, yield: 90.7%). LC-MS m / e: 380 (MH + )

[0385] Step 4 Synthesis of tert-butyl (R)-9-carbamoyl-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate. To a solution of (R)-3-(tert-butoxycarbonyl)-8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-9-carboxylic acid (3.5 g, 9.23 mmol) in DMF (40 mL) was added HATU (5.26 g, 13.8 mmol), NHCl (1.00 g, 18.5 mmol), and DIEA (3.57 g, 27.7 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with brine (200 mL × 2), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, PE to PE: EtOAc = 1:1) to give the title compound (3.4 g, 8.99 mmol, yield: 97.4%) as a white solid. LC-MS m / e: 379 (MH + )

[0386] Step 5 Synthesis of tert-butyl (R)-8-amino-9-carbamoyl-1,2,4a,5-tetrahydrobenzo[b]-pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate. To a solution of tert-butyl (R)-9-carbamoyl-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (3.4 g, 9 mmol) in MeOH (50 mL) was added Pd / C (700 mg, 10% and 55% by weight in water). The mixture was stirred at room temperature for 3 hours under a H2 balloon. The reaction mixture was filtered through a Celite® pad, and the cake was washed with MeOH (50 mL). The filtrate was concentrated to give the title compound (2.4 g, 6.89 mmol, 76.7% yield) as a green solid. LC-MS m / e: 349 (MH + ).

[0387] Step 6 Synthesis of tert-butyl (R)-11-oxo-1,2,4a,5,10,11-hexahydropyrazino[1',2':4,5][1,4]-oxazino[3,2-g]quinazoline-3(4H)-carboxylate. To a solution of tert-butyl (R)-8-amino-9-carbamoyl-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (1.2 g, 3.44 mmol) in EtOH (20 mL) was added triethoxymethane (7.65 g, 51.7 mmol) and AcOH (3.1 g, 51.7 mmol). The mixture was stirred in a sealed tube at 120 °C for 15 h. The reaction mixture was cooled to room temperature, concentrated, and purified by column chromatography (gradient, DCM to DCM:MeOH = 20:1) to give the title compound (500 mg, 1.4 mmol, yield: 40.5%) as a gray solid. LC-MS m / e: 359 (MH + ).

[0388] Step 7 Synthesis of tert-butyl (R)-11-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,2,4a,5-tetrahydropyrazino[1′,2′:4,5][1,4]oxazino[3,2-g]quinazoline-3(4H)-carboxylate. To a solution of tert-butyl (R)-11-oxo-1,2,4a,5,10,11-hexahydropyrazino[1',2':4,5][1,4]-oxazino[3,2-g]quinazoline-3(4H)-carboxylate (450 mg, 1.256 mmol) in ACN (5 mL) was added HCCP (524 mg, 1.51 mmol) and DIEA (649 mg, 5.03 mmol). The mixture was stirred at room temperature under a N atmosphere for 2 hours. (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (356 mg, 1.88 mmol) was added, and the reaction mixture was stirred at 100°C under a N atmosphere for 2 hours. The reaction mixture was cooled to room temperature, poured into water (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, DCM to DCM:MeOH = 20:1) to give the title compound (300 mg, 0.567 mmol, yield: 45.1%) as a yellow solid. LC-MS m / e: 530 (MH + ).

[0389] Step 8 Synthesis of (R)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazino[3,2-g]quinazolin-11-amine. To a solution of tert-butyl (R)-11-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-amino)-1,2,4a,5-tetrahydropyrazino[1',2':4,5][1,4]oxazino[3,2-g]quinazoline-3(4H)-carboxylate (300 mg, 0.567 mmol) in EtOAc (5 mL) was added HCl solution (5 mL, 4 M in EtOAc) and stirred at room temperature for 2 hours. The reaction mixture was poured into water (10 mL), basified with NaOH solution (12 mL, 2 M), and extracted with DCM (50 mL × 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, DCM to DCM:MeOH=10:1) to give the title compound (200 mg, 0.466 mmol, yield: 82.2%). LC-MS m / e: 430 (MH + ).

