WO2025188163A1 - Sos1 inhibitor and use thereof - Google Patents

Abstract

Provided are a novel compound of chemical formula (I) and a use thereof for preventing or treating SOS1-related diseases. The novel compound of one aspect of the present invention inhibits the interaction between SOS1 and RAS family proteins, thereby being useful for preventing or treating SOS1-mediated diseases such as cancer and RAS pathologies.

Description

SOS1 inhibitors and uses thereof

The present invention relates to a novel compound having SOS1 inhibitory activity, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same as an active ingredient for preventing or treating an SOS1-mediated disease, and a pharmaceutical use thereof.

The RAS gene is a gene that transmits signaling processes essential for cell differentiation and proliferation, and RAS mutations are found in approximately 30% of cancer patients. In humans, there are three types: H-Ras (Harvey murine sarcoma virus oncogene), N-Ras (neuroblastoma RAS viral oncogene homolog), and K-Ras (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog).

The RAS protein is a guanosine triphosphatase (GTPase) that acts as a molecular switch in cells, cycling between an active GTP-bound state and an inactive GDP-bound state. Mutations in the Ras gene reduce the GTPase ability of RAS to hydrolyze GTP, thereby activating RAS proteins in a state where the cell's growth signal, which should normally be turned on only when cells need to grow, is always on. This interacts with C-RAF and phosphoinositide 3-kinase (PI3K) to promote the RAF/mitogen or extracellular signal-regulated kinases (MEK/ERK) pathway, the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway, and the RalGDS (Ral guanine nucleotide dissociation stimulator) pathway, which are downstream signals of RAS proteins, causing uncontrolled cell proliferation and causing cancer. (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6; Young et al., Adv. Cancer Res., 2009, 102:1-17).

To date, various studies have been conducted to directly or indirectly inhibit RAS. However, direct inhibition of RAS has proven extremely difficult due to the picomolar affinity of GTP for its binding site, the lack of other well-defined pockets, and the fact that RAS interacts with GEFs, GAPs, and effectors via a broad and flat protein-protein interaction surface that makes small-molecule drugs difficult to apply. In this context, a novel strategy has been proposed: inhibiting RAS by inhibiting its interaction with a RAS-activating protein (GEF) instead of RAS itself, thereby preventing GTP reloading.

Binding of GTPase-activating proteins (GAPs), such as NF1, accelerates the weak intrinsic GTPase activity of RAS proteins, downregulating active RAS and reverting it to an inactive form. On the other hand, Son of Sevenless homolog 1 (SOS1), a guanine nucleotide exchange factor (GEF) that activates RAS proteins by mediating the exchange of GDP, binds to K-Ras+ GDP, removes GDP, and activates GTP (Hunter et al., Mol. Cancer Res., 2015, 13(9):1325-35). SOS1 inhibitors are expected to suppress signaling (e.g., ERK phosphorylation) downstream of RAS family proteins. Therefore, SOS1 inhibitors may exhibit anticancer effects (e.g., inhibition of proliferation, survival, metastasis, etc.) in cancer cells that depend on RAS family proteins (e.g., KRAS mutant cancer cell lines).

Currently, BI-3406, BI-1701963, MRTX0902, etc. are being developed as SOS1 activity inhibitors, but they are still in the early stages of development, and there is still a need in the art for the development of novel compounds and pharmaceutical compositions containing the same for treating cancer by inhibiting SOS1.

An object of the present invention is to provide a compound of formula (I), a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I), a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preventing or treating an SOS1-mediated disease by administering a compound of formula (I), a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

Each description and embodiment disclosed in this application may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this application fall within the scope of this application. Furthermore, the scope of this application is not limited by the specific descriptions described below.

One aspect of the present invention provides a compound of the following formula (I), a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof:

[Chemical formula (I)]

In the above formula,

Ring A is C ₆ -C ₁₀ aryl, or a 5- to 10-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S;

R ^A is halogen, CN, OH, NR'R'', C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, wherein said C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy may be optionally substituted with halogen, CN, OH or NR'R'';

R ¹ is H or C ₁ -C ₆ alkyl;

R ² and R ³ are each independently H, halogen, CN, OH, NR'R'', -COR', -SO ₂ R', -CONR'R'', -SO ₂ NR'R'', C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or saturated or partially unsaturated C ₃ -C ₇ cycloalkyl, wherein said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₇ cycloalkyl may each be optionally substituted independently with halogen, CN, OH or NR'R'';

R ⁴ is H, C ₁ -C ₆ alkyl, saturated or partially unsaturated C ₃ -C ₇ cycloalkyl, (C ₁ -C ₆ alkyl)(saturated or partially unsaturated C ₃ -C ₇ cycloalkyl), or (saturated or partially unsaturated C ₃ -C ₇ cycloalkyl)(C ₁ -C ₆ alkyl),

B is NR ^x R ^y , or ring B1;

One of R ^x and R ^y is H or C ₁ -C ₆ alkyl and the other is ring B2, or R ^x and R ^y can form ring B3 together with the nitrogen atom to which they are bonded;

Ring B1 and ring B2 are bonded to the 1,6-naphthyridin-2-one nucleus or the nitrogen atom of NR ^x R ^y through the carbon atom contained in each ring, and are each independently a 3- to 10-membered monocyclic or bicyclic saturated or partially unsaturated heterocyclyl, a 5- to 10-membered heteroaryl, or a saturated or partially unsaturated C ₃ -C ₇ cycloalkyl, wherein the heterocyclyl and heteroaryl contain 1 or 2 heteroatoms selected from N, O, and S;

Ring B3 is a 3- to 10-membered monocyclic or bicyclic saturated or partially unsaturated heterocyclyl or a 5- to 10-membered heteroaryl, which may optionally contain one additional heteroatom selected from N, O and ^S , together with the nitrogen atom to which R ^x and R y are bonded;

Ring B1, ring B2 and ring B3 may each be independently optionally substituted with 1 to 3 R ^B ;

R ^B is halogen, oxo, CN, OH, NR'R'', -COR', -SO ₂ R', -CONR'R'', -SO ₂ NR'R'', C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or saturated or partially unsaturated C ₃ -C ₇ cycloalkyl, wherein said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₇ cycloalkyl may each independently be optionally substituted with halogen, CN, OH, or NR'R'';

R' and R'' are each independently H or C ₁ -C ₆ alkyl;

n is an integer from 0 to 4.

In the above formula (I), ring A can be C ₆ -C ₁₀ aryl. For example, the C ₆ -C ₁₀ aryl can be, but is not limited to, phenyl or naphthyl. Alternatively, ring A can be a 5- to 10-membered heteroaryl comprising 1 or 2 heteroatoms selected from N, O, and S. In one embodiment, the 5- to 10-membered heteroaryl can be a 5- or 6-membered heteroaryl comprising 1 or 2 nitrogen atoms. For example, the 5- or 6-membered heteroaryl can be, but is not limited to, pyrrolyl, pyridinyl, or pyrimidinyl. For example, ring A can be phenyl or pyridinyl.

Ring A of formula (I) can be substituted with n R ^A . R ^A can be halogen, CN, OH, NR'R'', C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy. In R ^A , C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy can be optionally substituted with halogen, CN, OH or NR'R''. In one specific embodiment, R ^A can be halogen, CN, NR'R'', C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkyl. In this case, R' and R'' can each independently be H or C ₁ -C ₆ alkyl. n is an integer from 0 to 4. The haloalkyl can be substituted with one or two or more halogens. For example, the haloalkyl may include monohaloalkyl, dihaloalkyl, trihaloalkyl, tetrahaloalkyl, perhaloalkyl, etc. When the haloalkyl is substituted with two or more halogens, they may be substituted with the same or different halogens, and may be substituted at the same or different carbon atoms of the alkyl group. For example, R ^A may be, but is not limited to, F, Cl, CN, amino, methyl, methoxy, CHF ₂ and CF ₃ . In one embodiment, n may be an integer from 1 to 3, such as 2 or 3. In one embodiment, when n is 2 or greater, at least one R ^A may be halogen, CN, C ₁ -C ₆ haloalkyl. For example, when n is 2 or greater, at least one R ^A may be F, cyano, CHF ₂ or CF ₃ .

In the above chemical formula (I), R ¹ is H or C ₁ -C ₆ alkyl. For example, R ¹ is methyl. In one specific embodiment, the chiral carbon to which R ¹ is bonded may have a stereostructure of the (R)-form. In this case, the compound of chemical formula (I) is represented by the following chemical formula (I-1).

[Chemical formula (I-1)]

In the above formula (I), R ² and R ³ are each independently H, halogen, CN, OH, NR'R'', -COR', -SO ₂ R', -CONR'R'', -SO ₂ NR'R'', C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or saturated or partially unsaturated C ₃ -C ₇ cycloalkyl. In the above R ² and R ³ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₇ cycloalkyl may each be optionally substituted independently with halogen, CN, OH, or NR'R''. In the definition of the above R ² and R ³ and their substituents, R' and R'' are each independently H or C ₁ -C ₆ alkyl. In one embodiment, R ² and R ³ can each independently be, but are not limited to, H, halogen, CN, OH, CONH ₂ , or C ₁ -C ₆ alkyl. In one embodiment, R ² is H, CN, OH, or C ₁ -C ₆ alkyl (e.g., methyl), R ³ is H, halogen (e.g., F or Cl), CN, or CONH ₂ , and at least one of R ² and R ³ may not be H.

In the above formula (I), R ⁴ is H, C ₁ -C ₆ alkyl, saturated or partially unsaturated C ₃ -C ₇ cycloalkyl, (C ₁ -C ₆ alkyl)(saturated or partially unsaturated C ₃ -C ₇ cycloalkyl), or (saturated or partially unsaturated C ₃ -C ₇ cycloalkyl)(C ₁ -C ₆ alkyl). In one embodiment, R ⁴ can be H, C ₁ -C ₃ alkyl, saturated or partially unsaturated C ₃ -C ₅ cycloalkyl, -(C ₁ -C ₃ alkyl)(saturated or partially unsaturated C ₃ -C ₅ cycloalkyl), or -(saturated or partially unsaturated C ₃ -C ₅ cycloalkyl)(C ₁ -C ₃ alkyl). For example, R ⁴ can be, but is not limited to, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , cyclopropyl or methylcyclopropyl.

In the above chemical formula (I), B is NR ^x R ^y , or ring B1. In this case, one of R ^x and R ^y may be H or C ₁ -C ₆ alkyl and the other may be ring B2.

The above ring B1 is bonded to the 1,6-naphthyridin-2-one parent nucleus through the carbon atom contained therein. In chemical formula (I), the 1,6-naphthyridin 2-one parent nucleus refers to the following structure: . In addition, the ring B2 is bonded to the nitrogen atom of NR ^x R ^y through the carbon atom included therein.

Rings B1 and B2 are each independently a 3- to 10-membered monocyclic or bicyclic saturated or partially unsaturated heterocyclyl, a 5- to 10-membered heteroaryl, or a saturated or partially unsaturated C ₃ -C ₇ cycloalkyl. In this case, the heterocyclyl and heteroaryl of rings B1 and B2 may contain one or two heteroatoms selected from N, O, and S.

In one embodiment, ring B1 and ring B2 can each independently be a 3- to 7-membered monocyclic saturated or partially unsaturated heterocyclyl comprising one heteroatom selected from N and O. Alternatively, ring B1 and ring B2 can each independently be a 5- to 6-membered heteroaryl comprising one N. Alternatively, ring B1 and ring B2 can each independently be a saturated or partially unsaturated C ₃ -C ₅ cycloalkyl. For example, ring B1 and ring B2 can each independently be, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, or dihydropyranyl. For example, ring B1 can be, but is not limited to, piperidinyl, tetrahydropyridinyl, or dihydropyridinyl. For example, ring B2 can be, but is not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, or dihydropyranyl. Alternatively, ring B1 and ring B2 can be pyrrolyl or pyridinyl.

The above ring B1 and ring B2 may each be optionally substituted independently with 1 to 3 R ^B . In this case, R ^B may be halogen, oxo, CN, OH, NR'R'', -COR', -SO ₂ R', -CONR'R'', -SO ₂ NR'R'', C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or saturated or partially unsaturated C ₃ -C ₇ cycloalkyl. The C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and saturated or partially unsaturated C ₃ -C ₇ cycloalkyl of R ^B may each be optionally substituted independently with halogen, CN, OH, or NR'R''. In the definition of the above R ^B and its substituents, R' and R'' are each independently H or C ₁ -C ₆ alkyl. In one specific embodiment, R ^B can be halogen, CN, OH, NH ₂ , NHR', NR'R'', -COR', -SO ₂ R', C ₁ -C ₆ alkyl or saturated or partially unsaturated C ₃ -C ₇ cycloalkyl. In this case, R' and R'' are each independently C ₁ -C ₆ alkyl. For example, R ^B can be, but is not limited to, F, Cl, CN, OH, NH ₂ , methylamino, dimethylamino, acetyl (i.e., -C(O)CH ₃ ), methylsulfonyl (i.e., -S(O ₂ )CH ₃ ), methyl, ethyl, isopropyl, cyclopropyl, and the like.

Alternatively, B of formula (I) is NR ^x R ^y , wherein R ^x and R ^y together with the nitrogen atom to which they are bonded can form ring B3. Ring B3 is a 3- to 10-membered monocyclic or bicyclic saturated or partially unsaturated heterocyclyl or a 5- to 10-membered heteroaryl. Ring B3 together with the nitrogen atom to which R ^x and R ^y are bonded may optionally contain one additional heteroatom selected from N, O and S.

In one embodiment, ring B3 can be a 4-9 membered monocyclic or bicyclic saturated or partially unsaturated heterocyclyl, optionally comprising one additional heteroatom selected from N and O, together with the nitrogen atom to which R ^x and R ^y are bonded. When ring B3 is bicyclic heterocyclyl, it can be a spiro or bridged heterocyclyl. For example, the spiro or bridged heterocyclyl is azabicyclo[3.1.0]hexanyl, azabicyclo[2.2.0]hexanyl, azabicyclo[4.1.0]heptanyl, azabicyclo[3.2.0]heptanyl, azabicyclo[5.1.0]octanyl, azabicyclo[4.2.0]octanyl, azabicyclo[3.3.0]octanyl, oxaazabicyclo[3.1.0]hexanyl, oxaazabicyclo[2.2.0]hexanyl, oxaazabicyclo[4.1.0]heptanyl, oxaazabicyclo[3.2.0]heptanyl, oxaazabicyclo[5.1.0]octanyl, oxaazabicyclo[4.2.0]octanyl, Oxazabicyclo[3.3.0]octanyl, diazabicyclo[3.1.0]hexanyl, diazabicyclo[2.2.0]hexanyl, diazabicyclo[4.1.0]heptanyl, diazabicyclo[3.2.0]heptanyl, diazabicyclo[5.1.0]octanyl, diazabicyclo[4.2.0]octanyl, diazabicyclo[3.3.0]octanyl, azabicyclo[2.1.1]hexanyl, azabicyclo[3.1.1]heptanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[4.1.1]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.2]octanyl, Oxaazabicyclo[2.1.1]hexanyl, oxaazabicyclo[3.1.1]heptanyl, oxaazabicyclo[2.2.1]heptanyl, oxaazabicyclo[4.1.1]octanyl, oxaazabicyclo[3.2.1]octanyl, oxaazabicyclo[2.2.2]octanyl, diazabicyclo[2.1.1]hexanyl, diazabicyclo[3.1.1]heptanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[4.1.1]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[2.2.2]octanyl, azaspiro[2.3]hexanyl, azaspiro[2.4]heptanyl, Including, but not limited to, azaspiro[3.3]heptanyl, azaspiro[2.5]octanyl, azaspiro[3.4]octanyl, oxaazaspiro[2.3]hexanyl, oxaazaspiro[2.4]heptanyl, oxaazaspiro[3.3]heptanyl, oxaazaspiro[2.5]octanyl, oxaazaspiro[3.4]octanyl, diazaspiro[2.3]hexanyl, diazaspiro[2.4]heptanyl, diazaspiro[3.3]heptanyl, diazaspiro[2.5]octanyl and diazaspiro[3.4]octanyl.

For example, ring B3 may be azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, azepanyl, diazepanyl, , , or It may be, but is not limited to.

The above ring B3 may be optionally substituted with 1 to 3 R ^B independently. In this case, R ^B may be halogen, oxo, CN, OH, NR'R'', -COR', -SO ₂ R', -CONR'R'', -SO ₂ NR'R'', C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or saturated or partially unsaturated C ₃ -C ₇ cycloalkyl. The C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and saturated or partially unsaturated C ₃ -C ₇ cycloalkyl of the above R ^B may each be optionally substituted with halogen, CN, OH, or NR'R'' independently. In the definition of the above R ^B and its substituents, R' and R'' are each independently H or C ₁ -C ₆ alkyl. In one embodiment, ring B3 is optionally substituted with R ^B , wherein R ^B can be halogen, CN, OH, NH ₂ , NHR', NR'R'', -COR', -SO ₂ R', C ₁ -C ₆ alkyl or saturated or partially unsaturated C ₃ -C ₇ cycloalkyl. In this case, R' and R'' are each independently C ₁ -C ₆ alkyl. For example, R ^B can be, but is not limited to, F, Cl, CN, OH, NH ₂ , methylamino, dimethylamino, acetyl (i.e., -C(O)CH ₃ ), methylsulfonyl (i.e., -S(O ₂ )CH ₃ ), methyl, ethyl, isopropyl, cyclopropyl, and the like.

In one specific example, ring B3 optionally substituted with R ^B in formula (I) may be represented by the following structure, but is not limited thereto:

The compound of the above formula (I) may be a compound selected from Table 1 below:

definition

All technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art, and unless otherwise stated, conventional measuring methods, manufacturing methods, conventional ingredients or materials based on conventional techniques of pharmacology, pharmaceutical manufacturing, mass spectrometry, NMR, HPLC, biochemistry, etc. are used.

The individual features and components of each embodiment described and illustrated in this specification may be combined with the features and components of any other embodiment without departing from the scope or spirit of the present disclosure.

Unless otherwise specified, in this specification and any attached claims, "and" and "or" mean "and/or." The terms "comprises" and "comprised" are open-ended, meaning that the compound, composition, or method may include additional features or components in addition to the specific features or components listed.

In this specification, a numerical range indicated using the term “to” refers to a range that includes the numerical values described before and after the term “to” as the lower and upper limits, respectively.

As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, the term "optionally substituted" means that the occurrences include instances where the occurrences are either substituted or unsubstituted with the specified substituent.

compound

The term "halogen" refers to an atom belonging to Group 17 of the periodic table. Halogen atoms include fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). The term "halogen" may be used interchangeably with the term "halo," which refers to a monovalent functional group composed of a halogen.

The term "hydroxy" refers to the -OH functional group (hydroxyl group).

The term "-CN" or "cyano" refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom.

The term "amino" refers to a nitrogen atom with a hydrogen atom attached to it, i.e. -NH ₂ .

The term "alkylamino" refers to a functional group in which one hydrogen of amino is replaced by alkyl. For example, C ₁ -C ₆ alkylamino can include, but is not limited to, -NH(C ₁ -C ₆ alkyl) such as methylamino, ethylamino, propylamino, butylamino, etc.

"Dialkylamino" refers to a functional group in which two hydrogens of an amino group are each replaced by alkyl. In this case, the substituted alkyl groups may be the same or different. For example, di(C ₁ -C ₆ alkyl)amino may include, but is not limited to, -N(C ₁ -C ₆ alkyl) ₂ , dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, methylpropylamino, ethylpropylamino, etc.

The term "alkyl" refers to a fully saturated branched or unbranched (or straight-chain or linear) hydrocarbon. The alkyl may be a substituted or unsubstituted alkyl group. The alkyl may be an alkyl group having C ₁ to C ₆ , C ₁ to C ₅ , C ₁ to C ₄ , C ₁ to C ₃ , or C ₁ to C ₂ . Non-limiting examples of the alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, iso-amyl, or n-hexyl.

The term "haloalkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group having a specified number of carbon atoms, substituted with one or more halogen atoms. Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of the alkyl group are replaced by halogens (e.g., -CF ₃ , -CF ₂ CF ₃ ). The halogens may be the same (e.g., CHF ₂ , CF ₃ ) or different (e.g., CF ₂ Cl). Where specified, a haloalkyl group may be optionally substituted with one or more substituents other than halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

The term "alkenyl" refers to a linear or branched hydrocarbyl group having 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms and at least one site of vinyl unsaturation (>C=C<).

The term "alkoxy" refers to a substituent in which a substituted or unsubstituted straight or branched chain alkyl moiety is linked to another chemical structure by an oxygen atom. The alkoxy may include, without limitation, all possible isomers thereof, such as methoxy, ethoxy, propoxy, and butoxy, or isopropoxy, isobutoxy, and t-butoxy.

The term "cycloalkyl" refers to a saturated or partially unsaturated hydrocarbon ring having the specified number of carbon atoms as ring elements (i.e., C ₃ -C ₇ cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms as ring elements). The term "cycloalkyl" herein may refer to, for example, C ₃ -C ₇ cycloalkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₅ cycloalkyl. The cycloalkyl may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

The term "aryl" also includes groups in which an aromatic ring or an aromatic ring is fused to one or more carbon rings. The C ₆ -C ₁₂ aryl group may be, for example, an aryl group having C ₆ to C ₁₀ or C ₆ to C ₈ . Non-limiting examples of aryl include phenyl or naphthyl.

The term "heteroaryl" refers to a monocyclic or bicyclic group containing one or more heteroatoms selected from the group consisting of N, O, and S, with the remaining ring atoms being carbon. The heteroaryl group may contain, for example, 1 to 3 heteroatoms and may contain 5 to 10 ring atoms. For example, the heteroaryl may be a 5-membered or 6-membered monocyclic heteroaryl. The heteroaryl may contain, for example, 1 or 2 nitrogen atoms. The S or N may be oxidized to have multiple oxidation states. Examples of monocyclic heteroaryls include, but are not limited to, pyrimidinyl, pyridinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like.

One non-limiting example of the above-described heteroaryl group is a C ₁ -C ₅ heteroaryl, which is a monocyclic aromatic ring having 1 to 5 carbon ring atoms and one or more additional ring atoms that are independently heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) (preferably 1 to 4 additional ring atoms that are heteroatoms). Examples of C ₁ -C ₅ heteroaryl include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

The term "heterocyclyl" or "heterocyclic ring" refers to a saturated or partially unsaturated cyclic hydrocarbon group containing at least one heteroatom. A heterocyclyl group can be a monocyclic or a bicyclic group. The bicyclic group can be a spiro-ring, a bridged-ring, or a fused-ring. A spiro-ring group refers to a structure in which two rings share one common atom. A bridged-ring group refers to a structure in which two non-adjacent ring elements are connected to each other by one or more bridging elements. A heterocyclyl group can contain 3 to 20, 3 to 12, 3 to 10, 3 to 7, 3 to 6, 4 to 6, or 5 to 6 ring elements. The above heterocyclyl group may include one or more heteroatoms selected from the group consisting of N, O, and S. Non-limiting examples of monocyclic heterocyclic ring groups include aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, azepane, and the like. For example, spiro heterocyclyl groups include 2-azaspiro[3.3]heptan-2yl, 2,6-diazaspiro[3.3]heptan-2-yl, 6-oxa-2-azaspiro[3.3]heptan-2-yl, 2-azaspiro[3.4]octane-2yl, 2,6-diazaspiro[3.4]octane-2-yl, 6-oxa-2-azaspiro[3.4]octane-2-yl, 6-azaspiro[3.4]octane-6-yl, 2,6-diazaspiro[3.4]octane-6-yl, 2-oxa-6-azaspiro[3.4]octane-6-yl, 2-azaspiro[4.4]nonan-2-yl, Includes, but is not limited to, 2,7-diazaspiro[4.4]nonan-2-yl or 2-oxa-7-azaspiro[4.4]nonan-7-yl. For example, the bridged heterocyclyl group can be, but is not limited to, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, 2-oxa-5-azabicyclo[2,2,2]octan-5-yl, 8-azabicyclo[3.2.1]octan-8-yl, 3-azabicyclo[3.1.1]heptan-3-yl, or 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl. Also, non-limiting examples of bridged heterocyclyl include azabicyclo[2.1.1]hexanyl, azabicyclo[3.1.1]heptanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[4.1.1]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.2]octanyl, oxaazabicyclo[2.1.1]hexanyl, oxaazabicyclo[3.1.1]heptanyl, oxaazabicyclo[2.2.1]heptanyl, oxaazabicyclo[4.1.1]octanyl, oxaazabicyclo[3.2.1]octanyl, oxaazabicyclo[2.2.2]octanyl, diazabicyclo[2.1.1]hexanyl, Examples include diazabicyclo[3.1.1]heptanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[4.1.1]octanyl, diazabicyclo[3.2.1]octanyl, and diazabicyclo[2.2.2]octanyl.

The term "substitution" in the above "optionally substituted" refers to introducing a substituted hydrogen atom in the case where one or more hydrogen atoms in an organic compound are replaced with another atomic group to form a derivative, and "substituent" refers to the introduced atomic group. As used herein, a "substituted" group is one in which one or more hydrogen atoms are replaced with one or more non-hydrogen atomic groups, provided that the valence requirement is satisfied and a chemically stable compound is generated from the substitution. As used herein, unless explicitly described as "unsubstituted," all substituents should be interpreted as being either substituted or unsubstituted.

In this specification, when a combination of substituents is referred to as one group, for example, haloalkyl, hydroxyalkyl, etc., it is generally the last mentioned group that contains the atom attached to the residue of the compound.

