Tetrahydropyrido[3,4-d]pyrimidine compounds as HPK1 inhibitors

Abstract

There is provided a tetrahydropyrido[3,4-d]pyrimidine compound which is a potent HPK1 inhibitor. The compound is useful for treating or preventing cancer and / or inflammatory diseases and / or autoimmune diseases or symptoms thereof in mammals, particularly humans. The compound has a chemical structure of general formula (I), (II), (III), (IV) or (V), or an enantiomer or diastereomer or mixture or pharmaceutically acceptable salt thereof. JPEG2025521083000329.jpg96128

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Application No. 63 / 383,190, filed on November 10, 2022, and U.S. Provisional Application No. 63 / 340,191, filed on May 10, 2022, the entire contents of which are incorporated herein by reference.

Background Art

[0002] (Description of the Related Art) Hematopoietic progenitor kinase 1 (HPK1) is a serine / threonine kinase expressed in T cells, B cells, and dendritic cells (Jr-Wen Shui, Nature Immunology, vol. 8, 2007, pp. 84-91). In T cells, HPK1 acts as a rheostat for T cell activation by regulating the molecular circuitry of the T cell receptor (TCR) signaling pathway. HPK1 is recruited to the TCR complex, phosphorylates the SLP76 protein, resulting in its degradation and downregulation of TCR signal strength. Genetic ablation of HPK1 leads to T cell activation, lower TCR threshold, increased proliferation, and elevated levels of inflammatory cytokines such as IL-2, TNF-α, and IFN-γ. Loss of HPK1 expression enhances dendritic cell activation and antigen presentation. (Hernandez S. et al., Cell Reports, vol. 25, 2018, pp. 80-94). HPK1 kinase activity is thought to be important for conferring the inhibitory function of HPK1 in a wide range of immune cells such as CD8+, CD4+, DC, and NK to regulatory T cells (Tregs). Inactivation of the kinase domain of HPK1 was sufficient to induce a strong anti-tumor immune response (Liu et al., PLoS One, March 26, 2019). HPK1 knockout (KO) and kinase dead (KD) mice exhibit enhanced T cell function and anti-tumor efficacy (You D. et.al., J. Immunother. Cancer, 2021). Therefore, pharmacological inhibition of HPK1 has the potential to enhance effector T cell function and anti-tumor activity.

Summary of the Invention

[0003] In one embodiment, a compound of formula I

Chemical Formula

Chemical formula

[0004] In one embodiment, a compound of formula I is provided wherein R1 and R2 are hydrogen.

[0005] In one embodiment, a compound of formula I is provided wherein R3 is selected from the group consisting of hydrogen and -CH3.

[0006] In one embodiment, R4 is hydrogen,

Chemical formula

[0007] In one embodiment, a compound of formula I is provided wherein R5 and R6 are hydrogen.

[0008] In one embodiment, a compound of formula I is provided wherein R7 is selected from the group consisting of hydrogen and -CH3.

[0009] In one embodiment, a compound of Formula I is provided wherein X and Y are CH.

[0010] In one embodiment, a compound of Formula I is provided wherein X and Y are N.

[0011] In one embodiment, a compound of Formula I is provided wherein X is N and Y is CH.

[0012] In one embodiment, a compound of Formula I is provided wherein W is CR8.

[0013] In one embodiment, R8 is

Chemical formula

[0014] In one embodiment, R8 is

Chemical formula

[0015] In one embodiment, R8 is

Chemical formula

[0016] In one embodiment, R8 is

Chemical formula

[0017] In one embodiment, R8 is

Chemical formula

[0018] In one embodiment, R9 is F, Cl, Br, I, -CF3, -CH3, -CH2CH3,

Chemical formula

[0019] In one embodiment, the compound of formula II

Chemical formula

Chemical formula

[0020] In one embodiment, a compound of formula II wherein R 17 and R 18 are hydrogen is provided.

[0021] In one embodiment, a compound of formula II wherein R 19 is selected from the group consisting of hydrogen and -CH3 is provided.

[0022] In one embodiment, a compound of formula II wherein R 20 is hydrogen,

Chemical formula

[0023] In one embodiment, a compound of formula II wherein R 22 and R 23 are hydrogen is provided.

[0024] In one embodiment, a compound of formula II wherein R 21 is selected from the group consisting of hydrogen and -CH3 is provided.

[0025] In one embodiment, a compound of formula II wherein X' and Y' are CH is provided.

[0026] In one embodiment, a compound of formula II wherein X' and Y' are N is provided.

[0027] In one embodiment, there is provided a compound of Formula II wherein X’ is N and Y’ is CH.

[0028] In one embodiment, there is provided a compound of Formula II wherein r and s are 1.

[0029] In one embodiment, R 25 , R 26 , R 27 and R 28 are hydrogen, and there is provided a compound of Formula II.

[0030] In one embodiment, R 25 and R 26 are -CH3, and R 27 and R 28 are hydrogen, and there is provided a compound of Formula II.

[0031] In one embodiment, R 24 is selected from the group consisting of hydrogen, -CH3, -CF3, CH2F2, and

Chemical formula

[0032] In one embodiment, a compound of Formula III

Chemical formula

Chemical formula

[0033] In one embodiment, a compound of formula III is provided wherein R 29 and R 30 are hydrogen.

[0034] In one embodiment, a compound of formula III is provided wherein R 31 is selected from the group consisting of hydrogen and -CH3.

[0035] In one embodiment, a compound of formula III is provided wherein R 32 is hydrogen,

Chemical formula

[0036] In one embodiment, compounds of formula III in which R 34 and R 35 are hydrogen are provided.

[0037] In one embodiment, compounds of formula III in which R 33 is selected from the group consisting of hydrogen and -CH3 are provided.

[0038] In one embodiment, compounds of formula III in which X” and Y” are CH are provided.

[0039] In one embodiment, compounds of formula III in which X” and Y” are N are provided.

[0040] In one embodiment, compounds of formula III in which X” is N and Y” is CH are provided.

[0041] In one embodiment, R 36 is selected from hydrogen, -CH3, -CH2CH2OCH3, -CH2CH2F2,

Chemical formula

[0042] In one embodiment, compounds of formula IV

Chemical formula

Chemical formula

[0043] R 37 , R 38 , R 39 and R 40For each occurrence, independently, is selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl,

[0044] R 41 for each substitutable position, independently, is selected from the group consisting of hydrogen, halogen, -O-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl, and C3-C6 cycloalkyl, or its enantiomer or diastereomer or mixture or its pharmaceutically acceptable salt is provided.

[0045] In one embodiment, a compound of formula IV wherein R 37 is -CH3 is provided.

[0046] In one embodiment, a compound of formula IV wherein R 38 is -CH3 is provided.

[0047] In one embodiment, a compound of formula IV wherein R 39 and R 40 are hydrogen is provided.

[0048] In one embodiment, a compound of formula IV wherein R 41 is selected from the group consisting of hydrogen, -OCH3, and F is provided.

[0049] In one embodiment, a compound of formula V

Chemical Formula

Chemical Formula

[0050] In one embodiment, a compound of formula V wherein h is 1 is provided.

[0051] In one embodiment, R 42 is -CH3 and a compound of formula V is provided.

[0052] In one embodiment, a compound of formula I selected from the group consisting of:

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

[0053] In one embodiment, a compound of Formula II selected from the group consisting of the following,

Table 2-1

Table 2-2

Table 2-3

[0054] In one embodiment, a compound of Formula III selected from the group consisting of the following,

Table 3-1

Table 3-2

[0055] In one embodiment, a compound of formula IV selected from the group consisting of the following, [Table 4] and pharmaceutically acceptable salts thereof are provided.

[0056] In one embodiment, a compound of formula V selected from the group consisting of the following, [Table 5-1] [Table 5-2] and pharmaceutically acceptable salts thereof are provided.

[0057] In one embodiment, a pharmaceutical composition comprises a compound of formula I, II, III, IV or V as defined above and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

[0058] In one embodiment, a method of administering a therapeutically effective amount of a compound having the structure of formula I, II, III, IV or V as defined above or a pharmaceutically acceptable salt thereof to a patient having an HPK-1 mediated disorder is provided.

[0059] In one embodiment, a method of administering to a patient having an HPK-1 mediated disorder a pharmaceutical composition containing a therapeutically effective amount of a compound of formula I, II, III, IV or V and a pharmaceutically acceptable adjuvant, carrier, or vehicle is provided. The HPK1 mediated disorder can be cancer or an autoimmune and / or inflammatory disease.

[0060] The HPK-1 mediated disorder can be cancer. The cancer can be one or more of breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine gland, esophagus, endometrium, germ cell, head and neck, kidney, liver, lung, larynx and hypopharynx, ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, testis, stomach, skin, ureter, vagina, and vulvar cancers.

[0061] HPK-1-mediated disorders can be autoimmune diseases. Autoimmune diseases can be one or more of rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic lupus erythematosus (SLE), type I diabetes mellitus, multiple sclerosis (MS), antiphospholipid antibody syndrome (APS), sclerosing cholangitis, systemic-onset arthritis, inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft-versus-host disease (GvHD), autoimmune skin diseases, uveitis, pernicious anemia, and hypoparathyroidism. Autoimmune diseases also include, but are not limited to, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cold urticaria.

[0062] The compounds of formula I, II, III, IV or V or their pharmaceutical compositions can be used to treat inflammatory disorders, and / or the immune response is related to inflammatory disorders. The inflammatory disorder can be one or more of non-articular rheumatism, renal fibrosis, and hepatic fibrosis. The inflammatory disorder can be interface dermatitis. The inflammatory disorder can be skin disorders such as atopic dermatitis (eczema), aseptic inflammatory conditions such as drug-induced liver and / or pancreatic inflammation, inflammatory liver diseases, and / or inflammatory pancreatic disorders.

[0063] The therapeutically effective amount of the compound or pharmaceutical composition can be in the range consisting of 0.1 to 100 mg / kg of patient body weight, 0.1 to 50 mg / kg of patient body weight, 0.5 to 50 mg / kg of patient body weight, 1 to 20 mg / kg of patient body weight, 5 to 20 mg / kg of patient body weight, 10 to 20 mg / kg of patient body weight, 10 to 50 mg / kg of patient body weight, and 10 to 100 mg / kg of patient body weight. The compound or pharmaceutical composition can be administered to the patient continuously, multiple times a day, once a day, once every other day, weekly, every other week, monthly, or every other month. The compound or pharmaceutical composition can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, or via an implanted reservoir. The compound can be administered by injection or infusion techniques subcutaneously, intravenously, intramuscularly, intra-articularly, intrasynovially, intrasternal, intramedullary, intrahepatic, intralesional, and intracranial.

[0064] In one embodiment, a kit is provided that includes a therapeutically effective amount of a compound of Formula I, II, III, IV, or V as defined above, or a physiologically acceptable salt or prodrug thereof, and instructions for use of the compound.

[0065] Additional features, advantages, and embodiments of the subject matter of this disclosure are described in, or may be apparent from, the following detailed description and the claims. Further, it is to be understood that both the foregoing summary of the invention and the following detailed description are exemplary and intended to provide further explanation without limiting the scope of the claims.

DETAILED DESCRIPTION OF THE INVENTION

[0066] Disclosed herein are chemical structures of general formula I, II, III, IV, or V, or prodrugs or pharmaceutically acceptable salts thereof (including mixtures thereof in any ratio), for use in the treatment of, preferably, cancer, inflammatory diseases, and / or autoimmune diseases. Compounds of Formula I, II, III, IV, or V are capable of inhibiting HPK1 activity. Compounds disclosed herein have the general formula I:

CHEMICAL FORMULA

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0067] Alkyl can be a straight-chain or branched-chain alkyl group. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. The number of carbon atoms in the alkyl is not particularly limited. In some embodiments, the alkyl can have a specific number of carbon atoms, such as 1-6.

[0068] Halogen can refer to F, Cl, Br, or I. Haloalkyl can refer to one or more halogens attached to the alkyl. An example of haloalkyl can be CF3.

[0069] A heterocyclyl is a monovalent group formed by removing a hydrogen atom from any ring atom of a heterocyclic compound. It may contain one or more heteroatoms. The heteroatom may refer to one or more of oxygen, sulfur, nitrogen, phosphorus, or any oxidized form thereof. Heterocycle, heterocyclyl, and heterocyclic ring can be used interchangeably, and can be either saturated or partially unsaturated, and refer to a stable 5- to 7-membered monocyclic or 6- to 14-membered bicyclic heterocyclic moiety having, in addition to carbon atoms, one or more, preferably 1 to 4, of the heteroatoms defined above. The heterocycle can be bonded to its pendant group by any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of saturated or partially unsaturated heterocyclic rings include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, oxazepinyl, thiazepinyl, and morpholinyl. Heterocyclyl can include a group in which one or more aryl rings, heteroaryl rings, or alicyclic hydrocarbon rings are fused to the heterocyclyl ring, and the bonding group or bonding point is on the heterocyclyl ring. The heterocyclyl group can be monocyclic or bicyclic.

[0070] Partially unsaturated can refer to a ring moiety containing at least one double bond or triple bond. It can include rings having multiple unsaturation sites, but is not intended to include aryl or heteroaryl moieties. The term unsaturated can refer to a moiety having one or more unsaturation units.

[0071] Aryl (aromatic) can refer to aryl alone or a larger moiety such as aralkyl, aralkoxy, and / or aryloxyalkyl. It can refer to monocyclic and bicyclic rings. At least one ring in the system can be aromatic. Each ring in this system can contain 3 to 7 members. Exemplary aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl, etc., and these optionally contain one or more substituents. Aryl can also refer to a group in which an aromatic ring is fused to one or more non-aromatic rings (e.g., indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, tetrahydronaphthyl, etc.).

[0072] Heteroaryl (heteroaromatic) can refer to heteroaryl alone or as part of a larger moiety such as heteroaralkyl or heteroaralkoxy. It can mean a group having 5 to 14 ring atoms, preferably 5 or 6 ring atoms. In addition to carbon atoms, heteroaryl can contain 1 to 5 heteroatoms as provided above. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. Heteroaryl also includes groups in which the heteroaromatic ring is fused to one or more aryl, cycloaliphatic, and / or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group can be monocyclic or bicyclic. Heteroaralkyl can refer to an alkyl group substituted by heteroaryl, where the alkyl and heteroaryl moieties are each independently optionally substituted. The term optionally substituted can mean that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise specified, an optionally substituted group has a suitable substituent at each position where substitution is possible for that group, and in any structure, if there is more than one position substituted by a plurality of substituents selected from the designated group, the substituents can be the same or different at each position. Typical substituents include -F, -Cl, -Br, -I, deuterium, -OH, protected hydroxy, alkoxy, oxo, thioxo, -NO2, -CN, CF3, N3, -NH2, protected amino, -NH alkyl, -NH alkenyl, -NH alkynyl, -NH cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycle, -dialkylamino, -diarylamino, -diheteroarylamino, -O alkyl, -O alkenyl, -O alkynyl, -O cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycle, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkynyl, -C(O)-carbocyclic, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocyclic, -CONH2, -CONH-alkyl, -CONH-alkyl, -CONH-alkynyl, -CONH-carbocyclic, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocyclic, -OCO2-alkyl, -OCO2-alkenyl, -OCO2-alkynyl, -OCO2-carbocyclic, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocyclic, -OCONH2, -OCONH-alkyl, -OCONH-alkenyl, -OCONH-alkynyl, -OCONH-carbocyclic, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocyclic, -NHC(O)-alkyl, -NHC(O)-alkenyl, -NHC(O)-alkenyl, -NHC(O)-carbocyclic, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclic, -NHCO2-alkyl, -NHCO2-alkenyl, -NHCO2-alkynyl, -NHCO2-carbocyclic, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocyclic, -NHC(O)NH2, -NHC(O)NH-alkyl, -NHC(O)NH alkenyl, -NHC(O)NH alkynyl, -NHC(O)NH carbocyclic, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocyclic, NHC(S)NH2, -NHC(S)NH-alkyl, -NHC(S)NH alkenyl, -NHC(S)NH alkynyl,-NHC(S)NH carbocyclic, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocyclic, -NHC(NH)NH2, -NHC(NH)NH-alkyl, -NHC(NH)-alkenyl, -NHC(NH)NH-alkynyl, -NHC(NH)NH-carbocyclic, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocyclic, -NHC(NH)-alkyl, -NHC(NH)-alkenyl, -NHC(NH)-alkenyl, -NHC(NH)-carbocyclic, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocyclic, -C(NH)NH-alkyl, -C(NH)NH-alkenyl, -C(NH)NH-alkynyl, -C(NH)NH-carbocyclic, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocyclic, -S(O)-alkyl, -S(O)-alkenyl, -S(O)-alkynyl, -S(O)-carbocyclic, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocyclic, -SO2NH2, -SO2NH-alkyl, -SO2NH-alkenyl, -SO2NH-alkynyl, -SO2NH-carbocyclic, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocyclic, -NHSO2-alkyl, -NHSO2-alkenyl, -NHSO2-alkynyl, -NHSO2-carbocyclic, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocyclic, CH2NH2, -CH2SO2CH3, -mono-, -di- or -tri-alkylsilyl, -alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic, -heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-alkyl, -S-alkenyl, -S-alkynyl, -S-carbocyclic, -S-aryl, -S-heteroaryl, -S-heterocyclic, or methylthiomethyl, including but not limited to.

[0073] The term "stable" can refer to a compound that does not substantially change when subjected to the conditions that enable their production or synthesis, detection, recovery, purification, and / or use as disclosed herein. A pharmaceutically acceptable salt can refer to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that has a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed using an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or an organic acid (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0074] The salt can be derived from a suitable base including an alkali metal, alkaline earth metal, and ammonium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, alkylsulfonate ions, arylsulfonate ions, as necessary.

[0075] Unless otherwise indicated, the structures shown in this specification are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of that structure. For example, the R and S configurations of each chiral center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the present invention are within the scope of the present invention. In some cases, the enantiomeric excess is at least 50%, at least 60%, at least 70%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100%. Unless otherwise indicated, all tautomers of the compounds disclosed herein are within the scope of the present invention. Since the pharmaceutical activities of racemic or stereoisomeric forms of the compounds according to the present invention may differ, it may be desirable to use enantiomers. In these cases, the final product or even the intermediate can be separated into enantiomeric compounds by chemical or physical means known to those skilled in the art, or can be used as such in the synthesis.

[0076] If tautomerism of the compounds disclosed herein or their prodrugs can occur, for example, keto-enol tautomerism, the individual forms, for example the keto or enol form, are claimed separately and together as mixtures in any ratio. The same applies to stereoisomers, for example, enantiomers, cis / trans isomers, conformational isomers, etc. If necessary, the isomers can be separated by methods well known in the art, for example, by liquid chromatography. The same applies to enantiomers, for example, by using a chiral stationary phase. Further, enantiomers can be isolated by converting it to diastereomers, i.e., coupling with a mirror-image pure auxiliary compound, followed by separation of the resulting diastereomers and cleavage of the auxiliary group. Alternatively, any enantiomer of the compounds disclosed herein can be obtained from a stereoselective synthesis using optically pure starting materials.