[0390] Step 9 Synthesis of 1-((R)-11-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,2,4a,5-tetrahydropyrazino[1',2':4,5][1,4]oxazino[3,2-g]quinazolin-3(4H)-yl)ethan-1-one To a solution of (R)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazino[3,2-g]quinazolin-11-amine (200 mg, 0.466 mmol) in DCM (10 mL) was added EtN (71 mg, 0.703 mmol) and AcO (71 mg, 0.699 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (gradient, DCM to DCM:MeOH = 20:1) to give the title compound (200 mg, 0.424 mmol, yield: 91.1%). 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 2.0 Hz, 2H), 8.09 (d, J = 5.9 Hz, 1H), 7.70 (s, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 6.9 Hz, 1H), 7.26 (dt, J = 62.8, 42.5 Hz, 2H), 6.93 (d, J = 3.1 Hz, 1H), 5.78 (dd, J = 13.4, 6.8 Hz, 1H), 4.62~4.42 (m, 2H), 4.05 (dt, J = 25.4, 13.9Hz, 3H), 3.13~2.66 (m, 3H), 2.48~2.37 (m, 1H), 2.09 (t, J = 7.5 Hz, 3H), 1.60 (d, J = 6.9 Hz, 3H).LC-MS m / e: 472 (MH+).

[0391] Step 10 Synthesis of 1-((R,Z)-11-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-8-methyl-1,2,4a,5,8,11-hexahydropyrazino[1′,2′:4,5][1,4]oxazino[3,2-g]quinazolin-3(4H)-yl)ethan-1-one (Compound 92). To a solution of 1-((R)-11-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,2,4a,5-tetrahydropyrazino[1',2':4,5][1,4]oxazino[3,2-g]quinazolin-3(4H)-yl)ethan-1-one (60 mg, 0.127 mmol) in DMF (1 mL) was added MeI (27 mg, 0.191 mmol) and stirred at room temperature for 12 hours. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4, then filtered and concentrated to dryness. The residue was purified by preparative HPLC to afford the title compound (7 mg, 0.014 mmol, yield: 11.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.52 (s, 1H), 7.39~7.21 (m, 2H), 7.09 (s, 1H), 5.86 (d, J = 7.1 Hz, 1H), 4.53 (t, J = 17.1 Hz, 2H), 4.14~3.98 (m, 3H), 3.73 (s, 3H), 3.17~3.08 (m, 1H), 2.99~2.78 (m, 2H), 2.33 (s, 1H), 2.09 (d, J = 6.7 Hz, 3H), 1.57 (s, 3H).LC-MS m / e: 486 (MH+).

[0392] Synthesis of (R,Z)-3-(1-((6-(1-acetyl-4-fluoropiperidin-4-yl)-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-ylidene)amino)ethyl)-2-methylbenzonitrile (Compound 93) [ka]

[0393] The formate salt of the title compound was synthesized using the same steps as for compound 1. 1HNMR(400 MHz, DMSO-d6): δ 8.94 (s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 5.70 (q, J = 6.4 Hz, 1H), 4.44 (d, J = 12.4 Hz, 1H), 3.88 (d, J = 14.0 Hz, 1H), 3.68 (s, 3H), 3.40 (t, J = 12.9 Hz, 1H), 2.90 (t, J = 12.9 Hz, 1H), 2.62 (s, 3H), 2.51 (s, 3H), 2.37~2.12 (m, 2H), 2.08 (s, 3H), 2.02~1.90 (m, 2H), 1.43 (d, J = 6.5 Hz, 3H). LCMS m / e: 461.4 (MH + ).

[0394] Synthesis of (R,Z)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1-(difluoromethyl)-cyclopropyl)-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-imine (Compound 94) [ka]

[0395] The formate salt of the title compound was synthesized using similar steps to compound 18. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.21 (s, 1H, HCOOH), 8.16 (s, 1H), 7.92 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.0 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 54.4 Hz, 1H), 6.39 (t, J = 56.0 Hz, 1H), 5.79 (q, J = 6.6 Hz, 1H), 3.63 (s, 3H), 2.46 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H), 1.33~1.21 (m, 4H).LCMS m / e: 437.4 (MH + ).