In this specification " ", "*" or "-" are used to indicate the position at which the substituent is bonded to the residue of the compound. For example, when - is displayed at the end of a substituent, it means that the end is bonded to the remaining residue of the compound. Also, when two or more substituents are connected with "-", it means that the substituent immediately before "-" is bonded to the substitutable atom of the substituent immediately after "-".

The term "isotope" as used herein refers to an element having the same mass number but a different number of neutrons, i.e., the same number of protons but a different number of neutrons. Examples thereof include, but are not limited to, 2H, 3H, 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, 125I, etc. Compounds labeled with isotopes may have advantages in terms of improved stability in the body and a longer half-life.

The term "solvate" as used herein may refer to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric solvent bound by non-covalent intermolecular forces. Preferred solvents include those that are volatile, non-toxic, and/or suitable for human administration. Those skilled in the art will readily be able to prepare solvates, such as hydrates, of the compounds disclosed herein using appropriate techniques known in the art.

The term "stereoisomer" as used herein may mean a compound of the present invention or a salt thereof having the same chemical or molecular formula but different optically or sterically, and specifically may be a diastereomer, an enantiomer, or a geometric isomer.

In some embodiments, the compounds of the present invention may contain one or more asymmetric centers, and may be in the form of racemates, single enantiomers, mixtures of enantiomers, single diastereomers, mixtures of diastereomers, etc. In one embodiment, due to the nature or restricted rotation of the asymmetric center, the compounds of the present invention may exist in the form of enantiomers or diastereomers.

When two or more asymmetric centers are present in the compounds of the present invention, multiple diastereoisomers and enantiomers of the chemical structures disclosed herein may exist, and all such pure isomers, isolated isomers, partially pure isomers, or racemic mixtures are intended to fall within the scope of the present invention.

Purification of the above isomers and separation of the isomer mixture can be achieved by standard techniques known in the art. For example, a diastereomeric mixture can be separated into individual diastereoisomers by chromatographic processes or crystallization, and racemates can be separated into individual enantiomers by chiral phase chromatographic processes or resolution.

The term "salt" refers to inorganic and organic acid addition salts of a compound. The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The pharmaceutically acceptable salts may be salts that do not cause serious irritation to the organism to which the compound is administered and do not impair the biological activity and physical properties of the compound. The inorganic salts may be hydrochloride, bromate, phosphate, sulfate, or disulfate. The organic acid salt may be formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edicyl, trichloroacetic acid, trifluoroacetate, benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate. In addition, the metal salt may be calcium salt, sodium salt, magnesium salt, strontium salt, or potassium salt.

A pharmaceutically acceptable salt of the compound according to the present invention can be prepared by dissolving the compound of formula (I) in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, adding an excess of an organic acid or an aqueous solution of an inorganic acid, and then precipitating or crystallizing the mixture. Subsequently, the solvent or the excess of acid is evaporated from the mixture, followed by drying to obtain an addition salt, or the precipitated salt can be prepared by suction filtration.

Compounds of the present invention, including stereoisomers, isotopically labeled compounds, hydrates, solvates and salts, can be prepared by known organic synthetic methods and can be synthesized via a number of synthetic routes.

The reaction for preparing the compound of the present invention can be performed in a suitable solvent that can be appropriately selected by those skilled in the art of organic synthesis. Suitable solvents are those that are substantially non-reactive with the starting materials (reactants), intermediates, or target products at the temperature at which the reaction occurs. Those skilled in the art will be able to appropriately select the appropriate solvent for each specific reaction step.

During the synthesis of the compound of the present invention, protection and deprotection of various functional groups can be achieved. Those skilled in the art will readily be able to determine the necessity of protection and deprotection and select appropriate protecting groups.

Each reaction can be monitored by any suitable method known in the art. For example, the synthesis of the target compound can be monitored by spectroscopic means, such as NMR (e.g., 1H or 13C), mass spectroscopy, or chromatography (HPLC or TLC).

If necessary, the compounds of the present invention can be purified by, for example, chromatography, crystallization from a solvent or solvent mixture, distillation, extraction, etc. Chromatography can be, but is not limited to, reverse-phase, normal phase, size exclusion, ion exchange, preparative, or flash chromatography. Those skilled in the art will readily be able to select the optimal technique for purifying the target compound.

If the compounds of the present invention are stereoisomers, they can be isolated from the racemic mixture by any suitable method, if necessary. For example, separation by formation of ionic or diastereomeric salts using chiral compounds and fractional crystallization, formation and separation of diastereoisomers using chiral derivatizing reagents and subsequent conversion to pure stereoisomers, and methods for directly separating substantially pure stereoisomers under chiral conditions can be used.

The compound of the present invention can be synthesized according to the synthetic process described in the examples below, and based on this, the target compound can be manufactured by appropriately changing the reactants and reaction conditions according to the structure of the target compound.

In one specific embodiment, a compound of formula (I) wherein B is NR ^x R ^y and R ^x and R ^y together with the nitrogen atom to which they are bonded form ring B3 can be prepared according to the following steps 1 to 3:

Step 1: Preparation of halides of 1,6-naphthyridin-2-one parent nucleus (e.g., preparation of intermediate S1)

Step 2: A step of combining the product of Step 1 with an alkylamine compound containing ring A (e.g., preparation of intermediate S2); and

Step 3: A step of reacting an amine compound containing ring B3 after halogenating the bonding position of ring B3 in the product of step 2.

Medicinal uses, pharmaceutical compositions and methods of administration

Another aspect provides a pharmaceutical composition comprising a compound according to one aspect, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof. The compound, stereoisomer, isotopically labeled compound, solvate, and salt are as described above.

A compound according to one aspect of the present invention, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, selectively acts on SOS1 and is useful for the prevention or treatment of SOS1-mediated diseases.

As used herein, "SOS1-mediated disease" may be a disease caused by a dysfunction in a series of pathways resulting from the interaction between SOS1 and KRAS. For example, compounds according to the present invention may exhibit therapeutic effects on various diseases by inhibiting signal transduction (e.g., ERK phosphorylation) in downstream cells of RAS-family proteins.

The RAS protein is a guanosine triphosphatase (GTPase), which acts as a molecular switch in cells, cycling between an active GTP-bound state and an inactive GDP-bound state. Mutations in the RAS gene reduce the ability of the GTPase RAS to hydrolyze GTP, thereby activating the RAS protein in a perpetually active state, a growth signal that normally only activates when cells need to grow. It interacts with C-RAF and phosphoinositide 3-kinase (PI3K) to promote RAS protein downstream signals, such as the RAF/mitogen or extracellular signal-regulated kinases (MEK/ERK) pathway, the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway, and the RalGDS (Ral guanine nucleotide dissociation stimulator) pathway, thereby causing indiscriminate cell proliferation and cancer development (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6; Young et al., Adv. Cancer Res., 2009, 102:1-17).

Additionally, alterations in RAS family proteins are also well known as resistance mechanisms to anticancer drugs such as the EGFR antibodies cetuximab and panitumumab (Leto et al., J. Mol. Med. (Berl). 2014 July; 92(7):709-22) and the EGFR tyrosine kinase inhibitor osimertinib/AZD9291 (Ortiz-Cuaran et al., Clin. Cancer Res., 2016, 22(19):4837-47; Eberlein et al., Cancer Res., 2015, 75(12):2489-500).

Meanwhile, the SOS family includes SOS1 and SOS2, which share approximately 70% sequence identity. SOS1 appears to be significantly more active than SOS2 due to its rapid degradation.

Alterations in SOS1 are known to be associated with cancer. SOS1 mutations have been reported to be found in Noonan syndrome, embryonal teratomas, Sertoli cell tumor of the testis, granular cell tumor of the skin (Denayer et al., Genes Chromosomes Cancer, 2010, 49(3):242-52), and lung adenocarcinoma (Cancer Genome Atlas Research Network., Nature. 2014, 511(7511):543-50). On the other hand, overexpression of SOS1 has been reported to be found in bladder cancer (Watanabe et al., IUBMB Life., 2000, 49(4),317-20) and prostate cancer (Timofeeva et al., Int. J. Oncol., 2009; 35(4),751-60).

SOS1 has two binding sites for RAS family proteins: a catalytic site that binds GDP-bound RAS family proteins to catalyze guanine nucleotide exchange, and an allosteric site that upregulates the catalytic activity of SOS1 upon binding GTP-bound RAS family proteins. This has been reported to significantly enhance the GEF function of SOS1 (Freedman et al., Proc. Natl. Acad. Sci. USA., 2006, 103(45):16692-7; Pierre et al., Biochem. Pharmacol., 2011, 82(9):1049-56), (J. Med. Chem. 2021, 64, 10, 6569-6580). Selective pharmacological inhibition of SOS1 binding to the catalytic site of RAS family proteins is expected to prevent SOS1-mediated activation of RAS family proteins in the GTP-bound form. Mutant RAS proteins are sensitive to inhibition of upstream factors, such as SOS1 or SHP2, which are other upstream signaling molecules required for RAS activation (Hillig, 2019; Lito, 2016). Furthermore, SOS1 inhibitor compounds inhibit signaling downstream of RAS family proteins (e.g., ERK phosphorylation), and thus, SOS1 inhibitors may exhibit anticancer effects (e.g., inhibition of proliferation, survival, metastasis, etc.) in cancer cells that depend on RAS family proteins (e.g., KRAS mutant cancer cell lines).

Therefore, the compound according to the present invention, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof can prevent the activation of K-RAS by inhibiting the binding of K-RAS+ GDP to SOS1, and can prevent SOS1-mediated activation of RAS-family proteins into a GTP-bound form by selectively inhibiting the binding of SOS1 to the catalytic site of RAS-family proteins. That is, the compound according to the present invention, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof can be useful in the treatment of cancer by inhibiting the SOS1-KRAS interaction and thereby preventing the recycling of KRAS into an active GTP-bound form.

The above SOS1-mediated diseases include cancer and RAS diseases.

The cancers may include, but are not limited to, stomach cancer, lung cancer, lung adenocarcinoma, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, glioblastoma, head and neck squamous cell carcinoma, diffuse large cell type B lymphoma, bone cancer, melanoma, breast cancer, sclerosing adenoma, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, glioblastoma, prostate cancer, urethral cancer, urothelial cancer, bladder cancer, leukemia, multiple myeloma, myelodysplastic syndrome, cholangiocarcinoma, lymphoma, and fibroadenoma.

The pharmaceutical composition may include an additional anticancer agent. The pharmaceutical composition may be a single composition or individual compositions. For example, the pharmaceutical composition according to one aspect may be a composition in an oral dosage form, and the anticancer agent may be a composition in a parenteral dosage form.

When used in the treatment of cancer, the compounds of the present invention may be used alone or in combination with conventional surgery or radiotherapy, chemotherapy or immunotherapy.

For example, the compounds of the present invention may be used in combination with other anticancer therapies, such as radiation therapy, taxane derivatives (e.g., paclitaxel, docetaxel, cabazitaxel), platinum compounds (e.g., cisplatin, carboplatin), antimetabolites (e.g., 5-FU, gemcitabine, cytarabine), anti-CTLA4 therapies (e.g., ipilimumab, tremelimumab), anti-PD1 therapies (e.g., nivolumab, pembrolizumab), anti-PD-L1 therapies (e.g., atezolizumab, durvalumab), anti-VEGF therapies (e.g., bevacizumab, ramucirumab, aflivacept), anti-EGFR therapies (e.g., cetuximab), topoisomerase inhibitors (e.g., irinotecan), anti-HER2 therapies (e.g., trastuzumab, pertuzumab), anti-hormonal therapies (e.g., tamoxifen, exemestane, letrozole, anastrozole), estrogen receptor inhibitors (e.g., elacestrant, fulvestrant), ERK inhibitors (e.g., ulixertinib), PARP inhibitors (e.g., olaparib, niraparib, talazoparib), mTOR inhibitors (e.g., everolimus, temsirolimus), CDK4/6 inhibitors (e.g., abemaciclib, palbociclib), EGFR inhibitors (e.g., afatinib, erlotinib, osimertinib, gefitinib, dacomitinib), HER2 inhibitors (e.g., neratinib, lapatinib), ALK inhibitors (e.g., crizotinib, alectinib, brigatinib, ceritinib), tyrosine kinase inhibitors (e.g., avapritinib, ripretinib, sunitinib, sorafenib, pazopanib, Regorafenib, cabozantinib, lenvatinib), MEK inhibitors (e.g., trametinib), BCR-ABL inhibitors (e.g., imatinib, nilotinib, dasatinib), PI3K inhibitors (e.g., alpelisib), FGFR inhibitors (e.g., putivatinib, pemigatinib), ROS1 inhibitors (e.g., crizotinib, entrectinib), androgen biosynthesis inhibitors (e.g., abiraterone acetate), androgen receptor inhibitors (e.g., enzalutamide, darolutamide, apalutamide), Hedgehog inhibitors (e.g., sonidegib, vismodegib), MET inhibitors (e.g., capmatinib, tepotinib), AXL inhibitors, NTRK1 inhibitors, RET inhibitors (e.g., pralsetinib, selpercatinib), KRAS inhibitors (e.g., adagrasib, It can be administered in combination with other drugs such as sotorasib) or RAF inhibitors (e.g., encorafenib, vemurafenib).

In one specific embodiment, the compound according to the present invention, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, may be useful in the treatment of RAS diseases by modulating abnormal activity of SOS1 or a RAS family protein, or dysregulation of pathways of a RAS family protein.

The above RAS conditions may include, but are not limited to, Neurofibromatosis type 1 (NF1), Noonan Syndrome, Noonan Syndrome with Multiple Lentigines (NSML), also known as Leopard Syndrome, Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome, Cardio-Facio-Cutaneous Syndrome, Legius Syndrome (also known as NF1-like syndrome), or Hereditary gingival fibromatosis.

As used herein, the term "preventing" or "prevention" refers to preventing a disease, condition or disorder, for example, in a subject who may be predisposed to the disease, condition or disorder but does not yet experience or exhibit the pathology or signs of the disease.

As used herein, the term "treating" or "treatment" includes inhibiting a disease, condition or disorder, e.g., inhibiting the disease, condition or disorder in a subject experiencing or exhibiting the pathology or signs of the disease, condition or disorder, i.e., preventing recurrence or further development of the pathology and/or signs after treatment of the pathology and/or signs, or ameliorating a disease, condition or disorder, e.g., ameliorating the disease, condition or disorder in a subject experiencing or exhibiting the pathology or signs of the disease, condition or disorder, i.e., reversing the pathology and/or signs, e.g., reducing disease severity.

The pharmaceutical composition may comprise, in addition to the compound of the present invention, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, an additional therapeutically active agent. The additional therapeutically active agent may be an anticancer agent that can be administered in combination as described above. In this case, the compound of the present invention and the additional therapeutically active agent may be a single composition or separate compositions. For example, the compound of the present invention may be provided as a composition in an oral dosage form, and the additional therapeutically active agent may be provided in a parenteral dosage form, or the compound of the present invention may be provided as a parenteral dosage form, and the additional therapeutically active agent may be provided in an oral dosage form.

The pharmaceutical composition may include a pharmaceutically acceptable carrier. The carrier is used to mean an excipient, diluent, or auxiliary. The carrier may be selected from the group consisting of, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, saline, a buffer such as PBS, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil. The composition may include fillers, anticoagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, or combinations thereof.

The pharmaceutical composition described above may be prepared in any dosage form according to conventional methods. For example, the composition may be formulated as an oral dosage form (e.g., powder, tablet, capsule, syrup, pill, or granule) or a parenteral dosage form (e.g., injection). Furthermore, the composition may be prepared as a systemic dosage form or a topical dosage form.

In the pharmaceutical composition, the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule. The solid preparation may further include an excipient. The excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. In addition, the solid preparation may further include a lubricant such as magnesium stearate or talc. In the pharmaceutical composition, the liquid preparation for oral administration may be a suspension, an oral solution, an emulsion, or a syrup. The liquid preparation may include water or liquid paraffin. The liquid preparation may include an excipient such as a wetting agent, a sweetener, a flavoring agent, or a preservative. In the above pharmaceutical composition, the preparation for parenteral administration may be a sterile aqueous solution, non-aqueous solvent, suspension, emulsion, lyophilized product, or suppository. The non-aqueous solvent or suspension may contain a vegetable oil or ester. The vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil. The ester may be, for example, ethyl oleate. The base of the suppository may be witepsol, macrogol, Tween 61, cocoa butter, laurin butter, or glycerogelatin.

The pharmaceutical composition comprises a compound according to one aspect, a stereoisomer thereof, an isotopically labeled compound, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof as an active ingredient of the pharmaceutical composition. The term "active ingredient" refers to a physiologically active substance used to achieve pharmacological activity (e.g., anticancer).

The pharmaceutical composition may comprise an effective amount of a compound according to one aspect, a stereoisomer thereof, an isotopically labeled compound, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof. The term "effective amount" refers to an amount sufficient to exhibit the effect of preventing or treating a disease when administered to a subject in need of prevention or treatment. The effective amount can be appropriately selected by a person skilled in the art depending on the cell or subject selected. The preferred dosage of the pharmaceutical composition varies depending on the condition and body weight of the subject, the degree of the disease, the drug form, the route and duration of administration, but can be appropriately selected by a person skilled in the art. However, the compound, its stereoisomer, isotopically labeled compound, hydrate, solvate or pharmaceutically acceptable salt may be administered in an amount of, for example, about 0.0001 mg/kg to about 100 mg/kg, or about 0.001 mg/kg to about 100 mg/kg, once to 24 times a day, once to 7 times every 2 days to 1 week, or once to 24 times every 1 month to 12 months. In the pharmaceutical composition, the compound, its stereoisomer, isotopically labeled compound, hydrate, solvate or pharmaceutically acceptable salt may be included in an amount of about 0.0001 wt% to about 10 wt%, or about 0.001 wt% to about 1 wt%, based on the total weight of the entire composition.

Administration may be oral or parenteral. For example, the route of administration may be oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal. The composition may be administered systemically or locally, and may be administered alone or in combination with other therapeutically active agents.

Another aspect provides a method for treating a disease mediated by SOS1, comprising administering to a subject a compound according to one aspect, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof. The compound, the stereoisomer, the isotopically labeled compound, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, and the disease to be treated are as described above.

In addition, another aspect provides the use of a compound according to one aspect, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a SOS1-mediated disease, or for the manufacture of a medicament for the prevention or treatment of a SOS1-mediated disease. The compound, the stereoisomer, the isotopically labeled compound, the hydrate, the solvate or the pharmaceutically acceptable salt thereof and the treatable disease are as described above.

The compound of formula (I), a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, has an effective inhibitory activity against SOS1, and in particular, inhibits the interaction of SOS1 with RAS family proteins, thereby being useful for the prevention or treatment of SOS1-mediated diseases, specifically diseases associated with abnormal activity of SOS1 and/or RAS family proteins.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following examples.

The meanings of the abbreviations used in the examples below are as follows, and abbreviations not listed below have the meanings commonly used in the relevant fields.

THF: Tetrahydrofuran

TEA: Triethanolamine

DMF: N,N-dimethylformamide

DCM: Dichloromethane

TFA: Trifluoroacetic acid

NaOAc: sodium acetate

ACN: Acetonitrile

EA: Ethyl Acetate

DMSO: dimethyl sulfoxide

PE: petroleum ether

AcOH: acetic acid

DIEA: Diisopropylethylamine

NBS: N-bromosuccinimide

LDA: lithium diisopropylamide

CDI: 1,1'-carbonyldiimidazole

BINAP: 2,2'-bis(diphenylphosphinol)-1,1'-binaphthyl

DAST: Diethylaminosulfur trifluoride

MTBE: methyl t-butyl ether

NIS: N-iodosuccinimide

TFAA: Trifluoroacetic anhydride

[Manufacturing example]

Manufacturing Example 1: (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethanamine hydrochloride (intermediate D)

Step 1: 1-(3-nitro-5-(trifluoromethyl)phenyl)ethanol (Intermediate A)

A mixture of 1-bromo-3-nitro-5-(trifluoromethyl)benzene (186.76 g, 0.69 mol), tributyl(1-ethoxyvinyl)stannane (249.81 g, 0.69 mol), bis(triphenylphosphine)palladium(II) chloride (14.57 g, 0.02 mol), and triethylamine (209.98 g, 2. 07 mol) in 1,4-dioxane (1,000 mL) was filled with nitrogen and stirred at 80°C for 16 h. The mixture was concentrated, suspended in 3 M HCl (500 mL), stirred at 40°C for 5 h, and then extracted with EtOAc (500 mL * 3). The organic layer was concentrated, and the concentrated residue was purified by silica gel column chromatography (PE/EtOAc = 20:1) to obtain 1-(3-nitro-5-(trifluoromethyl)phenyl)ethanone (Intermediate A) (150 g, 83.71% yield) as a yellow oil.

^1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.69 (s, 1H), 8.54 (s, 1H), 2.76 (s, 3H).

Step 2: (R,Z)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (Intermediate B)

Intermediate A (130 g, 0.55 mol) and (R)-2-methylpropane-2-sulfinamide (67.29 g, 0.55 mol) were dissolved in THF (1,000 mL), and titanium ethoxide (379.94 g, 1.66 mol) was slowly added while stirring at room temperature. The reaction mixture was stirred at 80 °C for 16 h, concentrated, and then silica gel (300 g) was added. The mixture was concentrated, suspended in DCM/MeOH (10:1, 2,000 mL*3), and filtered. The concentrated filtrate was purified by column chromatography (PE/EtOAc 100:1 to 20:1) to obtain (R,Z)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (Intermediate B) (150 g, 72.08% yield) as a yellow oil.

^1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.60 (s, 1H), 8.42 (s, 1H), 2.89 (s, 3H), 1.36 (s, 9H).

Step 3: (R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (Intermediate C)

Intermediate B (83 g, 0.24 mol) was dissolved in THF (800 mL) and cooled to -78°C. Sodium biboride (16.75 g, 0.39 mol) was added little by little at -78°C over 10 minutes, the mixture was stirred for about 2 hours down to -40°C, and the reaction was quenched with ice water at -20°C. The mixture was extracted with EA (500 mL*3), and the concentrated organic layer was purified by silica gel column chromatography (PE/EtOAc=50:1) to give (R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (Intermediate C) (60 g, 64.67% yield) as a yellow oil.

MS: m/z = 339.3 (M+1, ESI+).

Step 4: (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethanamine hydrochloride (Intermediate D)

Intermediate C (60 g, 0.17 mol) was dissolved in 1,4-dioxane hydrochloric acid solution (4 M, 600 mL), the mixture was stirred at room temperature for 16 h, and the reaction mixture was concentrated. The concentrated residue was recrystallized from 2-methoxy-2-methylpropane (200 mL) and filtered. The filter cake was washed with 2-methoxy-2-methylpropane (50 mL*2) and concentrated in vacuo to give (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethanamine hydrochloride (25 g, 54.13% yield) (Intermediate D) as an off-white solid.

MS: m/z = 235.1 (M+1, ESI+).

Manufacturing Example 2: 5-Chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 6-chloro-4-(methylamino)nicotinonitrile

4,6-Dichloropyridine-3-carbonitrile (16 g, 92.33 mmol) and methylamine (ethanol 33%) (3.87 g, 0.12 mol) were dissolved in MeOH (160 mL) and stirred at 40°C for 16 h. The resulting mixture was concentrated in vacuo and purified by silica gel column chromatography (PE/EA=5:1) to obtain 6-chloro-4-(methylamino)nicotinonitrile (6.91 g, yield 42.92%) as a white solid.

MS: m/z = 168.1 (M+1, ESI+).

Step 2: 5-Bromo-6-chloro-4-(methylamino)nicotinonitrile

6-Chloro-4-(methylamino)nicotinonitrile (4.45 g, 26.80 mmol) and NBS (6.15 g, 34.63 mmol) were dissolved in acetic acid (50 mL) and stirred at 40°C for 2 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The pH was adjusted to 8-10 with NaHCO ₃ , and then extracted with EA (120 mL). The obtained organic layer was concentrated in vacuo to give 5-bromo-6-chloro-4-(methylamino)nicotinonitrile (6.75 g, 100% yield) as a white solid.

^1H NMR (400 MHz, DMSO- d6 ) δ: 8.35 (s, 1H), 7.40 (s, 1H), 3.28 (s, 3H).

Step 3: Ethyl (E)-3-(2-chloro-5-cyano-4-(methylamino)pyridin-3-yl)acrylate

5-Bromo-6-chloro-4-(methylamino)nicotinonitrile (6.1 g, 24.71 mmol), ethyl but-3-enoate (12.19 g, 0.12 mmol), Pd(AcO) ₂ ((1.49 g, 4.88 mmol), tri-o-tolylmethane (1.49 g, 4.88 mmol), TEA (7.50 g, 74.12 mmol) were dissolved in DMF (80 mL) and stirred at 120°C for 16 h under nitrogen. The mixture was extracted with EA (200 mL), and the combined organic layers were concentrated in vacuo and purified by silica gel column chromatography (PE/EA=5:1) to give ethyl (E)-3-(2-chloro-5-cyano-4-(methylamino)pyridin-3-yl)acrylate (6.1 mg, (48.55% yield) was obtained as a yellowish-gray solid.

MS: m/z = 266.1 (M+1, ESI+).

Step 4: 5-Chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (Intermediate S1)

Ethyl (E)-3-(2-chloro-5-cyano-4-(methylamino)pyridin-3-yl)acrylate (2.0 g, 7.52 mmol) was dissolved in HCl/1,4-dioxane (30 mL) and stirred in a sealed tube at 100 ^o C for 16 h. The mixture was concentrated and purified by chromatography (PE: EA = 3:1) to give intermediate S1 (1.1 g, 68.75% yield) as an off-white solid.

MS: m/z = 220.1 (M+1, ESI+).