[0077] It is also contemplated that the compounds disclosed herein may include their isotopically labeled forms. Isotopically labeled forms of the compounds disclosed herein are identical to the compounds except for the fact that one or more atoms of the compound are replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the atoms usually found in nature. Examples of isotopes that are readily commercially available and can be incorporated into the compounds of formula I, II, III, IV or V by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36Examples include, but are not limited to, Cl. Also contemplated in embodiments of the present disclosure are compounds of Formula I, II, III, IV, or V, prodrugs thereof, or any pharmaceutically acceptable salt containing one or more of the foregoing isotopes and / or other isotopes of other atoms. Isotopically labeled compounds of Formula I, II, III, IV, or V can be used in many useful ways. For example, 3 H or 14 Isotopically labeled compounds of Formula I, II, III, IV, or V incorporating radioactive isotopes such as C are suitable for drug and / or substrate tissue distribution assays. These radioactive isotopes are particularly preferred due to their ease of preparation and excellent detectability. Incorporating heavier isotopes, such as deuterium 2 H into compounds of Formula I, II, III, IV, or V can have therapeutic advantages due to the higher metabolic stability of this isotopically labeled compound. Higher metabolic stability directly leads to an improved in vivo half-life or lower dosage. Isotopically labeled compounds of Formula I, II, III, IV, or V can be prepared by readily substituting non-isotopically labeled reactants with readily available isotopically labeled reactants and adapting them to the synthetic schemes, and related descriptions, example sections, and preparation sections disclosed herein.

[0078] The compounds of the present disclosure can be in the form of prodrug compounds. A prodrug compound can refer to a derivative that is converted into a biologically active compound under physiological conditions in a living body, for example, by oxidation, reduction, hydrolysis, etc., each of which can be carried out enzymatically or without the involvement of an enzyme. Examples of prodrugs are compounds in which the amino group in the compound is acylated, alkylated or phosphorylated, the hydroxyl group is acylated, alkylated, phosphorylated or converted into a borate, the carboxyl group is esterified or amidated, or the sulfhydryl group forms a disulfide bridge with a carrier molecule, such as a peptide, that selectively delivers the drug to a target and / or the cytosol of a cell. These compounds can be produced from the compounds disclosed herein according to well-known methods. Another example of a prodrug is a compound in which the carboxylate in the compound is converted into, for example, an alkyl-, aryl-, choline-, amino, acyloxymethyl ester, or linolenoyl-ester.

[0079] According to one embodiment, the composition comprises a compound disclosed herein or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition disclosed herein can be effective to inhibit the measurement of HPK1 or its variant in a biological sample or a patient. A therapeutically effective amount of the compound can be administered to a patient in need thereof. The patient or subject can refer to an animal, preferably a mammal, and more preferably a human. The biological sample can refer to, but is not limited to, a cell culture or an extract thereof, a biopsy material obtained from a mammal or an extract thereof, and blood, saliva, urine, feces, semen, tears, or other body fluids or an extract thereof.

[0080] A pharmaceutically acceptable carrier, adjuvant, or vehicle can refer to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants, or vehicles used in the compositions disclosed herein include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, lanolin, but are not limited thereto. A pharmaceutically acceptable derivative means any non-toxic salt, ester, salt of an ester, or other derivative of the compounds disclosed herein that can provide the compounds disclosed herein directly or indirectly upon administration to a recipient.

[0081] The compositions disclosed herein can be administered orally, parenterally, by inhalation spray, topically, enterally, nasally, bucally, vaginally, or via an implanted reservoir. Parenteral administration can refer to injection or infusion techniques into the subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial regions. Preferably, the compositions can be administered orally, intraperitoneally, or intravenously. The sterile injectable forms of the compositions disclosed herein include aqueous or oily suspensions. These suspensions are formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectables can also be in the form of sterile injectable solutions or suspensions dissolved in a non-toxic parenterally acceptable diluent or solvent, for example, provided as a 1,3-butanediol solution. Acceptable vehicles and solvents are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils can conventionally be used as a solvent or suspending medium.

[0082] The pharmaceutically acceptable compositions disclosed herein can be administered orally in any orally acceptable dosage form. Exemplary oral dosage forms are capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient can be combined with an emulsifying and / or suspending agent. Optionally, certain sweetening, flavoring, and / or coloring agents can be added if desired. Most preferably, the pharmaceutically acceptable compositions disclosed herein are formulated for oral administration. Such formulations can be administered with or without food.

[0083] The amount of the compounds disclosed herein that can be combined with a carrier material to produce a single dosage form composition can vary depending on the host being treated and the particular mode of administration. Preferably, the compositions provided can be formulated such that a dosage of the compound from 0.01 to 100 mg / kg body weight / day can be administered to a patient receiving these compositions. In some examples, the dosage can be 0.1 to 100 mg / kg, 0.1 to 50 mg / kg, 0.5 to 50 mg / kg, 1 to 50 mg / kg, 1 to 20 mg / kg, 5 to 20 mg / kg, 10 to 20 mg / kg, 10 to 50 mg / kg patient body weight, or 10 to 100 mg / kg patient body weight, or any other dosage range disclosed herein. In some examples, the compounds or compositions herein are administered continuously, multiple times a day, once a day, once every other day, weekly, biweekly, monthly, or bimonthly. The therapeutically effective amount of the compounds or compositions herein can vary according to factors known in the art, but a dosage from about 0.1 to 100 mg / kg, 0.1 to 50 mg / kg, 0.5 to 50 mg / kg, 1 to 50 mg / kg, 1 to 20 mg / kg, 5 to 20 mg / kg, 10 to 20 mg / kg, or 10 to 50 mg / kg patient body weight, or 10 to 100 mg / kg patient body weight, or any other dosage range disclosed herein can be a therapeutically effective amount. The specific dosage and treatment regimen for any particular patient depends on a variety of factors including the activity of the specific compound being used, age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of the compounds disclosed herein in the composition also depends on the particular compound in the composition.

[0084] The compounds of formula I, II, III, IV or V disclosed herein can be administered one or more times, either before or after the onset of a disease, and act as therapeutic agents. The aforementioned compounds and pharmaceutical compositions of the invention are used in particular for therapeutic treatment. Due to the therapeutically relevant effects, one or more symptoms of the disorder are alleviated to some extent, or one or more physiological or biochemical parameters associated with or causative of the disease or pathological condition return partially or completely to normal. Monitoring is considered a kind of treatment when the compounds are administered at separate intervals, for example, as long as the efficacy is enhanced and the symptoms of the disease are completely eradicated. Either the same compound or different compounds can be applied. By using the methods disclosed herein, it is possible to reduce the likelihood of developing a disorder, or even prevent the onset of disorders related to HPK1 activity in advance, or treat the symptoms that occur and persist.

[0085] The host or patient can belong to any mammalian species, such as primate species, particularly humans, rodents (including mice, rats and hamsters), rabbits, horses, cows, dogs, cats, etc. Animal models are subjects in experimental investigations that provide models for the treatment of human diseases.

[0086] The compounds disclosed herein may be useful as anti-cancer agents for cancers responsive to HPK1 inhibition. In certain embodiments, cancers include, but are not limited to, breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine gland, esophagus, endometrium, germ cell, head and neck, kidney, liver, lung, larynx and hypopharynx, ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva cancers. In some examples, the cancer is mesothelioma, sarcoma, retinoblastoma, Wilms tumor, leukemia, lymphoma, non-Hodgkin lymphoma, chronic and acute myeloid leukemia, acute lymphoblastic leukemia, Hodgkin's disease, multiple myeloma, T-cell lymphoma, myelodysplastic syndrome, plasma cell neoplasms, and paraneoplastic syndromes.

[0087] Compounds of formula I, II, III, IV or V can be used in methods for ameliorating and / or treating symptoms associated with unwanted immune activation, including but not limited to symptoms associated with autoimmune conditions and / or the treatment of autoimmunity. The disclosed compounds may be useful for inhibiting the immune response and thereby preventing or delaying the onset of autoimmune diseases. Autoimmune diseases may be characterized by joint pain, positive antinuclear antibodies, malar rash, or discoid rash. Autoimmune diseases may be associated with the skin, muscle tissue, and / or connective tissue. In some embodiments, autoimmune diseases are not evidenced in an individual by symptoms of the skin, muscle tissue, and / or connective tissue. In some embodiments, autoimmune diseases are systemic. Autoimmune diseases include, but are not limited to, rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic lupus erythematosus (SLE), type I diabetes mellitus, multiple sclerosis (MS), antiphospholipid antibody syndrome (APS), sclerosing cholangitis, systemic onset arthritis, inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft-versus-host disease (GvHD), autoimmune skin diseases, uveitis, pernicious anemia, and hypoparathyroidism. Autoimmune diseases also include, but are not limited to, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cold agglutinin disease.

[0088] In some embodiments, the disclosed compounds can be used to treat inflammatory disorders, and / or the immune response is associated with an inflammatory disorder. As used herein, the term "inflammatory disorder" can include autoimmune diseases, as well as inflammatory conditions without known autoimmune components (e.g., atherosclerosis, asthma, etc.). In a further aspect, inhibiting the immune response can alleviate or mitigate one or more symptoms of an inflammatory disorder. Inhibiting the immune response can be useful for treating an inflammatory disorder and / or for preventing or delaying the onset of an inflammatory disorder. Examples of inflammatory disorders can include, but are not limited to, rheumatoid arthritis, renal fibrosis, and liver fibrosis. The inflammatory disorder can be interface dermatitis. Interface dermatitis can be one or more of lichen planus, lichenoid eruption, lichenoid keratosis, lichen striatus, chronic lichen, erythema multiforme, fixed drug eruption, pityriasis lichenoides, phototoxic dermatitis, radiation skin injury, viral exanthema, dermatomyositis, secondary syphilis, lichen sclerosus, condyloma acuminata, bullous pemphigoid, staphylococcal lichen, porokeratosis, chronic atrophic acrodermatitis, and regressive melanoma. The inflammatory disorder can be a skin disorder such as atopic dermatitis (eczema), an aseptic inflammatory condition such as drug-induced liver and / or pancreatic inflammation, an inflammatory liver disease, and / or an inflammatory pancreatic disorder.

[0089] The sensitivity of a given cancer to HPK1 inhibition can be evaluated, although not limited to, by a decrease in primary or metastatic tumor burden (mild, partial, or complete regression), changes in peripheral blood picture, changes in blood hormone or cytokine concentration, inhibition of the increase of tumor burden, stabilization of the disease in the patient, evaluation of disease-related biomarkers or surrogate markers, extension of overall survival in the patient, extension of progression-free survival in the patient, extension of disease-free survival in the patient, improvement of quality of life in the patient, or modulation of disease comorbidities (e.g., but not limited to, pain, cachexia, mobilization, hospitalization period, changes in peripheral blood picture, weight loss, wound healing, fever). A significant improvement in the pharmacokinetic profile of the compound of formula I, II, III, IV, or V can be obtained thereby and can be quantitatively represented in terms of an increase in in vivo half-life (t / 2), concentration at maximum therapeutic effect (Cmax), and area under the dose-response curve (AUC).

[0090] In various embodiments, the compounds of formula I, II, III, IV, or V and related formulas show an IC for inhibition of HPK1 of less than about 1000 nM, less than about 500 nM, less than 100 nM, less than 500 nM, or less than 1000 nM 50 In some embodiments, the compounds of formula (I) and related formulas show an IC for inhibition of HPK1 of at least 1 nM, at least 10 nM, at least 100 nM, or at least 500 nM 50 In some embodiments, the range is a combination of these values.

[0091] The compounds of formula I, II, III, IV, or V, and / or their pharmaceutically acceptable salts can be used as intermediates for the preparation of further pharmaceutical active ingredients. The pharmaceutical is preferably prepared non-chemically, for example, by combining the active ingredient with at least one solid, fluid, and / or semi-fluid carrier or excipient, optionally in combination with one or more other active substances in a suitable dosage form.

[0092] As used herein, there is provided a medicament that may comprise at least one compound disclosed herein or a prodrug or pharmaceutically acceptable salt thereof (including mixtures thereof in all ratios). The medicament comprises one or more compounds of Formula I, II, III, IV or V or a preparation thereof, such as a pharmaceutical composition or pharmaceutical formulation, and in the prevention, treatment, follow-up or aftercare of a patient suffering from a disease associated with HPK1 activity, in a manner such that a pathogenic modification of the overall condition or the condition of a particular region of the organism can be established at least temporarily, and may refer to any agent in the field of medicine.

[0093] In various embodiments, the active ingredient may be administered alone or in combination with other therapies. A synergistic effect can be achieved by using two or more compounds in a pharmaceutical composition, i.e., a compound of Formula I, II, III, IV or V can be combined as an active ingredient with at least one other agent, which is either another compound of Formula I, II, III, IV or V or a compound of a different structural backbone. The active ingredients can be administered simultaneously or sequentially. In some embodiments, the HPK1 inhibitor compounds disclosed herein are administered simultaneously with one or more additional therapeutic agents. In some embodiments, sequential administration comprises administering the HPK1 inhibitor or the additional therapeutic agent after any of about 1 minute, 5 minutes, 30 minutes, 1 hour, 5 hours, 24 hours, 48 hours, or 1 week. In some embodiments, the HPK1 inhibitor is administered by the same route of administration as the additional therapeutic agent. In some embodiments, the HPK1 inhibitor may be administered by a different route of administration than the additional therapeutic agent.

[0094] Therapeutic agents may include, but are not limited to, anti-inflammatory drugs and / or one or more anti-tumor agents conventionally used in chemotherapy or targeted therapy. The compounds or compositions disclosed herein may be used as monotherapy or in combination with therapeutic agents. Examples of anti-tumor agents include platinum compounds such as carboplatin, cisplatin, picoplatin, etc.; alkylating agents such as altretamine, carmustine, chlorambucil, mitobronitol, apaziquone, parifosfamide, etc.; DNA modifying agents such as bisantrene, decitabine, mitoxantrone, procarbazine, etc.; microtubule modifying agents such as docetaxel, eribulin, paclitaxel, vinblastine, etc.; topoisomerase inhibitors such as etoposide, razoxane, topotecan, etc.; anti-cancer antibodies such as bleomycin, mitomycin C, etc.; antimetabolites such as capecitabine, cladribine, etc.; hormones or antagonists such as tamoxifen, dexamethasone, etc.; cytokines such as interferon, etc.; antibodies such as pembrolizumab, nivolumab, ipilimumab, cetuximab, etc., but are not limited thereto.

[0095] A method for inhibiting abnormal cell growth or treating cancer in a mammal, preferably a human, may comprise administering to the mammal in combination with radiation therapy an amount of a compound of formula I, II, III, IV or V disclosed herein, or a prodrug or pharmaceutically acceptable salt thereof, wherein the amount of the compound, salt or prodrug is an amount effective to inhibit abnormal cell growth or treat cancer or its symptoms in the mammal in combination with radiation therapy. Techniques for administering radiation therapy are known in the art and these techniques can be used in the combination therapies described herein.

[0096] As used herein, the terms "treatment", "treating", and "treatment" may refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment is administered after one or more symptoms have occurred. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of the symptoms, or genetic or other susceptibility factors). Treatment may also be continued after the symptoms have resolved, for example, to prevent or delay recurrence.

[0097] Disclosed herein is a kit comprising separate packs of a therapeutically effective amount of a compound disclosed herein or a physiologically acceptable salt or prodrug thereof, and optionally a therapeutically effective amount of a therapeutic agent. The kit may include a suitable container, such as a box, individual bottle, bag, or ampoule, and instructions for using or applying the kit. The kit may include, for example, separate ampoules each containing a therapeutically effective amount of a compound disclosed herein and / or a pharmaceutically usable derivative, solvate, and stereoisomer thereof (including mixtures thereof in all ratios), and an effective amount of a further therapeutic agent in dissolved or lyophilized form.

[0098] Experimental Procedures As shown in the following examples, in certain exemplary embodiments, compounds are prepared according to the following general procedures. The general methods illustrate the synthesis of specific compounds, but it is understood that the following general methods, as well as other methods known to those of skill in the art, may be applied to all compounds and to each subclass and species of these compounds, as described herein.

[0099] The symbols and conventions used in the following description of processes, schemes, and examples are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0100] Unless otherwise indicated, all temperatures are expressed in °C (degrees Celsius).

[0101] All solvents used were commercially available and used without further purification. Reactions were typically carried out using anhydrous solvents under an inert atmosphere of nitrogen. Flash column chromatography was generally performed using silica gel 60 (particle size 0.035 - 0.070 mm).

[0102] All NMR experiments were recorded on either a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400 BBFO probe for proton NMR at 400 MHz, or a Bruker Mercury Plus 300 NMR spectrometer equipped with a Bruker 300 BBFO probe for proton NMR at 400 MHz, or a Bruker Avance III 400 NMR spectrometer equipped with a Bruker PABBO BB - 1H / D Z GRD probe for proton NMR at 300 MHz. Most deuterated solvents typically contained 0.03% - 0.05% v / v of tetramethylsilane, which was used as the reference signal (set to d 0.00 for both 1H and 13C). When tetramethylsilane was not included in the deuterated solvent, the residual peak of the non - deuterated solvent was used as the reference signal, which was in accordance with the published guidelines (J. Org. Chem., vol. 62, No. 21, 1997). LC - MS analysis was performed on either one of the following two instruments. 1. A SHIMADZU LC-MS apparatus consisting of a UFLC 20-AD system and an LCMS 2020 MS detector. The column used was Shim-pack XR-ODS, 2.2 μm, 3.0 × 50 mm. A linear gradient was applied, starting with 95% A (A: 0.05% trifluoroacetic acid (TFA) in water) for 2.2 minutes and ending with 100% B (B: 0.05% TFA (ACN) in acetonitrile), with a total running time of 3.6 minutes. The column temperature was 40 °C and the flow rate was 1.0 ml / min. The diode array detector was scanned at 200 - 400 nm. The mass spectrometer was equipped with an electrospray ionization source (ES) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90 - 900 with a scan time of 0.6 seconds. 2. An Agilent 1200 series mass spectrometer manufactured by Agilent Technologies, using either atmospheric pressure chemical ionization (APCI) or electrospray ionization (ESI). The diode array detector was scanned at 200 - 400 nm. The mass spectrometer was scanned between m / z 90 - 900 with a scan time of 0.6 seconds. Column: X Bridge C8, 3.5 μm, 4.6 × 50 mm, Solvent A: water + 0.1% TFA, Solvent B: ACN + 0.1% TFA, Flow rate: 2 mL / min, Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min: 5% B or LC / MS waters ZMD (ESI).

[0103] HPLC data was obtained from a SHIMAZU LC-MS apparatus or using an Agilent 1100 series HPLC manufactured by Agilent technologies with a column (XBridge C8, 3.5 μm, 4.6 × 50 mm) and two mobile phases (Mobile phase A: water + 0.1% TFA; Mobile phase B: ACN + 0.1% TFA). The flow rate was 2 mL / min. The gradient method was 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min: 5% B (unless otherwise indicated).

[0104] In general, the compounds of Formula I, II, III, IV or V and related formulas described herein can be prepared from readily available starting materials. If such starting materials are not commercially available, they can be prepared by standard synthetic techniques. In general, the synthetic route for any individual compound of Formula I, II, III, IV or V and related formulas depends on the specific substituents of each molecule, and such factors are understood by those skilled in the art. To prepare the compounds of Formula I, II, III, IV or V and related formulas, the following general methods and procedures described below in the Examples can be used. The reaction conditions (e.g., temperature, solvent, or co-reagents) shown in the following schemes are shown by way of example only and are not limiting. It is understood that other experimental conditions can also be used if not otherwise stated when typical or preferred experimental conditions (i.e., reaction temperature, time, molar amount of reagents, solvent, etc.) are shown. The optimal reaction conditions can vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art using routine optimization procedures. For all protection and deprotection methods, see Philip J. Kocienski, "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts, "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd Edition 1999. Example 1: Synthesis of Compound 1 N1-[2-(Dimethylamino)ethyl]-2-fluoro-N4-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)benzene-1,4-diamine

Chemical formula

[0105] N-[2-(Dimethylamino)ethyl]-2-fluoro-4-nitroaniline: A solution of 1,2-difluoro-4-nitrobenzene (3.00 g, 17.91 mmol), (2-aminoethyl)dimethylamine (1.70 g, 18.32 mmol), and TEA {triethylamine} (5.49 mL, 37.55 mmol) in AcOEt {ethyl acetate} (100.00 mL) was stirred at 80 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (PE {petroleum ether}:AcOEt = 7:3) to give N-[2-(dimethylamino)ethyl]-2-fluoro-4-nitroaniline (3.77 g, 90.9%) as a yellow oil.