[0396] Synthesis of (R,Z)-1-(4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-5,7,8,9-tetrahydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-3-yl)-4-hydroxypiperidin-1-yl)ethan-1-one (Compound 95) [ka]

[0397] The title compound was synthesized using similar steps to compound 26. 1HNMR (400 MHz, CDCl3) δ 9.63 (d, J = 8.8 Hz, 1H), 8.84 (d, J = 3.2 Hz, 1H), 8.54 (s, 1H), 7.96 (t, J = 7.0 Hz, 1H), 7.53~7.47 (m, 1H), 7.26~7.22 (m, 1H), 6.89 (t, J = 55.0 Hz, 1H), 6.11~6.08 (m, 1H), 4.62~4.49 (m, 3H), 3.68 (d, J = 6.8 Hz, 2H), 3.42~3.26 (m, 2H), 3.13 (t, J = 12.2 Hz, 1H), 2.62~2.55 (m, 2H), 2.25~1.99 (m, 5H), 1.85 (d, J = 7.2 Hz, 3H), 1.77~1.61 (m, 2H). LCMS m / e: 500.2 (MH + ).

[0398] Synthesis of (R,Z)-1-(4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-5,7,8,9-tetrahydropyrido[4,3-e]pyrrolo[1,2-a]pyrimidin-3-yl)-4-fluoropiperidin-1-yl)ethan-1-one (Compound 96) [ka]

[0399] The formate salt of the title compound was synthesized using similar steps to compound 27. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.65 (s, 1H), 8.44 (s, 1H), 7.96 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 6.8 Hz, 1H), 7.25~7.18 (m, 1H), 6.90 (t, J = 55.1 Hz, 1H), 5.95~6.01 (m, 1H), 4.66 (d, J = 10.3 Hz, 1H), 4.30~4.41 (m, 2H), 3.83 (d, J = 11.2 Hz, 1H), 3.57 (t, J = 13.1Hz, 1H), 3.31~3.10 (m, 2H), 3.04 (t, J = 13.1 Hz, 1H), 2.46~2.51 (m, 2H), 2.36~2.17 (m, 2H), 2.15 (s, 3H), 2.12~1.96 (m, 2H), 1.70 (d, J = 6.8 Hz, 3H). LCMS m / e: 502.3 (MH + ).

[0400] Synthesis of (R,Z)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1,2-dimethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrido[3,4-d]pyrimidin-4(1H)-imine (Compound 97) [ka]

[0401] The trifluoroacetate salt of the title compound was synthesized following similar steps to compound 42. 1HNMR(400 MHz, DMSO-d6) δ 10.72 (d, J = 6.9 Hz, 1H), 9.51 (s, 1H), 8.63 (s, 1H), 7.80 (t, J = 7.3 Hz, 1H), 7.59 (t, J = 6.9 Hz, 1H), 7.38 (t, J = 6.9 Hz, 1H) 7.11 (t, J = 52 Hz, 1H), 7.04~6.98 (m, 1H), 5.99~5.86 (m, 1H), 4.04 (s, 5H), 3.47 (t, J = 5.9 Hz, 2H), 2.99 (s, 3H), 2.84~2.73 (m, 5H), 1.74 (d, J = 7.0 Hz, 3H). LCMS m / e: 506.5 (MH + ).

[0402] Synthesis of N-(3-((Z)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)allyl)acetamide (Compound 98) [ka]

[0403] Step 1 Synthesis of tert-butyl ((E)-3-((Z)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)allyl)carbamate. To a solution of tert-butyl (E)-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)carbamate (200 mg, 0.7 mmol) in HO (1 mL) and dioxane (5 mL) was added KCO (292 mg, 2.118 mmol), Pd(dppf)Cl (51.66 mg, 0.071 mmol), and (R,Z)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1,2-dimethylpyrido[3,4-d]pyrimidin-4(1H)-imine (360.27 mg, 0.847 mmol). The mixture was stirred at 110 °C for 15 h. Water (30 mL) was added, the mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (PE:EA=3:1) to give the title compound (150 mg, 0.299 mmol, 42.35%). LC-MS m / e: 502 (MH + ).