Manufacturing Example 3: (R)-1-Methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S1 (1.21 g, 5.53 mmol), (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine (1.30 g, 5.53 mmol), and DIEA (2.14 g, 16.54 mmol) were added to DMSO (15 mL) and stirred at 90°C for 16 h. The mixture was adjusted to pH 8-10 with NaHCO ₃ and then extracted with EA (50 mL). The combined organic layers were concentrated in vacuo and purified by silica gel column chromatography (PE/EA = 1:1) to give intermediate S2 (943 mg, 41.12% yield) as a white solid.

MS: m/z = 418.4 (M+1, ESI+).

Manufacturing Example 4: (R)-3-Bromo-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

A mixture of (R)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (943 mg, 2.25 mmol), acetic acid (135 mg, 2.25 mmol), and NBS (802 mg, 4.51 mmol) was dissolved in acetonitrile (10 mL) and stirred at 60°C for 2 h. The mixture was extracted with EA (30 mL), and the combined organic layer was concentrated in vacuo to give intermediate S3 (820 mg, 73.28% yield) as a yellow solid.

MS: m/z = 497.1 (M+1, ESI+).

[Example]

Example 1: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-fluoro-1-methyl-3-morpholino-1,6-naphthyridin-2(1H)-one

Step 1: 2-chloro-5-fluoro-3-iodopyridin-4-amine

A mixture of 2-chloro-5-fluoropyridin-4-amine (2,000 mg, 13.64 mmol), iodine chloride (6647 mg, 40.94 mmol), and NaOAc (2,238 mg, 27.29 mmol) in AcOH (30 mL) was stirred at 70°C for 5 h. Most of the acetic acid was evaporated, and the reaction mixture was diluted with water (100 mL). The product was extracted with EA (100 mL x 3). The combined extracts were washed with 10% sodium carbonate solution (100 mL), 5% sodium thiosulfate solution (100 mL), and brine (100 mL), dried, and evaporated. The product was purified by flash column chromatography on silica gel (PE: EA = 10:1) to give 2-chloro-5-fluoro-3-iodopyridin-4-amine (3,380 mg, 90.91% yield) as a yellow solid.

MS: m/z = 273.0 (M+1, ESI+).

Step 2: Ethyl (E)-3-(4-amino-2-chloro-5-fluoropyridin-3-yl)acrylate

2-Chloro-5-fluoro-3-iodopyridin-4-amine (1,600 mg, 5.87 mmol), ethyl but-3-enoate (2,939 mg, 29.36 mmol), Pd(AcO) ₂ (195 mg, 1. 17 mmol), tri-o-tolylmethane (357 mg, 1.17 mmol), and TEA (1,782 mg, 17.61 mmol) were added to DMF (16 mL) and stirred at 120 °C for 12 h under nitrogen. The mixture was diluted with water (100 mL), extracted with EA (100 mL x 3), and the combined organic layers were concentrated. The concentrated residue was purified by silica gel column chromatography (PE/EA = 10:1) to obtain ethyl (E)-3-(4-amino-2-chloro-5-fluoropyridin-3-yl)acrylate (1,270 mg, 88.39% yield) as a yellow solid.

MS: m/z = 245.2 (M+1, ESI+).

Step 3: 5-Chloro-8-fluoro-1,6-naphthyridin-2(1H)-one

Ethyl (E)-3-(4-amino-2-chloro-5-fluoropyridin-3-yl)acrylate (1.0 g, 4.10 mmol) was dissolved in 1,4-dioxane/HCl (20 mL) and stirred in a sealed tube at 100°C for 16 h. The mixture was then concentrated to obtain 5-chloro-8-fluoro-1,6-naphthyridin-2(1H)-one (900 mg, 100% yield) as a yellow solid.

MS: m/z = 199.2 (M+1, ESI+).

Step 4: 5-Chloro-8-fluoro-1-methyl-1,6-naphthyridin-2(1H)-one

5-Chloro-8-fluoro-1,6-naphthyridin-2(1H)-one (900 mg, 4.54 mmol), CH ₃ I (1.9 g, 13.62 mmol), and Cs ₂ CO ₃ (4.4 g, 13.62 mmol) were dissolved in DMF (15 mL) and stirred at 0°C for 2 h. The mixture was diluted with water (30 mL) and extracted with EA (30 mL). The residue was dried over Na ₂ SO ₄ , concentrated, and purified by flash chromatography (PE/EA = 5:1) to give 5-chloro-8-fluoro-1-methyl-1,6-naphthyridin-2(1H)-one (600 mg, 62.37% yield) as a yellow solid.

MS: m/z = 213.1 (M+1, ESI+).

Step 5: (R)-8-Fluoro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one

5-Chloro-8-fluoro-1-methyl-1,6-naphthyridin-2(1H)-one (900 mg, 4.24 mmol), (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine (1.2 g, 5.09 mmol), RuPhos-Pd-G3 (351 mg, 0.42 mmol), RuPhos (196 mg, 0.42 mmol), and t-BuONa (1.2 g, 12.72 mmol) in 1,4-dioxane (15 mL) were stirred at 100 °C for 4 h. The mixture was diluted with H ₂ O (30 mL) and extracted with EA (30 mL). Drying and concentrating over Na ₂ SO ₄ and purification by flash chromatography (PE/EA = 1:1) gave (R)-8-fluoro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (600 mg, 35.29% yield) as a yellow solid.

MS: m/z = 411.0 (M+1, ESI+).

Step 6: (R)-3-Bromo-8-fluoro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one

A mixture of (R)-8-fluoro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (500 mg, 1.21 mmol), NBS (324 mg, 1.82 mmol), and AcOH (87 mg, 1.45 mmol) in ACN (8 mL) was stirred at 80 °C for 5 h. The reaction was diluted with water (20 mL) and extracted with EA (20 x 3 mL). The combined extracts were washed with saturated sodium carbonate solution (30 mL) and brine (30 mL), dried, and evaporated. The product was purified by prep-HPLC [(ACN-H20(0.1% _NH4HCO3 ))=35:65] _to give (R)-3-bromo-8-fluoro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (250 mg, 41.95% yield) as a yellow solid.

MS: m/z = 489.1 (M+1, ESI+).

Step 7: (R)-8-Fluoro-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one

(R)-3-Bromo-8-fluoro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (250 mg, 0. 51 mmol), morpholine (53 mg, 0.61 mmol), RuPhos (23 mg, 0.05 mmol), RuPhos Pd G3 (43 mg, 0.05 mmol), and tBuONa (147 mg, 1.53 mmol) were added to 1,4-dioxane (3 mL) and stirred at 100°C for 5 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH=30:1) to give (R)-8-fluoro-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (180 mg, 71.10% yield) as a yellow solid.

MS: m/z = 496.4 (M+1, ESI+).

Step 8: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-fluoro-1-methyl-3-morpholino-1,6-naphthyridin-2(1H)-one

(R)-8-Fluoro-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (120 mg, 0. 24 mmol), hypodiboric acid (65 mg, 0.72 mmol), and 4,4'-bipyridine (2 mg, 0.01 mmol) were added to DMF (2 mL) and stirred at room temperature for 10 min. The stirred mixture was purified by prep-HPLC [CAN:H ₂ O (0.1%NH ₄ HCO ₃ )=35:65] to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-fluoro-1-methyl-3-morpholino-1,6-naphthyridin-2(1H)-one (47 mg, 41.70% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 7.81 (d, 1H), 7.38 (s, 1H), 7.23 (d, 1H), 6.80 (d, 2H), 6.65 (s, 1H), 5.48 (s, 2H), 5.27-5.24 (m, 1H), 3.77-3.76 (m, 4H), 3.73 (d, 3H), 3.20 (s, 4H), 1.49 (d, 3H); MS: m/z = 466.0 (M+1, ESI+); HRMS: 466.1865.

Example 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-fluoro-1,7-dimethyl-3-morpholino-1,6-naphthyridin-2(1H)-one

Step 1: 6-Chloro-3-fluoro-4-iodo-2-methylpyridine

To a solution of 6-chloro-3-fluoro-2-methylpyridine (5 g, 34.3 mmol) in THF (50 mL) at -78°C under nitrogen, LDA (5.51 g, 51.4 mmol) was slowly added, and I ₂ (10.45 g, 41.1 mmol) solution was added dropwise. The reaction mixture was stirred at -78°C for 1 h, and saturated NH ₄ Cl aqueous solution (50 mL) was added. The residue was extracted with EA (3x50 mL), and the extract was dried and evaporated to obtain 6-chloro-3-fluoro-4-iodo-2-methylpyridine (8 g, 77.26% yield) as a brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.57-7.56 (m, 1H), 2.52-2.51 (m, 3H).

Step 2: 6-Chloro-3-fluoro-N,2-dimethylpyridin-4-amine

6-Chloro-3-fluoro-4-iodo-2-methylpyridine (6 g, 22.1 mmol) and methyl amine (6.86 g, 221 mmol) were dissolved in ethanol (60 mL), stirred in a sealed tube at 80°C for 24 h, and the reaction mixture was concentrated at 45°C. The resulting mixture was added to a silica gel column and eluted with PE/EA (10:1) to quantitatively obtain 6-chloro-3-fluoro-N,2-dimethylpyridin-4-amine.

MS: m/z = 175.1 (M+1, ESI+).

Step 3: 2-Chloro-5-fluoro-3-iodo-N,6-dimethylpyridin-4-amine

A mixture of 6-chloro-3-fluoro-N,2-dimethylpyridin-4-amine (3.4 g, 19.5 mmol), iodine monochloride (6.33 g, 39 mmol), and NaOAc (3.2 g, 39 mmol) was stirred in AcOH (30 mL) at 70 °C for 5 h. After diluting the mixture with water, the residue was extracted with EA (3 x 10 mL). The resulting mixture was added to a silica gel column and eluted with PE/EA (50: 1) to give 2-chloro-5-fluoro-3-iodo-N,6-dimethylpyridin-4-amine (5 g, 84.10% yield) as a yellow solid.

MS: m/z = 301.0 (M+1, ESI+).

Step 4: Ethyl (E)-3-(2-chloro-5-fluoro-6-methyl-4-(methylamino)pyridin-3-yl)acrylate

2-Chloro-5-fluoro-3-iodo-N,6-dimethylpyridin-4-amine (5 g, 16.6 mmol), ethyl but-3-enoate (8.31 g, 83 mmol), Pd(AcO) ₂ (0. 55 g, 3.3 mmol), tri-o-tolylmethane (1.01 g, 3.3 mmol), and TEA (5.04 g, 49.8 mmol) were added to DMF (50 mL) and stirred at 120 °C for 12 h under nitrogen. The residue was extracted with EA (3 × 50 mL) and purified on a silica gel column with PE/EA (10:1) to give ethyl (E)-3-(2-chloro-5-fluoro-6-methyl-4-(methylamino)pyridin-3-yl)acrylate (4 g, 81.33% yield) as a yellow solid.

MS: m/z = 273.2 (M+1, ESI+).

Step 5: 5-Chloro-8-fluoro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one

Ethyl (E)-3-(2-chloro-5-fluoro-6-methyl-4-(methylamino)pyridin-3-yl)acrylate (800 mg, 2.93 mmol) and hydrochloric acid (1069 mg, 29.33 mmol) dissolved in 1,4-dioxane (10 mL) were stirred at 90 °C for 36 h under nitrogen. The mixture was adjusted to pH = 7 with NaHCO ₃ , and the mixture was eluted with a silica gel column (PE/EA (10:1)) to give 5-chloro-8-fluoro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (800 mg, 96.26% yield) as a yellow solid.

MS: m/z = 227.1 (M+1, ESI+).

Step 6: (R)-8-Fluoro-1,7-dimethyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one

5-Chloro-8-fluoro-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (800 mg, 3.52 mmol), intermediate D (955 mg, 3. 52 mmol), RuPhos (165 mg, 0.35 mmol), RuPhos Pd G3 (148 mg, 0.18 mmol), and t-BuONa (1018 mg, 10.58 mmol) were added to dioxane (10 mL) and stirred at 100°C for 12 h under nitrogen. The mixture was concentrated in vacuo and purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH=200:1) to give (R)-8-fluoro-1,7-dimethyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (780 mg, 52.07% yield) as a yellow solid.

MS: m/z = 425.2 (M+1, ESI+).

Step 7: (R)-3-Bromo-8-fluoro-1,7-dimethyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one

(R)-8-Fluoro-1,7-dimethyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (780 mg, 1.83 mmol), NBS (491 mg, 2.75 mmol), and AcOH (221 mg, 3.67 mmol) were dissolved in ACN (10 mL) and stirred at 80°C for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 x 3 mL). The extracted mixture was washed with saturated sodium carbonate solution (20 mL) and brine (20 mL), dried, and concentrated. The concentrated residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH = 50:1) to give (R)-3-bromo-8-fluoro-1,7-dimethyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (240 mg, 38.48% yield) as a yellow solid.

MS: m/z = 503.1 (M+1, ESI+).

Step 8: (R)-8-Fluoro-1,7-dimethyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one

(R)-3-Bromo-8-fluoro-1,7-dimethyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (300 mg, 0. 59 mmol), morpholine (62 mg, 0.71 mmol), RuPhos (28 mg, 0.06 mmol), RuPhos Pd G3 (25 mg, 0.03 mmol), and t-BuONa (172 mg, 1.78 mmol) were added to 1,4-dioxane (5 mL) and stirred at 100°C for 5 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH=30:1) to give (R)-8-fluoro-1,7-dimethyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (150 mg, 49.40% yield) as a yellow solid.

MS: m/z = 510.4 (M+1, ESI+).

Step 9: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-fluoro-1,7-dimethyl-3-morpholino-1,6-naphthyridin-2(1H)-one

(R)-8-Fluoro-1,7-dimethyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (130 mg, 0. 25 mmol), hypoboric acid (68 mg, 0.76 mmol), and 4,4'-bipyridine (2 mg, 0.01 mmol) were added to DMF (2 mL) and stirred at room temperature for 10 min. The mixture was purified by prep-HPLC [ACN-H ₂ O (0.1 % NH ₄ HCO ₃ )=35:65] to obtain (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-fluoro-1,7-dimethyl-3-morpholino-1,6-naphthyridin-2(1H)-one (40 mg 32.71 % yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 7.34-7.32 (m, 1H), 7.15 (d, 1H), 6.85 (s, 1H), 6.82 (s, 1H), 6.65 (s, 1H), 5.47 (s, 2H), 5.33-5.29 (m, 1H), 3.77-3.75 (m, 4H), 3.72 (d, 3H), 3.17-3.16 (m, 4H), 2.23 (d, 3H), 1.49 (d, 3H); MS: m/z = 480.1 (M+1, ESI+); HRMS: 480.2019.

Example 3: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-1-Methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (820 mg, 1.65 mmol), morpholine (431 mg, 4.95 mmol), sodium tert-butoxide (475 mg, 4.95 mmol), RuPhos Pd G3 (33 mg, 0.17 mmol), and RuPhos (77 mg, 0.17 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 100 °C for 16 h. The mixture was extracted with EA (30 mL), and the combined organic layer was concentrated in vacuo to give (R)-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (210 mg, 25.27% yield) as a yellow solid.

MS: m/z = 503.2 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (Example 3)

(R)-1-Methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (210 mg, 0. 42 mmol), hypoboric acid (198 mg, 2.21 mmol) and 4,4'-bipyridine (3 mg, 0.02 mmol) were dissolved in DMF (5 mL) at room temperature and stirred at room temperature for 10 min. The mixture was concentrated in vacuo and purified by prep-HPLC[ACN-H ₂ O(0.1 % NH ₄ HCO ₃ )=7:3] to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (21.5 mg, 10.66% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.26 (s, 1H), 8.11 (d, 1H), 7.41 (s, 1H), 6.79 (d, 2H), 6.69 (s, 1H), 5.53 (s, 2H), 5.50-5.46 (m, 1H), 3.89 (s, 3H), 3.78-3.76 (m, 4H), 3.20 (m, 4H), 1.54 (d, 3H); MS: m/z = 473.1 (M+1, ESI+).

Example 4: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-ethyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 4,6-Dichloronicotinamide

A mixture of 4,6-dichloropyridine-3-carboxylic acid (92 g, 0.48 mol), CDI (93.24 g, 0.58 mol), and NH ₂ NH ₂ · H ₂ O (35 mL) in THF (950 mL) was stirred at 25 °C for 30 min under nitrogen. Afterwards, H ₂ O (500 mL) was added to stop the reaction, and the residue was extracted with EA (3 x 500 mL). The reaction mixture was concentrated under pressure at 45 °C to obtain 4,6-dichloronicotinamide (95 g, 100% yield) as a yellow solid.

MS: m/z = 191.0 (M+1, ESI+).

Step 2: 6-chloro-4-(ethylamino)nicotinamide

A mixture of 4,6-dichloronicotinamide (6,000 mg, 31.41 mmol) and ethylamine (4,240 mg, 94.23 mmol) in MeOH (60 mL) was stirred at 50°C for 16 h. The residue was extracted with EA (3x100 mL), and the organic phase was washed sequentially with water (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The concentrated mixture was purified by silica gel column chromatography (PE/EA = 2:1) to give 6-chloro-4-(ethylamino)nicotinamide (3,400 mg, 54.22% yield) as a white solid.

MS: m/z = 200.3 (M+1, ESI+).

Step 3: 6-chloro-4-(ethylamino)nicotinonitrile

6-Chloro-4-(ethylamino)nicotinamide (3,800 mg, 19.03 mmol), pyridine (9,033 mg, 114.20 mmol), and phosphoryl trichloride (8,755 mg, 57.10 mmol) were dissolved in ACN (40 mL), and the mixture was stirred at 60°C for 2 h. The residue was then extracted with EA (3x50 mL), and the organic layer was washed with water (30 mL). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO 4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 5:1) to obtain 6-chloro-4-(ethylamino)nicotinonitrile (1,700 mg, 49.17% yield) as a yellow solid.

MS: m/z = 182.3 (M+1, ESI+).

Step 4: 5-Bromo-6-chloro-4-(ethylamino)nicotinonitrile

A mixture of 6-chloro-4-(ethylamino)nicotinonitrile (1,700 mg, 9.36 mmol) and NBS (2,498 mg, 14.04 mmol) dissolved in acetic acid (18 mL) was stirred at 40°C for 16 h. The residue was extracted with EA (3 x 30 mL), and the organic phase was washed with water (20 mL) and brine (20 mL). Drying over Na ₂ SO ₄ , filtering, and concentrating. The residue was purified by silica gel column chromatography (PE/EA = 5:1) to give 5-bromo-6-chloro-4-(ethylamino)nicotinonitrile (2,000 mg, 82.02% yield) as a yellow solid.

MS: m/z = 262.0 (M+2, ESI+).

Step 5: Ethyl (E)-3-(2-chloro-5-cyano-4-(ethylamino)pyridin-3-yl)acrylate

5-Bromo-6-chloro-4-(ethylamino)nicotinonitrile (2,000 mg, 7.67 mmol), ethyl prop-2-enoate (1,152 mg, 11.51 mmol), tri(o-tolyl)phosphine (467 mg, 1.53 mmol), Pd(AcO) ₂ (172 mg, 0.76 mmol), and TEA (2,330 mg, 23.03 mmol) were sequentially added to DMF (20 mL), and the dissolved mixture was stirred at 90 °C for 16 h. The residue was extracted with EA (3 x 20 mL), and the organic phase was washed with water (10 mL), brine (10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. Purification by silica gel column chromatography (PE/EA = 5:1) yielded ethyl (E)-3-(2-chloro-5-cyano-4-(ethylamino)pyridin-3-yl)acrylate (700 mg, 32.60% yield) as a yellow solid.

MS: m/z = 280.3 (M+1, ESI+).

Step 6: 5-Chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Ethyl (E)-3-(2-chloro-5-cyano-4-(ethylamino)pyridin-3-yl)acrylate (600 mg, 2.14 mmol) was dissolved in 1,4-dioxane/HCl (10 mL) and stirred at 100°C for 16 h. The reaction mixture was concentrated under pressure at 45°C to give 5-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (500 mg, 99.76% yield) as a yellow solid.

MS: m/z = 234.1 (M+1, ESI+).

Step 7: (R)-1-Ethyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

5-Chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 1.28 mmol), (1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethanamine (300 mg, 1.28 mmol), and DIEA (829 mg, 6.41 mmol) were dissolved in DMSO (5 mL), and the dissolved mixture was stirred at 100°C for 16 h. The reaction mixture was concentrated under pressure at 45°C to obtain (R)-1-ethyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (375 mg, 67.71% yield) as a yellow solid.

MS: m/z = 430.5 (M-1, ESI-).

Step 8: (R)-3-Bromo-1-ethyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-1-Ethyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (375 mg, 0.86 mmol), NBS (231 mg, 1.30 mmol), and AcOH (52 mg, 0.86 mmol) were dissolved in ACN (5 mL) and stirred at 80 °C for 12 h under nitrogen. The reaction mixture was concentrated under pressure to 45 °C to give (R)-3-bromo-1-ethyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (400 mg, 90.21% yield) as a yellow solid.

MS: m/z = 510 (M+1, ESI+).

Step 9: (R)-1-Ethyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-1-ethyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (400 mg, 0.78 mmol), morpholine (136 mg, 1.56 mmol), Pd(AcO) ₂ (17 mg, 0.07 mmol), xantphos (45 mg, 0.07 mmol), Cs ₂ CO ₃ (766 mg, 2.35 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100 °C for 2 h. The residue was extracted with EA (3 x 10 mL), and the organic phase was washed with water (10 mL) and brine (10 mL). The mixture was dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by Prep-HPLC to give (R)-1-ethyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (165 mg, 40.76% yield) as a yellow solid.

MS: m/z = 517.5 (M+1, ESI+).

Step 10: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-ethyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-1-Ethyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (163 mg, 0.31 mmol), hypoboric acid (84 mg, 0.94 mmol), and 4,4'-bipyridine (4 mg, 0.03 mmol) were dissolved in DMF (3 mL) and stirred at room temperature for 10 min. The residue was purified by Prep-HPLC to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-ethyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (75 mg, 16.29% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.28 (s, 1H), 8.14 (d, 1H), 7.42 (s, 1H), 6.80 (d, 2H), 6.69 (s, 1H), 5.53-5.48 (m, 3H), 4.54-4.52 (m, 2H), 3.78-3.76 (m, 4H), 3.21 (m, 4H), 1.54 (d, 3H), 1.30 (t, 3H); MS: m/z = 487.1 (M+1, ESI+).

Example 5: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-isopropyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 6-chloro-4-(isopropylamino)nicotinonitrile

4,6-Dichloropyridine-3-carbonitrile (6.7 g, 38.7 mmol) and propan-2-amine (9.15 g, 154.8 mmol) were dissolved in DCM (50 mL), and the reaction mixture was stirred at 40°C for 12 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (PE/EA=5:1) to give 6-chloro-4-(isopropylamino)nicotinonitrile (8.37 g, 99.48% yield) as a white solid.

MS: m/z = 196.1 (M+1, ESI+).

Step 2: 5-Bromo-6-chloro-4-(isopropylamino)nicotinonitrile

6-Chloro-4-(isopropylamino)nicotinonitrile (8.37 g, 42.8 mmol) and NBS (11.43 g, 64.20 mmol) were dissolved in acetic acid (50 mL), and the mixture was stirred at 40°C for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo, adjusted to pH 8-10 with NaHCO ₃ , and extracted with EA (120 mL). The combined organic layers were concentrated in vacuo to obtain 5-bromo-6-chloro-4-(isopropylamino)nicotinonitrile (11.4 g, 87.38% yield) as a white solid.

MS: m/z = 276.0 (M+1, ESI+).

Step 3: Ethyl (E)-3-(2-chloro-5-cyano-4-(isopropylamino)pyridin-3-yl)acrylate

5-Bromo-6-chloro-4-(isopropylamino)nicotinonitrile (10.9 g, 39.7 mmol), ethyl prop-2-enoate (7.15 g, 71.4 mmol), Pd(AcO) ₂ (0.89 g, 3.97 mmol), tri(o-tolyl)phosphine (2.42 g, 7.94 mmol), and TEA (20.09 g, 198.5 mmol) were dissolved in DMF (100 mL) and stirred at 110 °C for 12 h under nitrogen. The mixture was extracted with EA (200 mL), and the combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=5:1) to obtain ethyl (E)-3-(2-chloro-5-cyano-4-(isopropylamino)pyridin-3-yl)acrylate (4.8 g, 39.04% yield) as a grayish yellow solid.

MS: m/z = 294.2 (M+1, ESI+)

Step 4: 5-Chloro-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Ethyl (E)-3-(2-chloro-5-cyano-4-(isopropylamino)pyridin-3-yl)acrylate (1.2 g, 4.1 mmol) was dissolved in 1,4-dioxane HCl (10 mL) and stirred in a sealed tube at 100°C for 16 h. The mixture was concentrated and purified by chromatography (PE: EA = 3:1) to give 5-chloro-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (0.45 g, 39.02% yield) as an off-white solid.

MS: m/z = 248.3 (M+1, ESI+).

Step 5: (R)-1-Isopropyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

5-Chloro-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (438 mg, 1.77 mmol), intermediate D (437 mg, 1.86 mmol), and DIEA (686 mg, 5.30 mmol) were dissolved in DMSO (10 mL) and stirred at 100°C for 12 h. The mixture was adjusted to pH 8-10 with NaHCO ₃ and then extracted with EA (50 mL). The combined organic layers were concentrated in vacuo and purified by silica gel column chromatography (PE/EA=1:1) to obtain (R)-1-isopropyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (800 mg, 91.21% yield) as a white solid.

MS: m/z = 446.4 (M+1, ESI+).