[0106] tert-Butyl N-[2-(dimethylamino)ethyl]-N-(2-fluoro-4-nitrophenyl)carbamate: A solution of N-[2-(dimethylamino)ethyl]-2-fluoro-4-nitroaniline (3.67 g, 15.85 mmol), (Boc)2O (17.25 mL, 76.61 mmol), DMAP {4-dimethylaminopyridine} (200.00 mg, 1.47 mmol), and TEA (6.30 mL, 43.06 mmol) in DCM {dichloromethane} (50.00 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 7:3) to give tert-butyl N-[2-(dimethylamino)ethyl]-N-(2-fluoro-4-nitrophenyl)carbamate (5.00 g, 96.4%) as a yellow oil.

[0107] tert-Butyl N-(4-amino-2-fluorophenyl)-N-[2-(dimethylamino)ethyl]carbamate: A solution of tert-butyl N-[2-(dimethylamino)ethyl]-N-(2-fluoro-4-nitrophenyl)carbamate (4.90 g, 14.97 mmol), NH4Cl (4.00 g, 74.03 mmol), Fe (4.00 g, 70.19 mmol) in water (32.00 mL) and EtOH (48.00 mL) was stirred at 80 °C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 1:99) to obtain tert-butyl N-(4-amino-2-fluorophenyl)-N-[2-(dimethylamino)ethyl]carbamate (2.00 g, 6.50 mmol, 43.4%) as an off-white solid.

[0108] tert-Butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a solution of tert-butyl 2,4-dichloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (20.00 g, 62.46 mmol) in EtOH (400.00 mL), Zn (22.00 g, 319.67 mmol) and NH4OH (24.00 mL) were added at room temperature. The resulting mixture was stirred at 90 °C for 15 hours under an N2 atmosphere. The reaction was cooled, filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column, eluting with ethyl acetate (EA):PE = 1:3 to obtain tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (13.00 g, 77.2%) as a pale yellow oil.

[0109] 2-Chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine hydrochloride: To a stirred mixture of tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (1.00 g, 3.71 mmol), EA (10.00 mL, 40.00 mmol) and EtOAc (10.00 mL) in HCl (g). The resulting mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. The resulting mixture was extracted with EA (3 × 50 mL). The filtrate was concentrated under reduced pressure to give 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine hydrochloride (700 mg, 98%) as a yellow solid.

[0110] tert-Butyl N-[2-(dimethylamino)ethyl]-N-[2-fluoro-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]carbamate: A solution of tert-butyl N-(4-amino-2-fluorophenyl)-N-[2-(dimethylamino)ethyl]carbamate (300.00 mg, 0.98 mmol), 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine hydrochloride (252.00 mg, 1.20 mmol), Ephos (46.00 mg, 0.08 mmol), EPhos Pd G4 (54.00 mg, 0.06 mmol) and Cs2CO3 (980.00 mg, 2.86 mmol) in DMF {N,N-dimethylformamide} (6.00 mL) was stirred at 120 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 7:3) to give tert-butyl N-[2-(dimethylamino)ethyl]-N-[2-fluoro-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]carbamate (270.00 mg, 50.9%) as a yellow solid.

[0111] 7-Bromo-8-methyl-1H,3H-pyrido[2,3-b][1,4]oxazin-2-one: To a stirred mixture of 3-amino-5-bromo-4-methylpyridin-2-ol (100.00 g, 467.90 mmol, 1.0 equiv) and K2CO3 (205.00 g, 1409.19 mmol) in N,N-dimethylmethanamide (DMF) (600.00 mL), chloroacetyl chloride (1.22 g, 10.294 mmol) was added dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature under an argon atmosphere. The resulting mixture was poured into ice-cold water (3.00 L) and stirred for 15 minutes. The solid was filtered and dried under vacuum to give 7-bromo-8-methyl-1H,3H-pyrido[2,3-b][1,4]oxazin-2-one (110 g, crude product) as a gray solid.

[0112] 7-Bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine: A mixture of 7-bromo-8-methyl-1H,3H-pyrido[2,3-b][1,4]oxazin-2-one (110.00 g, 424.19 mmol) and BH3 tetrahydrofuran (THF) (550.00 mL, 550.00 mmol, 1 Mol / L) was stirred at 40 °C for 4 hours under a nitrogen atmosphere. The resulting mixture was carefully quenched with MeOH (ca. 550 mL) at 0 °C. HCl (2 M, 550 mL) was added to the mixture with stirring. The solution was stirred at room temperature for about 30 minutes. The resulting mixture was concentrated to half of its volume and adjusted to pH = 7 - 8 with Na2CO3 (aqueous solution). The final solution was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine (65.00 g, crude product) as a brown solid.

[0113] tert-Butyl 7-bromo-8-methyl-2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine (59.00 g, 239.53 mmol), TEA (107.83 mL, 736.94 mmol) and DMAP (6.40 g, 49.77 mmol) in DCM (350 mL) was added Boc2O (169.30 g, 736.94 mmol) in DCM (150.00 mL) dropwise at 0 °C. The resulting mixture was stirred at 30 °C overnight under a nitrogen atmosphere (about 70% conversion by LCMS), then TEA (53.915 mL, 368.47 mmol) and Boc2O (84.65 g, 368.47 mmol) were added at room temperature. The resulting mixture was stirred at 30 °C for an additional 7 hours under a nitrogen atmosphere. Water was added to the resulting mixture. The resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 15% EtOAc in PE to give tert-butyl 7-bromo-8-methyl-2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (67.00 g, 79.7%) as a yellow solid.

[0114] tert-Butyl 7-{2-[(4-{[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino}-3-fluorophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: A solution of tert-butyl N-[2-(dimethylamino)ethyl]-N-[2-fluoro-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]carbamate (200.00 mg, 0.37 mmol), tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (305.00 mg, 0.88 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (40.00 mg, 0.05 mmol), and Cs2CO3 (450.00 mg, 1.31 mmol) in 1,4-dioxane (5.00 ml) was stirred at 120 °C for 4 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 7:3) to give tert-butyl 7-{2-[(4-{[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino}-3-fluorophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (130.00 mg, 44.3%) as a yellow solid.

[0115] N1-[2-(Dimethylamino)ethyl]-2-fluoro-N4-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)benzene-1,4-diamine: A solution of tert-butyl 7-{2-[(4-{[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino}-3-fluorophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (130.00 mg, 0.16 mmol) and TFA (2.00 mL) in DCM (6.0 mL) was stirred at room temperature for 1 hour under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by column: X Bridge Prep OBD C18 column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 25% B - 55% B in 9 minutes, 55% B, wavelength: 254 nm; RT1 (min): 7; number of runs: 4 times to obtain N1-[2-(dimethylamino)ethyl]-2-fluoro-N4-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)benzene-1,4-diamine (18.10 mg, 22.1%) as an off-white solid.

[0116] HPLC: Purity 95.03%, RT = 2.21 min. MS: m / z = 479.25 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.28 (s, 1H), 7.60 (dd, J = 14.5, 2.4 Hz, 1H), 7.27 (s, 1H), 7.26 (s, 1H), 6.69 (t, J = 9.4 Hz, 1H), 5.54 (s, 1H), 4.78 (s, 1H), 4.19 (s, 2H), 3.92 (s, 2H), 3.17 - 3.08 (m, 5H), 2.76 (s, 1H), 2.55 (s, 4H), 2.29 (s, 6H), 2.03 (s, 3H). Example 2: Synthesis of Compound 2 2-(azetidin-1-yl)-N-{4-[(6-{8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-2-methylphenyl}acetamide

Chem.

[0117] tert-Butyl 7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate: To a stirred solution of tert-butyl 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (400.00 mg, 1.46 mmol) and 3-methyl-4-nitroaniline (271.84 mg, 1.75 mmol) in 1,4-dioxane (5.00 mL) were added Xphos (146.44 mg, 0.29 mmol), Xphos Pd G3 (130.01 mg, 0.15 mmol) and K2CO3 (423.63 mg, 2.92 mmol) portionwise at room temperature. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (6:1) to give tert-butyl 7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (330.00 mg, 58.74%) as a yellow solid.

[0118] N-(3-Methyl-4-nitrophenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine: To a stirred solution of tert-butyl 7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (330.00 mg, 0.86 mmol, 1.00 eq) in DCM (15.00 mL) was added TFA (3.00 mL) portionwise at room temperature. After stirring at room temperature for 1 h, the mixture was basified to pH 7 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give N-(3-methyl-4-nitrophenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine (220.00 mg, crude product) as a yellow solid.

[0119] 5-Bromo-4-chloro-3-nitropyridin-2-ol: To a stirred solution of 4-chloro-3-nitropyridin-2-ol (75.00 g, 408.21 mmol) in THF (700.00 mL) was added N-bromosuccinimide (NBS) (89.88 g, 489.85 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (150 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was slurried and purified with PE:EA = 3:1. The solid was collected to give 5-bromo-4-chloro-3-nitropyridin-2-ol (110.00 g, crude product) as a yellow solid.

[0120] 3-Amino-5-bromo-4-chloropyridin-2-ol: To a stirred solution of 5-bromo-4-chloro-3-nitropyridin-2-ol (75.00 g, 270.15 mmol) and NH4Cl (60.84 g, 1080.62 mmol) in water (500.00 mL) and THF (900.00 mL) was added Fe (79.62 g, 1350.77 mmol) portionwise at room temperature. The resulting mixture was stirred at 70 °C for 1 hour. The resulting mixture was filtered and the filter cake was washed with THF (1000 mL). The resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 3-amino-5-bromo-4-chloropyridin-2-ol (70.00 g, crude product) as a brown solid.

[0121] 7-Bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one: To a stirred solution of 3-amino-5-bromo-4-chloropyridin-2-ol (60.00 g, 228.34 mmol) and K2CO3 (99.44 g, 685.02 mmol) in DMF (720.00 mL) was added 2-chloroacetyl chloride (47.79 mL, 570.85 mmol) portionwise at 0 °C under an argon atmosphere. The resulting mixture was stirred at room temperature for 6 hours and at 40 °C for 1 hour. The resulting mixture was diluted with water (3000 mL). The resulting mixture was filtered and the filter cake was washed with water (1000 mL). The filter cake was dried under reduced pressure to give 7-bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one (40.00 g, crude product) as a brown solid.

[0122] 7-Bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine: A solution of BH3 in THF (350.00 mL, 350.00 mmol) of 7-bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one (35.00 g, 350.00 mL) was stirred at 40 °C for 2 hours under a N2 atmosphere. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (150 mL). The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1) to give 7-bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine (26.00 g, 71.34%) as a white solid.

[0123] tert-Butyl 7-bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of 7-bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine (340.00 mg, 1.18 mmol) and di-tert-butyl dicarbonate (897.00 mg, 3.90 mmol) in dichloromethane (5.00 mL), triethylamine (0.57 mL, 3.91 mmol) and N,N-dimethylpyridin-4-amine (34.00 mg, 0.26 mmol) were added portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 30 °C for 4 hours under a N2 atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column, eluting with 15% EtOAc in PE to give tert-butyl 7-bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (340.00 mg, 68.6%) as a white solid.

[0124] tert-Butyl 8-chloro-7-{7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of N-(3-methyl-4-nitrophenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine (520.00 mg, 1.74 mmol) and tert-butyl 7-bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (765.73 mg, 2.08 mmol) in 1,4-dioxane (18.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (153.49 mg, 0.17 mmol) and Cs2CO3 (1190.50 mg, 3.47 mmol) portionwise at room temperature. The resulting mixture was stirred at 110 °C for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to afford tert-butyl 8-chloro-7-{7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (120.00 mg, 12.14%) as a yellow solid.

[0125] tert-Butyl 7-{7-[(4-amino-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a solution of tert-butyl 8-chloro-7-{7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (110.00 mg, 0.19 mmol) in MeOH (10.00 mL) was added Raney Ni (20.04 mg, 0.22 mmol) at room temperature. After stirring at room temperature for 1 hour under a hydrogen atmosphere, the resulting mixture was filtered. The filter cake was washed with MeOH and then the filtrate was concentrated under reduced pressure to give tert-butyl 7-{7-[(4-amino-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (40.00 mg, crude product) as a white solid.

[0126] tert-Butyl 7-[7-({4-[2-(azetidin-1-yl)acetamido]-3-methylphenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of tert-butyl 7-{7-[(4-amino-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (65.00 mg, 0.12 mmol) and 2-(azetidin-1-yl)acetic acid hydrochloride (36.73 mg, 0.23 mmol) in DMF (5.00 mL) were added HATU (93.11 mg, 0.23 mmol) and DIEA (47.46 mg, 0.35 mmol) portionwise at room temperature. The resulting mixture was stirred at 40 °C for 6 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give tert-butyl 7-[7-({4-[2-(azetidin-1-yl)acetamido]-3-methylphenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (50.00 mg, 59.40%) as a yellow solid.

[0127] 2-(Azetidin-1-yl)-N-{4-[(6-{8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-2-methylphenyl}acetamide: To a stirred mixture of tert-butyl 7-[7-({4-[2-(azetidin-1-yl)acetamido]-3-methylphenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (50.00 mg, 0.07 mmol) in DCM (4.00 mL) was added dropwise BBr3 in DCM (0.40 mL, 0.40 mmol) at -78 °C. The resulting mixture was stirred at -78 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC column under the following conditions: X Bridge Shield RP18 OBD column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 55% B to 85% B in 9 minutes, 85% B, wavelength: 254 nm; RT1 (min): 7, number of runs: 2 times to give 2-(azetidin-1-yl)-N-{4-[(6-{8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-2-methylphenyl}acetamide (7.30 mg, 020.23%) as a white solid.

[0128] HPLC: Purity 99.59%, RT = 2.14 min. MS: m / z = 520.15 [M+H] + . 11H NMR (300 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.74 (s, 1H), 7.99 (s, 1H), 7.40 (d, J = 9.5 Hz, 2H), 7.31 (d, J = 17.1 Hz, 2H), 6.58 (s, 1H), 6.10 (s, 1H), 4.24 (s, 2H), 4.10 (s, 2H), 3.30 (s, 4H), 3.19 (d, J = 16.2 Hz, 4H), 3.10 (s, 2H), 2.83 (s, 2H), 2.16 (s, 3H), 2.06 (q, J = 6.9 Hz, 2H). Example 3: Synthesis of Compound 3 2-(Azetidin-1-yl)-N-{2-methyl-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}acetamide

Chemical Structure

[0129] tert-Butyl 2-[(3-methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a stirred mixture of tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (800.00 mg, 2.89 mmol) and 3-methyl-4-nitroaniline (590.00 mg, 3.76 mmol) in 1,4-dioxane (15.00 mL) were added X-PHOS (290.00 mg, 0.58 mmol), K2CO3 (1261.00 mg, 8.67 mmol) and XPhos Pd G3 (257.00 mg, 0.29 mmol) portionwise at 25 °C. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluting with PE:EA = 70:30 to give tert-butyl 2-[(3-methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (1.00 g, 89.8%) as a yellow solid.

[0130] N-(3-Methyl-4-nitrophenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine: To a stirred mixture of tert-butyl 2-[(3-methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (980.00 mg, 2.54 mmol) in DCM (20.00 mL) was added TFA (4.00 mL) portionwise at 25 °C. The resulting mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The reaction was diluted with NaHCO3 (aqueous solution) at 25 °C. The resulting mixture was extracted with EA (3 × 80 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to afford N-(3-methyl-4-nitrophenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (700.00 mg, crude product) as a yellow solid.

[0131] tert-Butyl 8-methyl-7-{2-[(3-methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of N-(3-methyl-4-nitrophenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (700.00 mg, 2.45 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (600.00 mg, 1.64 mmol) in 1,4-dioxane (15.00 mL) were added Cs2CO3 (1.90 g, 5.54 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (130.00 mg, 0.15 mmol) portionwise at 25 °C. The resulting mixture was stirred at 100 °C for 12 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE:EA = 1:1, to afford tert-butyl 8-methyl-7-{2-[(3-methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (700.00 mg, 80.0%) as a yellow solid.

[0132] 7-{2-[(4-Amino-3-methylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of tert-butyl 8-methyl-7-{2-[(3-methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (680.00 mg, 1.27 mmol) and Fe (225.00 mg, 3.83 mmol) in EtOH (9.00 mL) was added NH4Cl (276.00 mg, 5.11 mmol) in H2O (6.00 mL) portionwise at 25 °C. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluting with EA to afford tert-butyl 7-{2-[(4-amino-3-methylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (600.00 mg, 93.5%) as a yellow solid.

[0133] tert-Butyl 7-[2-({4-[2-(azetidin-1-yl)acetamido]-3-methylphenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of tert-butyl 7-{2-[(4-amino-3-methylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (180.00 mg, 0.29 mmol) and 2-(azetidin-1-yl)acetic acid hydrochloride (82.21 mg, 0.58 mmol) in DMF (5.00 mL) were added HATU (349.35 mg, 0.87 mmol) and DIEA (79.14 mg, 0.58 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with ice / water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give tert-butyl 7-[2-({4-[2-(azetidin-1-yl)acetamido]-3-methylphenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (130.00 mg, 67.8%) as a yellow solid.

[0134] 2-(Azetidin-1-yl)-N-{2-methyl-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}acetamide: To a stirred mixture of tert-butyl 7-[2-({4-[2-(azetidin-1-yl)acetamido]-3-methylphenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (190.00 mg, 0.28 mmol) in DCM (5.00 mL) was added BBr3 in DCM (1.00 mL, 1.00 mmol) dropwise at -78 °C. The resulting mixture was quenched with NaHCO3 (aqueous solution) at -20 °C. The mixture was extracted with DCM and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xselect CSH C18 OBD column 30×150 mm 5 μm, n, mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 5% B - 27% B in 8 minutes, 27% B, wavelength: 254 / 220 nm; RT1 (min): 6.7) to give 2-(azetidin-1-yl)-N-{2-methyl-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}acetamide (17.10 mg, 11.9%) as a white solid.

[0135] HPLC: Purity 97.34%, RT = 2.29 min. MS: m / z = 501.30 [M+H] + 。 11H NMR (300 MHz, DMSO-d6): δ 9.40 (s, 1H), 9.05 (s, 1H), 8.30 (s, 1H), 7.58 - 7.49 (m, 2H), 7.34 (d, J = 9.3 Hz, 1H), 7.27 (s, 1H), 5.51 (s, 1H), 4.17 (t, J = 4.3 Hz, 2H), 3.93 (s, 2H), 3.30 (s, 6H), 3.13 (d, J = 14.3 Hz, 4H), 2.77 (t, J = 5.3 Hz, 2H), 2.14 (s, 3H), 2.11 - 1.95 (m, 1H), 2.02 (s, 4H). Example 4: Synthesis of Compound 4 2-Fluoro-N4-(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine [Chemical Structure Diagram]

[0136] 2-Fluoro-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline: To a stirred solution of 1-bromo-2-fluoro-4-nitrobenzene (6.40 g, 29.09 mmol, 1.00 equiv) and 2-(morpholin-4-yl)ethan-1-amine (3.80 g, 29.19 mmol) in toluene (100.00 mL), Pd2(dba)3 (2.70 g, 2.65 mmol), Xantphos (3.40 g, 5.82 mmol) and t-BuONa (8.40 g, 78.67 mmol) were added portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 100 °C for 2 h under a N2 atmosphere. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 5% EA in PE to give 2-fluoro-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline (6.40 g, 78.3%) as a yellow solid.