[0404] Step 2 Synthesis of (E)-3-((Z)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)prop-2-en-1-amine. To a solution of tert-butyl ((E)-3-((Z)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)-ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)allyl)carbamate (150 mg, 0.299 mmol) in DCM (5 mL) was added TFA (2 mL, 26.118 mmol). The mixture was stirred at room temperature for 1 hour and concentrated to give the desired product (110 mg, 0.274 mmol, 91.67%). LC-MS m / e: 402 (MH + ).

[0405] Step 3 Synthesis of N-((E)-3-((Z)-4-(((R)-1-(3-((difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)allyl)acetamide (Compound 98). To a solution of (E)-3-((Z)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)imino)-1,2-dimethyl-1,4-dihydropyrido[3,4-d]pyrimidin-6-yl)prop-2-en-1-amine (110 mg, 0.274 mmol) in DCM (2 mL) was added acetyl chloride (0.029 mL, 0.4 mmol) and TEA (0.114 mL, 0.8 mmol). The mixture was stirred at 0 °C for 0.5 h. Water (30 mL) was added, the mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated to dryness. The residue was purified by column chromatography (PE:EA=3:1) to give the title compound (27 mg, 0.061 mmol, 22.2%). 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.19 (s, 1H), 8.14 (t, J = 4.0 Hz, 1H), 8.00 (s, 1H), 7.96 (t, J = 6.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.34~7.07 (m, 2H), 6.72~6.64 (m, 2H), 5.79 (q, J = 8.0 Hz, 1H), 3.93~3.88 (m, 2H), 3.63 (s, 3H), 2.45 (s, 3H), 1.88 (s, 3H), 1.40 (d, J = 8.0 Hz, 3H).LC-MS m / e: 444.1 (MH + ).

[0406] Compounds 99-113 can be readily prepared following the steps outlined in general Scheme XII and compound 92.

[0407] HTRF-based protein-protein interaction studies The KRAS-G12D and SOS1 binding / interaction assay is designed to measure the interaction between KRAS-G12D and SOS1 proteins. Utilizing HTRF (homogeneous time-resolved fluorescence) technology, this assay allows for simple and rapid analysis of compound-protein interactions in a high-throughput format. This assay was used to investigate the potency of compounds to inhibit the protein-protein interaction between SOS1 and KRAS-G12D, demonstrating the compound's molecular mechanism of action. Low IC 50 The values ​​indicate the high potency of SOS1 inhibitors in inhibiting the interaction between SOS1 and KRAS-G12D.

[0408] Protein expression and purification The gene sequence corresponding to human SOS1 (residues 564-1049, UniProt ID: Q07889) was synthesized and fused in frame with a GST expression vector. The sequence was verified, and the plasmid containing the sequence was transformed into Escherichia coli (E. coli) strain BL21(DE3). Bacteria were grown at OD in LB medium containing 50 μg / ml kanamycin at 37°C. 600 The culture was continued until the chromatin reached 0.6-0.8. Then, 0.2 mM IPTG was added at 17°C to induce protein expression for 16 hours. The bacteria were collected by centrifugation and stored at -80°C. The bacterial pellet was resuspended in lysis buffer (25 mM Tris-HCl, 500 mM NaCl, 2 mM DTT, 2.3% sucrose, 0.3% dextran-10, 1 mM PMSF, pH 7.5) and lysed using a high-pressure homogenizer. The lysate was clarified by centrifugation (4°C, 12,000 rpm) for 30 minutes. The supernatant containing the GST-SOS1 fragment was purified by glutathione column and gel filtration (Hiload 16 / 600 Superdex). (R) The purified GST-SOS1 fragment was analyzed by SDS-PAGE and stored at -80°C in 25 mM Tris-HCl, 100 mM NaCl, 1 mM DTT, 2.3% sucrose, 0.3% dextran-10, pH 7.5.