Step 6: (R)-3-Bromo-1-isopropyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-1-Isopropyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (576 mg, 1.29 mmol), acetic acid (155 mg, 2.58 mmol), and NBS (344 mg, 1.93 mmol) were dissolved in acetonitrile (20 mL) and stirred at 80°C for 12 h. The mixture was extracted with EA (30 mL), and the combined organic layers were concentrated in vacuo to give (R)-3-bromo-1-isopropyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (600 mg, 79.67% yield) as a yellow solid.

MS: m/z = 524.3 (M+1, ESI+).

Step 7: (R)-1-Isopropyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-1-isopropyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (425 mg, 0.81 mmol), morpholine (141 mg, 1.62 mmol), Cs ₂ CO ₃ (791 mg, 2.43 mmol), Pd(AcO) ₂ (27 mg, 0.12 mmol)) and Xant-Phos (70 mg, 0.12 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 100°C for 16 h. The mixture was extracted with EA (30 mL), and the combined organic layers were concentrated in vacuo to give (R)-1-isopropyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (260 mg, 28.72% yield) as a yellow solid.

MS: m/z = 531.5 (M+1, ESI+).

Step 8: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-isopropyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-1-Isopropyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (210 mg, 0.39 mmol), hypoboric acid (106 mg, 1.18 mmol), and 4,4'-bipyridine (3 mg, 0.02 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 10 minutes. The mixture was concentrated in vacuo and separated by prep-HPLC (ACN:H ₂ O(0.1%NH ₄ HCO ₃ )=7:3) to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-isopropyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (80 mg, 39.96% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 8.32 (s, 1H), 7.47 (d, 1H), 7.39 (s, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 6.71 (s, 1H), 5.94 (s, 1H), 5.60 (s, 2H), 5.55-5.51 (m, 1H), 3.77-3.75 (m, 4H), 3.18-3.17 (m, 4H), 1.63 (d, 3H), 1.49 (d, 6H); MS: m/z = 501.0 (M+1, ESI+).

Example 6: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-(1-methylcyclopropyl)-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 6-chloro-4-((1-methylcyclopropyl)amino)nicotinonitrile

4,6-Dichloronicotinonitrile (10 g, 57.8 mmol) was dissolved in DMF (100 mL), and 1-methylcyclopropan-1-amine hydrochloride (7.46 g, 69.3 mmol) and DIEA (14.94 g, 115.6 mmol) were added. The mixture was stirred at 60 °C for 16 h and extracted with EA (3 x 100 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and then purified by silica gel column chromatography (PE/EA = 5:1) to give 6-chloro-4-((1-methylcyclopropyl)amino)nicotinonitrile (5 g, 41.67% yield) as a white solid.

MS: m/z = 208.1 (M+1, ESI+).

Step 2: 5-Bromo-6-chloro-4-((1-methylcyclopropyl)amino)nicotinonitrile

6-Chloro-4-[(1-methylcyclopropyl)amino]pyridine-3-carbonitrile (5 g, 24.13 mmol) and NBS (8.59 g, 48.25 mmol) were added to TFA (50 mL) and stirred at 60°C for 16 h. The residue was adjusted to pH 8 with NaHCO ₃ . The residue was extracted with EA (3 x 50 mL), and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 5:1) to obtain 5-bromo-6-chloro-4-((1-methylcyclopropyl)amino)nicotinonitrile (5 g, 32.02% yield) as a yellow solid.

MS: m/z = 286.0 (M+1, ESI+).

Step 3: Ethyl (E)-3-(2-chloro-5-cyano-4-((1-methylcyclopropyl)amino)pyridin-3-yl)acrylate

5-Bromo-6-chloro-4-((1-methylcyclopropyl)amino)nicotinonitrile (2.2 g, 7.7 mmol), ethyl prop-2-enoate (3.85 g, 38.5 mmol), and Pd(AcO) ₂ (0.34 g, 1.54 mmol) were dissolved in DMF (20 mL), and then tri-o-tolylmethane (0.48 g, 1.54 mmol) and TEA (2.33 g, 23.1 mmol) were added. The reaction mixture was stirred at 110 °C for 32 h under nitrogen, and the residue was extracted with EA (3 x 10 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and then purified through silica gel column chromatography (PE/EA = 5:1) to obtain ethyl (E)-3-(2-chloro-5-cyano-4-((1-methylcyclopropyl)amino)pyridin-3-yl)acrylate (1.8 g, 76.73% yield) as a yellow solid.

MS: m/z = 306.1 (M+1, ESI+).

Step 4: 5-Chloro-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

A solution of ethyl (E)-3-(2-chloro-5-cyano-4-((1-methylcyclopropyl)amino)pyridin-3-yl)acrylate (1 g, 3.28 mmol) in 1,4-dioxane/6N HCl=1/1 (5 mL) was placed in a sealed tank, and the mixture was stirred at 100°C for 16 h. The mixture was concentrated to obtain 5-chloro-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (80 mg, 9.2% yield) as a yellow solid.

MS: m/z = 260.1 (M+1, ESI+).

Step 5: (R)-1-(1-Methylcyclopropyl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

5-Chloro-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (80 mg, 0.31 mmol) and intermediate D (87 mg, 0.37 mmol) were dissolved in DMSO (5 mL), DIEA (120 mg, 0.92 mmol) was added, and the mixture was stirred at 100 ℃ for 4 h. The mixture was concentrated and purified by flash chromatography (DCM: MeOH = 50:1) to give (R)-1-(1-methylcyclopropyl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (80 mg, 56.74% yield) as a yellow solid.

LCMS: m/z = 458.5 (M+1, ESI+).

Step 6: (R)-3-Bromo-1-(1-methylcyclopropyl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-1-(1-Methylcyclopropyl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (80 mg, 0.17 mmol) was dissolved in ACN (2 mL), and acetic acid (11 mg, 0.18 mmol) and NBS (62 mg, 0.35 mmol) were added. The mixture was stirred at 60°C for 2 minutes and then concentrated. The concentrated residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH = 30:1) to obtain (R)-3-bromo-1-(1-methylcyclopropyl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (90 mg, 96.72% yield) as a yellow solid.

LCMS: m/z = 536.4 (M+1, ESI+).

Step 7: (R)-1-(1-Methylcyclopropyl)-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-1-(1-methylcyclopropyl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (80 mg, 0.15 mmol), morpholine (39 mg, 0.44 mmol), Ruphos (7 mg, 0.02 mmol), Pd ₂ (dba) ₃ (14 mg, 0.02 mmol), and t-BuONa (43 mg, 0.45 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was stirred at 100 °C for 16 h. The mixture was concentrated in vacuo and separated by silica gel column chromatography (CH ₂ Cl ₂ /MeOH=30:1) to obtain (R)-1-(1-methylcyclopropyl)-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (50 mg, 61.73% yield) as a yellow solid.

MS: m/z = 543.5 (M+1, ESI+).

Step 8: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-(1-methylcyclopropyl)-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-1-(1-Methylcyclopropyl)-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (50 mg, 0.09 mmol), B ₂ (OH) ₄ (16 mg, 0.18 mmol) and 4,4'-bipyridine (1 mg, 0.01 mmol) were dissolved in DMF (2 mL) and stirred at 0°C for 20 min. The mixture was concentrated and purified via Prep-HPLC to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-(1-methylcyclopropyl)-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (11 mg, 23.91% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 8.26 (s, 1H), 8.06-8.02 (m, 1H), 7.33 (d, 1H), 6.81-6.78 (m, 2H), 6.68 (s, 1H), 5.53-5.44 (m, 3H), 3.76-3.75 (m, 4H), 3.28-3.22 (m, 2H), 3.13-3.06 (m, 2H), 1.68 (d, 3H), 1.52 (d, 3H), 1.26-1.21 (m, 2H), 1.18-1.15 (m, 2H); MS: m/z = 513.0 (M+1, ESI+).

Example 7: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-3-(piperazin-1-yl)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: tert -Butyl (R)-4-(8-cyano-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)piperazine-1-carboxylate

Intermediate S3 (200 mg, 0.40 mmol), tert-butyl piperazine-1 carboxylate (150 mg, 0. 80 mmol), 5-Bis(diphenylphosphino)-9,9-dimethylxanthene (46 mg, 0.08 mmol), Pd(AcO) ₂ (18 mg, 0.08 mmol), and Cs ₂ CO ₃ (393 mg, 1.20 mmol) were dissolved in 1,4-dioxane (3 mL) and stirred at 80 °C for 16 h under nitrogen. The reaction mixture was concentrated in vacuo and eluted with a silica gel column CH ₂ Cl ₂ /MeOH (100:1) to give tert-butyl (R)-4-(8-cyano-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)piperazine-1-carboxylate (180 mg, 70.55% yield) as a yellow solid.

MS: m/z = 602.5 (M+1, ESI+).

Step 2: tert -Butyl (R)-4-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-cyano-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)piperazine-1-carboxylate

tert -Butyl (R)-4-(8-cyano-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)piperazine-1-carboxylate (180 mg, 0. 29 mmol), hypoboric acid (80 mg, 0.89 mmol), and 4,4'-bipyridine (3 mg, 0.02 mmol) were dissolved in DMF (3 mL) and stirred at 25°C for 10 minutes. The residue was extracted with DCM (3x10 mL), concentrated in vacuo and purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH=100:1) to give tert-butyl (R)-4-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-cyano-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)piperazine-1-carboxylate (100 mg, 55.55% yield) as a yellow solid.

MS: m/z = 572.6 (M+1, ESI+).

Step 3: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-3-(piperazin-1-yl)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Tert-Butyl (R)-4-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-cyano-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.17 mmol) was added to HCl (3 mL) dissolved in 1,4-dioxane, and the reaction mixture was stirred at 25°C for 3 h. The reaction mixture was concentrated in vacuo, and the residue was purified by Prep-HPLC to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-3-(piperazin-1-yl)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (50 mg, 57.58% yield) as a white solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 8.25 (s, 1H), 8.10 (d, 1H), 7.38 (s, 1H), 6.80 (d, 2H), 6.68 (s, 1H), 5.53-5.45 (m, 3H), 3.89 (s, 3H), 3.13 (m, 4H), 2.90-2.89 (m, 4H), 1.54 (d, 3H); MS: m/z = 472.2 (M+1, ESI+).

Example 8: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(4-methylpiperazin-1-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-1-Methyl-3-(4-methylpiperazin-1-yl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (250 mg, 0. 50 mmol), 1-methylpiperazine (505 mg, 5.04 mmol), Pd(AcO) ₂ (11 mg, 0.05 mmol), BINAP (63 mg, 0.10 mmol) and Cs ₂ CO ₃ (492 mg, 1.51 mmol) were stirred in 1,4-dioxane (3 mL) at 100 °C for 4 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH=30:1) to give (R)-1-methyl-3-(4-methylpiperazin-1-yl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (200 mg, 77.58% recovery) as a yellow solid.

MS: m/z = 516.2 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(4-methylpiperazin-1-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-1-Methyl-3-(4-methylpiperazin-1-yl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (200 mg, 0. 39 mmol), hypoboric acid (104 mg, 1.16 mmol), and 4,4'-bipyridine (3 mg, 0.02 mmol) were added to DMF (3 mL) and stirred at room temperature for 10 min. The mixture was purified with ACN:H ₂ O (0.1%NH ₄ HCO ₃ )=55:45 to obtain (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(4-methylpiperazin-1-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (56 mg, 29.72% yield) as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.20 (s, 1H), 7.46 (s, 1H), 6.91 (s, 2H), 6.77 (s, 1H), 5.51-5.46 (m, 1H), 3.99 (s, 3H), 3.26 (s, 4H), 2.66 (s, 4H), 2.37 (s, 3H), 1.61 (d, 3H); MS: m/z = 486.2 (M+1, ESI+).

Example 9: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3-hydroxyazetidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-3-(3-hydroxyazetidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (300 mg, 0.60 mmol), azetidin-3-ol (132 mg, 1.81 mmol), Pd(AcO) ₂ (17 mg, 0.08 mmol), xant-phos (45 mg, 0.08 mmol) and Cs ₂ CO ₃ (1,179 mg, 3.62 mmol) were stirred in 1,4-dioxane (5 mL) at 100 °C for 12 h. The mixture was extracted with EA (50 mL), and the combined organic layer was concentrated in vacuo to give (R)-3-(3-hydroxyazetidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (165 mg, 53.09% yield) as a yellow solid.

MS: m/z = 489 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3-hydroxyazetidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-(3-hydroxyazetidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (150 mg, 0. 31 mmol), hypoboric acid (82 mg, 0.92 mmol), and 4,4'-bipyridine (2 mg, 0.02 mmol) were dissolved in DMF (3 mL) and stirred at room temperature for 10 min. The mixture was concentrated in vacuo and purified by prep-HPLC (ACN: H ₂ O(0.1%NH ₄ HCO ₃ )=7:3) to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3-hydroxyazetidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (80 mg, 56.25% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.16 (s, 1H), 7.86 (d, 1H), 6.92 (s, 1H), 6.79 (d, 2H), 6.68 (s, 1H), 5.59 (d, 1H), 5.53 (s, 2H), 5.44 (t, 1H), 4.54-4.52 (m, 1H), 4.31-4.29 (m, 2H), 3.86 (s, 3H), 3.76-3.71 (m, 2H), 1.53 (d, 3H); MS: m/z = 459.1 (M+1, ESI+).

Example 10: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3,3-difluoroazetidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-3-(3,3-difluoroazetidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (350 mg, 0. 70 mmol), 3,3-difluoroazetidine (98 mg, 1.06 mmol), Pd(AcO) ₂ (20 mg, 0.09 mmol), Xant-Phos (52 mg, 0.09 mmol) and Cs ₂ CO ₃ (688 mg, 2.11 mmol) were stirred in 1,4-dioxane (5 mL) at 100 °C for 12 h. The mixture was extracted with EA (50 mL), and the combined organic layer was concentrated in vacuo to give (R)-3-(3,3-difluoroazetidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (200 mg, 51.14% yield) as a yellow solid.

MS: m/z =509.4 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3,3-difluoroazetidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-(3,3-Difluoroazetidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (155 mg, 0. 30 mmol), hypoboric acid (81 mg, 0.91 mmol), and 4,4'-bipyridine (2 mg, 0.02 mmol) were dissolved in DMF (3 mL) and stirred at room temperature for 10 minutes. The mixture was concentrated in vacuo and prep-HPLC [ACN:H ₂ O(0.1%NH ₄ HCO ₃ )=7:3] was used to obtain (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3,3-difluoroazetidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (78 mg, 54.29% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.23 (s, 1H), 7.92 (d, 1H), 7.16 (s, 1H), 6.79-6.78 (m, 2H), 6.68 (s, 1H), 5.53 (s, 2H), 5.45 (t, 1H), 4.48-4.41 (m, 4H), 3.88 (s, 3H), 1.54 (d, 3H); MS: m/z = 479.1 (M+1, ESI+).

Example 11: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(4,4-difluoropiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-3-(4,4-difluoropiperidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (200 mg, 0. 42 mmol), 4,4-difluoropiperidine (62 mg, 0.51 mmol), Xant-Phos (49.0 mg, 0.08 mmol), palladium diacetate (9.51 mg, 0.04 mmol), and cesium carbonate (276 mg, 0.85 mmol) were dissolved in 1,4-dioxane (1 mL) and stirred at 100°C for 6 h. The reaction mixture was concentrated to obtain a residue, which was purified by silica gel column chromatography (PE: EA = 1: 1) to obtain (R)-3-(4,4-difluoropiperidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (90 mg, 41.5% yield) as a yellow solid.

MS: m/z = 537.4 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(4,4-difluoropiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

To a solution of (R)-3-(4,4-difluoropiperidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (90 mg, 0.17 mmol) in DMF (2 mL) were added diborane-1,1,2,2-tetrol (31 mg, 0.65 mmol) and 2-(pyridin-2-yl)pyridine (5 mg, 0.04 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h, diluted with EA (10 mL), and washed three times with brine (10 mL). The organic layer was concentrated to obtain the residue, which was purified by Pre-HPLC to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(4,4-difluoropiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (20 mg, 23.6%) as a yellow solid.

^1H NMR (400 MHz, DMSO- d6 ) δ: 8.27 (s, 1H), 8.10 (d, 1H), 7.52 (s, 1H), 6.79 (d, 2H), 6.69 (s, 1H), 5.53 (s, 2H), 5.46 (t, 1H), 3.90 (s, 3H), 3.37-3.31 (m, 4H), 2.17-2.09 (m, 4H), 1.54 (d, 3H). MS: m/z = 507.1 (M+1, ESI+).

Example 12: 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 1-Methyl-3-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (200 mg, 0. 40 mmol), 3-methyl-3,8-diazabicyclo[3.2.1]octane (152 mg, 1.20 mmol), t-BuONa (116 mg, 1.20 mmol), and PEPPSI IHept-Cl (196 mg, 0.20 mmol) were dissolved in THF (3 mL) and stirred at 80°C for 3 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH = 30:1) to give 1-methyl-3-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (180 mg, 82.50% yield) as a yellow solid.

MS: m/z = 542.5 (M+1, ESI+).

Step 2: 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

1-Methyl-3-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (150 mg, 0. 27 mmol), hypoboric acid (74 mg, 0.82 mmol), and 4,4'-bipyridine (2 mg, 0.01 mmol) were added to DMF (2 mL) and stirred at room temperature for 10 min. The mixture was purified by prep-HPLC [ACN-H ₂ O (0.1% NH ₄ HCO ₃ )=55:45] to obtain 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (100 mg, 70.56% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.18 (s, 1H), 7.94 (d, 1H), 7.27 (s, 1H), 6.79 (d, 2H), 6.68 (s, 1H), 5.53-5.49 (m, 3H), 4.76 (d, 2H), 3.89 (s, 3H), 2.54 (d, 2H), 2.27 (d, 2H), 2.12 (s, 3H), 1.89-1.84 (m, 4H), 1.54 (d, 3H); MS: m/z = 512.1 (M+1, ESI+).

Example 13: 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: tert-Butyl 3-(8-cyano-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

Intermediate S3 (500 mg, 1.00 mmol), tert-butyl 3,6-diazabicyclo[3. 1.1]heptane-6-carboxylate (399 mg, 2.01 mmol), Pd(AcO) ₂ (23 mg, 0.10 mmol), BINAP (125 mg, 0.20 mmol), Cs ₂ CO ₃ (983 mg, 3.01 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100°C for 4 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH = 30:1) to afford tert-butyl 3-(8-cyano-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (400 mg, 64.83% yield) as a yellow solid.

MS: m/z = 614.6 (M+1, ESI+).

Step 2: 3-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

400 mg (0.65 mmol) of tert-butyl 3-(8-cyano-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate was dissolved in DCM (3 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to afford 3-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (330 mg, 98.59% yield) as a yellow oil.

MS: m/z = 514.2 (M+1, ESI+).

Step 3: 1-Methyl-3-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

3-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 0. 58 mmol) and formaldehyde (131 mg, 1.75 mmol) were dissolved in DCM (4 mL), and NaBH ₃ CN (73 mg, 1.16 mmol) was slowly added little by little. The reaction mixture was stirred at room temperature for 2 h, diluted with water (10 mL) to stop the reaction, and extracted with DCM (3x10 mL). The combined organic layer was washed with brine (15 mL) and concentrated in vacuo to afford 1-methyl-3-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 97.33% yield) as a yellow solid.

MS: m/z = 528.4 (M+1, ESI+).

Step 4: 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

1-Methyl-3-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (250 mg, 0. 47 mmol), hypoboric acid (127 mg, 1.42 mmol), and 4,4'-bipyridine (4 mg, 0.02 mmol) were added to DMF (3 mL) and stirred for 10 min. The mixture was purified by Prep-HPLC [ACN-H ₂ O (0.1 % NH ₄ HCO ₃ ) = 55:45] to give 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (50 mg, 21.21% yield) as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.14 (s, 1H), 7.09 (s, 1H), 6.91 (s, 2H), 6.77 (s, 1H), 5.51-5.46 (m, 1H), 3.98-3.88 (m, 7H), 3.71 (s, 2H), 2.63-2.55 (m, 1H), 2.24-2.19 (m, 3H), 1.90-1.85 (m, 1H), 1.61 (d, 3H); MS: m/z = 498.0 (M+1, ESI+).

Example 14: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(4-methyl-1,4-diazepan-1-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile formate

Step 1: (R)-1-Methyl-3-(4-methyl-1,4-diazepan-1-yl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (250 mg, 0. 50 mmol), 1-methyl-1,4-diazepane (402 mg, 3.51 mmol), Pd(AcO) ₂ (11 mg, 0.05 mmol), BINAP (63 mg, 0.10 mmol) and Cs ₂ CO ₃ (491 mg, 1.51 mmol) were stirred in 1,4-dioxane (2 mL) at 100 °C for 4 h. The reaction was concentrated in vacuo and purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH = 30:1) to afford (R)-1-methyl-3-(4-methyl-1,4-diazepan-1-yl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (130 mg, 48.83% yield) as a yellow solid.

MS: m/z = 530.3 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(4-methyl-1,4-diazepan-1-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile formate

(R)-1-Methyl-3-(4-methyl-1,4-diazepan-1-yl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (130 mg, 0. 25 mmol), hypoboric acid (66 mg, 0.74 mmol), and 4,4'-bipyridine (2 mg, 0.01 mmol) were added to DMF (2 mL) and stirred at room temperature for 10 minutes. The mixture was purified by prep-HPLC [[ACN-H ₂ O(0.1 % NH ₄ HCO ₃ )=45:55] to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(4-methyl-1,4-diazepan-1-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile formate (50 mg, 40.77% yield) as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.53 (s, 1H), 8.19 (s, 1H), 7.26 (s, 1H), 6.90 (s, 2H), 6.77 (s, 1H), 5.51-5.46 (m, 1H), 4.00 (s, 3H), 3.58-3.56 (m, 2H), 3.48-3.43 (m, 4H), 3.27-3.25 (m, 2H), 2.80 (s, 3H), 2.30-2.24 (m, 2H), 1.60 (d, 3H); MS: m/z = 500.2 (M+1, ESI+).

Example 15: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(4-cyclopropylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-3-(4-cyclopropylpiperazin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (150 mg, 0.30 mmol), 1-cyclopropylpiperazine (267 mg, 2.11 mmol), Pd(AcO) ₂ (8 mg, 0.04 mmol), Xant-Phos (21 mg, 0.04 mmol), and Cs ₂ CO ₃ (295 mg, 0.91 mmol) were dissolved in 1,4-dioxane (4 mL) and stirred at 100 °C for 2 h under nitrogen. The reaction mixture was diluted with water (10 mL), extracted with EA (3x10 mL), and the combined organic layers were washed with brine (15 mL). The residue, concentrated in vacuo, was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH = 30) to give (R)-3-(4-cyclopropylpiperazin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (100 mg, 61.22% yield) as a yellow solid.

MS: m/z = 542.5 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(4-cyclopropylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-(4-Cyclopropylpiperazin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (100 mg, 0. 18 mmol), hypoboric acid (50 mg, 0.55 mmol), and 4,4'-bipyridine (1 mg, 0.01 mmol) were added to DMF (3 mL) and stirred at room temperature for 10 min. The mixture was purified by Prep-HPLC [ACN-H ₂ O (0.1 % NH ₄ HCO ₃ ) = 45:55] to obtain (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(4-cyclopropylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (36 mg, 38.12% yield) as a light yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.25 (s, 1H), 8.07 (d, 1H), 7.38 (s, 1H), 6.79 (d, 2H), 6.68 (s, 1H), 5.53 (s, 2H), 5.49-5.45 (m, 1H), 3.89 (s, 3H), 3.16 (s, 4H), 2.71-2.66 (m, 4H), 1.72-1.67 (m, 1H), 1.53 (d, 3H), 0.47-0.43 (m, 2H), 0.35-0.32 (m, 2H); MS: m/z = 512.2 (M+1, ESI+).

Example 16: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-1-Methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (150 mg, 0.30 mmol), 2-oxa-6-azaspiro[3.3]heptane (209 mg, 2.11 mmol), Pd(AcO) ₂ (8 mg, 0.04 mmol), Xant-Phos (21 mg, 0.05 mmol), and Cs ₂ CO ₃ (295 mg, 0.91 mmol) were dissolved in 1,4-dioxane (4 mL) and stirred at 100 °C for 2 h under nitrogen. The reaction mixture was diluted with water (10 mL), extracted with EA (3 × 10 mL), and the combined extracts were washed with brine (15 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH = 30:1) to give (R)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (150 mg, 96.65% yield) as a yellow solid.

MS: m/z = 515.5 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-1-Methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (130 mg, 0. 25 mmol), hypoboric acid (68 mg, 0.76 mmol), and 4,4'-bipyridine (2 mg, 0.01 mmol) were added to DMF (3 mL) and stirred at room temperature for 10 min. The mixture was purified by prep-HPLC [ACN-H ₂ O (0.1% NH ₄ HCO ₃ )=55:45] to obtain (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (45 mg, 36.76% yield) as a light yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.16 (s, 1H), 7.89 (d, 1H), 6.94 (s, 1H), 6.79 (d, 2H), 6.68 (s, 1H), 5.52 (s, 2H), 5.46-5.42 (m, 1H), 4.72 (s, 4H), 4.21 (s, 4H), 3.85 (s, 3H), 1.53 (d, 3H); MS: m/z = 485.1 (M+1, ESI+).

Example 17: 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (200 mg, 0.40 mmol), 3-oxa-8-azabicyclo[3. 2.1]octane (136 mg, 1.21 mmol), Pd ₂ (dba) ₃ (37 mg, 0.04 mmol), Ruphos (19 mg, 0.40 mmol), and t-BuONa (116 mg, 1.21 mmol) were dissolved in 1,4-dioxane (6 mL) and stirred at 100°C for 16 h. The mixture was concentrated and purified by flash column chromatography on silica gel (DCM: MeOH = 50:1) to give 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (120 mg, 56.34% yield) as a yellow solid.