[0137] tert-Butyl N-(2-fluoro-4-nitrophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate: To a stirred solution of 2-fluoro-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline (6.20 g, 22.23 mmol) and di-tert-butyl dicarbonate (15.00 g, 65.29 mmol) in dichloromethane (100.00 mL), triethylamine (9.62 mL, 65.72 mmol) and N,N-dimethylpyridin-4-amine (563.00 mg, 4.38 mmol) were added portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 30 °C for 4 h under a N2 atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with 30% EtOAc in PE to give tert-butyl N-(2-fluoro-4-nitrophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (7.20 g, 87.7%) as a yellow solid.

[0138] tert-Butyl N-(4-amino-2-fluorophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate: To a stirred solution of tert-butyl N-(2-fluoro-4-nitrophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (7.00 g, 18.95 mmol) in EtOH (3.00 mL) and water (2.00 mL), NH4Cl (4.00 g, 74.03 mmol) and Fe (5.30 g, 89.91 mmol) were added portionwise at room temperature under a N2 atmosphere. The solid was filtered off. The filtrate was diluted with water (500 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure to give tert-butyl N-(4-amino-2-fluorophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (6.50 g, crude product) as a yellow solid.

[0139] 7-Chloro-1,2,3,4-tetrahydro-2,6-naphthyridine hydrochloride: EA (16.00 mL, 64.00 mmol) of tert-butyl 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (800.00 mg, 2.83 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine hydrochloride (560.00 mg, crude product) as a white solid.

[0140] tert-Butyl N-{2-fluoro-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}-N-[2-(morpholin-4-yl)ethyl]carbamate: To a stirred solution of tert-butyl N-(4-amino-2-fluorophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (913.00 mg, 2.69 mmol) and 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine hydrochloride (460.00 mg, 2.24 mmol) in 1,4-dioxane (20.00 mL), Ephos Pd G4 (210.00 mg, 0.22 mmol), Ephos (126.00 mg, 0.22 mmol) and Cs2CO3 (1477.00 mg, 4.49 mmol) were added at room temperature under a N2 atmosphere. The resulting mixture was stirred at 100 °C for 16 hours under a N2 atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (4:1) to obtain tert-butyl N-{2-fluoro-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}-N-[2-(morpholin-4-yl)ethyl]carbamate (650.00 mg, 60.1%) as a yellow solid.

[0141] tert-Butyl 7-{7-[(4-{[(tert-butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-3-fluorophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: A solution of tert-butyl N-{2-fluoro-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}-N-[2-(morpholin-4-yl)ethyl]carbamate (250.00 mg, 0.52 mmol), tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (285.00 mg, 0.78 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (46.00 mg, 0.05 mmol), and Cs2CO3 (356.00 mg, 1.04 mmol) in 1,4-dioxane (10.00 ml) was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (DCM:MeOH = 6:1) to give tert-butyl 7-{7-[(4-{[(tert-butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-3-fluorophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (100.00 mg, 0.13 mmol, 25.7%) as a yellow solid.

[0142] 2-Fluoro-N4-(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine: A solution of tert-butyl 7-{7-[(4-{[(tert-butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-3-fluorophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (90.00 mg, 0.12 mmol) in DCM (3.00 mL) was stirred, and TFA (1.00 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X Bridge Shield RP18 OBD column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 26% B to 56% B in 9 minutes, 56% B, wavelength: 254 nm; RT1 (min): 7). Thereby, 2-fluoro-N4-(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine (30.40 mg, 48.5%) was obtained as a yellow solid.

[0143] HPLC: Purity 99.51%, RT = 3.26 min. MS: m / z = 520.20 [M + H] + 。 11H NMR (300 MHz, methanol-d4) δ 7.86 (s, 1H), 7.24 (s, 1H), 7.17 (dd, J = 13.5, 2.4 Hz, 1H), 6.97 (m, J = 8.6, 2.4, 1.2 Hz, 1H), 6.75 (dd, J = 9.7, 8.6 Hz, 1H), 6.46 (s, 1H), 4.33 - 4.25 (m, 2H), 3.98 (s, 2H), 3.76 - 3.67 (m, 4H), 3.45 - 3.36 (m, 2H), 3.26 (t, J = 6.4 Hz, 2H), 3.16 (t, J = 5.8 Hz, 2H), 2.86 (t, J = 5.8 Hz, 2H), 2.65 (t, J = 6.4 Hz, 2H), 2.53 (dd, J = 5.5, 3.6 Hz, 4H), 2.12 (s, 3H). Example 5: Synthesis of Compound 5 5-Chloro-6-(methanesulfonylmethyl)-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine [Chemical formula]

[0144] 5-Bromo-2-(bromomethyl)-3-chloropyridine: To a stirred mixture of 5-bromo-3-chloropyridin-2-yl)methanol (1.00 g, 3.96 mmol) in DCM (30 mL) was added pBR3 (0.51 mL, 5.15 mmol) dropwise at -78 °C. The mixture was then warmed to room temperature and stirred at room temperature for 12 h. The resulting mixture was quenched with ice / water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give 5-bromo-2-(bromomethyl)-3-chloropyridine (446.00 mg, 38.1%) as a yellow oil.

[0145] 5-Bromo-3-chloro-2-(methanesulfonylmethyl)pyridine: Sodium methanesulfinate (281.26 mg, 2.73 mmol) was added to a stirred solution of 5-bromo-2-(bromomethyl)-3-chloropyridine (400.00 mg, 1.36 mmol) in DMF (15.00 mL). The resulting mixture was stirred at 60 °C for 4 h under a nitrogen atmosphere. The resulting mixture was quenched with ice / water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 5-bromo-3-chloro-2-(methanesulfonylmethyl)pyridine (380.00 mg, 94.9%) as a yellow solid.

[0146] tert-Butyl N-[5-chloro-6-(methanesulfonylmethyl)pyridin-3-yl]carbamate: Pd2(dba)3 (109.83 mg, 0.11 mmol), XantPhos (133.19 mg, 0.23 mmol) and Cs2CO3 (781.56 mg, 2.28 mmol) were added to a stirred mixture of 5-bromo-3-chloro-2-(methanesulfonylmethyl)pyridine (370.00 mg, 1.14 mmol) and tert-butyl carbamate (210.75 mg, 1.71 mmol, 1.50 equiv) in 1,4-dioxane (15.00 mL) at room temperature. The mixture was stirred at 90 °C for 16 h under a nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (19:1), to give tert-butyl N-[5-chloro-6-(methanesulfonylmethyl)pyridin-3-yl]carbamate (420.00 mg, 90.3%) as a yellow solid.

[0147] 5-Chloro-6-(methanesulfonylmethyl)pyridin-3-amine: A mixture of tert-butyl N-[5-chloro-6-(methanesulfonylmethyl)pyridin-3-yl]carbamate (410.00 mg, 1.28 mmol) in HCl (20.00 mL, 4 M) in MeOH was at 25 °C. The resulting mixture was stirred at 25 °C for 12 h under a nitrogen atmosphere. The resulting mixture was quenched with ice / water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 5-chloro-6-(methanesulfonylmethyl)pyridin-3-amine (360.00 mg, crude product) as a brown solid.

[0148] tert-Butyl 2-{[5-chloro-6-(methanesulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a solution of 5-chloro-6-(methanesulfonylmethyl)pyridin-3-amine (300.00 mg, 1.35 mmol) and tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (364.00 mg, 1.35 mmol) in 1,4-dioxane (20.00 mL) were added Ephos (152.00 mg, 0.27 mmol), Cs2CO3 (925.00 mg, 2.70 mmol) and EPhos Pd G4 (131.00 mg, 0.14 mmol). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (24:1) to give tert-butyl 2-{[5-chloro-6-(methanesulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (180.00 mg, 25.5%) as a yellow solid.

[0149] 5-Chloro-6-(methanesulfonylmethyl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine: To a stirred solution of tert-butyl 2-{[5-chloro-6-(methanesulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (170.00 mg, 0.33 mmol) in DCM (10.00 mL) was added TFA (2.00 mL) portionwise at room temperature. The resulting mixture was stirred at 25 °C for 4 h under a nitrogen atmosphere. The mixture was basified to pH [7] with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 5-chloro-6-(methanesulfonylmethyl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine (100.00 mg, 81.5%) as a yellow solid.

[0150] tert-Butyl 7-(2-{[5-chloro-6-(methanesulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a solution of 5-chloro-6-(methanesulfonylmethyl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine (100.00 mg, 0.26 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (86.00 mg, 0.26 mmol) in 1,4-dioxane (2.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (23.00 mg, 0.03 mmol) and Cs2CO3 (169.00 mg, 0.51 mmol). The resulting mixture was stirred at 100 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (6:1), to give tert-butyl 7-(2-{[5-chloro-6-(methanesulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (45.00 mg, 21.8%) as a yellow solid.

[0151] 5-Chloro-6-(methanesulfonylmethyl)-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine: To a stirred solution of tert-butyl 7-(2-{[5-chloro-6-(methanesulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (40.00 mg, 0.05 mmol) in DCM (5.00 mL) was added TFA (1.00 mL) portionwise at room temperature. The resulting mixture was stirred at 25 °C for 4 h under a nitrogen atmosphere. The mixture was basified to pH = 7 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 18% B to 48% B in 9 min, 48% B, wavelength: 254 nm; RT1 (min): 7) to give 5-chloro-6-(methanesulfonylmethyl)-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine (4.60 mg, 18.1%) as a white solid.

[0152] HPLC: Purity 97.69%, RT = 2.63 min. MS: m / z = 502.00 [M + H] + 。 11H NMR (300 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.87 (d, J = 2.3 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.46 (s, 1H), 7.30 (s, 1H), 5.53 (s, 1H), 4.67 (s, 2H), 4.30 - 4.11 (m, 2H), 4.02 (s, 2H), 3.32 (s, 2H), 3.13 (d, J = 5.5 Hz, 2H), 3.06 (s, 3H), 2.85 (d, J = 5.8 Hz, 2H), 2.05 (s, 3H). Example 6: Synthesis of Compound 6 2-Fluoro-N4-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine

Chemical Structure

[0153] tert-Butyl N-[2-fluoro-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]-N-[2-(morpholin-4-yl)ethyl]carbamate: To a stirred solution of tert-butyl N-(4-amino-2-fluorophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (400.00 mg, 1.18 mmol) and 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine (267.00 mg, 1.53 mmol) in 1,4-dioxane (5.00 mL) were added EPhos Pd G4 (76.00 mg, 0.08 mmol), Ephos (63.00 mg, 0.11 mmol), and Cs2CO3 (1.20 g, 3.50 mmol) portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 100 °C for 2 h under a N2 atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with 15% MeOH in DCM to afford tert-butyl N-[2-fluoro-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]-N-[2-(morpholin-4-yl)ethyl]carbamate (340.00 mg, 53.6%) as an off-white solid.

[0154] tert-Butyl 7-{2-[(4-{[(tert-butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-3-fluorophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of tert-butyl N-[2-fluoro-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]-N-[2-(morpholin-4-yl)ethyl]carbamate (320.00 mg, 0.59 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (267.00 mg, 0.81 mmol) in 1,4-dioxane (5.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (57.00 mg, 0.06 mmol) and Cs2CO3 (664.00 mg, 1.94 mmol, 3.25 equiv) portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 100 °C overnight under a N2 atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with 100% EtOAc to afford tert-butyl 7-{2-[(4-{[(tert-butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-3-fluorophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (280.00 mg, 60.4%) as a yellow solid.

[0155] 2-Fluoro-N4-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine: To a stirred solution of tert-butyl 7-{2-[(4-{[(tert-butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-3-fluorophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (260.00 mg, 0.33 mmol) in DCM (3.00 mL) under N2 atmosphere, TFA (1.00 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 26% B - 56% B in 9 min, 56% B, wavelength: 254 nm; RT1 (min): 7) to give 2-fluoro-N4-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine (37.60 mg, 19.5%) as a yellow solid.

[0156] HPLC: Purity 90.02%, RT = 2.17 min. MS: m / z = 521.15 [M + H] + 。 11H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.27 (s, 1H), 7.59 (dd, J = 14.5, 2.4 Hz, 1H), 7.26 (d, J = 9.0 Hz, 2H), 6.74 - 6.62 (m, 1H), 5.53 (s, 1H), 4.77 (s, 1H), 4.19 (s, 2H), 3.92 (s, 2H), 3.58 (t, J = 4.6 Hz, 4H), 3.30 (s, 2H), 3.14 (dd, J = 12.6, 6.3 Hz, 4H), 2.76 (s, 2H), 2.54 (s, 2H), 2.40 (t, J = 4.6 Hz, 4H), 2.03 (s, 3H). Example 7: Synthesis of Compound 7 2-[(6-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one [Chemical Structure]

[0157] Methyl 2-(3-bromo-5-methyl-1H-pyrazol-1-yl)acetate: To a stirred solution of 3-bromo-5-methyl-1H-pyrazole (20.00 g, 118.01 mmol), tetra-n-butylammonium iodide (TBAI) (2.40 g, 6.17 mmol) and K2CO3 (31.10 g, 213.78 mmol) in DMF (200.00 mL) under N2 atmosphere, methyl 2-chloroacetate (20.30 g, 177.70 mmol) was added dropwise at room temperature. The resulting mixture was stirred overnight at room temperature under N2 atmosphere. The resulting mixture was diluted with water (1.5 L) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (1 L) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with 30% EA in PE to give methyl 2-[3-bromo-5-methyl-1H-pyrazol-1-yl]acetate (29.00 g, 98.5%).

[0158] Methyl 2-[3-bromo-5-(bromomethyl)-1H-pyrazol-1-yl]acetate: To a stirred solution of methyl 2-(3-bromo-5-methyl-1H-pyrazol-1-yl)acetate (25.00 g, 107.27 mmol) and NBS (20.10 g, 107.27 mmol) in PhCF3 (500.00 mL), 2-[(1Z)-2-(1-cyano-1-methylethyl)diazen-1-yl]-2-methylpropanenitrile (18.54 g, 107.27 mmol) was added portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 105 °C for 3 h under a N2 atmosphere. The reaction mixture was diluted with water (1 L) and extracted with DCM (3 × 400 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc:PE = 8:1, to give methyl 2-[3-bromo-5-(bromomethyl)-1H-pyrazol-1-yl]acetate (22.00 g, 46.85%).

[0159] Methyl 2-[3-bromo-5-(cyanomethyl)-1H-pyrazol-1-yl]acetate: To a stirred solution of methyl 2-[3-bromo-5-(bromomethyl)-1H-pyrazol-1-yl]acetate (22.00 g, 50.25 mmol) in DMSO (200.00 mL), sodium cyanide (3.77 g, 75.38 mmol) and water (4.00 mL, 219.76 mmol) were added portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 25 °C for 1 h under a N2 atmosphere. The resulting mixture was quenched with FeSO4 (aqueous solution) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EA = 7:1, and concentrated to give methyl 2-[3-bromo-5-(cyanomethyl)-1H-pyrazol-1-yl]acetate (8.50 g, 57.01%) as a yellow solid.

[0160] Methyl 2-(3-bromo-5-{2-[(propan-2-yl)amino]ethyl}-1H-pyrazol-1-yl)acetate: To a stirred mixture of methyl 2-[3-bromo-5-(cyanomethyl)-1H-pyrazol-1-yl]acetate (20.00 g, 58.08 mmol) in MeOH (50.00 mL) and acetone (12.50 mL), dioxoplatinum (6.00 g, 25.10 mmol) and AcOH (60.00 mg, 0.99 mmol) were added dropwise under nitrogen at room temperature. The resulting mixture was stirred for 1.5 h at room temperature under a hydrogen atmosphere (11.71 g, 5807.68 mmol). The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column eluting with DCM / MeOH (20:1) to give methyl 2-(3-bromo-5-{2-[(propan-2-yl)amino]ethyl}-1H-pyrazol-1-yl)acetate (13.00 g, 64.99%) as a yellow solid.

[0161] 2-(3-Bromo-5-{2-[(propan-2-yl)amino]ethyl}-1H-pyrazol-1-yl)acetic acid: To a stirred mixture of methyl 2-(3-bromo-5-{2-[(propan-2-yl)amino]ethyl}-1H-pyrazol-1-yl)acetate (7.00 g, 58.07 mmol) in THF (100.00 mL), LiOH (5.13 g, 116.14 mmol) in water (200.00 mL) was added dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature under a nitrogen atmosphere. The resulting mixture was adjusted to pH = 5 - 6 with HCl (6N) and concentrated under reduced pressure to give 2-(3-bromo-5-{2-[(propan-2-yl)amino]ethyl}-1H-pyrazol-1-yl)acetic acid (30.00 g, crude product) as a white solid, which was used in the next step without further purification.

[0162] 2-Bromo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one: To a stirred solution of 2-(3-bromo-5-{2-[(propan-2-yl)amino]ethyl}-1H-pyrazol-1-yl)acetic acid (25.00 g, 74.24 mmol) and HATU (29.71 g, 74.24 mmol) in DMF (250.00 mL), TEA (16.29 mL, 111.35 mmol) was added portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at [temperature not provided] °C for 1 hour under a N2 atmosphere. The resulting mixture was diluted with water (1 L) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was slurried with PE:EtOAc = 2:1 (30 mL), and the solid was filtered to obtain 2-bromo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (11.70 g, 54.55%) as a white solid.

[0163] 2-Amino-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one: To a stirred solution of 2-bromo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (1.00 g, 3.46 mmol) and NH3-H2O (2.00 mL, 759.13 mmol) in DMSO (10.00 mL), CuI (139.00 mg, 0.69 mmol), L-proline (168.00 mg, 1.39 mmol) and K2CO3 (1008.00 mg, 6.93 mmol) were added. The resulting mixture was stirred at 110 °C overnight using a sealed tube under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography under the following conditions (column, C18 silica gel, mobile phase, MeCN in water, gradient from 10% to 50% in 10 minutes, detector, UV 254 nm). Thereby, 2-amino-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (380.00 mg, 52.7%) was obtained as a yellow solid.

[0164] tert-Butyl 7-{[7-oxo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate: To a stirred solution of 2-amino-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (330.00 mg, 1.51 mmol) in 1,4-dioxane (6.00 mL) were added tert-butyl 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (468.42 mg, 1.66 mmol), EPhos Pd G4 (145.55 mg, 0.15 mmol), Ephos (84.74 mg, 0.15 mmol) and Cs2CO3 (1548.84 mg, 4.52 mmol) portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 120 °C for 3 h under a N2 atmosphere. The residue was purified by silica gel column eluting with 91% EtOAc in PE to give tert-butyl 7-{[7-oxo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (200.00 mg, 29.9%) as a white solid.

[0165] 6-(Propan-2-yl)-2-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one: To a stirred solution of tert-butyl 7-{[7-oxo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (190.00 mg, 1.00 eq) in DCM (2.40 mL) under an N2 atmosphere, TFA (0.80 mL) was added portionwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h under an N2 atmosphere. The resulting mixture was adjusted to pH 10 with NaHCO3 (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure to afford 6-(propan-2-yl)-2-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (140.00 mg, crude product) as a brown solid.

[0166] tert-Butyl 8-methyl-7-(7-{[7-oxo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of 6-(propan-2-yl)-2-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (110.00 mg, 0.32 mmol) in 1,4-dioxane (3.00 mL) were added tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (221.70 mg, 0.64 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (28.29 mg, 0.03 mmol), and Cs2CO3 (329.14 mg, 0.96 mmol) portionwise at room temperature under a N2 atmosphere. The residue was purified by silica gel column eluting with 75% EtOAc in PE to afford the crude product. The crude product was repurified by C18 flash column eluting with 55% ACN in water to give tert-butyl 8-methyl-7-(7-{[7-oxo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (120.00 mg, 57.4%) as a brown oil.