[0409] Kras-G12D protein purification The sequence corresponding to human KRAS-G12D (residues 1-169, UniProt P01116-2) was synthesized and fused in frame to the His-AVI-TEV vector. The plasmid was transformed into Escherichia coli (E. coli) BL21 (containing a plasmid capable of producing the BirA enzyme). Bacteria were grown at OD in TB medium containing 100 μg / ml ampicillin and 50 μg / ml kanamycin at 37°C. 600 The cells were cultured until the chromatin density reached 0.6-0.8. Protein expression was then induced for 16 hours at 25°C with 0.5 mM IPTG and 50 mg / L biotin. Bacteria were collected by centrifugation and stored at -80°C. The bacterial pellet was resuspended in lysis buffer (20 mM Tris-HCl, 500 mM NaCl, 5 mM MgCl2, 2 mM β-ME, 5% glycerol, pH 8) and lysed using a high-pressure homogenizer. The lysate was clarified by centrifugation (4°C, 12,000 rpm) for 30 minutes. The supernatant containing the HIS-AVI-TEV-KRAS-G12D fragment was purified by Ni-NTA column (SMART), Streptactin (R) Column (SMART), gel filtration (Hiload 16 / 600 Superdex (R) The purified HIS-AVI-TEV-KRAS-G12D fragment was analyzed by SDS-PAGE and stored at -80°C in a buffer containing 50 mM HEPES-NaOH, 100 mM NaCl, 1 mM DTT, and 5 mM MgCl, pH 7.5.

[0410] Protein-protein interaction studies A test buffer containing 50 mM HEPES (pH 7.5), 50 mM NaCl, 0.01% Brij-35, 1 mM TCEP, and 0.1% BSA was prepared. A concentration series of test compounds was generated in a 384-well test plate, with ten 3-fold serial dilutions ranging from 0.5 nM to 10 μM, in a volume of 20 pL. Purified GST-SOS1 catalytic domain (residues 564–1049) was first diluted in test buffer, and 5 μl of SOS1 (final concentration in the test mixture: 2.5 nM) was dispensed directly into the compound plate. After centrifugation at 1000 RPM for 30 seconds, the SOS1 / compound mixture was incubated at 25°C for 15 minutes to allow the compounds to react with SOS1. The KRAS-G12D mixture was prepared by incubating avi-tagged Kras-G12D (residues 1-169) and GDP in assay buffer containing 10 mM MgCl2 for 10 minutes at room temperature. The KRAS-G12D and GDP mixture (5 μL) was added to the assay plate, resulting in a final KRAS-G12D concentration of 100 nM and a GDP concentration of 10 μM. The plate was centrifuged at 1000 rpm for 30 seconds and incubated at 25°C for 60 minutes. Tb cryptate and GST monoclonal antibodies coupled to streptavidin-XL665 were prepared in 1X assay buffer, and 10 μL of the detection mixture was added to each well. The plate was incubated at 25°C for 5 hours. At the end of the incubation period, the PerkinElmer Envision TM Readings were performed in HTRF mode using a plate reader. Test buffer containing KRAS-G12D + DMSO and a mixture of SOS1 + KRAS-G12D + DMSO were used as negative controls (minimum signal, columns 1 and 2) and positive controls (maximum signal, columns 23 and 24), respectively. The percent inhibition of each compound dilution was calculated as follows: [% inhibition = (1 - (sample signal - negative control) / (positive control - negative control)) × 100]. Two to three independent experiments were performed for each compound, and the data were analyzed using a four-parameter logistic fit.

[0411] A group of exemplary compounds was evaluated in the above studies. These data demonstrate that the compounds of the present invention are potent inhibitors of the protein-protein interaction between SOS1 and KRAS-G12D.

[0412] pERK efficacy test This test measured the ability of compounds to inhibit SOS1 function in cells. SOS1 activates RAS proteins by catalyzing the conversion of RAS GDP to RAS GTP in response to receptor tyrosine kinase activation. RAS activation induces a series of intracellular signaling events, resulting in increased phosphorylation of ERK at threonine 202 and tyrosine 204 (pERK). The following steps (i.e., the in cell ELISA method described below) measure intracellular pERK levels in response to test compounds in NCI-H1975 cells (EGFR / L858R-T790M).