MS: m/z = 529.5 (M+1, ESI+).

Step 2: 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (120 mg, 0. 23 mmol), hypoboric acid (41 mg, 0.46 mmol), and 4,4'-bipyridine (3.6 mg, 0.02 mmol) were added to DMF (2 mL) and stirred at room temperature for 10 min. The mixture was purified by Prep-HPLC to give the product 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (60 mg, 52.17% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.20 (s, 1H), 7.96 (d, 1H), 7.29 (s, 1H), 6.79 (d, 2H), 6.68 (s, 1H), 5.53-5.49 (m, 3H), 4.62 (s, 2H), 3.89 (s, 3H), 3.74 (d, 2H), 3.51 (d, 2H), 1.93 (s, 4H), 1.54 (d, 3H); MS: m/z = 499.2 (M+1, ESI+).

Example 18: 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 3-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (200 mg, 0.40 mmol), 6-oxa-3-azabicyclo[3.1.1]heptane (80 mg, 0.80 mmol), and Pd2(dba)3 (36 mg, 0.04 mmol), RuPhos (19 mg, 0.04 mmol), and t-BuONa (116 mg, 1.21 mmol) were dissolved in dioxane (5 mL) and stirred at 100°C for 16 h. The residue was purified by silica gel column chromatography (PE/EA=2:1) to give the product 3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (110 mg, 25% yield) as a yellow solid.

MS: m/z = 515.5 (M+1, ESI+).

Step 2: 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

3-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (110 mg, 0.21 mmol), B ₂ (OH) ₄ (115 mg, 1.28 mmol), and 4,4'-bipyridine (2 mg, 0.01 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 10 min. The residue was purified by Chiral-Prep-HPLC to give 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (14 mg, 13.99% yield) as a yellow solid.

^1H NMR (DMSO- d6 , 400 MHz): δ 8.20 (s, 1H), 8.01 (d, 1H), 7.22 (s, 1H), 6.80 (d, 2H), 6.68 (s, 1H), 5.53 (s, 2H), 5.50-5.46 (m, 1H), 4.65 (d, 2H), 4.15 (d, 1H), 4.06 (d, 1H), 3.90 (s, 3H), 3.59-3.50 (m, 2H), 3.11-3.06 (m, 1H), 2.10 (d, 1H), 1.55 (d, 3H); MS: m/z = 485.1 (M+1, ESI+).

Example 19: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3,3-difluoropyrrolidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-3-(3,3-difluoropyrrolidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (300 mg, 0.60 mmol), 3,3-difluoropyrrolidine (129 mg, 1.21 mmol), Pd(AcO) ₂ (17 mg, 0.08 mmol), Xant-Phos (45 mg, 0.08 mmol), and Cs ₂ CO ₃ (982 mg, 3.62 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100°C for 12 h. The mixture was extracted with EA (50 mL), and the combined organic layers were concentrated in vacuo to give ((R)-3-(3,3-difluoropyrrolidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (170 mg, 51.14% yield) as a yellow solid.

MS: m/z =523 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3,3-difluoropyrrolidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-(3,3-difluoropyrrolidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (150 mg, 0.29 mmol), hypoboric acid (77 mg, 0.86 mmol), and 4,4'-bipyridine (2 mg, 0.01 mmol) were added to a solution of DMF (3 mL) at room temperature for 10 min. The mixture was concentrated in vacuo and purified by prep-HPLC [ACN-H ₂ O (0.1% NH ₄ HCO ₃ )=7:3] to give the product (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3,3-difluoropyrrolidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (73 mg, 56.25% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.21 (s, 1H), 7.96 (d, 1H), 7.06 (s, 1H), 6.79 (d, 2H), 6.68 (s, 1H), 5.53 (s, 2H), 5.47 (m, 1H), 3.98-3.94 (m, 2H), 3.89 (s, 3H), 3.69-3.67 (m, 2H), 2.52-2.50 (m, 2H), 1.54 (d, 3H); MS: m/z = 493.1 (M+1, ESI+).

Example 20: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-1-Methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (150 mg, 0.30 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (101 mg, 0.45 mmol), K ₂ CO ₃ (125 mg, 0.90 mmol), and Pd(dppf)Cl ₂ (43 mg, 0.06 mmol) were dissolved in 1,4-dioxane/H ₂ O (=4:1) (3 mL) and stirred at 100°C for 4 h. The reaction mixture was concentrated under pressure at 45°C, and the residue was separated through a silica gel column (DCM/MeOH=20:1) to obtain (R)-1-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (140 mg, 90.37% yield) as a yellow solid.

MS: m/z = 513.5 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-1-Methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (150 mg, 0.29 mmol), hypoboric acid (80 mg, 0.89 mmol), and 4,4'-bipyridine (4 mg, 0.02 mmol) were dissolved in DMF (3 mL) and stirred at room temperature for 10 minutes. The residue was purified by Prep-HPLC to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (16 mg, 11.10% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 8.36-8.34 (m, 2H), 8.23 (s, 1H), 6.79 (d, 2H), 6.68 (s, 1H), 6.43 (m, 1H), 5.53 (s, 2H), 5.47-5.43 (m, 1H), 3.87 (s, 3H), 3.04-3.03 (m, 2H), 2.56-2.54 (m, 4H), 2.28 (s, 3H), 1.53 (d, 3H); MS: m/z = 483.2 (M+1, ESI+).

Example 21: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-3-(1,2,3,6-tetrahydropyridin-4-yl)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: tert-Butyl (R)-4-(8-cyano-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

Intermediate S3 (150 mg, 0.30 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (140 mg, 0.45 mmol), and sodium carbonate (96 mg, 0.91 mmol) were dissolved in 1,4-dioxane/H ₂ O (3 mL), and Pd(dppf)Cl ₂ (22 mg, 0.03 mmol) was stirred at 100 °C for 16 h under nitrogen. The residue was concentrated and purified by silica gel column chromatography (PE/EA=5:1) to give tert-butyl (R)-4-(8-cyano-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 82.77% yield) as a brown oil.

MS: m/z = 599.6 (M+1, ESI+).

Step 2: tert-Butyl (R)-4-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-cyano-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

Tert-Butyl (R)-4-(8-cyano-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.33 mmol) and 4,4'-bipyridine (5 mg, 0.03 mmol) were added to DMF (2 mL) and stirred at room temperature, followed by the addition of hypoboric acid (89 mg, 1.00 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 h. After the reaction mixture was diluted with water (10 mL), extracted with EA (30 mL*3), and the combined organics were washed with brine (30 mL) and concentrated to obtain tert-butyl (R)-4-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-cyano-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 56.65% yield) as a brown oil.

MS: m/z = 569.6 (M+1, ESI+).

Step 3: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-3-(1,2,3,6-tetrahydropyridin-4-yl)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

tert-Butyl (R)-4-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-cyano-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.35 mmol) was dissolved in 1,4-dioxane/HCl (5 mL), and the reaction mixture was stirred at room temperature for 1 h. The residue was then concentrated and purified by Prep-HPLC to obtain (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-3-(1,2,3,6-tetrahydropyridin-4-yl)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (20 mg, 12.15% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 8.52 (d, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 6.82-6.79 (m, 2H), 6.69 (s, 1H), 6.59 (s, 1H), 5.55 (s, 2H), 5.47 (t, 1H), 3.88 (s, 3H), 3.70-3.65 (m, 2H), 3.21 (t, 2H), 2.70-2.67 (m, 2H), 1.55 (d, 3H); MS: m/z = 469.2 (M+1, ESI+).

Example 22: (R)-3-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-3-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (150 mg, 0.30 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (91 mg, 0.36 mmol), sodium carbonate (96 mg, 0.90 mmol), and tetrakis(triphenylphosphine)palladium (34 mg, 0.03 mmol) (0.5 mL) were dissolved in 1,4-dioxane (2 mL) and H ₂ O (0.5 mL), and stirred at 100 °C for 4 h. The reaction mixture was concentrated and separated through a silica gel column (CH ₂ Cl ₂ /MeOH = 20:1) to obtain (R)-3-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (140 mg, 85.68% yield) as a yellow solid.

MS: m/z = 541.5 (M+1, ESI+).

Step 2: (R)-3-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (140 mg, 0.25 mmol), hypoboric acid (69 mg, 0.77 mmol), and 4,4'-bipyridine (2 mg, 0.01 mmol) were dissolved in DMF (2 mL) and stirred at room temperature for 10 minutes. The residue was purified by Prep-HPLC to give (R)-3-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (35 mg, 26.49% yield) as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.32 (s, 1H), 8.21 (d, 1H), 6.91 (s, 2H), 6.78 (s, 1H), 6.40-6.26 (m, 1H), 5.49-5.47 (m, 1H), 4.23-4.20 (m, 2H), 3.99 (s, 3H), 3.79-3.70 (m, 2H), 2.66-2.56 (m, 2H), 2.15 (d, 3H), 1.60-1.58 (m, 3H); MS: m/z = 511.2 (M+1, ESI+).

Example 23: 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3-(dimethylamino)pyrrolidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 3-(3-(dimethylamino)pyrrolidin-1-yl)-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (350 mg, 0.70 mmol), N,N-dimethylpyrrolidin-3-amine (120 mg, 1.06 mmol), Pd(AcO) ₂ (20 mg, 0.09 mmol), Xant-Phos (52 mg, 0.09 mmol), and Cs ₂ CO ₃ (688 mg, 2.11 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100°C for 12 h. The mixture was extracted with EA (50 mL), and the combined organic layers were concentrated in vacuo to give 3-(3-(dimethylamino)pyrrolidin-1-yl)-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (200 mg, 48.20% yield) as a yellow solid.

MS: m/z =530.5 (M+1, ESI+).

Step 2: 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3-(dimethylamino)pyrrolidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

3-(3-(Dimethylamino)pyrrolidin-1-yl)-1-methyl-5-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (112 mg, 0.21 mmol), hypoboric acid (56 mg, 0.63 mmol), and 4,4'-bipyridine (1 mg, 0.01 mmol) were dissolved in DMF (3 mL) and stirred at room temperature for 10 min. The mixture was concentrated in vacuo and purified by prep-HPLC [ACN-H ₂ O(0.1 % NH ₄ HCO ₃ )=7:3] to give the product 5-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(3-(dimethylamino)pyrrolidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (61 mg, 57.13% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.13 (s, 1H), 7.84 (d, 1H), 6.84 (d, 1H), 6.80 (s, 1H), 6.78 (s, 1H), 6.68 (s, 1H), 5.52 (s, 2H), 5.48-5.45 (m, 1H), 3.87 (s, 3H), 3.73-3.69 (m, 1H), 3.60-3.53 (m, 2H), 3.46-3.40 (m, 1H), 2.76-2.73 (m, 1H), 2.20 (s, 6H), 2.11-2.07 (m, 1H), 1.76 (m, 1H), 1.54 (d, 3H); MS: m/z = 500.2 (M+1, ESI+).

Example 24: (R)-3-(4-acetylpiperazin-1-yl)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-3-(4-acetylpiperazin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (300 mg, 0.60 mmol), 1-(piperazin-1-yl)ethanone (775 mg, 6.04 mmol), Pd(AcO) ₂ (14 mg, 0.06 mmol), BINAP (75 mg, 0.12 mmol), and Cs ₂ CO ₃ (591 mg, 1.81 mmol) were dissolved in 1,4-dioxane (3 mL) and stirred at 100°C for 4 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH = 30:1) to afford (R)-3-(4-acetylpiperazin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (170 mg, 51.75% yield) as a yellow solid.

MS: m/z = 544.5 (M+1, ESI+).

Step 2: (R)-3-(4-acetylpiperazin-1-yl)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-(4-acetylpiperazin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (170 mg, 0.31 mmol), hypoboric acid (84 mg, 0.94 mmol), and 4,4'-bipyridine (2 mg, 0.02 mmol) were dissolved in DMF (3 mL) and stirred at room temperature for 10 minutes. The mixture was purified by prep-HPLC [ACN-H ₂ O (0.1% NH ₄ HCO ₃ ) = 55:45] to obtain (R)-3-(4-acetylpiperazin-1-yl)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (80 mg, 44.82% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.27 (s, 1H), 8.10 (d, 1H), 7.45 (s, 1H), 6.79 (d, 2H), 6.69 (s, 1H), 5.53-5.45 (m, 3H), 3.90 (s, 3H), 3.62-3.61 (m, 4H), 3.21-3.12 (m, 4H), 2.07-2.05 (m, 3H), 1.54 (d, 3H); MS: m/z = 514.2 (M+1, ESI+).

Example 25: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(4-isopropylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-3-(4-isopropylpiperazin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (250 mg, 0.50 mmol), 1-isopropyl piperazine (646 mg, 5.04 mmol), Pd(AcO) ₂ (11 mg, 0.05 mmol), BINAP (63 mg, 0.10 mmol), and Cs ₂ CO ₃ (492 mg, 1.51 mmol) were dissolved in 1,4-dioxane (3 mL) and stirred at 100°C for 4 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH = 30:1) to afford (R)-3-(4-isopropylpiperazin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (80 mg, 29.22% yield) as a yellow solid.

MS: m/z = 544.5 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(4-isopropylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-(4-Isopropylpiperazin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (80 mg, 0.15 mmol), hypoboric acid (40 mg, 0.44 mmol), and 4,4'-bipyridine (1 mg, 0.01 mmol) were dissolved in DMF (2 mL) and stirred at room temperature for 10 minutes. The mixture was purified by prep-HPLC [ACN-H ₂ O (0.1 % NH ₄ HCO ₃ ) = 55:45] to obtain (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(4-isopropylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (25 mg, 33.08% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.24 (s, 1H), 8.07 (d, 1H), 7.38 (s, 1H), 6.80 (d, 2H), 6.68 (s, 1H), 5.34 (s, 2H), 5.49-5.45 (m, 1H), 3.89 (s, 3H), 3.19 (m, 4H), 2.71-2.66 (m, 1H), 2.60 (m, 4H), 1.54 (d, 3H), 1.01 (d, 6H); MS: m/z = 514.2 (M+1, ESI+).

Example 26: (R)-5-((1-(3-cyano-2-methylphenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-5-((1-(3-cyano-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S1 (250 mg, 1.14 mmol), (R)-3-(aminoethyl)-2-methylbenzonitrile (182 mg, 1.14 mmol) and DIEA (441 mg, 3.41 mmol) were dissolved in DMSO (5 mL) and stirred at 100°C for 2 h. The mixture was extracted with EA (10 mL*3), and the combined organic layers were compressed in vacuo to obtain (R)-5-((1-(3-cyano-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (360 mg, 92.07% yield) as a yellow solid.

MS: m/z = 344.4 (M+1, ESI+).

Step 2: (R)-3-Bromo-5-((1-(3-cyano-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-5-((1-(3-cyano-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (200 mg, 0.58 mmol), acetic acid (35 mg, 0.58 mmol), and NBS (155 mg, 0.88 mmol) were stirred in DMF (5 mL) at 60 °C for 2 h. The mixture was extracted with EA/Na ₂ CO ₃ (40 mL*3) to obtain (R)-3-bromo-5-((1-(3-cyano-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (200 mg, 100%) as a yellow solid.

MS: m/z = 422.3 (M+1, ESI+).

Step 3: (R)-5-((1-(3-cyano-2-methylphenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

3-Bromo-5-{[(1R)-1-(3-cyano-2-methylphenyl)ethyl]amino}-1-methyl-2-oxo-1,6-naphthyridine-8-carbonitrile (200 mg, 0.47 mmol), morpholine (206 mg, 2.37 mmol), Pd(AcO) ₂ (11 mg, 0.047 mmol), Xantphos (27 mg, 0.047 mmol), and Cs ₂ CO ₃ (463 mg, 1.42 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100°C for 2 h. The mixture was purified by flash chromatography (MeCN/TFA 0.1%) to give the product (R)-5-((1-(3-cyano-2-methylphenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (100 mg, 49.27% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 8.24 (s, 1H), 8.17 (d, 1H), 7.74-7.72 (m, 1H), 7.64-7.62 (m, 1H), 7.42-7.34 (m, 2H), 5.61-5.58 (m, 1H), 3.87 (s, 3H), 4.78-3.76 (m, 4H), 3.21-3.20 (m, 4H), 2.61 (s, 3H), 1.54 (d, 3H); MS: m/z = 429.0 (M+1, ESI+).

Example 27: (R)-1-Methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-1-Methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S1 (250 mg, 1.14 mmol), (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (231 mg, 1.14 mmol), and DIEA (441 mg, 3.41 mmol) were dissolved in DMSO (5 mL) and stirred at 100°C for 2 h. Then, the mixture was extracted with EA (10 mL*3) to obtain (R)-1-methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (551 mg, 100% yield) as a red solid.

MS: m/z = 387.3 (M+1, ESI+).

Step 2: (R)-3-Bromo-1-methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-1-Methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (551 mg, 1.42 mmol), _CH3COOH (86 mg, 1.42 mmol), and NBS (508 mg, 2.85 mmol) were dissolved in ACN (5 mL) and stirred at 60°C for 2 h. Then, the mixture was extracted with EA/Na2CO3 (40 mL*3) to obtain (R)-3-bromo-1-methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (513 mg, 77.37%) as a yellow solid.

MS: m/z = 463.2 (M-1, ESI-).

Step 3: (R)-1-Methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-1-methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (513 mg, 1.10 mmol), morpholine (192 mg, 2.20 mmol), Pd(AcO) ₂ (25 mg, 11.16 mmol), xantphos (68 mg, 0.11 mmol), and Cs ₂ CO ₃ (1077 mg, 3.30 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100°C for 2 h. The mixture was purified by flash chromatography to give (R)-1-methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (50 mg, 9.63% yield) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.29 (s, 1H), 7.57 (t, 2H), 7.29 (d, 1H), 6.58 (s, 1H), 5.79-5.75 (m, 1H), 5.28 (d, 1H), 4.06 (s, 3H), 3.92-3.90 (m, 4H), 3.25-3.24 (m, 4H), 2.52 (s, 3H), 1.63 (d, 3H); MS: m/z = 472.1 (M+1, ESI+).

Example 28: (R)-5-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-5-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S1 (300 mg, 1.36 mmol), (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethan-1-amine (284 mg, 1.36 mmol), and DIEA (530 mg, 4.09 mmol) were dissolved in DMSO (3 mL) and stirred at 80°C for 2 h. The solution was diluted with water (15 mL), filtered, and the filter cake was washed with H ₂ O (20 mL) and dried in vacuo to obtain (R)-5-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (500 mg, 94.34%) as a yellow solid.

MS: m/z = 391.3 (M+1, ESI+).

Step 2: (R)-3-Bromo-5-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-5-((1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (500 mg, 1.28 mmol), AcOH (77 mg, 1.28 mmol), and NBS (273 mg, 1.53 mmol) were dissolved in DMF (5 mL) and stirred at 60°C for 2 h. The solution was diluted with water (20 mL), filtered, and the filter cake was washed with saturated NaHCO ₃ (10 mL) and H ₂ O (10 mL) to obtain (R)-3-bromo-5-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (450 mg, 75.00%) as a yellow solid.

MS: m/z = 469.3 (M+1, ESI+).

Step 3: (R)-5-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-5-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (397 mg, 0.84 mmol), morpholine (220 mg, 2.53 mmol), Pd(AcO) ₂ (28 mg, 0.13 mmol), Xant-Phos (73 mg, 0.13 mmol), and Cs ₂ CO ₃ (825 mg, 2.53 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100°C for 12 h. The mixture was extracted with EA (50 mL), and the combined organic layers were concentrated in vacuo to give (R)-5-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (80 mg, 19.88% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.23 (s, 1H), 8.17 (d, 1H), 7.73 (t, 1H), 7.64 (t, 1H), 7.45 (s, 1H), 7.36 (t, 1H), 5.76-5.73 (m, 1H), 3.88 (s, 3H), 3.79-3.77 (m, 4H), 3.23-3.22 (m, 4H), 1.61 (d, 3H); MS: m/z = 476.1 (M+1, ESI+).

Example 29: (R)-5-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 1-Bromo-3-(difluoromethyl)-2-methylbenzene

-3-Bromo-2-methylbenzaldehyde (2 g, 10 mmol) was dissolved in DCM (20 mL) under nitrogen at -70°C, DAST (2.42 g, 15 mmol) was added dropwise, and the mixture was stirred at 25°C for 4 h. The reaction was quenched with ice water, and the mixture was diluted with water and EA (30 mL), and the organic layer was concentrated through workup. The residue was purified by chromatography on silica gel (PE/EA = 30/1) to give 1-bromo-3-(difluoromethyl)-2-methylbenzene (2 g, 86.00% yield) as a yellow oil.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 7.79 (d, 1H), 7.56 (d, 1H), 7.35-7.08 (m, 2H), 2.43 (s, 3H).

Step 2: 1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-one

1-Bromo-3-(difluoromethyl)-2-methylbenzene (7 g, 31.7 mmol), tributyl(1-ethoxyethenyl)stannane (13.74 g, 38 mmol), and Pd(PPh ₃ )Cl ₂ (0.67 g, 9 mmol) were dissolved in 1,4-dioxane (70 mL) and stirred at 80 °C for 16 h under nitrogen. The mixture was concentrated, suspended in 3 M HCl, and stirred at 40 °C for an additional 2 h. The reaction was quenched with ice-water (30 mL), after which the mixture was diluted with water (30 mL) and EA (30 mL), and the organic layer was concentrated. The residue was purified by chromatography on silica gel (PE/EA = 50/1) to give 1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-one (5 g, 81.39% yield) as a yellow oil.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 7.82 (d, 1H), 7.67 (d, 1H), 7.44 (t, 1H), 7.38-7.10 (m, 1H), 2.56 (s, 3H), 2.38 (s, 3H).

Step 3: (Z)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide

1-(3-(Difluoromethyl)-2-methylphenyl)ethan-1-one (7 g, 38 mmol), (R)-2-methylpropane-2-sulfinamide (5.53 g, 45.6 mmol), and Ti(OEt)4 (13 g, 57 mmol) were dissolved in THF (70 mL), and the reaction mixture was stirred at 80 °C for 12 h. The reaction was quenched with ice water (30 mL), and the mixture was diluted with water and EA (30 mL), and the organic layer was concentrated. The residue was purified by chromatography on silica gel (PE/EA=50/1) to give (Z)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (10 g, 87.11% yield) as a yellow oil.

MS: m/z = 288.3 (M+1, ESI+).

Step 4: N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide

(Z)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (3 g, 104 mmol) was dissolved in THF (30 mL) and cooled to -78 °C. Sodium borohydride (0.71 g, 187 mmol) was added little by little, and the mixture was slowly maintained at -40 °C while stirring for 2 h. The reaction was quenched with ice water (30 mL), diluted with water and EtOAc (30 mL), and the organic layer was concentrated. The residue was purified by chromatography on silica gel (PE/EA = 50/1) to give N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (2 g, 63.46% yield) as a yellow solid.

MS: m/z = 290.3 (M+1, ESI+).

Step 5: (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-amine hydrochloride

N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (1 g, 35 mmol) was dissolved in 1,4-dioxane HCl (10 mL), and the reaction mixture was stirred at 25°C for 3 h. The mixture was concentrated to obtain the compound (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-amine (0.6 g, 88.57% yield) as a white solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.47 (s, 3H), 7.75 (d, 1H), 7.54 (d, 1H), 7.44 (t, 1H), 7.37-7.10 (m, 1H), 4.69-4.66 (m, 1H), 2.39 (s, 3H), 1.48 (d, 3H).

Step 6: 5-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S1 (400 mg, 1.82 mmol), (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-amine (269 mg, 1.46 mmol), and DIEA (706 mg, 5.46 mmol) were dissolved in DMSO (4 mL) and stirred at 100°C for 12 h. The reaction was quenched with ice water (15 mL), the mixture was diluted with water and EA (30 mL), and the organic layer was concentrated. The concentrated residue was purified by chromatography on silica gel (PE/EA = 10/1) to give 5-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (400 mg, 59.62% yield) as a yellow solid.

MS: m/z = 367.5 (M-1, ESI-).

Step 7: 3-Bromo-5-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

5-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 0.81 mmol), NBS (188 mg, 1.06 mmol), and AcOH (49 mg, 0.81 mmol) were dissolved in ACN (3 mL) and stirred at 60°C for 2 h. The reaction was quenched with ice water (10 mL), diluted with water and EA (30 mL), and the organic layer was concentrated. The residue was purified by chromatography on silica gel (PE/EA = 5/1) to give 3-bromo-5-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 78.24% yield) as a yellow solid.

MS: m/z = 447.3 (M+1, ESI+).

Step 8: (R)-5-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

3-Bromo-5-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (120 mg, 0.27 mmol), morpholine (70 mg, 0.80 mmol), Pd(AcO) ₂ (8 mg, 0.03 mmol), Xant-Phos (19 mg, 0.03 mmol), and Cs ₂ CO ₃ (262 mg, 0.801 mmol) were dissolved in 1,4-dioxane (2 mL) and stirred at 100 °C for 5 h. The residue was purified by Prep-HPLC [[ACN-H ₂ O (0.1 % NH ₄ HCO ₃ )=95:5] to give (R)-5-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (50 mg, 39.02% yield) as a white solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.24 (s,1H), 8.16 (d, 1H), 7.61 (d, 1H), 7.44 (s, 1H), 7.40-7.38 (m, 1H), 7.34-7.31 (m, 1H), 7.27-7.06 (m, 1H), 5.73-5.69 (m, 1H), 3.88 (s, 3H), 3.79-3.76 (m, 4H), 3.12-3.17 (m, 4H), 2.44 (s, 3H), 1.54 (d, 3H); MS: m/z = 454.1 (M+1, ESI+).