[0167] 2-[(6-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one: To a stirred solution of tert-butyl 8-methyl-7-(7-{[7-oxo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (115.00 mg, 0.195 mmol) in DCM (1.50 mL) under N2 atmosphere, TFA (0.50 mL) was added portionwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h under N2 atmosphere. The residue was purified by preparative HPLC (column: X Bridge Prep OBD C18 column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 25% B to 55% B in 9 min, 55% B, wavelength: 254 nm; RT1 (min): 7) to give 2-[(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (24.30 mg, 24.70%) as a white solid.

[0168] HPLC: Purity 96.17%, RT = 2.445 min. MS: m / z = 489.30 [M + H] + 。 11H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.93 (s, 1H), 7.26 (s, 1H), 7.00 (s, 1H), 6.17 (s, 1H), 5.49 (s, 1H), 4.90 (s, 2H), 4.58 (m, J = 6.8 Hz, 1H), 4.21 - 4.15 (m, 2H), 3.97 (s, 2H), 3.76 (d, J = 11.7 Hz, 2H), 3.33 (s, 2H), 3.07 (s, 2H), 2.96 (t, J = 5.9 Hz, 2H), 2.79 (s, 2H), 2.02 (s, 3H), 1.11 (d, J = 6.8 Hz, 6H). Example 8: Synthesis of Compound 8 3-Methyl-N-{5-[(7-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]pyridin-2-yl}oxetane-3-carboxamide

Chemical Structure

[0169] To a stirred solution of tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (1037.00 mg, 3.77 mmol) and N-(5-aminopyridin-2-yl)acetamide (500.00 mg, 3.14 mmol) in 1,4-dioxane (50.00 mL) were added PEPPSI™-IPr (269.00 mg, 0.31 mmol) and Cs2CO3 (2150.00 mg, 6.27 mmol) portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 100 °C for 4 h under a N2 atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (MeOH:DCM = 1:9) to give tert-butyl 2-[(6-acetamidopyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (740.00 mg, 61.3%) as a yellow solid.

[0170] N-[5-({5H,6H,7H,8H-Pyrido[3,4-d]pyrimidin-2-yl}amino)pyridin-2-yl]acetamide: A solution of tert-butyl 2-[(6-acetamidopyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (720.00 mg, 1.87 mmol) and TFA (3.00 mL) in DCM (9.00 mL) was stirred at room temperature for 1 hour under a nitrogen atmosphere. The mixture was adjusted to pH 12 with NaOH (aqueous solution) and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Thereby, N-[5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)pyridin-2-yl]acetamide (280.00 mg, 52.6%) was obtained as a yellow solid.

[0171] tert-Butyl 7-{2-[(6-acetamidopyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: A solution of N-[5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)pyridin-2-yl]acetamide (260.00 mg, 0.91 mmol), tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (402.00 mg, 1.10 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (81.00 mg, 0.09 mmol), and Cs2CO3 (627.00 mg, 1.83 mmol) in 1,4-dioxane (13.00 ml) was stirred at 100 °C for 4 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (DCM:MeOH = 8:2) to give tert-butyl 7-{2-[(6-acetamidopyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (460.00 mg, 94.4%) as a yellow solid.

[0172] tert-Butyl 7-{2-[(6-aminopyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: A solution of tert-butyl 7-{2-[(6-acetamidopyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (420.00 mg, 0.79 mmol) and NaOH (330.00 mg, 7.84 mmol) in MeOH (8.00 mL) was stirred at 80 °C for 10 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions (column, C18 silica gel, mobile phase, H2O / MeCN in water, gradient of 10% - 50% in 10 min, detector, UV 254 nm). This gave tert-butyl 7-{2-[(6-aminopyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (280.00 mg, 72.4%) as an off-white solid.

[0173] tert-Butyl 8-methyl-7-(2-{[6-(3-methyloxetan-3-amido)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of tert-butyl 7-{2-[(6-aminopyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (260.00 mg, 0.53 mmol), N,N-diisopropylethylamine (DIEA) (0.29 mL, 1.56 mmol), and 3-methyloxetane-3-carboxylic acid (33.00 mg, 0.27 mmol) in DMF (7.00 mL) was added hexafluorophosphate azabenzotriazole tetramethyluronium (HATU) (355.00 mg, 0.89 mmol) at room temperature under a N2 atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (3:1) to give tert-butyl 8-methyl-7-(2-{[6-(3-methyloxetan-3-amido)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (200.00 mg, 61.5%) as a yellow solid.

[0174] 3-Methyl-N-{5-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]pyridin-2-yl}oxetane-3-carboxamide: To a stirred solution of tert-butyl 8-methyl-7-(2-{[6-(3-methyloxetane-3-amide)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (180.00 mg, 0.29 mmol) in DCM (9.00 mL) was added dropwise TFA (3.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was purified by preparative HPLC under the following conditions: column: Xselect CSH C18 OBD column 30×150 mm 5 μm, mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 3% B to 25% B in 8 minutes, 25% B, wavelength: 254 / 220 nm, RT1 (min): 7.4). Thereby, 3-methyl-N-{5-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]pyridin-2-yl}oxetane-3-carboxamide (13.40 mg, 9.2%) was obtained as a yellow solid.

[0175] HPLC: 98.38% purity, RT = 2.47 min. MS: m / z = 489.10 [M+H] + . 11H NMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 7.91 (dd, J = 9.5, 2.4 Hz, 1H), 7.30 (s, 1H), 6.92 (d, J = 9.5 Hz, 1H), 5.55 (s, 1H), 4.36 (d, J = 14.0 Hz, 1H), 4.23 - 4.11 (m, 3H), 4.01 (s, 2H), 3.46 (d, J = 10.8 Hz, 2H), 3.33 (d, J = 7.9 Hz, 2H), 3.13 (s, 2H), 2.82 (s, 2H), 2.04 (s, 3H), 1.00 (s, 3H). Example 9: Synthesis of Compound 9 2-(Azetidin-1-yl)-N-{2-methyl-4-[(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}acetamide [Chemical formula]

[0176] tert-Butyl 7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate: To a stirred solution of tert-butyl 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (800.00 mg, 2.92 mmol) and 3-methyl-4-nitroaniline (543.69 mg, 3.50 mmol) in 1,4-dioxane (8.00 mL), X-PHOS (292.88 mg, 0.58 mmol), Xphos Pd G3 (260.01 mg, 0.29 mmol) and K2CO3 (847.27 mg, 5.84 mmol) were added portionwise at room temperature. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give tert-butyl 7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (580.00 mg, 51.11%) as a yellow oil.

[0177] N-(3-Methyl-4-nitrophenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine: To a stirred solution of tert-butyl 7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (580.00 mg, 1.49 mmol) in DCM (15.00 mL), TFA (3.00 mL) was added portionwise at room temperature. After stirring at room temperature for 1 h, the mixture was basified to pH = 7 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaCl (aqueous solution) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give N-(3-methyl-4-nitrophenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine (400.00 mg, crude product) as a yellow oil.

[0178] tert-Butyl 8-methyl-7-{7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of N-(3-methyl-4-nitrophenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine (180.00 mg, 0.62 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (213.26 mg, 0.62 mmol) in 1,4-dioxane (10.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (54.48 mg, 0.06 mmol) and Cs2CO3 (422.54 mg, 1.23 mmol) portionwise at room temperature. The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:100), to give tert-butyl 8-methyl-7-{7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (130.00 mg, 31.25%) as a yellow solid.

[0179] tert-Butyl 7-{7-[(4-amino-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of tert-butyl 8-methyl-7-{7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (130.00 mg, 0.19 mmol) and Fe (56.74 mg, 0.96 mmol) in EtOH (6.00 mL) and H2O (4.00 mL) was added NH4Cl (43.36 mg, 0.77 mmol) portionwise at room temperature. After stirring at 80 °C for 2 h, the resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaCl (aqueous solution) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 7-{7-[(4-amino-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (90.00 mg, crude product) as a black oil.

[0180] tert-Butyl 7-[7-({4-[2-(azetidin-1-yl)acetamido]-3-methylphenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of tert-butyl 7-{7-[(4-amino-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (90.00 mg, 0.16 mmol) and 2-(azetidin-1-yl)acetic acid hydrochloride (49.51 mg, 0.31 mmol) in DMF (10.00 mL) were added HATU (125.50 mg, 0.31 mmol) and DIEA (63.97 mg, 0.47 mmol) portionwise at room temperature. The resulting mixture was stirred at 40 °C for 6 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to afford tert-butyl 7-[7-({4-[2-(azetidin-1-yl)acetamido]-3-methylphenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (80.00 mg, 81.80%) as a yellow solid.

[0181] 2-(Azetidin-1-yl)-N-{2-methyl-4-[(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}acetamide: To a stirred mixture of tert-butyl 7-[7-({4-[2-(azetidin-1-yl)acetamido]-3-methylphenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (80.00 mg, 0.13 mmol) in DCM (4.00 mL) was added BBr3 in DCM (0.40 mL, 0.40 mmol) dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 1 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC column under the following conditions: X Bridge Shield RP18 OBD column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 20% B to 50% B in 9 min, 50% B, wavelength: 254 nm; RT1 (min): 7 to give 2-(azetidin-1-yl)-N-{2-methyl-4-[(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}acetamide (11.40 mg, 17.70%) as a yellow solid.

[0182] HPLC: Purity 99.4%, RT = 2.91 min. MS: m / z = 500.2 [M + H] + . 11H NMR (300 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.73 (s, 1H), 7.99 (s, 1H), 7.40 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 8.5 Hz, 1H), 7.27 (s, 1H), 6.57 (s, 1H), 5.50 (s, 1H), 4.19 (s, 2H), 3.98 (s, 2H), 3.45 (s, 2H), 3.34 (d, J = 7.0 Hz, 4H), 3.17 (s, 2H), 3.08 (d, J = 6.0 Hz, 2H), 2.82 (s, 2H), 2.16 (s, 3H), 2.13 - 1.98 (m, 5H). Example 10: Synthesis of Compound 10 N-{2-Methyl-4-[(7-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}-2-(pyrrolidin-1-yl)acetamide

Chemical Structure

[0183] tert-Butyl 2-[(3-Methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a stirred mixture of tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (800.00 mg, 2.89 mmol) and 3-methyl-4-nitroaniline (590.00 mg, 3.76 mmol) in 1,4-dioxane (15.00 mL) were added X-PHOS (290.00 mg, 0.58 mmol), K2CO3 (1261.00 mg, 8.67 mmol) and XPhos Pd G3 (257.00 mg, 0.29 mmol) portionwise at room temperature. The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE:EA = 70:30 to give tert-butyl 2-[(3-methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (1.00 g, 89.8%) as a yellow solid.

[0184] N-(3-Methyl-4-nitrophenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine: To a stirred mixture of tert-butyl 2-[(3-methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (980.00 mg, 2.54 mmol) in DCM (20.00 mL) was added TFA (4.00 mL) portionwise at 25 °C. The resulting mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. The reaction was diluted with NaHCO3 (aqueous solution) at 25 °C. The resulting mixture was extracted with EA (3 × 80 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give N-(3-methyl-4-nitrophenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (700.00 mg, crude product) as a yellow solid.

[0185] tert-Butyl 8-methyl-7-{2-[(3-methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of N-(3-methyl-4-nitrophenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (700.00 mg, 2.45 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (600.00 mg, 1.64 mmol) in 1,4-dioxane (15.00 mL) were added Cs2CO3 (1.90 g, 5.54 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (130.00 mg, 0.15 mmol) portionwise at 25 °C. The resulting mixture was stirred at 100 °C for 12 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE:EA = 1:1 to give tert-butyl 8-methyl-7-{2-[(3-methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (700.00 mg, 80.0%) as a yellow solid.

[0186] tert-Butyl 7-{2-[(4-amino-3-methylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of tert-butyl 8-methyl-7-{2-[(3-methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (680.00 mg, 1.27 mmol) and Fe (225.00 mg, 3.83 mmol) in EtOH (9.00 mL) was added NH4Cl (276.00 mg, 5.11 mmol) and H2O (6.00 mL) portionwise at 25 °C. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EA, to afford tert-butyl 7-{2-[(4-amino-3-methylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (600.00 mg, 93.5%) as a yellow oil.

[0187] tert-Butyl 8-methyl-7-[2-({3-methyl-4-[2-(pyrrolidin-1-yl)acetamido]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of tert-butyl 7-{2-[(4-amino-3-methylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (200.00 mg, 0.32 mmol) and DMF (8.00 mL) were added HATU (388.16 mg, 0.97 mmol) and DIEA (87.93 mg, 0.65 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with ice / water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to afford tert-butyl 8-methyl 7-[2-({3-methyl-4-[2-(pyrrolidin-1-yl)acetamido]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (100.00 mg, 43.1%) as a yellow oil.

[0188] N-{2-Methyl-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}-2-(pyrrolidin-1-yl)acetamide: To a stirred mixture of tert-butyl 8-methyl-7-[2-({3-methyl-4-[2-(pyrrolidin-1-yl)acetamido]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (80.00 mg, 0.11 mmol) in DCM (4.00 mL) was added BBr3 in DCM (0.10 mL, 0.10 mmol) dropwise at -78 °C. The mixture was stirred at -78 °C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xselect CSH C18 OBD column 30×150 mm 5 μm, n, mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 5% B - 27% B in 8 minutes, 27% B, wavelength: 254 / 220 nm; RT1 (min): 6.7) to give N-{2-methyl-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}-2-(pyrrolidin-1-yl)acetamide (12.20 mg, 19.7%) as a yellow solid.

[0189] HPLC: Purity 95.2%, RT = 2.39 min. MS: m / z = 515.25 [M+H] + . 11H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.21 (s, 1H), 8.32 (s, 1H), 7.59 (d, J = 2.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 5.53 (s, 1H), 4.19 (t, J = 4.2 Hz, 2H), 3.95 (s, 2H), 3.28 (d, J = 17.6 Hz, 4H), 3.12 (t, J = 5.6 Hz, 2H), 2.79 (d, J = 5.7 Hz, 2H), 2.65 (p, J = 3.6 Hz, 4H), 2.15 (s, 3H), 2.04 (s, 3H), 1.77 (p, J = 3.1 Hz, 4H). Example 11: Synthesis of Compound 11 N-{4-[(3R)-3-(Dimethylamino)pyrrolidine-1-carbonyl]phenyl}-6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine

Chemical formula

[0190] tert-Butyl 7-{[4-(methoxycarbonyl)phenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate: To a stirred mixture of methyl 4-aminobenzoate (235.00 mg, 1.55 mmol) and tert-butyl 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (400.00 mg, 1.41 mmol) in 1,4-dioxane (5.00 mL), Cs2CO3 (970.00 mg, 2.83 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (125.00 mg, 0.14 mmol) were added portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 90 °C for 1 h under a N2 atmosphere. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 90% EtOAc in PE, to give tert-butyl 7-{[4-(methoxycarbonyl)phenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (300.00 mg, 53.23%) as a yellow solid.

[0191] Methyl 4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]benzoate: To a stirred solution of tert-butyl 7-{[4-(methoxycarbonyl)phenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (290.00 mg, 0.73 mmol) in DCM (5.00 mL), TFA (1.00 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was basified with saturated NaHCO3 (aqueous solution) and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA, to give methyl 4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]benzoate (90.00 mg, 96.68%) as a yellow oil.

[0192] tert-Butyl 7-(7-{[4-(methoxycarbonyl)phenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a solution of methyl 4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]benzoate (60.00 mg, 0.21 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (82.00 mg, 0.23 mmol) in 1,4-dioxane (15.00 mL) were added Cs2CO3 (145.00 mg, 0.42 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (9.00 mg, 0.01 mmol). The resulting mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (10:1) to give tert-butyl 7-(7-{[4-(methoxycarbonyl)phenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (40.00 mg, 25.08%) as a yellow solid.

[0193] 4-[(6-{1-[(tert-Butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]benzoic acid: To a solution of tert-butyl 7-(7-{[4-(methoxycarbonyl)phenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (110.00 mg, 0.20 mmol) in MeOH (2.00 mL) and water (1.00 mL) was added sodium hydroxide (26.00 mg, 0.62 mmol). The resulting mixture was stirred at 25 °C for 2 h. The mixture was basified to pH [7] with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaCl (aqueous solution) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 4-[(6-{1-[(tert-Butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]benzoic acid (85.00 mg, 73.22%) as a yellow solid.

[0194] tert-Butyl 7-[7-({4-[(3R)-3-(dimethylamino)pyrrolidine-1-carbonyl]phenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of 4-[(6-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]benzoic acid (80.00 mg, 0.14 mmol) and (3R)-N,N-dimethylpyrrolidine-3-amine dihydrochloride (43.00 mg, 0.22 mmol) in DMF (10.00 mL) were added HATU (112.00 mg, 0.28 mmol) and DIEA (0.08 mL, 0.42 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The mixture was extracted with EtOAc. The combined organic layers were washed with NaCl (aqueous solution) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with C18, to give tert-butyl 7-[7-({4-[(3R)-3-(dimethylamino)pyrrolidine-1-carbonyl]phenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (60.00 mg, 59.01%) as a yellow solid.

[0195] N-{4-[(3R)-3-(Dimethylamino)pyrrolidine-1-carbonyl]phenyl}-6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine: To a stirred solution of tert-butyl 7-[7-({4-[(3R)-3-(dimethylamino)pyrrolidine-1-carbonyl]phenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (60.00 mg, 0.08 mmol) and DCM (5.00 mL) at room temperature, TFA (1.00 mL) was added dropwise. The resulting mixture was stirred at room temperature for 1 hour. The mixture was adjusted to pH 7 with saturated aqueous NaHCO3 and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm, Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), Mobile phase B: ACN, Flow rate: 60 mL / min; Gradient: 25% B to 55% B in 8 minutes, 55% B; Wavelength: 254 nm; RT1 (min): 7), N-{4-[(3R)-3-(dimethylamino)pyrrolidine-1-carbonyl]phenyl}-6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine (13.10 mg, 30.71%) was obtained as a yellow solid.

[0196] HPLC: Purity 99.7%, RT = 4.54 min. MS: m / z = 514.4 [M+H] + 。 11H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.05 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.28 (s, 1H), 6.65 (s, 1H), 5.52 (s, 1H), 4.19 (s, 2H), 4.01 (s, 2H), 3.57 (m, 6H), 3.10 (s, 2H), 2.85 (s, 2H), 2.66 (s, 1H), 2.16 (d, J = 18.4 Hz, 7H), 2.04 (s, 3H), 1.71 (s, 1H). Example 12: Synthesis of Compound 12 N-{4-[(7-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}-2-(morpholin-4-yl)acetamide

Chemical Structure

[0197] tert-Butyl 2-[(4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a solution of tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (600.00 mg, 2.22 mmol) and 4-nitroaniline (383.00 mg, 2.67 mmol) in 1,4-dioxane (15.00 mL) were added Cs2CO3 (1526.00 mg, 4.45 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (98.00 mg, 0.11 mmol). The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (6:1) to give tert-butyl 2-[(4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (650.00 mg, 77.57%) as a yellow solid.

[0198] N-(4-Nitrophenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine: To a stirred solution of tert-butyl 2-[(4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (650.00 mg, 1.73 mmol) and DCM (5.00 mL) was added dropwise TFA (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was basified to pH = 7 with saturated NaHCO3 (aqueous solution) and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA, to give N-(4-nitrophenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (470.00 mg, 91.85%) as a yellow solid.

[0199] tert-Butyl 8-methyl-7-{2-[(4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a solution of N-(4-nitrophenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (470.00 mg, 1.69 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (596.00 mg, 1.69 mmol) in 1,4-dioxane (15.00 mL) were added Cs2CO3 (1162.00 mg, 3.39 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (75.00 mg, 0.08 mmol). The resulting mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (10:1), to give tert-butyl 8-methyl-7-{2-[(4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (140.00 mg, 12.71%) as a yellow oil.