[0413] First, NCI-H1975 cells were grown and maintained using the medium and steps recommended by ATCC. The day before compound addition, the cells were plated onto poly-D-lysine-coated 96-well cell culture plates (Corning (R) BioCoat (R) Cells were seeded at 25,000 cells / well in 100 μL of DMSO (Cat. #356640) and cultured overnight in an incubator at 37°C and 5% CO2. Test compound solutions were prepared by 3-fold serial dilutions in DMSO to a maximum concentration of 6 mM. On the day of the test, 50 μL of the test compound dilution in medium was added to each well of the cell culture plate, resulting in final compound concentrations ranging from 0.001 μM to 20 μM. After compound addition, the cells were cultured for 1 hour at 37°C and 5% CO2, after which the medium was removed. The cells were fixed with phosphate-buffered saline (PBS) containing 4% formaldehyde and cultured at room temperature for 20 minutes. The plate was then resuspended in PBST (0.05% Tween (R)After washing three times with PBS containing -20°C, 100 μL of pre-chilled methanol was added and incubated at -20°C for 20 minutes. After incubation, the methanol was removed. The plate was washed again with PBST. Next, the cells were permeabilized with 100 μL / well of 0.1% Triton X-100 in PBS for 20 minutes, and then quenched with quenching buffer (PBST containing 1% H2O2 and 0.1% sodium azide) for 20 minutes at room temperature with gentle shaking. After washing once with PBST, the cells were added to blocking buffer (250 μL / well, Pierce TM Protein-free PBS blocking buffer (Cat. #37572) was added and incubated at room temperature for 1 hour. Anti-pERK antibody (Cell Signaling, 1:1000 dilution in 5% BSA in PBST) was then added overnight at 4°C. Secondary antibody HRP (Jackson immunoresearch, 1:3000 dilution in 5% BSA in PBST) was added for 1 hour at room temperature. After each step, the cells were washed three times with PBST. Substrate (Advansta ELISABright TM Before adding the IgG, the plate was washed twice with PBS to remove detergent residue. Intracellular pERK levels were measured using a microplate reader (Biotek Synergy TM IC was measured by detecting the chemiluminescence signal using a chemiluminescent detector (H1). 50 was determined by fitting a four-parameter sigmoidal concentration-effect curve.

[0414] Compounds 1-98 were evaluated using the pERK potency assay described above. Compounds 1-62, 64-69, 71-82, 84, 85, 89, and 92-98 each had an IC 50 was less than 100 nM.

[0415] In vivo efficacy testing The antitumor activity of the SOS1 inhibitor of the present invention was evaluated using a mouse subcutaneous xenograft human tumor model. The evaluation was performed in accordance with an animal use protocol approved by the local animal welfare committee. Experimental animals were housed in a barrier facility fully accredited by the Association for Assessment and Accreditation of Animals International (AAALAC). Six- to eight-week-old female mice (BALB / c nude mice or NOD SCID mice) were subcutaneously injected with cell line-derived tumors (NCI-H1975, Miapaca-2, Kyse-410, NCI-H358) or inoculated with patient-derived tumors (LU11692 and CR6256). Tumor volumes of approximately 150 to 200 mm were used. 3 Mice reaching 100 mg / kg were randomly assigned to groups and treated with vehicle control, SOS1 inhibitors (3, 10, 30 mg / kg), osimertinib (1 mg / kg), sotorasib (5, 10, 50 mg / kg), or a combination of SOS1 inhibitors and osimertinib, or sotorasib, or both, orally administered depending on the tumor model. Compounds were administered twice daily (SOS1 inhibitors) or once daily (osimertinib and sotorasib) for 21 to 28 days. Body weight and tumor volume were measured twice weekly. Tumor volumes were calculated as the mean and standard error for each treatment group. The compounds tested in this invention showed good tumor regression in in vivo efficacy studies.

[0416] Other Examples All features disclosed herein may be combined in any combination. Each feature disclosed herein may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

[0417] From the above description, those skilled in the art can easily grasp the essential features of the present invention, and can make various changes and modifications to the present invention to adapt it to various uses and conditions without departing from the spirit and scope of the present invention. For example, compounds structurally similar to the compounds of the present invention can be prepared and screened for their effectiveness in treating conditions associated with SOS1. Therefore, other embodiments are also included within the scope of the claims.