Example 30: (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S1 (250 mg, 1.14 mmol), (R)-1-(3-(difluoro-13-methyl)-2-fluorophenyl)ethan-1-amine (215 mg, 1.14 mmol) and DIEA (441 mg, 3.41 mmol) were dissolved in DMSO (5 mL) and stirred at 100°C for 2 h. Then, the mixture was extracted with EA (10 mL*3) to obtain (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (crude product, 647 mg, 100% yield) as a red solid.

MS: m/z = 373.3 (M+1, ESI+).

Step 2: (R)-3-Bromo-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (647 mg, 1.74 mmol), CH ₃ COOH (104 mg, 1.74 mmol), and NBS (619 mg, 3.48 mmol) were dissolved in ACN (5 mL) and stirred at 60°C for 2 h. The mixture was extracted with EA/Na ₂ CO ₃ (40 mL*3) to obtain (R)-3-bromo-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (crude product, 557 mg, 71.05%) as a yellow solid.

MS: m/z = 453.2 (M+2, ESI+).

Step 3: (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (557 mg, 1.23 mmol), morpholine (215 mg, 2.47 mmol), Pd(AcO) ₂ (28 mg, 0.12 mmol), xantphos (71 mg, 0.12 mmol), and Cs ₂ CO ₃ (1207 mg, 3.70 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100 °C for 2 h. The residue was extracted with EA (3x5 mL), and the combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. The concentrated residue was purified by Prep-HPLC to give (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (100 mg, 17.71% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.24 (s, 1H), 8.15 (d, 1H), 7.61-7.57 (m, 1H), 7.51-7.48 (m, 1H), 7.45 (s, 1H), 7.37-7.09 (m, 2H), 5.77-5.73 (m, 1H), 3.89 (s, 3H), 3.79-3.72 (m, 4H), 3.25-3.19 (m, 4H), 1.60 (d, 3H); MS: m/z = 458.1 (M+1, ESI+).

Example 31: (R)-5-((1-(3-cyanophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-5-((1-(3-cyanophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S1 (250 mg, 1.14 mmol), (R)-3-(1-aminoethyl)benzonitrile (166 mg, 1.14 mmol), and DIEA (883 mg, 6.83 mmol) were dissolved in DMSO (5 mL) and stirred at 100°C for 2 h. The mixture was extracted with EA/Na ₂ CO ₃ (10 mL*3) and concentrated to give (R)-5-((1-(3-cyanophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (400 mg, 100% yield) as a yellow solid.

MS: m/z =330 (M+1, ESI+).

Step 2: (R)-3-Bromo-5-((1-(3-cyanophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-5-((1-(3-cyanophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (350 mg, 1.06 mmol), CH ₃ COOH (64 mg, 1.06 mmol), and NBS (473 mg, 2.66 mmol) were dissolved in DMF (5 mL) and stirred at 60°C for 4 h. After the reaction was terminated by adjusting the pH to 8 with NaHCO ₃ , the mixture was extracted with EA/H ₂ O (10 mL*3) and evaporated to obtain (R)-3-bromo-5-((1-(3-cyanophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (400 mg, 80.65% yield) as a yellow solid.

MS: m/z =408.2 (M+1, ESI+)

Step 3: (R)-5-((1-(3-cyanophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-5-((1-(3-cyanophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (200 mg, 0.49 mmol), morpholine (128 mg, 1.47 mmol), Pd(AcO) ₂ (11 mg, 0.049 mmol), xantphos (28 mg, 0.049 mmol), and Cs ₂ CO ₃ (479 mg, 1.47 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100 °C for 2 h under nitrogen. After this, the mixture was extracted with EA (20 mL) and the concentrated organic layer was purified by prep-HPLC [MeCN/TFA 0.1% = 50%] to obtain (R)-5-((1-(3-cyanophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (30 mg, 14.85% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 8.24 (s, 1H), 8.12 (d, 1H), 7.83 (s, 1H), 7.73-7.68 (m, 2H), 7.55-7.51 (m, 1H), 7.41 (s, 1H), 5.55 (m, 1H), 3.89 (s, 3H), 3.78-3.76 (m, 4H), 3.22-3.21 (m, 4H), 1.59 (d, 3H); MS: m/z = 415.0 (M+1, ESI+).

Example 32: (R)-5-((1-(2,4-difluorophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-5-((1-(2,4-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S1 (250 mg, 1.14 mmol), (1R)-1-(2,4-difluorophenyl)ethanamine (179 mg, 1.14 mmol), and DIEA (441 mg, 3.41 mmol) were dissolved in DMSO (5 mL) and stirred at 100°C for 2 h. The mixture was extracted with EA/H ₂ O (10 mL*3), and the organic layer was concentrated to obtain (R)-5-((1-(2,4-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (383 mg, 98% yield) as a red solid.

MS: m/z = 341.3 (M+1, ESI+).

Step 2: (R)-3-Bromo-5-((1-(2,4-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-5-((1-(2,4-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (383 mg, 1.13 mmol), CH ₃ COOH (68 mg, 1.13 mmol), and NBS (401 mg, 2.25 mmol) were dissolved in ACN (5 mL) and stirred at 60 °C for 2 h. The mixture was adjusted to pH=8 with NaHCO ₃ , extracted with EA (10 mL*3), and the organic layer was concentrated to obtain (R)-3-bromo-5-((1-(2,4-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (247 mg, 52.48% yield) as a yellow solid.

MS: m/z =421.2 (M+2, ESI+).

Step 3: (R)-5-((1-(2,4-difluorophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-5-((1-(2,4-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (90 mg, 0.21 mmol), morpholine (56 mg, 0.64 mmol), Pd(AcO) ₂ (4.8 mg, 0.021 mmol), xantphos (12 mg, 0.021 mmol), and Cs ₂ CO ₃ (210 mg, 0.64 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100°C for 2 h. The mixture was extracted with EA (20 mL), the organic layer was concentrated, and the residue was purified with MeCN/TFA 0.1% = 50% to obtain (R)-5-((1-(2,4-difluorophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (16 mg, 17.53% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.24 (s, 1H), 8.10 (d, 1H), 7.47-7.41 (m, 2H), 7.21-7.16 (m, 1H), 7.05-7.00 (m, 1H), 5.70-5.66 (m, 1H), 3.83 (s, 3H), 3.79-3.76 (m, 4H), 3.25-3.18 (m, 4H), 1.57 (d, 3H); MS: m/z = 426.0 (M+1, ESI+).

Example 33: (R)-5-((1-(2,3-difluorophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (Z)-1-(1-(tert-butylsulfinyl)prop-1-en-2-yl)-2,3-difluorobenzene

1-(2,3-Difluorophenyl)ethanone (2,500 mg, 16.01 mmol) and (R)-2-methylpropane-2-sulfinamide (1,940 mg, 16.01 mmol) were dissolved in THF (30 mL) and stirred at room temperature. Tetraethyl titanate (10,959 mg, 48.03 mmol) was slowly added dropwise, and the reaction mixture was stirred at 80°C for 16 h. After completion of the reaction, the crude mixture was purified by silica gel column (PE/EA = 10:1) to obtain (Z)-1-(1-(tert-butylsulfinyl)prop-1-en-2-yl)-2,3-difluorobenzene (3,000 mg, 72.25% yield) as a yellow oil.

MS: m/z = 260.1 (M+2, ESI+).

Step 2: N-((R)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

(Z)-1-(1-(tert-Butylsulfinyl)prop-1-en-2-yl)-2,3-difluorobenzene (3,000 mg, 11.56 mmol) was dissolved in THF (30 mL) and cooled to -78 °C. Sodium borohydride (787 mg, 20.82 mmol) was added portionwise within 10 min at -78 °C. The mixture was warmed to -40 °C for about 2 h and quenched with ice at -20 °C. The residue was extracted with EA (3 x 100 mL). The organic phase was washed with water (50 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The unseparated mixture was purified by silica gel column chromatography (PE/EA = 3:1) to obtain N-((R)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1,500 mg, 49.61% yield) as a white solid.

MS: m/z = 262.2 (M+1, ESI+).

Step 3: (R)-1-(2,3-difluorophenyl)ethan-1-amine

N-((R)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1,500 mg, 5.73 mmol) was dissolved in 1,4-dioxane/HCl (10 mL) and stirred at room temperature for 2 hours. The mixture was filtered, and the filtered solid was recrystallized from 2-methoxy-2-methylpropane to obtain (R)-1-(2,3-difluorophenyl)ethan-1-amine (300 mg, 33.26% yield) as a white solid.

MS: m/z = 158.3 (M+1, ESI+)

Step 4: (R)-5-((1-(2,3-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S1 (300 mg, 1.36 mmol), (R)-1-(2,3-difluorophenyl)ethan-1-amine (171 mg, 1.09 mmol), and DIEA (529 mg, 4.09 mmol) were dissolved in DMSO (3 mL) and stirred at 80°C for 12 h under nitrogen. The residue was extracted with EA (3x10 mL). The organic phase was washed with water (5 mL). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ , and filtered. The concentrated residue was purified by silica gel column chromatography (PE/EA = 5:1) to give (R)-5-((1-(2,3-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (385 mg, 82.82% yield) as a yellow solid.

MS: m/z = 341 (M+1, ESI+).

Step 5: (R)-3-Bromo-5-((1-(2,3-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-5-((1-(2,3-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 0.88 mmol), NBS (156 mg, 0.88 mmol), and AcOH (52 mg, 0.88 mmol) were dissolved in ACN (4 mL) and stirred at 60 °C for 1 h under nitrogen. The reaction mixture was concentrated under pressure at 45 °C, and the residue was purified by silica gel column (PE/EA (5:1)) to give (R)-3-bromo-5-((1-(2,3-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 81.18% yield) as a yellow solid.

MS: m/z = 419.3 (M+1, ESI+).

Step 6: (R)-5-((1-(2,3-difluorophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-5-((1-(2,3-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 0.71 mmol), morpholine (249 mg, 2.86 mmol), Pd(AcO) ₂ (20 mg, 0.09 mmol), Xant-Phos (49 mg, 0.08 mmol), and Cs ₂ CO ₃ (699 mg, 2.14 mmol) were dissolved in 1,4-dioxane (3 mL) and stirred at 100 °C for 12 h. The reaction product was purified by Prep-HPLC to give (R)-5-((1-(2,3-difluorophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (140 mg, 45.99% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 8.25 (s, 1H), 8.15 (d, 1H), 7.44 (s, 1H), 7.29-7.14 (m, 3H), 5.74-5.70 (m, 1H), 3.88 (s, 3H), 3.79-3.77 (m, 4H), 3.22-3.21 (m, 4H), 1.60 (d, 3H); MS: m/z = 426.1 (M+1, ESI+).

Example 34: (R)-5-((1-(2-chloro-3-(difluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 1-Bromo-2-chloro-3-(difluoromethyl)benzene

3-Bromo-2-chlorobenzaldehyde (5 g, 0.02 mol) was dissolved in DCM (50 mL), and DAST (11.03 g, 0.07 mol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 h, and the residue was concentrated to obtain 1-bromo-2-chloro-3-(difluoromethyl)benzene (5 g, 90.79% yield) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.76-7.74 (m, 1H), 7.64-7.62 (m, 1H), 7.27-7.23 (m, 1H), 7.08-6.81 (m, 1H).

Step 2: 1-(2-chloro-3-(difluoromethyl)phenyl)ethan-1-one

1-Bromo-2-chloro-3-(difluoromethyl)benzene (5,500 mg, 22.78 mmol), tributyl(1-ethoxyvinyl)stannane (12,339 mg, 34.17 mmol), and TEA (5,762 mg, 56.95 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (1,598 mg, 2.28 mmol) were dissolved in 1,4-dioxane (100 mL) and stirred at 100 °C under nitrogen for 16 h. Then, 3 M HCl (40 mL) was added at 40 °C for 1 h, and the reaction mixture was concentrated under pressure at 40 °C. The mixture was added to a silica gel column and eluted with PE/EA (20:1) to obtain 1-(2-chloro-3-(difluoromethyl)phenyl)ethan-1-one (5,500 mg, 85.83% yield) as a brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.83-7.80 (m, 1H), 7.65-7.62 (m, 1H), 7.52-7.47 (m, 1H), 7.23-6.87 (m, 1H), 2.69 (s, 3H).

Step 3: (Z)-N-(1-(2-chloro-3-(difluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide

1-(2-Chloro-3-(difluoromethyl)phenyl)ethan-1-one (4.2 g, 0.02 mol), tetraethyl titanate (14.03 g, 0.06 mol), and (R)-2-methylpropane-2-sulfinamide (3.73 g, 0.03 mol) were dissolved in THF (42 mL), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under pressure at 40 °C. The mixture was added to a silica gel column and eluted with PE/EA (20:1) to give (Z)-N-(1-(2-chloro-3-(difluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (5 g, 79.02% yield) as a brown oil.

MS: m/z = 308.2 (M+1, ESI+).

Step 4: N-((R)-1-(2-chloro-3-(difluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

(Z)-N-(1-(2-chloro-3-(difluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (5,000 mg, 16.25 mmol) was dissolved in THF (50 mL), and sodium borohydride (1,106 mg, 29.24 mmol) was slowly added at 0°C. The mixture was stirred for 2 hours. The reaction was quenched with ice water (30 mL) to stop the reaction, extracted with EA (50 mL*3), and the combined organic layers were washed with brine (40 mL) and concentrated. The residue was purified by eluting with PE/EA (1:1) on a silica gel column to obtain N-((R)-1-(2-chloro-3-(difluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1,500 mg, 29.80% yield) as a yellow oil.

MS: m/z = 310.2 (M+1, ESI+)

Step 5: (R)-1-(2-chloro-3-(difluoromethyl)phenyl)ethan-1-amine

N-((R)-1-(2-chloro-3-(difluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1,500 mg, 4.84 mmol) was dissolved in HCl/dioxane (10 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated under pressure at 40 °C, MTBE (20 mL) was added, and filtered to obtain (R)-1-(2-chloro-3-(difluoromethyl)phenyl)ethan-1-amine (800 mg, 80.35% yield) as a yellow solid.

MS: m/z = 206.3 (M+1, ESI+).

Step 6: (R)-5-((1-(2-chloro-3-(difluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

A mixture of intermediate S1 (250 mg, 1.14 mmol), (R)-1-(2-chloro-3-(difluoromethyl)phenyl)ethan-1-amine (234 mg, 1.14 mmol), and DIEA (441 mg, 3.41 mmol) in DMSO (4 mL) was stirred at 100°C for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine (30 mL) and concentrated to give (R)-5-((1-(2-chloro-3-(difluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (400 mg, 90.38% yield) as a brown oil.

MS: m/z = 389.3 (M+1, ESI+).

Step 7: (R)-3-Bromo-5-((1-(2-chloro-3-(difluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-5-((1-(2-chloro-3-(difluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (500 mg, 1.29 mmol), CH ₃ COOH (77 mg, 1.29 mmol), and NBS (457 mg, 2.57 mmol) were dissolved in ACN (5 mL), and the mixture was stirred at 60°C for 2 h. The reaction mixture was diluted with aqueous NaHCO ₃ solution (20 mL), and then extracted with EA (30 mL*3). The collected organic layer was washed with brine (20 mL) and concentrated to give (R)-3-bromo-5-((1-(2-chloro-3-(difluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (400 mg, 66.51% yield) as a brown oil.

MS: m/z = 467.2 (M+1, ESI+).

Step 8: (R)-5-((1-(2-chloro-3-(difluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-5-((1-(2-chloro-3-(difluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (650 mg, 1.33 mmol), morpholine (464 mg, 5.33 mmol), and Pd(AcO) ₂ (29 mg, 0.13 mmol), Xant-phos (77 mg, 0.13 mmol), and Cs ₂ CO ₃ (1,302 mg, 4.00 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 100°C for 2 h under nitrogen. The residue was concentrated and purified by Prep-HPLC to give (R)-5-((1-(2-chloro-3-(difluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (50 mg, 7.92% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 9.42 (d, 1H), 8.35 (s, 1H), 7.70 (d, 1H), 7.62 (d, 1H), 7.50 (t, 1H), 7.27 (t, 1H), 6.30 (s, 1H), 5.78-5.75 (m, 1H), 3.88-3.85 (m, 1H), 3.80 (s, 3H), 3.77-3.74 (m, 1H), 3.54 (m, 1H), 3.11-3.01 (m, 3H), 2.81-2.76 (m, 2H), 1.61-1.59 (m, 3H); MS: m/z = 474.1 (M+1, ESI+).

Example 35: (R)-5-((1-(3-cyano-2,5-difluorophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 3-Bromo-2,5-difluorobenzaldehyde

1,3-Dibromo-2,5-difluorobenzene (8,000 mg, 29.42 mmol) was dissolved in _Et2O (80 mL) solution, and i-PrMgCl 2M (14.7 mL, 29.42 mmol) was added at 0°C and stirred for 2 h. Then, DMF (2,151 mg, 29.42 mmol) was added to the mixture, and stirred at room temperature for 10 h. The reaction was quenched by adding _NH4Cl (80 mL) and extracted with PE (80 mL x 3). The collected extracts were concentrated to obtain the product 3-bromo-2,5-difluorobenzaldehyde (6,400 mg, 98.42% yield) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 10.30 (s, 1H), 7.58-7.54 (m, 1H), 7.53-7.49 (m, 1H).

Step 2: (R,E)-N-(3-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide

3-Bromo-2,5-difluorobenzaldehyde (5,400 mg, 24.43 mmol), (R)-2-methylpropane-2-sulfinamide (3,554 mg, 29.32 mmol), and Ti(OEt) ₄ (8,357 mg, 36.65 mmol) were dissolved in THF (60 mL) and stirred at 70°C for 12 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (PE/EA = 100:1) to give (R,E)-N-(3-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (2,800 mg, 35.35% yield) as a yellow oil.

MS: m/z = 324.0 (M+1, ESI+).

Step 3: (R)-N-((R)-1-(3-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

(R,E)-N-(3-Bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (2800 mg, 8.64 mmol) was dissolved in DCM (30 mL) at -60°C, and methylmagnesium bromide (3.0 M, 8.6 mL, 25.91 mmol) was slowly added dropwise. The mixture was heated to 0°C and stirred for 1 h. The mixture was diluted with aqueous ammonium chloride solution (20.0 mL), and the resulting aqueous solution was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE/EA=7/1) to obtain (R)-N-((R)-1-(3-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1,500 mg, 51.05% yield) as a white solid.

MS: m/z = 342.2 (M+2, ESI+).

Step 4: (R)-N-((R)-1-(3-cyano-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

(R)-N-((R)-1-(3-Bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1,500 mg, 4.41 mmol), Zn(CN)2 (1,553 mg, 13.22 mmol), and Pd(PPh3)4 (509 mg, 0.44 mmol) were dissolved in DMF (3 mL) and stirred at 110 °C for 16 h under nitrogen. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was concentrated and separated by silica gel column chromatography (PE/EA = 7:1) to obtain (R)-N-((R)-1-(3-cyano-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1,000 mg, 79.21% yield) as a yellow oil.

^1H NMR (400 MHz, CDCl ₃ ) δ: 7.43-7.37 (m, 1H), 7.27-7.22 (m, 1H), 4.91-4.87 (m, 1H), 3.44-3.43 (m, 1H), 1.59-1.57 (m, 3H), 1.28-1.23 (m, 9H).

Step 5: (R)-3-(1-aminoethyl)-2,5-difluorobenzonitrile

(R)-N-((R)-1-(3-cyano-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (740 mg, 2.58 mmol) was dissolved in 1,4-dioxane HCl (10 mL), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo, solidified with ether, and filtered to give (R)-3-(1-aminoethyl)-2,5-difluorobenzonitrile (400 mg, 84.97% yield) as a white solid.

MS: m/z = 183.3 (M+1, ESI+).

Step 6: (R)-5-((1-(3-cyano-2,5-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S1 (300 mg, 1.36 mmol), (R)-3-(1-aminoethyl)-2,5-difluorobenzonitrile (249 mg, 1.37 mmol), and DIEA (530 mg, 4.09 mmol) were dissolved in DMSO (3 mL) and stirred at 80°C for 2 h. The mixture was diluted with water (20 mL), filtered, and the filter cake was washed with water (20 mL) to obtain (R)-5-((1-(3-cyano-2,5-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (400 mg, 80.15%) as a yellow solid.

MS: m/z = 366.4 (M+1, ESI+).

Step 7: (R)-3-Bromo-5-((1-(3-cyano-2,5-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-5-((1-(3-cyano-2,5-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 0.82 mmol), AcOH (49 mg, 0.82 mmol), and NBS (219 mg, 1.23 mmol) were dissolved in DMF (3 mL) and stirred at 60°C for 2 h. The solution was diluted with water (20 mL) and filtered. The filter cake was washed with saturated NaHCO ₃ (20 mL) and water (20 mL) to obtain (R)-3-bromo-5-((1-(3-cyano-2,5-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (360 mg, 98.68%) as a yellow solid.

MS: m/z = 442.5 (M-1, ESI-).

Step 8: (R)-5-((1-(3-cyano-2,5-difluorophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-5-((1-(3-cyano-2,5-difluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 0.68 mmol), morpholine (177 mg, 2.03 mmol), Pd(AcO) ₂ (30 mg, 0.14 mmol), Xant-Phos (78 mg, 0.14 mmol), and Cs ₂ CO ₃ (660 mg, 2.03 mmol) were dissolved in 1,4-dioxane (3 mL) and stirred at 100 °C for 3 h. The reaction mixture was diluted with water (15 mL) and extracted with EA (20 mL x3). The collected organic layer was washed with brine (20 mL), concentrated in vacuo, and purified by Prep-TLC (CH ₂ Cl ₂ /MeOH=20:1) to give (R)-5-((1-(3-cyano-2,5-difluorophenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (50 mg, 16.44% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 8.25 (s, 1H), 8.09 (d, 1H), 7.85-7.82 (m, 1H), 7.67-7.62 (m, 1H), 7.39 (s, 1H), 5.66-5.62 (m, 1H), 3.89 (s, 3H), 3.79-3.77 (m, 4H), 3.22 (m, 4H), 1.60 (d, 3H); MS: m/z = 451.0 (M+1, ESI+).

Example 36: (R)-5-((1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethan-1-one

2-Chloro-6-(trifluoromethyl)pyridin-4-amine (3.00 g, 15.18 mmol), tributyl(1-ethoxyvinyl)stannane (4.17 g, 15.18 mmol), and bis(triphenylphosphine)palladium(II) chloride (1.07 g, 1.52 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 80°C for 12 h. After cooling to room temperature, the reaction mixture was quenched with 1 M aqueous HCl solution, stirred for 30 min, basified with aqueous NaHCO ₃ solution, and extracted three times with EA (200 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (PE: EA = 10:1) to obtain 1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethan-1-one (2.30 g, 73.8% yield) as a yellow solid.

MS: m/z = 205.1 (M+1, ESI+).

Step 2: (R,Z)-N-(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide

1-(4-Amino-6-(trifluoromethyl)pyridin-2-yl)ethan-1-one (2.30 g, 11.21 mmol) and 2-methylpropane-2-sulfinamide (17.66 g, 14.57 mmol) were dissolved in THF (30 mL), and tetraethoxytitanium (3.84 g, 16.82 mmol) was added. The mixture was stirred at 80 °C for 8 h, and the reaction was concentrated. The residue was purified by silica gel column chromatography (PE: EA = 8:1) to give (R,Z)-N-(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (3.00 g, 86.8% yield) as a yellow solid.

MS: m/z = 308.2 (M+1, ESI+).

Step 3: (R)-N-((R)-1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

(R,Z)-N-(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (2.60 g, 8.43 mmol) was dissolved in MeOH (30 mL), and sodium borohydride (957 mg, 25.30 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with NH ₄ Cl(aq) (100 mL) and extracted with EA (100 mL). The organic layer was concentrated to obtain a residue, which was purified by silica gel column chromatography (PE:EA = 2:1) to obtain (R)-N-((R)-1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (900 mg, 34.4% yield) as a yellow oil.

MS: m/z = 310.2 (M+1, ESI+).

Step 4: (R)-2-(1-aminoethyl)-6-(trifluoromethyl)pyridin-4-amine

(R)-N-((R)-1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (1.00 g, 3.22 mmol) was dissolved in 1,4-dioxane (5 mL), and HCl/1,4-dioxane (5 mL) was added. The mixture was stirred at 25 °C for 4 h, and the reaction mixture was concentrated to give (R)-2-(1-aminoethyl)-6-(trifluoromethyl)pyridin-4-amine (600 mg, 90.3% yield) as a white solid.

MS: m/z = 206.1 (M+1, ESI+).

Step 5: 3-Bromo-5-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S1 (1,000 mg, 4.97 mmol), NBS (1,327 mg, 7.45 mmol), and AcOH (895 mg, 14.91 mmol) were dissolved in acetonitrile (10 mL) and stirred at 50°C for 16 h. The mixture was diluted with water (35 mL) and filtered. The filter cake was washed with water (30 mL) to afford 3-bromo-5-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (1,000 mg, 71.83%) as a yellow solid.

MS: m/z = 278.3 (M-1, ESI-).

Step 6: 5-Hydroxy-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

3-Bromo-5-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 1.07 mmol), morpholine (933 mg, 10.71 mmol), Pd(AcO) ₂ (24.05 mg, 0.11 mmol), BINAP (133 mg, 0.24 mmol), and Cs ₂ CO ₃ (1,047 mg, 3.21 mmol) were dissolved in 1,4-dioxane (4 mL) and stirred at 100 °C for 4 h. The mixture was diluted with water (35 mL) and filtered. The filter cake was washed with H ₂ O (35 mL) to obtain 5-hydroxy-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 97.83%) as a yellow solid.