[0200] tert-Butyl 7-{2-[(4-aminophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: Palladium on activated carbon (17.00 mg, 0.02 mmol) was added to a solution of tert-butyl 8-methyl-7-{2-[(4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (130.00 mg, 0.20 mmol) in MeOH (5.00 mL) in a pressure tank. The mixture was hydrogenated at room temperature for 2 hours under a hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered and the filter cake was washed with 30 mL of EA. The filtrate was concentrated under reduced pressure and purified by C18 to obtain tert-butyl 7-{2-[(4-aminophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (60.00 mg, 53.63%) as a yellow oil.

[0201] tert-Butyl 8-methyl-7-[2-({4-[2-(morpholin-4-yl)acetamido]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of tert-butyl 7-{2-[(4-aminophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (80.00 mg, 0.16 mmol) and 2-(morpholin-4-yl)acetic acid (49.00 mg, 0.32 mmol) in DMF (10.00 mL) were added HATU (126.44 mg, 0.32 mmol) and DIEA (0.09 mL, 0.47 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The mixture was extracted with EtOAc. The combined organic layers were washed with aqueous NaCl and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with C18 to give tert-butyl 8-methyl-7-[2-({4-[2-(morpholin-4-yl)acetamido]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (80.00 mg, 78.03%) as a yellow oil.

[0202] N-{4-[(7-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}-2-(morpholin-4-yl)acetamide: To a stirred solution of tert-butyl 8-methyl-7-[2-({4-[2-(morpholin-4-yl)acetamido]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (75.00 mg, 0.12 mmol) and DCM (5.00 mL) at room temperature was added dropwise TFA (1.00 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was basified to pH = 7 with saturated NaHCO3 (aqueous solution) and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X Bridge Prep OBD C18 column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 25% B to 55% B in 8 minutes, 55% B; wavelength: 254 nm; RT1 (min): 7, number of runs: 2) to give N-{4-[(7-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}-2-(morpholin-4-yl)acetamide (9.40 mg, 15.12%) as a yellow solid.

[0203] HPLC: Purity 96.0%, RT = 1.97 min. MS: m / z = 517.15 [M+H] + 。 11H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.45 (s, 1H), 8.31 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.28 (s, 1H), 5.53 (s, 1H), 4.19 (s, 2H), 3.95 (s, 2H), 3.61 (d, J = 19.3 Hz, 8H), 3.12 (d, J = 9.7 Hz, 4H), 2.79 (s, 2H), 2.04 (s, 3H). Example 13: Synthesis of Compound 14 1,1-Dimethyl-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-2,3-dihydro-1H-isoindol-5-amine [Chemical formula]

[0204] 3,3-Dimethyl-2,3-dihydro-1H-isoindol-1-one: To a stirred solution of 2-cyanobenzoic acid (6.00 g, 38.74 mmol) in THF (200.00 mL), CH3Li (250.00 mL, 400.00 mmol) was added portionwise at -78 °C under a N2 atmosphere. The resulting mixture was stirred at room temperature overnight under a N2 atmosphere. The reaction was quenched with brine and then extracted twice with ethyl acetate. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate, and water, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography to afford the desired product 3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (2.80 g, 44.8%) as a yellow solid.

[0205] 3,3-Dimethyl-6-nitro-2,3-dihydro-1H-isoindol-1-one: To a stirred solution of sulfuric acid (42.00 mL) of 3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (2.80 g, 17.37 mmol), KNO3 (2.80 mL) was added portionwise at 0 °C. The mixture was stirred overnight while gradually warming to room temperature. The reaction solution was poured into ice water and then extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate and brine. The organic layer was dried and evaporated to give 3,3-dimethyl-6-nitro-2,3-dihydro-1H-isoindol-1-one (3.30 g, 92.1%) as a yellow oil.

[0206] 1,1-Dimethyl-5-nitro-2,3-dihydro-1H-isoindole: A solution of BH3 in THF (20.00 mL, 20.00 mmol) of 3,3-dimethyl-6-nitro-2,3-dihydro-1H-isoindol-1-one (3.15 g, 15.28 mL) was stirred at 60 °C overnight under a nitrogen atmosphere. NaOH (aqueous solution) and MeOH were added to the mixture and refluxed for 2 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 7:3) to give 1,1-dimethyl-5-nitro-2,3-dihydro-1H-isoindole (2.60 g, 83.1%) as a yellow solid.

[0207] tert-Butyl 1,1-dimethyl-5-nitro-2,3-dihydro-1H-isoindole-2-carboxylate: To a solution of 1,1-dimethyl-5-nitro-2,3-dihydro-1H-isoindole (1.30 g, 6.76 mmol) in THF (40.00 mL) was added NaH (1.30 g, 32.50 mmol) at 0 °C. The mixture was stirred for 1 hour. (Boc)2O (4.41 mL, 19.59 mmol) was added and the mixture was warmed to room temperature and stirred for 1 hour. The reaction was then quenched by adding 20 mL of water and extracted with ethyl acetate. The organic phase was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 / 1) to give tert-butyl 1,1-dimethyl-5-nitro-2,3-dihydro-1H-isoindole-2-carboxylate (1.80 g, 91.0%) as a yellow solid.

[0208] tert-Butyl 5-amino-1,1-dimethyl-2,3-dihydro-1H-isoindole-2-carboxylate: A solution of tert-butyl 1,1-dimethyl-5-nitro-2,3-dihydro-1H-isoindole-2-carboxylate (2.00 g, 6.84 mmol), NH4Cl (2.40 g, 43.97 mmol) and Fe (2.40 g, 42.11 mmol) in EtOH (12.00 mL) and water (8.00 mL) was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with (PE:EtOAc = 7:3) to give tert-butyl 5-amino-1,1-dimethyl-2,3-dihydro-1H-isoindole-2-carboxylate (1.00 g, 55.7%) as a dark brown oil.

[0209] tert-Butyl 1,1-dimethyl-5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)-2,3-dihydro-1H-isoindole-2-carboxylate: A solution of tert-butyl 5-amino-1,1-dimethyl-2,3-dihydro-1H-isoindole-2-carboxylate (500.00 mg, 1.91 mmol), 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine hydrochloride (511.00 mg, 2.41 mmol), Cs2CO3 (1.85 g, 5.39 mmol), Ephos (200.00 mg, 0.36 mmol), and EPhos Pd G4 (200.00 mg, 0.21 mmol) in 1,4-dioxane (10.00 mL) was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 7:3) to give tert-butyl 1,1-dimethyl-5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)-2,3-dihydro-1H-isoindole-2-carboxylate (380.00 mg, 50.4%) as a yellow solid.

[0210] tert-Butyl 5-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-1,1-dimethyl-2,3-dihydro-1H-isoindole-2-carboxylate: A solution of tert-butyl 1,1-dimethyl-5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)-2,3-dihydro-1H-isoindole-2-carboxylate (340.00 mg, 0.86 mmol), tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (560.00 mg, 1.58 mmol), Pd-PEPPSI-IPentCl, 2-methylpyridine (o-picoline) (75.00 mg, 0.08 mmol), and Cs2CO3 (837.00 mg, 2.44 mmol) in 1,4-dioxane (5.00 mL) was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 7:3), to give tert-butyl 5-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-1,1-dimethyl-2,3-dihydro-1H-isoindole-2-carboxylate (300.00 mg, 54.2%) as a yellow solid.

[0211] 1,1-Dimethyl-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-2,3-dihydro-1H-isoindol-5-amine: To a stirred solution of tert-butyl 5-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-1,1-dimethyl-2,3-dihydro-1H-isoindole-2-carboxylate (270.00 mg, 0.42 mmol) in DCM (6.00 mL) was added BBr3 in DCM (2.00 mL, 2.00 mmol) dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 2 hours under a nitrogen atmosphere. The reaction was quenched with ice water at -20 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC column under the following conditions: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 20% B - 50% B in 8 minutes, 50% B, wavelength: 254 nm; RT1 (min): 7, thereby obtaining 1,1-dimethyl-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-2,3-dihydro-1H-isoindol-5-amine (37.30 mg, 19.4%) as a yellow solid.

[0212] HPLC: Purity 97.0%, RT = 2.44 min. MS: m / z = 444.25 [M + H] + 。 11H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.31 (s, 1H), 7.60 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 7.05 (d, J = 8.2 Hz, 1H), 5.53 (s, 1H), 4.19 (t, J = 4.4 Hz, 2H), 3.99 (s, 2H), 3.93 (s, 2H), 3.12 (s, 3H), 2.78 (s, 2H), 2.03 (s, 3H), 1.28 (s, 6H). Example 14: Synthesis of Compound 15 N1-[2-(Dimethylamino)ethyl]-2-methyl-N4-(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)benzene-1,4-diamine [Chemical formula]

[0213] N-[2-(Dimethylamino)ethyl]-2-methyl-4-nitroaniline: To a stirred mixture of 1-fluoro-2-methyl-4-nitrobenzene (1.00 g, 6.12 mmol) and (2-aminoethyl)dimethylamine (1.14 g, 12.25 mmol) in DMF (10.00 mL) was added K2CO3 (2.67 g, 18.37 mmol) portionwise at room temperature. The resulting mixture was stirred at 80 °C for 5 h under a N2 atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give N-[2-(dimethylamino)ethyl]-2-methyl-4-nitroaniline (1.30 g, crude product) as a yellow solid.

[0214] tert-Butyl N-[2-(dimethylamino)ethyl]-N-(2-methyl-4-nitrophenyl)carbamate: To a stirred solution of N-[2-(dimethylamino)ethyl]-2-methyl-4-nitroaniline (1.26 g, 5.57 mmol) in DCM (13.00 mL) were added 4-dimethylaminopyridine (DMAP) (0.13 g, 1.11 mmol), TEA (1.78 g, 16.71 mmol), and Boc2O (3.68 g, 16.71 mmol) at 0 °C. The resulting mixture was stirred at 30 °C for 2 days under a N2 atmosphere. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (10:1) to afford tert-butyl N-[2-(dimethylamino)ethyl]-N-(2-methyl-4-nitrophenyl)carbamate (1.10 g, 48.2%) as a yellow solid.

[0215] tert-Butyl N-(4-amino-2-methylphenyl)-N-[2-(dimethylamino)ethyl]carbamate: To a stirred solution of tert-butyl N-[2-(dimethylamino)ethyl]-N-(2-methyl-4-nitrophenyl)carbamate (1.00 g, 2.44 mmol) in EtOH (10.00 mL) and water (3.00 mL) were added Fe (0.72 g, 12.21 mmol) and NH4Cl (0.82 g, 14.65 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (10:1) to afford tert-butyl N-(4-amino-2-methylphenyl)-N-[2-(dimethylamino)ethyl]carbamate (900.00 mg, 119.7%) as a dark brown solid.

[0216] tert-Butyl N-[2-(dimethylamino)ethyl]-N-{2-methyl-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}carbamate: To a stirred mixture of tert-butyl N-(4-amino-2-methylphenyl)-N-[2-(dimethylamino)ethyl]carbamate (200.00 mg, 0.65 mmol) and 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine (135.00 mg, 0.78 mmol) in 1,4-dioxane (2.00 mL) were added Ephos (37.00 mg, 0.07 mmol), EPhos Pd G4 (63.00 mg, 0.07 mmol) and Cs2CO3 (668.00 mg, 1.95 mmol) portionwise at room temperature. The resulting mixture was stirred at 120 °C for 1 hour using a microwave reaction tube under a N2 atmosphere. The resulting mixture was extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (10:1) to give tert-butyl N-[2-(dimethylamino)ethyl]-N-{2-methyl-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}carbamate (260.00 mg, 91.3%) as a yellow solid.

[0217] tert-Butyl 7-{7-[(4-{[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino}-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of tert-butyl N-[2-(dimethylamino)ethyl]-N-{2-methyl-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}carbamate (240.00 mg, 0.55 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (219.00 mg, 0.66 mmol) in 1,4-dioxane (3.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (48.00 mg, 0.05 mmol) and Cs2CO3 (563.00 mg, 1.64 mmol) portionwise at room temperature. The resulting mixture was stirred at 100 °C overnight under a N2 atmosphere. The resulting mixture was extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The residue was purified by preparative TLC (DCM:tMeOH (30:1)) to give tert-butyl 7-{7-[(4-{[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino}-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (200.00 mg, 51.8%) as a yellow solid.

[0218] N1-[2-(Dimethylamino)ethyl]-2-methyl-N4-(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)benzene-1,4-diamine: To a stirred mixture of tert-butyl 7-{7-[(4-{[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino}-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (180.00 mg, 0.26 mmol) in DCM (3.00 mL) was added dropwise TFA (1.00 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 hour under a N2 atmosphere. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC (column: Atlantis Prep T3 OBD column, 19×250 mm, 10 um, mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 20 mL / min, gradient: 20% - 50% over 8 minutes, wavelength: 254 nm; RT1 (min): 7.53, number of runs: 4) to give N1-[2-(dimethylamino)ethyl]-2-methyl-N4-(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)benzene-1,4-diamine (28.60 mg, 23.6%) as a yellow solid.

[0219] HPLC: Purity 99.8%, RT = 2.13 min. MS: m / z = 474.3 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 6.9 Hz, 2H), 7.88 (s, 1H), 7.26 - 7.16 (m, 2H), 7.08 (d, J = 2.5 Hz, 1H), 6.50 (d, J = 8.6 Hz, 1H), 6.40 (s, 1H), 5.49 (d, J = 3.5 Hz, 1H), 4.21 - 4.14 (m, 2H), 3.92 (s, 2H), 3.30 (d, J = 4.7 Hz, 2H), 3.15 (t, J = 6.5 Hz, 2H), 3.06 (t, J = 5.7 Hz, 2H), 2.77 (t, J = 5.7 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 2.30 (s, 6H), 2.04 (d, J = 15.2 Hz, 6H). Example 15: Synthesis of Compound 16 2-Methyl-N4-(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine

Chemical Structure

[0220] 2-Methyl-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline: To a stirred mixture of 2-(morpholin-4-yl)ethan-1-amine (1.86 g, 13.61 mmol) and 1-bromo-2-methyl-4-nitrobenzene (2.00 g, 9.07 mmol) in 1,4-dioxane (30.00 mL), Pd2(dba)3 (0.87 g, 0.91 mmol), BINAP (1.19 g, 1.81 mmol) and Cs2CO3 (6.22 g, 18.15 mmol) were added portionwise at 25 °C. The resulting mixture was stirred at 100 °C for 3 h under an argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give 2-methyl-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline (1.90 g, 75.46%) as a yellow solid.

[0221] tert-Butyl N-(2-methyl-4-nitrophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate: To a stirred solution of 2-methyl-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline (1.30 g, 4.68 mmol) and di-tert-butyl dicarbonate (3.23 g, 14.05 mmol) in DMF (20.00 mL) were added N,N-dimethylpyridin-4-amine (0.12 g, 0.94 mmol) and TEA (2.06 mL, 14.05 mmol) portionwise at room temperature under an argon atmosphere. The resulting mixture was stirred at 50 °C for 1 day under an argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with 15% EtOAc in PE to give tert-butyl N-(2-methyl-4-nitrophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (0.30 g, 15.80%) as a yellow solid.

[0222] tert-Butyl N-(4-amino-2-methylphenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate: To a solution of tert-butyl N-(2-methyl-4-nitrophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (300.00 mg, 0.74 mmol) in MeOH (10.00 mL) was added Raney Ni (190.30 mg, 0.22 mmol) at room temperature. The mixture was stirred at room temperature for 2 h under a H2 atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (50 mL), and the filtrate was concentrated under reduced pressure to give tert-butyl N-(4-amino-2-methylphenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (240.00 mg, crude product) as a yellow oil.

[0223] tert-Butyl N-{2-methyl-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}-N-[2-(morpholin-4-yl)ethyl]carbamate: To a solution of tert-butyl N-(4-amino-2-methylphenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (230.00 mg, 0.50 mmol) and 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine hydrochloride (157.61 mg, 0.75 mmol) in 1,4-dioxane (15.00 mL) were added Cs2CO3 (512.60 mg, 1.49 mmol), Ephos (56.09 mg, 0.10 mmol) and EPhos Pd G4 (48.17 mg, 0.05 mmol). The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (11:1), to give tert-butyl N-{2-methyl-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}-N-[2-(morpholin-4-yl)ethyl]carbamate (180.00 mg, 76.01%) as a yellow solid.

[0224] tert-Butyl 7-{7-[(4-{[(tert-butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a solution of tert-butyl N-{2-methyl-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}-N-[2-(morpholin-4-yl)ethyl]carbamate (170.00 mg, 0.36 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (178.63 mg, 0.54 mmol) in 1,4-dioxane (15.00 mL) were added Cs2CO3 (368.00 mg, 1.07 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (31.63 mg, 0.04 mmol). The resulting mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (12:1), to give tert-butyl 7-{7-[(4-{[(tert-butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (160.00 mg, 56.46%) as a yellow oil.

[0225] 2-Methyl-N4-(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine: To a stirred mixture of tert-butyl 7-{7-[(4-{[(tert-butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (150.00 mg, 0.19 mmol) in DCM (5.00 mL) was added TFA (1.00 mL) at room temperature. After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30×150 mm 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: from 25% B to 55% B in 8 minutes, 55% B; wavelength: 254 nm; RT1 (min): 7) to give 2-methyl-N4-(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine (34.20 mg, 34.67%) as a yellow solid.

[0226] HPLC: Purity 98.9%, RT = 3.58 min. MS: m / z = 516.35 [M+H] + 。 11H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.88 (s, 1H), 7.24 (s, 1H), 7.18 (dd, J = 8.5, 2.6 Hz, 1H), 7.08 (d, J = 2.5 Hz, 1H), 6.50 (d, J = 8.6 Hz, 1H), 6.40 (s, 1H), 5.50 (t, J = 2.7 Hz, 1H), 4.43 (s, 1H), 4.18 (dd, J = 5.1, 3.5 Hz, 2H), 3.92 (s, 2H), 3.59 (q, J = 4.8 Hz, 4H), 3.29 (dt, J = 6.8, 3.3 Hz, 2H), 3.13 (s, 2H), 3.05 (t, J = 5.4 Hz, 2H), 2.77 (t, J = 5.6 Hz, 2H), 2.56 (t, J = 6.5 Hz, 2H), 2.41 (s, 4H), 2.10 - 1.99 (m, 6H). Example 16: Synthesis of Compound 13 2-(Dimethylamino)-N-{4-[(7-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}acetamide [Chemical Structure]

[0227] tert-Butyl 7-[2-({4-[2-(dimethylamino)acetamido]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of tert-butyl 7-{2-[(4-aminophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (60.00 mg, 0.11 mmol) and 2-(dimethylamino)acetic acid (23.00 mg, 0.21 mmol) in DMF (10.00 mL) were added HATU (85.84 mg, 0.21 mmol) and DIEA (0.06 mL, 0.32 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaCl (aqueous solution) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (6:1) to give tert-butyl 7-[2-({4-[2-(dimethylamino)acetamido]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (70.00 mg, 98.04%) as a yellow solid.

[0228] 2-(Dimethylamino)-N-{4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}acetamide: To a stirred solution of tert-butyl 7-[2-({4-[2-(dimethylamino)acetamido]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (80.00 mg, 0.12 mmol) and DCM (5.00 mL) at room temperature, TFA (1.00 mL) was added dropwise. The resulting mixture was stirred at room temperature for 1 hour. The mixture was basified to pH = 7 with saturated NaHCO3 (aqueous solution) and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure (column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: from 25% B to 55% B in 8 minutes, 55% B; wavelength: 254 nm; RT1 (min): 7), and 2-(dimethylamino)-N-{4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}acetamide (7.80 mg, 13.14%) was obtained as a yellow solid.