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof. 【Chemistry 1】 (however, A is C ３ ~C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, aryl, or 5- to 10-membered heteroaryl; L is a single bond, —O—, —C(O)—, —C(O)O—, —O—CO—, —C(O)NR′—, —NR′—, —NR′CO—, or —NR′SO ２ -, -SO ２ NR'-, -S-, -SO-, -S(O) ２ -, C １ ~C ３ Alkylene, C １ ~C ３ Haloalkylene, C ２ ~C ３ Alkenylene, or C ２ ~C ３ Alkynylene, where R' is H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or 6- to 10-membered aryl; M is C ５ ~C １０ cycloalkyl, 5- to 15-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; Q represents the left ring of formula I to which M is fused; R １ is CN, C １ ~C ３ Alkyl, C ２ ~C ３ Alkenyl, or C ２ ~C ３ is alkynyl, R ２ is H, CN, halogen, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C ２ ~C ３ Alkynyl, or C ３ ~C ６ is cycloalkyl, R ３ is C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or phenyl; or R ２ and R ３ is R ２ and the carbon atom to which R ３ together with the nitrogen atom to which it is attached form a 4- to 7-membered heterocycloalkyl; R ４ is H, C １ ~C １０ Alkyl, C １ ~C １０ Alkylamino, C １ ~C １０ Alkylamide, C ２ ~C １０ Alkylcarbonyl, C １ ~C １０ Alkylsulfonyl, C １ ~C １０ Alkyl sulfonamides, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkylcarbonyl, C ３ ~C ６ cycloalkylamide, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; 【Chemistry 2】 is a single or double bond, and Each alkyl, alkylene, alkenyl, alkynyl, alkoxy, haloalkylene, alkylamino, alkylamido, alkylcarbonyl, alkylsulfonyl, alkylsulfonamido, alkynylene, cycloalkyl, cycloalkylcarbonyl, cycloalkylamido, heterocycloalkyl, heterocyclyl, phenyl, aryl, and heteroaryl may be unsubstituted or substituted with deuterium, halogen, CN, oxo, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Haloalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, -OR', -C(O)R', -C(O)OR', -O-COR', -C(O)NR'R", -NR'R", -SR', -SOR', -S(O) ２ and -POR'R'', where R' and R'' are each independently H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or 6- to 10-membered aryl.

2. M is C ５ ~C １０ cycloalkyl, 5- to 12-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R １ is CN, C １ ~C ３ alkyl, ethenyl, or ethynyl; R ２ is H, CN, halogen, C １ ~C ３ Alkyl, C １ ~C ３ alkoxy, ethenyl, or cyclopropyl; R ３ is C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or phenyl; or R ２ and R ３ is R ２ and the carbon atom to which R ３ together with the nitrogen atom to which it is attached form a 4- to 7-membered heterocycloalkyl; R ４ is H, C １ ~C １０ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; and Each alkyl, cycloalkyl, heterocycloalkyl, phenyl, aryl, and heteroaryl is unsubstituted or substituted with deuterium, halogen, CN, oxo, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Haloalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, -OR', -C(O)R', -C(O)OR', -O-COR', -C(O)NR'R", -NR'R", -SR', -SOR', -S(O) ２ and -POR'R" or -POR'R", where R' and R" are each independently H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ The compound of claim 1, which is a cycloalkyl, a 3- to 6-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, or a 6- to 10-membered aryl.

3. 3. The compound of claim 1 or 2, which is a compound of formula II: 【Transformation 3】 (however, 【Chemistry 4】 is a single bond or a double bond, and in formula II 【Transformation 5】 The number of double bonds represented by is 2 or 3, X is C or N, and Y and Z are each independently C=O, C-Rx, or N-Ry. However, when X is N, Y is C=O, and Z is C-Rx, and Rx is H, CN, halogen, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ haloalkyl, cyclopropyl, 4- to 6-membered heterocycloalkoxy, or NR'R", and Ry is absent, H, C １ ~C ３ alkyl, or cyclopropyl.