MS: m/z = 285.6 (M-1, ESI-).

Step 7: 5-Chloro-1-methyl-3-(morpholin-4-yl)-2-oxo-1,6-naphthyridine-8-carbonitrile

5-Hydroxy-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (1.0 g, 3.49 mmol) was dissolved in POCl ₃ (10 mL) and stirred at 100°C for 2 h. The mixture was concentrated and diluted with H ₂ O (10 mL). After filtration, the filter cake was dried in vacuo to give 5-chloro-1-methyl-3-(morpholin-4-yl)-2-oxo-1,6-naphthyridine-8-carbonitrile (300 mg, 28.30% yield) as a yellow solid.

MS: m/z = 305.3 (M+1, ESI+).

Step 8: (R)-5-((1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

5-Chloro-1-methyl-3-(morpholin-4-yl)-2-oxo-1,6-naphthyridine-8-carbonitrile (80 mg, 0.26 mmol), (R)-2-(1-aminoethyl)-6-(trifluoromethyl)pyridin-4-amine (271 mg, 1.3 mmol) and DIEA (204 mg, 1.58 mmol) were dissolved in DMSO (5 mL) and stirred at 100°C for 2 h. Afterwards, the mixture was extracted with EA (20 mL) and separated by prep-HPLC [MeCN/H ₂ O (TFA 0.1%) = 50:50] to obtain (R)-5-((1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (30 mg, 24.07% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.27 (s, 1H), 8.16 (d, 1H), 7.45 (s, 1H), 6.75 (d, 1H), 6.61 (d, 1H), 6.49 (s, 2H), 5.38-5.35 (m, 1H), 3.91 (s, 3H), 3.78-3.76 (m, 4H), 3.24-3.19 (m, 4H), 1.56 (d, 3H); MS: m/z = 474.0 (M+1, ESI+).

Example 37: (R)-5-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethan-1-one

3-Bromo-4-fluoro-5-(trifluoromethyl)aniline (4 g, 15.5 mmol), tributyl(1-ethoxyvinyl)stannane (5.60 g, 15.5 mmol), and Pd(PPh ₃ ) ₂ Cl ₂ (0.33 g, 0.4 mmol) were dissolved in 1,4-dioxane (40 mL) and heated at 80 °C for 16 h under nitrogen. The mixture was concentrated, suspended in 3 M HCl (10 mL), and stirred at 40 °C for 5 h. The mixture was added to a silica gel column and eluted with PE/EA (100:1) to give 1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethan-1-one (3.2 g, 83.87% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 7.19-7.17 (m, 1H), 7.09-7.07 (m, 1H), 5.66 (s, 2H), 2.55-2.54 (m, 3H).

Step 2: (Z)-N-(1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide

1-(5-Amino-2-fluoro-3-(trifluoromethyl)phenyl)ethan-1-one (3.2 g, 14.5 mmol) and (R)-2-methylpropane-2-sulfinamide (2.11 g, 17.4 mmol) were dissolved in THF (40 mL) under nitrogen, Ti(OEt) ₄ (4.96 g, 21.7 mmol) was added, and the mixture was stirred at 80 °C for 12 h. The reaction mass was concentrated in vacuo, and the concentrate was poured onto a silica gel column and eluted with PE/EA (50:1) to give (Z)-N-(1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (3.5 g, 66.90% yield) as a yellow solid.

MS: m/z = 325.1 (M+1, ESI+).

Step 3: N-((R)-1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

(Z)-N-(1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (3,600 mg, 11.10 mmol) was dissolved in THF (5 mL) and cooled to -78 °C. Sodium borohydride (839 mg, 22.20 mmol) was added slowly in portions at -78 °C over 10 min, and the mixture was warmed to -40 °C for about 2 h. The reaction was quenched with ice water (20 mL), separated with EA, the organic layers were combined, and concentrated in vacuo. The concentrated residue was separated by silica gel column chromatography [PE/EA (50:1)] to give N-((R)-1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (3,000 mg, 74.54% yield) as a yellow oil.

MS: m/z = 327.2 (M+1, ESI+).

Step 4: (R)-3-(1-aminoethyl)-4-fluoro-5-(trifluoromethyl)aniline

N-((R)-1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (3,000 mg, 9.19 mmol) was dissolved in 1,4-dioxane HCl (50 mL), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo, and the concentrated residue was triturated with ether (3x10 mL), dried in vacuo, and (R)-3-(1-aminoethyl)-4-fluoro-5-(trifluoromethyl)aniline (2,000 mg, 88.13% yield) was obtained as a yellow solid.

MS: m/z = 223.2 (M+1, ESI+)

Step 5: (R)-5-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

5-Chloro-1-methyl-3-(morpholin-4-yl)-2-oxo-1,6-naphthyridine-8-carbonitrile (80 mg, 0.26 mmol), (R)-3-(1-aminoethyl)-4-fluoro-5-(trifluoromethyl)aniline (293 mg, 1.31 mmol) and DIEA (204 mg, 1.58 mmol) were dissolved in DMSO (5 mL) and stirred at 100°C for 2 h. The mixture was extracted with EA (20 mL) and purified by prep-HPLC (MeCN: H ₂ O containing 0.1% TFA: 50:50) to obtain (R)-5-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (30 mg, 69.7% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.26 (s,1H), 8.11 (d, 1H), 7.47 (s, 1H), 6.78-6.76 (m, 1H), 6.70-6.68 (m, 1H), 5.63-5.60 (m, 1H), 5.37 (s, 2H), 3.90 (s, 3H), 3.80-3.77 (m, 4H), 3.26-3.19 (m, 4H), 1.55 (d, 3H); MS: m/z = 491.0 (M+1, ESI+).

Example 38: (R)-5-((1-(3-cyano-2-methoxyphenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 3-Acetyl-2-methoxybenzonitrile

3-Bromo-2-methylbenzonitrile (5 g, 0.02 mol), tributyl(1-ethoxyvinyl)stannane (8.5 g, 0.02 mol), bis(triphenylphosphine)palladium(II) chloride (0.83 g, 1 mmol), and triethylamine (7.16 g, 0.07 mol) were dissolved in 1,4-dioxane (50 mL) and stirred at 80 °C for 16 h under nitrogen. The mixture was then concentrated, suspended in 3 M HCl (30 mL), and stirred at 40 °C for 5 h. The residue was extracted with EA (3 × 100 mL), and the organic layer was washed with water (50 mL) and brine (50 mL). The organic layer was dried, filtered and concentrated, and purified by silica gel column chromatography (PE/EA=10:1) to obtain 3-acetyl-2-methoxybenzonitrile (3 g, 72.46% yield) as a yellow oil.

MS: m/z = 176 (M+1, ESI+).

Step 2: (S,Z)-N-(1-(3-cyano-2-methoxyphenyl)ethylidene)-2-methylpropane-2-sulfinamide

3-Acetyl-2-methoxybenzonitrile (3 g, 0.01 mol) and (R)-2-methylpropane-2-sulfinamide (2.07 g, 17 mmol) were dissolved in THF (30 mL) solution, and tetraethyl titanate (11.70 g, 0.05 mol) was added dropwise. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under pressure at 45 °C. The mixture was added to a silica gel column and eluted with PE/EA (5:1) to give (S,Z)-N-(1-(3-cyano-2-methoxyphenyl)ethylidene)-2-methylpropane-2-sulfinamide (4 g, 84.21% yield) as a yellow oil.

MS: m/z = 279.3 (M+1, ESI+).

Step 3: (S)-N-((R)-1-(3-cyano-2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide

(S,Z)-N-(1-(3-cyano-2-methoxyphenyl)ethylidene)-2-methylpropane-2-sulfinamide (4,000 mg, 14.36 mmol) was dissolved in THF (40 mL) and cooled to -40°C. L-Selectride (2,731 mg, 14.36 mmol) was slowly added dropwise in portions at -40°C over 10 min, and the mixture was slowly warmed to -20°C and stirred for about 2 h. The reaction was quenched by adding ice water (40 mL), and the residue was extracted with EA (3x100 mL). The organic phase was washed with water (50 mL) and brine (50 mL), dried, and filtered. The concentrated residue was purified by silica gel column chromatography (PE/EA=3:1) to obtain (S)-N-((R)-1-(3-cyano-2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (3,400 mg, 75.95% yield) as a yellow oil.

MS: m/z = 281.4 (M+1, ESI+).

Step 4: (R)-3-(1-aminoethyl)-2-methoxybenzonitrile

(S)-N-((R)-1-(3-cyano-2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (3,400 mg, 12.12 mmol) was dissolved in 1,4-dioxane/HCl solution (30 mL) and stirred at room temperature for about 2 h. The mixture was filtered. The filter cake was recrystallized from 2-methoxy-2-methylpropane to give (R)-3-(1-aminoethyl)-2-methoxybenzonitrile (2,000 mg, 84.24% yield) as a yellow oil.

MS: m/z = 177.4 (M+1, ESI+).

Step 5: (R)-5-((1-(3-cyano-2-methoxyphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S1 (300 mg, 1.36 mmol), (R)-3-(1-aminoethyl)-2-methoxybenzonitrile (240 mg, 1.36 mmol), and DIEA (529 mg, 4.09 mmol) were dissolved in DMSO (3 mL) and stirred at 80 °C for 12 h under nitrogen. The residue was extracted with EA (3 × 10 mL), and the organic phase was washed with water (5 mL) and brine (5 mL), and concentrated. The concentrated residue was purified by silica gel column chromatography (PE/EA = 5:1) to give (R)-5-((1-(3-cyano-2-methoxyphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (180 mg, 36.67% yield) as a yellow solid.

MS: m/z = 360.4 (M+1, ESI+).

Step 6: (R)-3-Bromo-5-((1-(3-cyano-2-methoxyphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-5-((1-(3-cyano-2-methoxyphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (180 mg, 0.50 mmol), NBS (89 mg, 0.50 mmol), and AcOH (30 mg, 0.50 mmol) were dissolved in DMF (3 mL) and stirred at 60 °C for 1 h under nitrogen. The reaction mixture was concentrated under pressure at 45°C, and the concentrated residue was eluted with PE/EA (5:1) through a silica gel column to obtain (R)-3-bromo-5-((1-(3-cyano-2-methoxyphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (140 mg, 63.77% yield) as a yellow solid.

MS: m/z = 438.3 (M+1, ESI+).

Step 7: (R)-5-((1-(3-cyano-2-methoxyphenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-5-((1-(3-cyano-2-methoxyphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (180 mg, 0.41 mmol), morpholine (143 mg, 1.64 mmol), Pd(AcO) ₂ (11 mg, 0.05 mmol), Xant-Phos (28 mg, 0.04 mmol), and Cs ₂ CO ₃ (401 mg, 1.23 mmol) were dissolved in 1,4-dioxane (2 mL) and stirred at 100°C for 12 h. The residue was purified by Prep-HPLC to give (R)-5-((1-(3-cyano-2-methoxyphenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (25 mg, 13.68% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 8.22 (s, 1H), 8.14 (d, 1H), 7.71-7.64 (m, 2H), 7.74 (s, 1H), 7.24 (t, 1H), 5.72-5.69 (m, 1H), 4.11 (s, 3H), 3.88 (s, 3H), 3.79-3.77 (m, 4H), 3.23-3.22 (m, 4H), 1.53 (d, 3H); MS: m/z = 445.0 (M+1, ESI+).

Example 39: (R)-5-((1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 3-Bromo-5-fluoro-2-methylbenzoic acid

5-Fluoro-2-methylbenzoic acid (10 g, 65 mmol) and NBS (11.55 g, 65 mmol) were dissolved in H2SO4 (100 mL), and the mixture was stirred at 0°C for 16 h. The reaction was slowly quenched with ice water (200 mL), filtered, and the filter cake was collected to obtain 3-bromo-5-fluoro-2-methylbenzoic acid (8 g, 50.23% yield) as a yellow solid.

MS: m/z = 230.9 (M-1, ESI-).

Step 2: 3-Bromo-5-fluoro-N-methoxy-N,2-dimethylbenzamide

3-Bromo-5-fluoro-2-methylbenzoic acid (12 g, 51.5 mmol), N,O-dimethylhydroxylamine (10.05 g, 103 mmol), DIEA (33.28 g, 258 mmol), and HATU (29.37 g, 77 mmol) were dissolved in DMF (120 mL), and the reaction mixture was stirred at 25 °C for 16 h. The reaction was quenched with ice water (200 mL) and diluted with water and EA (300 mL). The organic layer was concentrated, and the residue was purified by silica gel column chromatography (PE/EA = 30/1) to give 3-bromo-5-fluoro-N-methoxy-N,2-dimethylbenzamide (10 g, 66.80%) as a yellow solid.

MS: m/z = 278.2 (M+2, ESI+).

Step 3: 1-(3-bromo-5-fluoro-2-methylphenyl)ethan-1-one

3-Bromo-5-fluoro-N-methoxy-N,2-dimethylbenzamide (5 g, 18.1 mmol) was dissolved in THF (50 mL), and CH ₃ MgBr (12.95 g, 108.6 mmol) was slowly added dropwise at 0 °C and stirred at 0 °C for 2 h. The reaction mixture was quenched with ice water (50 mL), diluted with water and EA (30 mL), and the organic layer was separated and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 40/1) to give 1-(3-bromo-5-fluoro-2-methylphenyl)ethan-1-one (3 g, 67.96% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ:7.76-7.73 (m, 1H), 7.65-7.62 (m, 1H), 2.55 (s, 3H), 2.33 (s, 3H).

Step 4: (S,Z)-N-(1-(3-bromo-5-fluoro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide

1-(3-Bromo-5-fluoro-2-methylphenyl)ethan-1-one (4 g, 17.3 mmol) and (S)-2-methylpropane-2-sulfinamide (2.94 g, 24.2 mmol) were dissolved in THF (50 mL), and Ti(OEt) ₄ (5.92 g, 25.9 mmol) was added. The reaction mixture was stirred at 80 °C for 12 h, and then quenched with ice water. The mixture was diluted with water and EA (30 mL), and the organic layer was concentrated. The residue was purified by silica gel column chromatography (PE/EA = 10/1) to give (S,Z)-N-(1-(3-bromo-5-fluoro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (5 g, 82.08% yield) as a yellow oil.

MS: m/z = 336.1 (M+2, ESI+).

Step 5: (S)-N-((R)-1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide

(S,Z)-N-(1-(3-Bromo-5-fluoro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (5.22 g, 16.3 mmol) was dissolved in THF (10 mL), and sodium borohydride (4.45 g, 23.3 mmol) was added dropwise at -78°C. The mixture was warmed to -40°C for about 2 h, and then the reaction was quenched with ice water. The mixture was diluted with water and EA (30 mL), and the organic layer was concentrated. The residue was purified by silica gel column chromatography (PE/EA = 5/1) to give (S)-N-((R)-1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (4 g, 72.44% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ:7.46-7.42 (m, 1H), 7.31-7.27 (m, 1H), 5.48 (d, 1H), 4.68-4.65 (m, 1H), 2.35 (s, 3H), 1.41 (d, 3H), 1.10 (s, 9H).

Step 6: (S)-N-((R)-1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide

(S)-N-((R)-1-(3-Bromo-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (1 g, 3 mmol), Zn(CN) ₂ (0.7 g, 6 mmol), and Pd(PPh ₃ ) ₄ (0.69 g, 0.6 mmol) were dissolved in DMF (10 mL) and stirred at 120 °C under nitrogen for 2 h. The reaction was quenched with ice-water (30 mL), diluted with water and EA (20 mL), and the organic layer was concentrated. The residue was purified by silica gel column chromatography (PE/EA = 1/1) to give (S)-N-((R)-1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (0.8 g, 80.00% yield) as a yellow solid.

MS: m/z = 283.4 (M-1, ESI-).

Step 7: (R)-3-(1-aminoethyl)-5-fluoro-2-methylbenzonitrile

(S)-N-((R)-1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 2.12 mmol) was dissolved in 1,4-dioxane/HCl (10 mL) and stirred at 0°C for 1 h. The mixture was concentrated to obtain (R)-3-(1-aminoethyl)-5-fluoro-2-methylbenzonitrile (300 mg, 75.27% yield) as a yellow solid.

MS: m/z = 179.4 (M+1, ESI+).

Step 8: (R)-5-((1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S1 (300 mg, 1.37 mmol), (R)-3-(1-aminoethyl)-5-fluoro-2-methylbenzonitrile (194 mg, 1.09 mmol), and DIEA (529 mg, 4.10 mmol) were dissolved in DMSO (3 mL), and the reaction was quenched with ice-water (10 mL). The mixture was diluted with water and EA (20 mL). The organic layer was concentrated. The residue was purified by silica gel column chromatography (PE/EA = 1/1) to give (R)-5-((1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 57.74% yield) as a yellow solid.

MS: m/z = 362.4 (M+1, ESI+).

Step 9: (R)-3-Bromo-5-((1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-5-((1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 0.83 mmol), NBS (147 mg, 0.83 mmol), and AcOH (49 mg, 0.83 mmol) were dissolved in ACN (3 mL) and stirred at 60 °C for 2 h. The reaction was quenched with ice-water, the mixture was diluted with water and EA (30 mL), and the organic layer was concentrated. The residue was purified by silica gel column chromatography (PE/EA = 1/1) to give (R)-3-bromo-5-((1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (200 mg, 51.99% yield) as a yellow solid.

MS: m/z = 442.2 (M+2, ESI+).

Step 10: (R)-5-((1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-5-((1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (300 mg, 0.68 mmol), morpholine (178 mg, 2.04 mmol), Pd(AcO) ₂ (30 mg, 0.14 mmol), Xant-Phos (78 mg, 0.14 mmol), and Cs ₂ CO ₃ (666 mg, 2.04 mmol) were dissolved in 1,4 dioxane (3 mL) and stirred at 100°C for 5 h. The residue was purified by Prep-HPLC [ACN-H ₂ O (0.1% NH ₄ HCO ₃ )=95:5] to give (R)-5-((1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (80 mg, 25.77% yield) as a white solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.24 (s,1H), 8.11 (d, 1H), 7.65-7.57 (m, 2H), 7.39 (s, 1H), 5.57-5.54 (m, 1H), 3.87 (s, 3H), 3.79-3.76 (m, 4H), 3.23-3.22 (m, 4H), 2.58 (s, 3H), 1.54 (d, 3H); MS: m/z = 447.0 (M+1, ESI+).

Example 40: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-chloro-1-methyl-3-morpholino-1,6-naphthyridin-2(1H)-one

Step 1: 2,5-Dichloro-N-methylpyridin-4-amine

A solution of 2,4,5-trichloropyridine (4 g, 22 mmol) dissolved in methanamine (40 mL) was stirred at 80°C for 2–3 h. The combined extracts were concentrated in vacuo to afford the product 2,5-dichloro-N-methylpyridin-4-amine (5 g, 100% yield) as a white solid.

MS: m/z = 177 (M+1, ESI+).

Step 2: 3-Bromo-2,5-dichloro-N-methylpyridin-4-amine

2,5-Dichloro-N-methylpyridin-4-amine (4.2 g, 24 mmol) and NBS (6.33 g, 36 mmol) were mixed in acetic acid (50 mL) and stirred at 50°C for 2 h. After adjusting the pH of the mixture to 8, extraction was performed with EA (50 mL x 3) to obtain 3-bromo-2,5-dichloro-N-methylpyridin-4-amine (5 g, 82.54% yield) as a gray solid.

MS: m/z = 257.1 (M+2, ESI+).

Step 3: Ethyl (E)-3-(2,5-dichloro-4-(methylamino)pyridin-3-yl)acrylate

3-Bromo-2,5-dichloro-N-methylpyridin-4-amine (5 g, 19.5 mmol), ethyl but-3-enoate (9.76 g, 97.5 mmol), Pd(AcO) ₂ (0.88 g, 3.9 mmol), tri-o-tolylmethane (1.19 g, 3.9 mmol), and TEA (9.87 g, 97.5 mmol) were dissolved in DMF (20 mL) and stirred at 120 °C for 16 h. The combined extracts were concentrated in vacuo and purified by column chromatography (PE/EA = 5:1) to give ethyl (E)-3-(2,5-dichloro-4-(methylamino)pyridin-3-yl)acrylate (3.3 g, 61.53% yield) as a yellow oil.

MS: m/z = 275.1 (M+1, ESI+).

Step 4: 5,8-Dichloro-1-methyl-1,6-naphthyridin-2(1H)-one

Ethyl (E)-3-(2,5-dichloro-4-(methylamino)pyridin-3-yl)acrylate (2.3 g, 8.4 mmol)) was dissolved in 1,4-dioxane/HCl (20 mL) and stirred at 100°C for 12 h. The collected extract was concentrated in vacuo to give 5,8-dichloro-1-methyl-1,6-naphthyridin-2(1H)-one (0.73 g, 37.72% yield) as a white solid.

MS: m/z = 229.0 (M+1, ESI+).

Step 5: (R)-8-chloro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one

5,8-Dichloro-1-methyl-1,6-naphthyridin-2(1H)-one (500 mg, 2.18 mmol), intermediate D (1,027 mg, 4.36 mmol), Pd(AcO) ₂ (98 mg, 0.44 mmol), Xant-Phos (253 mg, 0.43 mmol), and Cs ₂ CO ₃ (2,134 mg, 6.54 mmol) were dissolved in 1,4-dioxane (8 mL) and stirred at 100°C for 1 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography (CH ₂ Cl ₂ /MeOH = 20:1) to give a yellow solid, which was then purified by Prep-HPLC ACN- H ₂ O (95%) to give (R)-8-chloro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (400 mg, 42.83% yield) as a yellow solid.

MS: m/z = 427.1 (M+1, ESI+).

Step 6: (R)-3-Bromo-8-chloro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one

(R)-8-Chloro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (400 mg, 0.93 mmol), CH ₃ COOH (56 mg, 0.93 mmol), and NBS (333 mg, 1.87 mmol) were dissolved in ACN (8 mL) and stirred at 60°C for 2 h. The mixture was concentrated in vacuo and purified by column chromatography (CH ₂ Cl ₂ /MeOH = 20:1) to give (R)-3-bromo-8-chloro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (240 mg, 50.66% yield) as a yellow solid.

MS: m/z = 505.2 (M+1, ESI+).

Step 7: (R)-8-chloro-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one

(R)-3-Bromo-8-chloro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (180 mg, 0.36 mmol), morpholine (310 mg, 3.56 mmol), and Pd(AcO) ₂ (7.99 mg, 0.04 mmol), BINAP (44 mg, 0.07 mmol), and Cs ₂ CO ₃ (348 mg, 1.06 mmol) were dissolved in 1,4-dioxane (4 mL) and stirred at 100 °C for 1 h. The mixture was treated with water (20 mL), and the resulting mixture was extracted with EA (20 mL x 3), and the organic phase was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography (CH ₂ Cl ₂ /MeOH = 30:1) to give (R)-8-chloro-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (80 mg, 43.90% yield) as a yellow solid.

MS: m/z = 512.3 (M+1, ESI+).

Step 8: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-chloro-1-methyl-3-morpholino-1,6-naphthyridin-2(1H)-one

(R)-8-Chloro-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (80 mg, 0.16 mmol), hypoboric acid (42 mg, 0.46 mmol), and 4,4'-bipyridine (1 mg, 0.01 mmol) were dissolved in DMF (2 mL) and stirred at room temperature for 10 minutes. The mixture was purified by Prep-HPLC [ACN-H ₂ O (0.1 % NH ₄ HCO ₃ )=55:45] to obtain a yellow solid, which was then purified by Prep-TLC (CH ₂ Cl ₂ /MeOH=20:1) to obtain (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-chloro-1-methyl-3-morpholino-1,6-naphthyridin-2(1H)-one (32 mg, 42.48% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 7.83 (s, 1H), 7.46 (d, 1H), 7.36 (s, 1H), 6.79 (d, 2H), 6.66 (s, 1H), 5.50 (s, 2H), 5.32-5.28 (m, 1H), 3.80-3.76 (m, 7H), 3.22-3.19 (m, 4H), 1.50 (d, 3H); MS: m/z = 482.0 (M+1, ESI+).

Example 41: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carboxamide

The compound of Example 3 (300 mg, 0.63 mmol), K ₂ CO ₃ (262 mg, 1.90 mmol), and urea hydrogen peroxide (179 mg, 1.90 mmol) were dissolved in DMSO/H ₂ O = 2:1 (3 mL), and the mixture was stirred at 100 °C for 16 h. The residue was purified by Prep-HPLC [ACN-H ₂ O (0.1 % NH ₄ HCO ₃ ) = 95:5] to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carboxamide (50 mg, 15.25% yield) as a white solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 7.94 (s,1H), 7.86 (s, 1H), 7.58 (d, 1H), 7.45 (s, 1H), 7.41 (s, 1H), 6.80 (d, 2H), 6.65 (s, 1H), 5.49 (s, 2H), 5.40-5.37 (m, 1H), 3.79-3.77 (m, 4H), 3.46 (s, 3H), 3.21-3.20 (m, 4H), 1.52 (d, 3H); MS: m/z = 491.1 (M+1, ESI+).

Example 42: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile

Step 1: 2,6-dichloro-4-(methylamino)nicotinaldehyde

To a solution of 2,4,6-trichloronicotinaldehyde (10 g, 47.6 mmol) in THF (100 mL) was added CH ₃ NH ₂ (2.96 g, 95.2 mmol) at 0°C, and the mixture was stirred at 0°C for 2 hours. The residue was extracted with EA (3x50 mL), and the combined organic layers were dried over Na ₂ SO ₄ and filtered. The concentrated residue was purified by silica gel column chromatography (PE/EA=5:1) to obtain 2,6-dichloro-4-(methylamino)nicotinaldehyde (2.4 g, 24.64% yield) as a white solid.