[0229] HPLC: Purity 96.0%, RT = 2.23 min. MS: m / z = 475.15 [M + H] + . 11H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.44 (s, 1H), 8.23 (d, J = 49.4 Hz, 1H), 7.66 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H), 7.29 (s, 1H), 5.52 (d, J = 3.3 Hz, 1H), 4.34 - 4.11 (m, 2H), 3.95 (s, 2H), 3.11 (d, J = 6.9 Hz, 6H), 2.79 (t, J = 5.5 Hz, 2H), 2.31 (s, 6H), 2.04 (s, 3H). Example 17: Synthesis of Compound 17 N1,2-Dimethyl-N4-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine, formic acid [Chemical formula]

[0230] N,2-Dimethyl-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline: To a stirred mixture of 1-fluoro-2-methyl-4-nitrobenzene (384.00 mg, 2.01 mmol) and methyl[2-(morpholin-4-yl)ethyl]amine (319.65 mg, 2.22 mmol) in ACN (15.00 mL) was added K2CO3 (586.28 mg, 4.03 mmol) at room temperature. The mixture was stirred at 80 °C for 16 h. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give N,2-dimethyl-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline (240.00 mg, 41.2%) as a yellow oil.

[0231] N1,2-Dimethyl-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine: Raney Ni (40.00 mg, 0.44 mmol) was added to a solution of N,2-dimethyl-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline (230.00 mg, 0.81 mmol) in MeOH (4.00 mL) at room temperature. After stirring for 2 hours at room temperature under a hydrogen atmosphere, the resulting mixture was filtered. The filter cake was washed with MeOH. The crude product was used directly in the next step without further purification. Thereby, N1,2-dimethyl-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine (190.00 mg, 69.8%) was obtained as a brown oil.

[0232] tert-Butyl 2-[(3-methyl-4-{methyl[2-(morpholin-4-yl)ethyl]amino}phenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (103.56 mg, 0.12 mmol) and Cs2CO3 (803.26 mg, 2.34 mmol) were added to a stirred mixture of tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (582.05 mg, 1.76 mmol) and N1,2-dimethyl-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine (292.00 mg, 1.17 mmol, 1.00 equivalent) in 1,4-dioxane (13.00 mL) at room temperature. The mixture was stirred at 100 °C for 2 hours. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE / EtOAc (1:1), to give tert-butyl 2-[(3-methyl-4-{methyl[2-(morpholin-4-yl)ethyl]amino}phenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (320.00 mg, 50.5%) as a yellow oil.

[0233] N1,2-Dimethyl-N1-[2-(morpholin-4-yl)ethyl]-N4-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}benzene-1,4-diamine: To a stirred mixture of tert-butyl 2-[(3-methyl-4-{methyl[2-(morpholin-4-yl)ethyl]amino}phenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (530.00 mg, 0.97 mmol) and TFA (3.00 mL) in DCM (15.00 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was basified to pH = 9 with saturated NaHCO3 (aqueous solution) and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave N1,2-dimethyl-N1-[2-(morpholin-4-yl)ethyl]-N4-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}benzene-1,4-diamine (230.00 mg, 59.7%) as a yellow oil.

[0234] tert-Butyl 8-methyl-7-{2-[(3-methyl-4-{methyl[2-(morpholin-4-yl)ethyl]amino}phenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of N1,2-dimethyl-N1-[2-(morpholin-4-yl)ethyl]-N4-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}benzene-1,4-diamine (410.00 mg, 0.87 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (574.45 mg, 1.75 mmol) in 1,4-dioxane (10.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (77.16 mg, 0.09 mmol) and Cs2CO3 (598.49 mg, 1.75 mmol) at room temperature. The mixture was stirred at 100 °C for 2 hours. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to afford tert-butyl 8-methyl-7-{2-[(3-methyl-4-{methyl[2-(morpholin-4-yl)ethyl]amino}phenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (160.00 mg, 23.8%) as a yellow oil.

[0235] N1,2-Dimethyl-N4-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine, formic acid: tert-butyl 8-methyl-7-{2-[(3-methyl-4-{methyl[2-(morpholin-4-yl)ethyl]amino}phenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (150.00 mg) and TFA (1.00 mL, 12.79 mmol) in DCM (5.00 mL) were stirred at room temperature. The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X select CSH C18 OBD column 30×150 mm, 5 μm, n, mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 5% B to 27% B in 8 minutes, 27% B, wavelength: 254 / 220 nm, RT1 (min): 6.7, number of runs: 3) to give N1,2-dimethyl-N4-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine, formic acid (47.20 mg, 52.1%) as a yellow solid.

[0236] HPLC: 97.9% purity, RT = 2.83 min. MS: m / z = 531.6 [M+H] + . 11H NMR (300 MHz, DMSO-d6): δ 9.46 (s, 1H), 9.35 (s, 1H), 8.29 (s, 1H), 7.62 - 7.53 (m, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.27 (s, 1H), 7.05 (d, J = 8.7 Hz, 1H), 4.19 (d, J = 1.3 Hz, 2H), 3.93 (s, 2H), 3.26 (s, 4H), 3.30 (s, 10H), 3.10 (s, 2H), 2.77 (s, 2H), 2.54 (d, J = 9.9 Hz, 3H), 2.22 (s, 3H), 2.03 (s, 3H). Example 18: Synthesis of Compound 18 6-(1-Methanesulfonylcyclopropyl)-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine

Chemical formula

[0237] 2-(Bromomethyl)-5-nitropyridine: To a stirred solution of 2-methyl-5-nitropyridine (10.00 g, 70.95 mmol) in CCl4 (10.00 mL), NBS (38.66 g, 212.85 mmol) and AIBN (4.76 g, 28.38 mmol) were added portionwise at room temperature. After stirring at 80 °C for 16 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (6:1) to give 2-(bromomethyl)-5-nitropyridine (6.20 g, 38.58%) as a yellow solid.

[0238] 2-(Methanesulfonylmethyl)-5-nitropyridine: Sodium methanesulfinate (2.73 g, 26.49 mmol) was added to a stirred solution of 2-(bromomethyl)-5-nitropyridine (3.00 g, 13.24 mmol) in DMF (7.00 mL) at room temperature. The resulting mixture was stirred at 65 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1), to give 2-(methanesulfonylmethyl)-5-nitropyridine (1.20 g, 41.13%) as a yellow solid.

[0239] 2-(1-Methanesulfonylcyclopropyl)-5-nitropyridine: To a solution of 2-(methanesulfonylmethyl)-5-nitropyridine (696.00 mg, 3.16 mmol) in DMF (10.00 mL) were added NaH (400 mg, 15.80 mmol, 60% purity) and 1,2-dibromoethane (2499.11 mg, 12.64 mmol) at 0 °C. After stirring at 30 °C for 4 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1), to give 2-(1-methanesulfonylcyclopropyl)-5-nitropyridine (155.00 mg, 19.77%) as a yellow oil.

[0240] 6-(1-Methanesulfonylcyclopropyl)pyridin-3-amine: Raney Ni (134.99 mg, 1.50 mmol) was added to a solution of 2-(1-methanesulfonylcyclopropyl)-5-nitropyridine (323.00 mg, 1.30 mmol) in MeOH (20.00 mL) at room temperature. After stirring at room temperature for 1 h under a hydrogen atmosphere, the resulting mixture was filtered. The filter cake was washed with MeOH and then the filtrate was concentrated under reduced pressure to give 6-(1-methanesulfonylcyclopropyl)pyridin-3-amine (273.00 mg, 97.10%) as a brown oil.

[0241] tert-Butyl 2-{[6-(1-methanesulfonylcyclopropyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a stirred solution of 6-(1-methanesulfonylcyclopropyl)pyridin-3-amine (263.00 mg, 1.22 mmol) and tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (332.13 mg, 1.22 mmol) in 1,4-dioxane (10.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (107.67 mg, 0.12 mmol) and Cs2CO3 (835.08 mg, 2.43 mmol). The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:100) to give tert-butyl 2-{[6-(1-methanesulfonylcyclopropyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (263.00 mg, 47.62%) as a yellow oil.

[0242] 6-(1-Methanesulfonylcyclopropyl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine: To a stirred solution of tert-butyl 2-{[6-(1-methanesulfonylcyclopropyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (253.00 mg, 0.56 mmol) in DCM (10.00 mL) was added TFA (2.00 mL) portionwise at room temperature. After stirring at room temperature for 1 h, the resulting mixture was concentrated under reduced pressure to give 6-(1-methanesulfonylcyclopropyl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine (130.00 mg, 66.16%) as a brown oil.

[0243] tert-Butyl 7-(2-{[6-(1-methanesulfonylcyclopropyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of 6-(1-methanesulfonylcyclopropyl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine (130.00 mg, 0.37 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (127.72 mg, 0.37 mmol) in 1,4-dioxane (10.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (32.63 mg, 0.04 mmol) and Cs2CO3 (253.07 mg, 0.74 mmol). The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to afford tert-butyl 7-(2-{[6-(1-methanesulfonylcyclopropyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (196.00 mg, 75.05%) as a yellow oil.

[0244] 6-(1-Methanesulfonylcyclopropyl)-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine: To a stirred solution of tert-butyl 7-(2-{[6-(1-methanesulfonylcyclopropyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (196.00 mg, 0.28 mmol) in DCM (10.00 mL) was added TFA (2.00 mL) portionwise at room temperature. After stirring at room temperature for 1 hour, the resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 18% B - 48% B in 9 minutes, 48% B, wavelength: 254 nm; RT1 (min): 7; number of runs: 2 times to give 6-(1-methanesulfonylcyclopropyl)-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine (32.90 mg, 23.90%) as a yellow solid.

[0245] HPLC: 99.2% purity, RT = 2.79 min. MS: m / z = 494.2.6[M+H] + 。 11H NMR (300 MHz, DMSO-d6): δ 9.90 (s, 1H), 8.91 (d, J = 2.6 Hz, 1H), 8.40 (s, 1H), 8.25 (dd, J = 8.6, 2.7 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.29 (s, 1H), 5.54 (s, 1H), 4.19 (d, J = 4.9 Hz, 2H), 4.00 (s, 2H), 3.33 (s, 2H), 3.13 (s, 2H), 3.01 (s, 3H), 2.82 (s, 2H), 2.04 (s, 3H), 1.63 (q, J = 4.8, 4.3 Hz, 2H), 1.38 (t, J = 3.7 Hz, 2H). Example 19: Synthesis of Compound 19 5-Fluoro-6-(methylsulfonylmethyl)-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine

Chemical Structure

[0246] 5-Bromo-2-(bromomethyl)-3-fluoropyridine: To a solution of (5-bromo-3-fluoropyridin-2-yl)methanol (0.99 g, 4.71 mmol) in DCM (30.00 mL) was added PBr3 (0.61 mL, 6.12 mmol) at -20 °C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NaHCO3 (aqueous solution) (20 ml) at 0 °C. The resulting mixture was extracted with DCM (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 5-bromo-2-(bromomethyl)-3-fluoropyridine (670.00 mg, 51.5%).

[0247] 5-Bromo-3-fluoro-2-(methanesulfonylmethyl)pyridine: Sodium methanesulfinate (1232.00 g, 11.95 mmol) was added to a stirred solution of 5-bromo-2-(bromomethyl)-3-fluoropyridine (660.00 mg, 2.39 mmol) in DMF (20.00 mL). The resulting mixture was stirred at 60 °C for 4 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to afford 5-bromo-3-fluoro-2-(methanesulfonylmethyl)pyridine (430.00 mg, 64.4%) as a yellow solid.

[0248] tert-Butyl N-[5-fluoro-6-(methanesulfonylmethyl)pyridin-3-yl]carbamate: Pd2(dba)3 (245.00 mg, 0.25 mmol), Xantphos (297.00 mg, 0.51 mmol) and Cs2CO3 (1738.00 mg, 5.07 mmol) were added to a stirred mixture of 5-bromo-3-fluoro-2-(methanesulfonylmethyl)pyridine (775.00 mg, 2.53 mmol) and tert-butyl carbamate (469.00 mg, 3.80 mmol) in 1,4-dioxane (20.00 mL) at room temperature. The mixture was stirred at 90 °C for 16 h under a nitrogen atmosphere, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (19:1) to afford tert-butyl N-[5-fluoro-6-(methanesulfonylmethyl)pyridin-3-yl]carbamate (770.00 mg, 87.5%) as a yellow solid.

[0249] 5-Fluoro-6-(methanesulfonylmethyl)pyridin-3-amine tert-Butyl N-[5-fluoro-6-(methanesulfonylmethyl)pyridin-3-yl]carbamate: To a stirred solution of (770.00 mg, 2.22 mmol) in MeOH (10.00 mL), HCl(g) in MeOH was added portionwise at room temperature. The resulting mixture was stirred at 40 °C overnight under a nitrogen atmosphere. The filtrate was concentrated under reduced pressure. The mixture was basified to pH

[14] with saturated NaOH (aqueous solution). The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (6:1) to give 5-fluoro-6-(methanesulfonylmethyl)pyridin-3-amine (310.00 mg, 67.8%) as a yellow solid.

[0250] tert-Butyl 2-{[5-fluoro-6-(methanesulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a solution of 5-fluoro-6-(methanesulfonylmethyl)pyridin-3-amine (300.00 mg, 1.46 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (513.00 mg, 1.46 mmol) in 1,4-dioxane (20.00 mL) were added Ephos (164.00 mg, 0.29 mmol), Cs2CO3 (999.00 mg, 2.91 mmol) and EPhos Pd G4 (141.00 mg, 0.15 mmol). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (24:1) to give tert-butyl 2-{[5-fluoro-6-(methanesulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (610.00 mg, 84.8%) as a yellow solid.

[0251] 5-Fluoro-6-(methanesulfonylmethyl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine: To a stirred solution of tert-butyl 2-{[5-fluoro-6-(methanesulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (400.00 mg, 0.82 mmol) in DCM (10.00 mL) was added TFA (2.00 mL) portionwise at room temperature. The resulting mixture was stirred at 25 °C for 4 h under a nitrogen atmosphere. The mixture was basified to pH

[14] , the filter cake was washed with H2O (2 × 50 mL), and dried under reduced pressure to give 5-fluoro-6-(methanesulfonylmethyl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine (240.00 mg, 84.7%) as a yellow solid.

[0252] tert-Butyl 7-(2-{[5-Fluoro-6-(methanesulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a solution of 5-fluoro-6-(methanesulfonylmethyl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine (320.00 mg, 0.93 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (328.00 mg, 0.93 mmol) in 1,4-dioxane (20.00 mL) were added Cs2CO3 (638.00 mg, 1.86 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (93.00 mg, 0.11 mmol). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give tert-butyl 7-(2-{[5-fluoro-6-(methanesulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (60.00 mg, 9.9%) as a yellow oil.

[0253] 5-Fluoro-6-(methanesulfonylmethyl)-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine: To a stirred solution of tert-butyl 7-(2-{[5-fluoro-6-(methanesulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (55.00 mg, 0.08 mmol) in DCM (5.00 mL) was added TFA (1.00 mL) dropwise at room temperature. The mixture was basified to pH 7 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: X Bridge Prep OBD C18 column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 18% B to 48% B over 9 minutes, 48% B, wavelength: 254 nm; RT1 (min): 7; number of runs: 2) to give 5-fluoro-6-(methanesulfonylmethyl)-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine (20.90 mg, 50.7%) as a yellow solid.

[0254] HPLC: Purity 99.5%, RT = 3.17 min. MS: m / z = 486.0 [M+H] + 。 11H NMR (300 MHz, DMSO-d6) δ 10.19 (d, J = 1.4 Hz, 1H), 8.68 (dd, J = 2.2, 1.2 Hz, 1H), 8.43 (s, 1H), 8.35 (dd, J = 12.6, 2.1 Hz, 1H), 7.29 (s, 1H), 5.52 (s, 1H), 4.61 - 4.52 (m, 2H), 4.18 (t, J = 4.4 Hz, 2H), 4.01 (s, 2H), 3.30 - 3.23 (m, 2H), 3.11 (d, J = 5.8 Hz, 2H), 3.02 (s, 3H), 2.82 (t, J = 5.6 Hz, 2H), 2.03 (s, 3H). Example 20: Synthesis of Compound 20 6-(2-Methanesulfonylpropan-2-yl)-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine [Chemical Structure]

[0255] 2-(Bromomethyl)-5-nitropyridine: To a stirred solution of 2-methyl-5-nitropyridine (10.00 g, 70.95 mmol) in CCl4 (100.00 mL), NBS (38.66 g, 212.85 mmol) and AIBN (4.76 g, 28.38 mmol) were added portionwise at room temperature. After stirring at 80 °C for 16 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (6:1) to give 2-(bromomethyl)-5-nitropyridine (6.20 g, 31.65%) as a yellow solid.

[0256] 2-(Methanesulfonylmethyl)-5-nitropyridine: Sodium methanesulfinate (3.73 g, 36.21 mmol) was added to a stirred solution of 2-(bromomethyl)-5-nitropyridine (5.00 g, 18.11 mmol) in DMF (10.00 mL). The resulting mixture was stirred at 65 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1), to give 2-(methanesulfonylmethyl)-5-nitropyridine (3.25 g, 81.55%) as a yellow solid.

[0257] 2-(2-Methanesulfonylpropan-2-yl)-5-nitropyridine: NaH (0.27 g, 6.81 mmol) and CH3I (2.12 g, 14.20 mmol) were added to a solution of 2-(methanesulfonylmethyl)-5-nitropyridine (1.25 g, 5.68 mmol) in DMF (12.00 mL) at 0 °C. After stirring at 40 °C for 4 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1), to give 2-(2-methanesulfonylpropan-2-yl)-5-nitropyridine (270.00 mg, 19.44%) as a yellow solid.

[0258] 6-(2-Methanesulfonylpropan-2-yl)pyridin-3-amine: Raney Ni (114.49 mg, 1.27 mmol) was added to a solution of 2-(2-methanesulfonylpropan-2-yl)-5-nitropyridine (270.00 mg, 1.10 mmol) in MeOH (15.00 mL) at room temperature. After stirring at room temperature for 1 h under a hydrogen atmosphere, the resulting mixture was filtered. The filter cake was washed with MeOH and then the filtrate was concentrated under reduced pressure to give 6-(2-methanesulfonylpropan-2-yl)pyridin-3-amine (217.00 mg, 88.26%) as a brown oil.

[0259] tert-Butyl 2-{[6-(2-methanesulfonylpropan-2-yl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a stirred solution of 6-(2-methanesulfonylpropan-2-yl)pyridin-3-amine (210.00 mg, 0.94 mmol) and tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (257.25 mg, 0.94 mmol) in 1,4-dioxane (10.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (83.39 mg, 0.09 mmol) and Cs2CO3 (646.81 mg, 1.89 mmol). The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give tert-butyl 2-{[6-(2-methanesulfonylpropan-2-yl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (120.00 mg, 27.11%) as a yellow oil.

[0260] 6-(2-Methanesulfonylpropan-2-yl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine: To a stirred solution of tert-butyl 2-{[6-(2-methanesulfonylpropan-2-yl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (120.00 mg, 0.26 mmol) in DCM (10.00 mL) was added TFA (2.00 mL) portionwise at room temperature. After stirring at room temperature for 1 h, the resulting mixture was concentrated under reduced pressure to give 6-(2-methanesulfonylpropan-2-yl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine (80.00 mg, 86.46%) as a yellow oil.

[0261] tert-Butyl 7-(2-{[6-(2-methanesulfonylpropan-2-yl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of 6-(2-methanesulfonylpropan-2-yl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine (120.00 mg, 0.33 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (114.78 mg, 0.33 mmol) in 1,4-dioxane (10.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (29.32 mg, 0.03 mmol) and Cs2CO3 (227.42 mg, 0.66 mmol). The resulting mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1), to afford tert-butyl 7-(2-{[6-(2-methanesulfonylpropan-2-yl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (47.00 mg, 21.78%) as a yellow oil.