4. The compound of claim 3, which is a compound of any one of formulas II-A to II-F. 【Transformation 6】

5. The compound of claim 3, which is a compound of formula II-G or II-H. 【Transformation 7】 (wherein n is 2, 3, or 4, preferably 2, and Rg １ , Rg ２ , Rg ３ , Rg ４ , Rh １ , and Rh ２ are each independently H, halogen, or methyl. 【Request Item 6】 【Chemistry 8】 teeth, 【Chemistry 9】 The compound according to any one of claims 1 to 5,

7. 4. The compound of claim 3, which is a compound of formula III: 【Chemistry 10】 (However, Ra １ , Ra ２ , Ra ３ , Ra ４ , and Ra ５ are each independently H, halogen, amino, CN, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ cycloalkyl, or 4- to 6-membered heterocycloalkyl.

8. 8. The compound of claim 7, which is a compound of formula IIIa: 【Chemistry 11】

9. R １ The compound according to any one of claims 1 to 8, wherein is methyl or ethynyl.

10. R ２ is H, C １ ~C ３ The compound of any one of claims 1 to 9, which is alkyl, or cyclopropyl.

11. R ３ is C １ ~C ４ Alkyl, C ３ ~C ６ cycloalkyl, or 4- to 6-membered heterocycloalkyl, preferably R ３ is C １ ~C ４ The compound of any one of claims 1 to 4 and 6 to 10, which is alkyl or cyclopropyl.

12. Rx is H, halogen, C １ ~C ３ Alkyl, cyclopropyl, C １ ~C ３ Alkoxy, NH ２ , C １ ~C ３ alkylamino, and Ry is H, C １ ~C ３ The compound of any one of claims 3 to 8, which is alkyl, or cyclopropyl.

13. A is phenyl, 2,3-dihydro-1H-indene, or benzofuran, and A is unsubstituted or is selected from the group consisting of deuterium, halogen, NH ２ , C.N., C. １ ~C ４ Alkyl, C ２ ~C ４ Alkenyl, C １ ~C ４ haloalkyl, or C ３ ~C ６ cycloalkyl, and preferably A is F, Cl, Br, NH ２ , C.N., C. １ ~C ３ Alkyl, and C １ ~C ３ The compound of any one of claims 1 to 12, which is phenyl substituted by one or more groups selected from haloalkyl.

14. A is, 【Chemistry 12】 The compound according to any one of claims 1 to 13,

15. A is, 【Chemistry 13】 15. The compound of claim 14, wherein:

16. L is a single bond, —O—, —C(O)—, —NHC(O)—, or —NHS(O) ２ -, C ２ ~C ３ Alkenylene, or C ２ ~C ３ The compound of any one of claims 1 to 15, which is alkynylene.

17. The compound of any one of claims 1 to 16, wherein L is a single bond.

18. R ４ The compound according to any one of claims 1 to 17, wherein is selected from the group consisting of: 【Chemistry 14】 【Chemistry 15】

19. R ４ 19. The compound of claim 18, wherein is selected from the group consisting of: 【Chemistry 16】

20. 3. The compound of claim 1 or 2, which is a compound of formula IV, V, or VI. 【Chemistry 17】 (wherein m is 0, 1, or 2, and Rx is H or C) １ ~C １０ It is alkoxy.)

21. R １ is methyl or ethynyl, R ２ is H, C １ ~C ３ alkyl, or cyclopropyl; R ３ is C １ ~C ４ Alkyl, C ３ ~C ６ cycloalkyl, or 4- to 6-membered heterocycloalkyl; R ４ is H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ cycloalkyl, or 4- to 6-membered heterocycloalkyl; A is, [Chemistry 18] and 21. The compound of claim 20, wherein m is 1 or 2.

22. R ３ is C １ ~C ４ 22. The compound of claim 20 or 21, which is alkyl or cyclopropyl.

23. 10. The compound of claim 1, which is a compound of formula IV: 【Chemistry 19】 (However, R １ is methyl, and R ２ is H or methyl, and R ３ is methyl, or R ２ and R ３ is R ２ and the carbon atom to which R ３ together with the nitrogen atom to which R is attached form a 5- or 6-membered heterocycloalkyl; ４ is methyl or cyclopropyl, and m is 1 or 2.

24. The compound of claim 1, which is any one of compounds 1 to 113.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 and a pharmaceutically acceptable carrier thereof.

26. A method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 24 or a pharmaceutical composition according to claim 25.

27. A method for inhibiting SOS1, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 24 or a pharmaceutical composition according to claim 25.

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