MS: m/z = 205.1 (M+1, ESI+).

Step 2: 5,7-Dichloro-1-methyl-3-morpholino-1,6-naphthyridin-2(1H)-one

Lithiobis(trimethylsilyl)amine (3.91 g, 23.4 mmol) was stirred in THF (30 mL) at 0°C for 5 minutes, then added dropwise to the mixture and stirred at 0°C for 30 minutes. The residue was washed with EA: H ₂ O = 1:1 (60 mL), filtered, and the filter cake was concentrated to give 5,7-dichloro-1-methyl-3-morpholino-1,6-naphthyridin-2(1H)-one (2.9 g, 59.18% yield) as a yellow solid.

MS: m/z = 314.1 (M+1, ESI+).

Step 3: (R)-7-chloro-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one

5,7-Dichloro-1-methyl-3-morpholino-1,6-naphthyridin-2(1H)-one (1.9 g, 6.05 mmol), intermediate D (2.84 g, 12.1 mmol), Pd(AcO) ₂ (0.27 g, 1.21 mmol), Xant-Phos (0.7 g, 1.21 mmol) and Cs ₂ CO ₃ (5.91 mg, 18.15 mmol) were dissolved in 1,4-dioxane (20 mL), stirred at 100 °C for 1 h and the residue was extracted with EA (2x30 mL). The collected organic layer was dried over Na ₂ SO ₄ , filtered, concentrated, and purified by silica gel column chromatography (DCM/MeOH = 20:1) to obtain (R)-7-chloro-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (1.2 g, 38.95% yield) as a yellow solid.

MS: m/z = 512.2 (M+1, ESI+).

Step 4: (R)-1-Methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile

(R)-7-Chloro-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1,6-naphthyridin-2(1H)-one (200 mg, 0.39 mmol), Zn(CN)2 (229 mg, 1.95 mmol), Pd(PPh ₃ ) ₄ (45 mg, 0.04 mmol), and CuCl (4 mg, 0.04 mmol) were dissolved in DMF (2 mL) and stirred in a microwave at 120 °C for 4 h. The mixture was purified by Prep-HPLC [ACN- H ₂ O (75%)] to give (R)-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile (30 mg, 15.28% yield) as a yellow solid.

MS: m/z = 503.4 (M+1, ESI+).

Step 5: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile

(R)-1-Methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile (70 mg, 0.14 mmol), hypoboric acid (37 mg, 0.42 mmol), and 4,4'-bipyridine (1 mg, 0.01 mmol) were dissolved in DMF (1 mL) and stirred at room temperature for 10 minutes. The mixture was purified by Prep-HPLC [ACN-H ₂ O (0.1 % NH ₄ HCO ₃ )=55:45] to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile (30 mg, 45.59% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 7.71 (d, 1H), 7.43 (s, 1H), 7.35 (s, 1H), 6.85 (s, 1H), 6.81 (s, 1H), 6.69 (s, 1H), 5.52 (s, 2H), 5.35-5.31 (m, 1H), 3.78-3.76 (m, 4H), 3.58 (s, 3H), 3.26 (m, 4H), 1.52 (d, 3H); MS: m/z = 473.1 (M+1, ESI+).

Example 43: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(4-(methylsulfonyl)piperazin-1-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-1-Methyl-3-(4-(methylsulfonyl)piperazin-1-yl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

1-Methanesulfonylpiperazine (198 mg, 1.21 mol), intermediate S3 (200 mg, 0.40 mmol), sodium tert-butoxide (116 mg, 1.21 mmol), RuPhos (19 mg, 0.04 mmol), and RuPhos Pd G3 (34 mg, 0.04 mmol) were dissolved in 1,4-dioxane (2 mL), and stirred at 100 °C for 1 h under nitrogen and then at 100 °C for 12 h. The mixture was extracted with EA (10 mL x 3) to obtain (R)-1-methyl-3-(4-(methylsulfonyl)piperazin-1-yl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (176 mg, 75.86% yield) as a yellow solid.

MS: m/z = 580 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(4-(methylsulfonyl)piperazin-1-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-1-Methyl-3-(4-(methylsulfonyl)piperazin-1-yl)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (176 mg, 0.30 mmol), hypoboric acid (109 mg, 1.21 mmol), and 4,4'-bipyridine (2 mg, 0.02 mmol) were dissolved in DMF (2 mL) and stirred at 0°C for 1 h. After the mixture was extracted with EA/Na2CO3 (10 mL*3), the mixture was purified by Prep-HPLC to obtain (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(4-(methylsulfonyl)piperazin-1-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (60 mg, 35.94% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.28 (s, 1H), 8.14 (d, 1H), 7.50 (s, 1H), 6.80 (d, 2H), 6.69 (s, 1H), 5.54 (s, 2H), 5.49-5.46 (m, 1H), 3.90 (s, 3H), 3.30 (s, 8H), 2.95 (s, 3H), 1.55 (d, 3H); MS: m/z = 550.1 (M+1, ESI+).

Example 44: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-hydroxy-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: 2,4,6-Trichloronicotinamide

Oxalyl chloride (6.73 g, 53.0 mmol) was added dropwise to a solution of 2,4,6-trichloronicotinic acid (10 g, 44.2 mmol) in THF (100 mL) at 0°C, and the reaction mixture was stirred at 0°C for 1 h. NH ₃ ·H ₂ O (3.10 g, 88 mmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated to obtain 2,4,6-trichloronicotinamide (4 g, 38.24% yield) as a white solid.

MS: m/z =224.9 (M+1, ESI+).

Step 2: 2,6-dichloro-4-(methylamino)nicotinamide

A mixture of 2,4,6-trichloronicotinamide (5 g, 22.2 mmol) dissolved in methylamine (50 mL) was stirred at 25°C for 2 h. The reaction mixture was concentrated to obtain compound 2,6-dichloro-4-(methylamino)nicotinamide (3 g, 58.56% yield) as a white solid.

MS: m/z =220.0 (M+1, ESI+).

Step 3: 2,6-Dichloro-5-iodo-4-(methylamino)nicotinamide

A solution of 2,6-dichloro-4-(methylamino)nicotinamide (1,000 mg, 4.54 mmol) and NIS (2,044 mg, 9.10 mmol) in AcOH (10 mL) was stirred at 40°C for 16 h. The reaction was quenched with ice water (20 mL), and the mixture was filtered. The filter cake was collected to obtain 2,6-dichloro-5-iodo-4-(methylamino)nicotinamide (1.5 g, 90.64% yield) as a yellow solid.

MS: m/z =346.0 (M+1, ESI+).

Step 4: Ethyl (E)-3-(5-carbamoyl-2,6-dichloro-4-(methylamino)pyridin-3-yl)acrylate

2,6-Dichloro-5-iodo-4-(methylamino)nicotinamide (300 mg, 3.76 mmol), ethyl prop-2-enoate (451 mg, 4.51 mmol), tri-o-tolylphosphine (228 mg, 0.75 mmol), Pd(OAc) ₂ (62 mg, 0.38 mmol), and TEA (1901 mg, 18.78 mmol) were dissolved in DMF (15 mL) and stirred at 100 °C for 3 h under nitrogen. The reaction was quenched with ice-water (30 mL), the mixture was diluted with water and EA (30 mL), and the organic layer was concentrated. The concentrated residue was purified by silica gel column chromatography (PE/EA = 30/1) to obtain ethyl (E)-3-(5-carbamoyl-2,6-dichloro-4-(methylamino)pyridin-3-yl)acrylate (600 mg, 47.68% yield) as a yellow solid.

MS: m/z =318.1 (M+1, ESI+).

Step 5: 5,7-Dichloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carboxamide

Ethyl (E)-3-(5-carbamoyl-2,6-dichloro-4-(methylamino)pyridin-3-yl)acrylate (7,000 mg, 22.00 mmol) was dissolved in 1,4-dioxane/HCl (60 mL) and stirred at 100°C for 16 h under nitrogen. The reaction was quenched with ice-water (100 mL) and filtered. The filter cake was collected to afford 5,7-dichloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carboxamide (2 g, 31.74% yield) as a yellow solid.

MS: m/z =272.0 (M+1, ESI+).

Step 6: (R)-7-chloro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carboxamide

5,7-Dichloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carboxamide (1,000 mg, 4.41 mmol), intermediate D (1,193 mg, 4.41 mmol), and DIEA (2,850 mg, 22.05 mmol) were dissolved in DMF (12 mL) and stirred at 100 °C for 16 h. The reaction was quenched with ice-water (20 mL), the mixture was diluted with water and EA (30 mL), and the organic layer was concentrated. The residue was purified by silica gel column chromatography (PE/EA = 10/1) to give (R)-7-chloro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carboxamide (1,000 mg, 45.85% yield) as a yellow solid.

MS: m/z =472.1 (M+2, ESI+).

Step 7: (R)-7-Chloro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-7-Chloro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carboxamide (1,100 mg, 2.34 mmol) was dissolved in THF (20 mL) with TFAA (1,474 mg, 7.02 mmol) and pyridine (554 mg, 7.02 mmol), and the mixture was stirred at 60°C for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography (PE/EA = 1/1) to give (R)-7-chloro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (900 mg, 85.30% yield) as a yellow solid.

MS: m/z = 452.3 (M+1, ESI+).

Step 8: (R)-7-methoxy-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-7-Chloro-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (550 mg, 1.21 mmol) and sodium methanolate (656 mg, 12.15 mmol) were dissolved in CH ₃ OH (8 mL) and stirred at 75 °C for 12 h under nitrogen. The residue was extracted with EA (3 x 100 mL), and the combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. The concentrated residue was purified by flash chromatography (ACN/H ₂ O = 6:4) to afford (R)-7-methoxy-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (500 mg, 87.21% yield) as a white solid.

MS: m/z = 448.0 (M+1, ESI+).

Step 9: (R)-3-Bromo-7-methoxy-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-7-Methoxy-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (437 mg, 0.97 mmol), NBS (260 mg, 1.46 mmol), and acetic acid (117 mg, 1.95 mmol) were dissolved in ACN (8 mL), and the reaction mixture was stirred at 80 °C for 12 h. The residue was extracted with EA (3 × 50 mL), and the combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. The concentrated residue was purified by flash chromatography (ACN/H ₂ O =6:4) to give (R)-3-bromo-7-methoxy-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (480 mg, 88.73% yield) as a yellow solid.

MS: m/z = 526.2 (M+1, ESI+).

Step 10: (R)-7-methoxy-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-3-Bromo-7-methoxy-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (252 mg, 0.48 mmol), morpholine (83 mg, 0.96 mmol), and Pd(AcO) ₂ (16 mg, 0.07 mmol), Xant-Phos (41 mg, 0.07 mmol), Cs ₂ CO ₃ (467 mg, 1.43 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100 °C under nitrogen for 12 h. The residue was extracted with EA (3x50 mL) and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ACN/H2O = 55:45) to give (R)-7-methoxy-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (200 mg, 66.69% yield) as a yellow solid.

MS: m/z = 533.4 (M+1, ESI+).

Step 11: (R)-7-Hydroxy-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-7-Methoxy-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (160 mg, 0.29 mmol) was dissolved in 6N HCl (2 mL) and stirred at 100°C for 12 h under nitrogen. The residue was extracted with EA (3x30 mL), and the combined organic layers were dried _{over Na2SO4} and filtered/concentrated. The residue was purified by flash chromatography (ACN/H ₂ O =6:4) to give (R)-7-hydroxy-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (24 mg, 16.24% yield) as a yellow solid.

MS: m/z = 519.3 (M+1, ESI+).

Step 12: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-hydroxy-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-7-Hydroxy-1-methyl-3-morpholino-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (24 mg, 0.05 mmol), hypoboric acid (12 mg, 0.14 mmol) and 4,4'-bipyridine (1 mg, 0.01 mmol) were dissolved in DMF (1 mL) and stirred at 0 °C for 30 min. The residue was extracted with EA (3x5 mL) and the combined organic layers were dried over Na ₂ SO ₄ and filtered. The concentrated residue was purified by Prep-HPLC (ACN/H ₂ O=1:1) to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-hydroxy-1-methyl-3-morpholino-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (4 mg, 6.6% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 11.68 (s, 1H), 8.09 (s, 1H), 7.37 (s, 1H), 6.81 (s, 1H), 6.79 (s, 1H), 6.72 (s, 1H), 5.56 (s, 2H), 5.52-5.49 (m, 1H), 3.82 (s, 3H), 3.75-3.73 (m, 4H), 3.07 (s, 4H), 1.54 (d, 3H); MS: m/z = 489.1 (M+1, ESI+).

Example 45: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-3-((tetrahydro-2H-pyran-4-yl)amino)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-1-Methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-3-((tetrahydro-2H-pyran-4-yl)amino)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (400 mg, 0.80 mmol), oxan-4-amine (244 mg, 2.41 mmol), and RuPhos Pd G3 (67 mg, 0.08 mmol), RuPhos (37 mg, 0.08 mmol), and t-BuONa (154 mg, 1.61 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100°C for 2 h. Then, the mixture was extracted with EA (10 mL x 3) to obtain (R)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-3-((tetrahydro-2H-pyran-4-yl)amino)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (crude product, 650 mg, 100% yield) as a yellow solid.

MS: m/z = 517 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-3-((tetrahydro-2H-pyran-4-yl)amino)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-1-Methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-3-((tetrahydro-2H-pyran-4-yl)amino)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (650 mg, 1.26 mmol), hypoboric acid (450 mg, 5.02 mmol), and 4,4'-bipyridine (10 mg, 0.06 mmol) were dissolved in DMF (6 mL), and the reaction mixture was stirred at 0°C for 30 min. The mixture was extracted with EA/Na ₂ CO ₃ (10 mL x 3), and the concentrated residue was purified by prep-HPLC (ACN/NH ₄ HCO ₃ 0.1%) to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-2-oxo-3-((tetrahydro-2H-pyran-4-yl)amino)-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (40 mg, 6.53% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d 6) δ: 8.15 (s, 1H), 7.76 (d, 1H), 7.00 (s, 1H), 6.81-6.77 (m, 2H), 6.68 (s, 1H), 5.78 (d, 1H), 5.54 (s, 2H), 5.50-5.47 (m, 1H), 3.96 (s, 3H), 3.92-3.89 (m, 2H), 3.75-3.72 (m, 1H), 3.51-3.44 (m, 2H), 1.91 (d, 2H), 1.60-1.52 (m, 5H); MS: m/z = 487.1 (M+1, ESI+).

Example 46: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-1-Methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (500 mg, 1.00 mmol), N-methyloxan-4-amine (347 mg, 3.01 mmol), and RuPhos Pd G3 (84 mg, 0.10 mmol), RuPhos (47 mg, 0.10 mmol), and t-BuONa (193 mg, 2.01 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100°C for 2 h. Then, the mixture was extracted with EA (10 mL x 3) to obtain (R)-1-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (686 mg, 100% yield) as a yellow solid.

MS: m/z = 531.4 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

(R)-1-Methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (686 mg, 1.29 mmol), hypoboric acid (463 mg, 5.16 mmol), and 4,4'-bipyridine (10 mg, 0.07 mmol) were dissolved in DMF (6 mL), and the reaction mixture was stirred at 0°C for 30 min. After extracting the mixture with EA/Na ₂ CO ₃ (10 mL x 3), the mixture was purified by prep-HPLC ([ACN/H ₂ O containing 0.1% NH ₄ HCO ₃ ) to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (20 mg, 2.62% yield) as a yellow solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ: 8.22 (s, 1H), 8.05 (d, 1H), 7.31 (s, 1H), 6.79 (d, 2H), 6.68 (s, 1H), 5.54 (s, 2H), 5.46-5.44 (m, 1H), 4.13 (m, 1H), 3.90 (m, 5H), 3.28-3.25 (m, 2H), 2.76 (s, 3H), 1.79-1.76 (m, 2H), 1.58-1.53 (m, 5H); MS: m/z = 501.2 (M+1, ESI+).

Example 47: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Step 1: (R)-3-(4-hydroxypiperidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

Intermediate S3 (300 mg, 0.6 mmol), piperidin-4-ol (183 mg, 1.81 mmol), Pd(AcO) ₂ (18 mg, 0.08 mmol), Xant-Phos (45 mg, 0.08 mmol), and Cs ₂ CO ₃ (1,179 mg, 3.62 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100 °C for 12 h under nitrogen. The mixture was extracted with EA (10 mL x 3) to obtain (R)-3-(4-hydroxypiperidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (340 mg, 75.86% yield) as a brown solid.

MS: m/z = 517.3 (M+1, ESI+).

Step 2: (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile

A solution of (R)-3-(4-hydroxypiperidin-1-yl)-1-methyl-5-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (340 mg, 0.66 mmol), tetrahydroxydiboron (235 mg, 2.62 mmol), and 4,4'-bipyridine (5 mg, 0.03 mmol) in DMF (2 mL) was stirred at 0°C for 1 h. After extracting the mixture with EA/Na ₂ CO ₃ (10 mL x 3), the mixture was purified by prep- HPLC (ACN/H ₂ O containing 0.1% NH ₄ HCO ₃ ) to give (R)-5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine-8-carbonitrile (17 mg, 5.31% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 8.24 (s, 1H), 8.09 (d, 1H), 7.41 (s, 1H), 6.80-6.78 (m, 2H), 6.68 (s, 1H), 5.54 (s, 2H), 5.48-5.44 (m, 1H), 4.71-4.70 (m, 1H), 3.89 (s, 3H), 3.68-3.67 (m, 1H), 3.56-3.50 (m, 2H), 2.85-2.79 (m, 2H), 1.87-1.85 (m, 2H), 1.58-1.53 (m, 5H); MS: m/z = 487.1 (M+1, ESI+).

[Experimental Example]

Experimental Example 1: Protein-protein interaction inhibition assay of KRAS G12C or KRAS G12D and SOS1 (KRAS G12C/KRAS G12D::SOS1 protein-protein interaction (PPI) inhibition assay)

Protein-protein interactions between SOS1 and KRAS G12C or KRAS G12D were measured by the HTRF method.

SOS1 was diluted 1.5x in assay buffer (10 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM DTT, 10 mM EDTA, 0.05% BSA, 0.005% Triton X100) and dispensed 10 μL of the solution into each well of the plate, while the blank wells contained only the assay buffer. The inhibitor compounds were prepared by diluting them 400x in DMSO and dispensed into each well of the plate using an ECHO acoustic dispenser (Beckman) and incubated with gentle mixing for 15 minutes. After mixing KRAS and the detection reagent, they were incubated for 45-60 minutes. The HTRF signal generated thereafter was measured using a plate signal detector, and the result was calculated as the ratio of the signals emitted at 665 nm and 620 nm as shown below.

Result = 665 nm signal / 620 nm signal x 10 ⁴

The IC ₅₀ values of each inhibitor compound were analyzed using Graphad Prism 4.0 software.

The degree of inhibition of the interaction between SOS1 and KRAS G12C or KRAS G12D by the inhibitor compound measured by the above method was evaluated based on the following criteria, and the results are shown in Table 2.

IC ₅₀ range ≤100 nM 100 nM ＜ IC ₅₀ ≤ 1,000 nM > 1,000 nM rating A B C

Claims (22)

A compound of the following formula (I), a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof: [Chemical formula (I)] In the above formula, Ring A is C ₆ -C ₁₀ aryl, or a 5- to 10-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S; R ^A is halogen, CN, OH, NR'R'', C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, wherein said C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy may be optionally substituted with halogen, CN, OH or NR'R''; R ¹ is H or C ₁ -C ₆ alkyl; R ² and R ³ are each independently H, halogen, CN, OH, NR'R'', -COR', -SO ₂ R', -CONR'R'', -SO ₂ NR'R'', C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or saturated or partially unsaturated C ₃ -C ₇ cycloalkyl, wherein said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₃ -C ₇ cycloalkyl may each be optionally substituted independently with halogen, CN, OH or NR'R''; R ⁴ is H, C ₁ -C ₆ alkyl, saturated or partially unsaturated C ₃ -C ₇ cycloalkyl, -(C ₁ -C ₆ alkyl)(saturated or partially unsaturated C ₃ -C ₇ cycloalkyl), or -(saturated or partially unsaturated C ₃ -C ₇ cycloalkyl)(C ₁ -C ₆ alkyl), B is NR ^x R ^y , or ring B1; One of R ^x and R ^y is H or C ₁ -C ₆ alkyl and the other is ring B2, or R ^x and R ^y can form ring B3 together with the nitrogen atom to which they are bonded; Ring B1 and ring B2 are bonded to the 1,6-naphthyridin-2-one nucleus or the nitrogen atom of NR ^x R ^y through the carbon atom contained in each ring, and are each independently a 3- to 10-membered monocyclic or bicyclic saturated or partially unsaturated heterocyclyl, a 5- to 10-membered heteroaryl, or a saturated or partially unsaturated C ₃ -C ₇ cycloalkyl, wherein the heterocyclyl and heteroaryl contain 1 or 2 heteroatoms selected from N, O, and S; Ring B3 is a 3- to 10-membered monocyclic or bicyclic saturated or partially unsaturated heterocyclyl or a 5- to 10-membered heteroaryl, which may optionally contain one additional heteroatom selected from N, O and ^S , together with the nitrogen atom to which R ^x and R y are bonded; Ring B1, ring B2 and ring B3 may each be independently optionally substituted with 1 to 3 R ^B ; R ^B is halogen, oxo, CN, OH, NR'R'', -COR', -SO ₂ R', -CONR'R'', -SO ₂ NR'R'', C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or saturated or partially unsaturated C ₃ -C ₇ cycloalkyl, wherein said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₇ cycloalkyl may each independently be optionally substituted with halogen, CN, OH, or NR'R''; R' and R'' are each independently H or C ₁ -C ₆ alkyl; n is an integer from 0 to 4. In the first paragraph, A compound, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms. In the second paragraph, Ring A is phenyl or pyridinyl, R ^A is halogen, CN, NR'R'', C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkyl, A compound, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein R' and R'' are each independently H or C ₁ -C ₆ alkyl, and n is 2 or 3. In the first paragraph, A compound, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl. In the first paragraph, A compound, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ are each independently H, halogen, CN, OH, CONH ₂ , or C ₁ -C ₆ alkyl. In paragraph 5, R ² is H, CN, OH or C ₁ -C ₆ alkyl, R ³ is H, halogen, CN or CONH ₂ , A compound, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein at least one of R ² and R ³ is not H. In the first paragraph, A compound, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein R ⁴ is -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , cyclopropyl or methylcyclopropyl. In the first paragraph, A compound, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein ring B1 and ring B2 are each independently a 3- to 7-membered monocyclic saturated or partially unsaturated heterocyclyl containing one heteroatom selected from N and O. In paragraph 8, A compound, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein ring B1 and ring B2 are each independently azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl or dihydropyranyl. In paragraph 8, Rings B1 and B2 are each independently optionally substituted with R ^B , wherein R ^B is halogen, CN, OH, NH ₂ , NHR', NR'R'', -COR', -SO ₂ R', C ₁ -C ₆ alkyl or saturated or partially unsaturated C ₃ -C ₇ cycloalkyl, R' and R'' are each independently C ₁ -C ₆ alkyl, a compound, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. In the first paragraph, A compound, a stereoisomer, an isotopically labeled compound, a ^hydrate , a solvate or a ^{pharmaceutically} acceptable salt thereof, wherein ring B3 is a 4- to 9-membered monocyclic or spiro or bridged bicyclic saturated or partially unsaturated heterocyclyl, optionally containing one additional heteroatom selected from N and O, together with the nitrogen atom to which R x and R y are bonded. In Article 11, Ring B3 is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, azepanyl, diazepanyl, , , and A compound, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, selected from: In Article 11, Ring B3 is optionally substituted with R ^B , wherein R ^B is halogen, CN, OH, NH ₂ , NHR', NR'R'', -COR', -SO ₂ R', C ₁ -C ₆ alkyl or saturated or partially unsaturated C ₃ -C ₇ cycloalkyl, R' and R'' are each independently C ₁ -C ₆ alkyl, a compound, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. In the first paragraph, A compound selected from the group consisting of: a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof; A pharmaceutical composition comprising a compound of any one of claims 1 to 14, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof as an active ingredient. In Article 15, A pharmaceutical composition for preventing or treating an SOS1-mediated disease. In Article 16, A pharmaceutical composition wherein the SOS1-mediated disease is cancer or RAS disease. In Article 17, A pharmaceutical composition wherein the cancer is selected from the group consisting of gastric cancer, lung cancer, lung adenocarcinoma, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, glioblastoma, head and neck squamous cell carcinoma, diffuse large cell type B lymphoma, bone cancer, melanoma, breast cancer, sclerosing adenoma, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, glioblastoma, prostate cancer, urethral cancer, urothelial cancer, bladder cancer, leukemia, multiple myeloma, myelodysplastic syndrome, cholangiocarcinoma, lymphoma, and fibroadenoma. In Article 17, A pharmaceutical composition, wherein the RAS disease is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome, Noonan Syndrome with Multiple Lentigines, Capillary Malformation-Arteriovenous Malformation Syndrome, Costello Syndrome, Cardio-Facio-Cutaneous Syndrome, Legius Syndrome, and Hereditary gingival fibromatosis. A method for preventing or treating an SOS1-mediated disease, comprising administering to a subject a compound of any one of claims 1 to 14, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. Use of a compound according to any one of claims 1 to 14, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, for the prevention or treatment of a SOS1-mediated disease. Use of a compound according to any one of claims 1 to 14, a stereoisomer, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing or treating a SOS1-mediated disease.