[0262] 6-(2-Methanesulfonylpropan-2-yl)-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine: To a stirred solution of tert-butyl 7-(2-{[6-(2-methanesulfonylpropan-2-yl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (47.00 mg, 0.07 mmol) in DCM (5.00 mL) was added TFA (1.00 mL) portionwise at room temperature. After stirring at room temperature for 1 hour, the resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: column: X Bridge Prep OBD C18 column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 20% B - 50% B in 9 minutes, 50% B, wavelength: 254 nm; RT1 (min): 7; number of runs: 2 times to give 6-(2-methanesulfonylpropan-2-yl)-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine (7.10 mg, 19.51%) as a yellow solid.

[0263] HPLC: 98.3% purity, RT = 3.19 min. MS: m / z = 496.2 [M+H] + 。 1 1H NMR (300 MHz, DMSO-d6): 9.89 (s, 1H), 8.95 (d, J = 2.7 Hz, 1H), 8.40 (s, 1H), 8.25 (dd, J = 8.8, 2.7 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.29 (s, 1H), 5.54 (s, 1H), 4.20 (d, J = 4.8 Hz, 2H), 4.01 (s, 2H), 3.43 (s, 2H), 3.13 (s, 2H), 2.80 (d, J = 14.5 Hz, 5H), 2.05 (s, 3H), 1.75 (s, 6H). Example 21: Synthesis of Compound 21 6-(Methanesulfonylmethyl)-5-methyl-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine [Chemical formula]

[0264] Methyl 3-methyl-5-nitropyridine-2-carboxylate: To a stirred solution of methyl 3-methylpyridine-2-carboxylate (5.00 g, 31.42 mmol) in DCM (10.00 mL), TFAA (13.20 g, 59.71 mmol) and nitro-3-oxidanyl, tetrabutylazanium (15.10 g, 47.11 mmol) were added at 0 °C under a nitrogen atmosphere. The resulting mixture was then stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:7) to give methyl 3-methyl-5-nitropyridine-2-carboxylate (3.80 g, 55.8%) as a yellow solid.

[0265] (3-Methyl-5-nitropyridin-2-yl)methanol: To a stirred solution of methyl 3-methyl-5-nitropyridine-2-carboxylate (3.40 g, 15.70 mmol) in DCM (60.00 mL), diisobutylaluminum hydride (1.0 M in dichloromethane; 32.00 mL, 32.00 mmol) was added at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched at 0 °C by the addition of H2O (3 mL). The resulting mixture was filtered and the filter cake was washed with EA (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give (3-methyl-5-nitropyridin-2-yl)methanol (350.00 mg, 11.7%) as a yellow solid.

[0266] 2-(Bromomethyl)-3-methyl-5-nitropyridine: To a solution of (3-methyl-5-nitropyridin-2-yl)methanol (320.00 mg, 1.67 mmol) in DCM (3.00 mL) was added PBr3 (0.20 mL, 2.00 mmol) at -20 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 (aqueous solution) (20 ml) at 0 °C. The resulting mixture was extracted with DCM (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-(bromomethyl)-3-methyl-5-nitropyridine (440.00 mg, 1.61 mmol, 96.5%) as a red solid.

[0267] 2-(Methanesulfonylmethyl)-3-methyl-5-nitropyridine: To a stirred solution of 2-(bromomethyl)-3-methyl-5-nitropyridine (430.00 mg, 1.57 mmol) in DMF (10.00 mL) was added sodium methanesulfinate (325.00 mg, 3.15 mmol). The resulting mixture was stirred at 60 °C for 4 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give 2-(methanesulfonylmethyl)-3-methyl-5-nitropyridine (210.00 mg, 52.1%) as a yellow oil.

[0268] 6-(Methanesulfonylmethyl)-5-methylpyridin-3-amine: To a stirred solution of 2-(methanesulfonylmethyl)-3-methyl-5-nitropyridine (300.00 mg, 1.17 mmol) and NH4Cl (264.00 mg, 4.69 mmol) in water (10.00 mL) and EtOH (15.00 mL) was added Fe (345.00 mg, 5.85 mmol) portionwise at room temperature. The resulting mixture was stirred at 80 °C for 2 hours. The resulting mixture was filtered and the filter cake was washed with EtOAc (100 mL). The filtrate was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 6-(methanesulfonylmethyl)-5-methylpyridin-3-amine (240.00 mg, 96.0%) as a black oil.

[0269] tert-Butyl 2-{[6-(methanesulfonylmethyl)-5-methylpyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a solution of tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (278.00 mg, 1.03 mmol) and 6-(methanesulfonylmethyl)-5-methylpyridin-3-amine (220.00 mg, 1.03 mmol) in 1,4-dioxane (20.00 mL) were added Cs2CO3 (707.00 mg, 2.06 mmol), and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (92.00 mg, 0.10 mmol). The resulting mixture was stirred under a nitrogen atmosphere at 90 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:9) to give tert-butyl 2-{[6-(methanesulfonylmethyl)-5-methylpyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (250.00 mg, 50.7%) as a yellow oil.

[0270] 6-(Methanesulfonylmethyl)-5-methyl-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine: To a stirred solution of tert-butyl 2-{[6-(methanesulfonylmethyl)-5-methylpyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (240.00 mg, 0.50 mmol) in DCM (10.00 mL) was added TFA (2.00 mL) portionwise at room temperature. The mixture was basified to pH [7] with saturated NaHCO3 (aqueous solution). The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (4:1) to afford 6-(methanesulfonylmethyl)-5-methyl-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine (170.00 mg, 95.1%) as a yellow oil.

[0271] tert-Butyl 7-(2-{[6-(Methanesulfonylmethyl)-5-methylpyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a solution of 6-(methanesulfonylmethyl)-5-methyl-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}pyridin-3-amine (160.00 mg, 0.45 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (159.00 mg, 0.45 mmol) in 1,4-dioxane (10.00 mL) were added Cs2CO3 (309.00 mg, 0.90 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (41.00 mg, 0.05 mmol). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give tert-butyl 7-(2-{[6-(methanesulfonylmethyl)-5-methylpyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (120.00 mg, 36.4%) as a yellow oil.

[0272] 6-(Methanesulfonylmethyl)-5-methyl-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine: To a stirred solution of tert-butyl 7-(2-{[6-(methanesulfonylmethyl)-5-methylpyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (110.00 mg, 0.15 mmol) in DCM (10.00 mL) was added TFA (2.00 mL) portionwise at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 18% B - 48% B over 9 minutes, 48% B, wavelength: 254 nm; RT1 (min): 7) to give 6-(methanesulfonylmethyl)-5-methyl-N-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridin-3-amine (20.10 mg, 27.7%) as a yellow solid.

[0273] HPLC: Purity 99.8%, RT = 2.67 min. MS: m / z = 482.0 [M + H] + 。 1 1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.79 (d, J = 2.5 Hz, 1H), 8.40 (s, 1H), 8.07 (d, J = 2.5 Hz, 1H), 7.30 (s, 1H), 5.53 (t, J = 2.5 Hz, 1H), 4.55 (s, 2H), 4.20 (t, J = 4.2 Hz, 2H), 4.00 (s, 2H), 3.33 (s, 2H), 3.13 (t, J = 5.6 Hz, 2H), 2.98 (s, 3H), 2.82 (t, J = 5.6 Hz, 2H), 2.37 (s, 3H), 2.05 (s, 3H). Example 22: Synthesis of Compound 22 6-Methyl-2-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one [Chemical formula]

[0274] 2-Bromo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one: To a stirred solution of methyl 2-[3-bromo-5-(cyanomethyl)-1H-pyrazol-1-yl]acetate (1.50 g, 5.06 mmol) and cobalt(II) chloride hexahydrate (2.46 g, 10.11 mmol) in MeOH (50.00 mL) was added NaBH4 (1.06 g, 25.28 mmol) portionwise at 0 °C under a N2 atmosphere. The resulting mixture was stirred at 25 °C for 4 h under a N2 atmosphere. The reaction was quenched with water (50 mL), and the resulting mixture was concentrated under reduced pressure. The mixture was extracted with EtOAc (3 × 50 mL), and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-bromo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (1.10 g, 64.27%) as a white solid.

[0275] 2-Bromo-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one: To a stirred solution of 2-bromo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (1.10 g, 3.07 mmol) and MeI (0.40 mL, 6.15 mmol) in THF (15.00 mL) was added THF (5.99 mL) at room temperature under a N2 atmosphere. The resulting mixture was stirred at 25 °C for 3 h under a N2 atmosphere. The resulting mixture was diluted with water (50 mL). The solution was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by C18 flash eluting with 67% ACN in water to give 2-bromo-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (700.00 mg, 91.38%) as a white solid.

[0276] 2-Amino-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one: To a stirred solution of 2-bromo-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (240.00 mg, 0.96 mmol) and potassium carboperoxoate (280.11 mg, 1.93 mmol) in DMSO (3.00 mL) and NH4OH (0.6 mL) were added CuI (38.60 mg, 0.19 mmol) and L-proline (46.67 mg, 0.39 mmol) portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 110 °C overnight using a sealed tube under a N2 atmosphere. The residue was purified by C18 flash column eluting with 30% ACN in water to give a crude product. The crude product was repurified by silica gel column eluting with 5% MeOH in DCM to give 2-amino-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (50.00 mg, 27.67%) as a white solid.

[0277] tert-Butyl 2-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a stirred solution of 2-amino-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (500.00 mg, 2.66 mmol) and tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (756.00 mg, 2.66 mmol) in N,N-dimethylformamide (5.00 mL), XPhos Pd G3 (237.00 mg, 0.27 mmol), X-PHOS (267.00 mg, 0.53 mmol) and potassium carbonate (1.16 g, 7.99 mmol) were added portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 100 °C for 1 h under a N2 atmosphere. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (DCM:MeOH = 10:1) to give tert-butyl 2-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (600.00 mg, 49.6%).

[0278] 6-Methyl-2-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one: To a stirred solution of tert-butyl 2-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (580.00 mg, 1.28 mmol) in dichloromethane (6.00 mL) was added dropwise TFA (2.00 mL) at 0 °C under a N2 atmosphere. The resulting mixture was stirred at room temperature for 30 minutes under a N2 atmosphere. The resulting mixture was concentrated under reduced pressure to give 6-methyl-2-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}a.o)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (400.00 mg, 97.1%) as a yellow oil.

[0279] tert-Butyl 8-methyl-7-[2-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of 6-methyl-2-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (150.00 mg, 0.45 mmol) in 1,4-dioxane (3.00 mL) were added tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (311.87 mg, 0.91 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (40.22 mg, 0.05 mmol), and Cs2CO3 (467.89 mg, 1.36 mmol) portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 100 °C overnight under a N2 atmosphere. The residue was purified by silica gel column eluting with 8% MeOH in DCM to afford tert-butyl 8-methyl-7-[(2-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl}amino)-5H,6H,7H,8H-pyrido[3,4-d]piperidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (90.00 mg, 30.7%) as a yellow oil.

[0280] 6-Methyl-2-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one: To a stirred mixture of tert-butyl 8-methyl-7-[2-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (70.00 mg, 0.11 mmol) in DCM (3.00 mL) was added BBr3 in DCM (0.22 mL, 0.22 mmol) dropwise at -78 °C under a N2 atmosphere. The resulting mixture was stirred at -78 °C for 0.5 h under a N2 atmosphere. The resulting mixture was quenched with NaHCO3 and then diluted with water (15 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X Bridge Prep OBD C18 column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: from 25% B to 55% B in 8 min, 55% B; wavelength: 254 nm; RT1 (min): 7, number of runs: 1) to give 6-methyl-2-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (15.50 mg, 29.9%) as a yellow solid.

[0281] HPLC: 99.9% purity, RT = 2.54 min. MS: m / z = 462.3 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.26 (s, 1H), 7.26 (s, 1H), 6.53 (s, 1H), 5.52 (d, J = 3.1 Hz, 1H), 4.90 (s, 2H), 4.19 (t, J = 4.4 Hz, 2H), 3.91 (s, 2H), 3.86 - 3.78 (m, 2H), 3.10 (t, J = 5.5 Hz, 2H), 3.04 (t, J = 5.7 Hz, 4H), 2.94 (s, 3H), 2.76 (s, 2H), 2.03 (s, 3H). Example 23: Synthesis of Compound 23 2-Methyl-N4-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine [Chemical formula]

[0282] 2-Methyl-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline: To a stirred mixture of 2-(morpholin-4-yl)ethan-1-amine (1.86 g, 13.61 mmol) and 1-bromo-2-methyl-4-nitrobenzene (2.00 g, 9.07 mmol) in 1,4-dioxane (30.00 mL), Pd2(dba)3 (0.87 g, 0.91 mmol), BINAP (1.19 g, 1.81 mmol) and Cs2CO3 (6.22 g, 18.15 mmol) were added portionwise at 25 °C. The resulting mixture was stirred at 100 °C for 3 h under an argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give 2-methyl-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline (1.90 g, 75.46%) as a yellow solid.

[0283] tert-Butyl N-(2-methyl-4-nitrophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate: To a stirred solution of 2-methyl-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline (1.80 g, 6.49 mmol) and di-tert-butyl dicarbonate (4.47 g, 19.46 mmol) in DMF (25.00 mL) was added N,N-dimethylpyridin-4-amine (0.17 g, 1.30 mmol) portionwise at room temperature under an argon atmosphere. The resulting mixture was stirred at 50 °C for 2 days under an argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 15% EtOAc in PE to give tert-butyl N-(2-methyl-4-nitrophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (400.00 mg, 15.73%) as a yellow solid.

[0284] tert-Butyl N-(4-amino-2-methylphenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate: To a solution of tert-butyl N-(2-methyl-4-nitrophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (320.00 mg, 0.82 mmol) in MeOH (10.00 mL) was added Raney Ni (209.76 mg, 0.24 mmol) at room temperature. The mixture was stirred at room temperature for 2 h under a H2 atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give tert-butyl N-(4-amino-2-methylphenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (340.00 mg, 94.76%) as a brown oil.

[0285] tert-Butyl N-[2-methyl-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]-N-[2-(morpholin-4-yl)ethyl]carbamate: To a solution of tert-butyl N-(4-amino-2-methylphenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (150.00 mg, 0.34 mmol) and 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine hydrochloride (112.04 mg, 0.51 mmol) in 1,4-dioxane (10.00 mL) were added Cs2CO3 (351.01 mg, 1.02 mmol), Ephos (38.41 mg, 0.07 mmol), and EPhos Pd G4 (32.99 mg, 0.03 mmol). The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (12:1), to afford tert-butyl N-[2-methyl-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]-N-[2-(morpholin-4-yl)ethyl]carbamate (140.00 mg, 75.33%) as a yellow oil.

[0286] tert-Butyl 7-{2-[(4-{[(tert-butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-3-methylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a solution of tert-butyl N-[2-methyl-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]-N-[2-(morpholin-4-yl)ethyl]carbamate (130.00 mg, 0.24 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (119.17 mg, 0.36 mmol) in 1,4-dioxane (10.00 mL) were added Cs2CO3 (245.51 mg, 0.72 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (21.10 mg, 0.02 mmol). The resulting mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (12:1), to give tert-butyl 7-{2-[(4-{[(tert-butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-3-methylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (120.00 mg, 54.32%) as a yellow oil.

[0287] 2-Methyl-N4-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine: To a stirred mixture of tert-butyl 7-{2-[(4-{[(tert-butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-3-methylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (110.00 mg, 0.12 mmol) in DCM (5.00 mL) was added TFA (1.00 mL) at room temperature. After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: X Bridge Prep OBD C18 column, 30×150 mm 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 25% B to 52% B in 8 minutes, 52% B, wavelength: 254 nm; RT1 (min): 7) to give 2-methyl-N4-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine (9.50 mg, 14.11%) as a yellow solid.

[0288] HPLC: 91.1% purity, RT = 2.41 min. MS: m / z = 517.3 [M+H] + 。 1 1H NMR (300 MHz, DMSO-d6): 9.02 (s, 1H), 8.23 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 6.1 Hz, 2H), 6.58 (d, J = 8.7 Hz, 1H), 5.57 (s, 1H), 4.20 (t, J = 4.4 Hz, 2H), 3.89 (d, J = 8 Hz, 8H), 3.49 (s, 2H), 3.34 (s, 6H), 3.11 (s, 2H), 2.75 (s, 2H), 2.11 (s, 3H), 2.04 (s, 3H). Example 24: Synthesis of Compound 24 N-(4-Methanesulfonylphenyl)-7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine [Chemical formula]

[0289] tert-Butyl 2-[(4-methanesulfonylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a stirred solution of tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (300.00 mg, 1.10 mmol) in 1,4-dioxane (10.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (97.25 mg, 0.11 mmol) and Cs2CO3 (754.30 mg, 2.20 mmol). The resulting mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1), to give tert-butyl 2-[(4-methanesulfonylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (340.00 mg, 71.52%) as a yellow solid.

[0290] N-(4-Methanesulfonylphenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine: To a stirred solution of tert-butyl 2-[(4-methanesulfonylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (330.00 mg, 0.76 mmol) in DCM (10.00 mL) was added TFA (2.00 mL) portionwise at room temperature. After stirring at room temperature for 1 hour, the resulting mixture was concentrated under reduced pressure to afford N-(4-methanesulfonylphenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (130.00 mg, 51.82%) as a yellow oil.

[0291] tert-Butyl 7-{2-[(4-methanesulfonylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of N-(4-methanesulfonylphenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (130.00 mg, 0.40 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (136.96 mg, 0.40 mmol) in 1,4-dioxane (10.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (34.99 mg, 0.04 mmol) and Cs2CO3 (271.37 mg, 0.79 mmol). The resulting mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to afford tert-butyl 7-{2-[(4-methanesulfonylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (57.00 mg, 25.32%) as a yellow oil.

[0292] N-(4-Methanesulfonylphenyl)-7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine: To a stirred solution of tert-butyl 7-{2-[(4-methanesulfonylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (57.00 mg, 0.10 mmol) in DCM (5.00 mL) was added TFA (1.00 mL) portionwise at room temperature. After stirring at room temperature for 1 h, the resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 22% B - 52% B in 8 min, 52% B, wavelength: 254 nm; RT1 (min): 7, number of runs: 2 to give N-(4-methanesulfonylphenyl)-7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (18.00 mg, 38.91%) as a yellow solid.

[0293] HPLC: Purity 97.9%, RT = 3.25 min. MS: m / z = 453.1 [M + H] + 。 1 H NMR (300 MHz, DMSO-d6): 10.14 (s, 1H), 8.44 (s, 1H), 8.06 - 7.96 (m, 2H), 7.84 - 7.75 (m, 2H), 7.30 (s, 1H), 5.54 (s, 1H), 4.20 (d, J = 5.0 Hz, 2H), 4.02 (s, 2H), 3.17 (d, J = 5.4 Hz, 2H), 3.14 (s, 5H), 2.83 (d, J = 6.0 Hz, 2H), 2.05 (s, 3H). Example 25: Synthesis of Compound 25 N-[4-(Methanesulfonylmethoxy)phenyl]-7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine

Chemical Structure

[0294] 1-[(Methylsulfanyl)methoxy]-4-nitrobenzene: To a stirred solution of 4-nitrophenol (1.00 g, 6.83 mmol) in DMF (15.00 mL), sodium hydride (683.00 mg, 17.08 mmol) was added at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 10 minutes under a nitrogen atmosphere. After 10 minutes, chloro(methylsulfanyl)methane (1041.00 mg, 10.24 mmol) was added to the above solution at 0 °C under a nitrogen atmosphere. The resulting mixture was then stirred at room temperature for an additional 2 hours. The reaction was quenched at room temperature by the addition of H2O and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1), to give 1-[(methylsulfanyl)methoxy]-4-nitrobenzene (500.00 mg, 35.93%) as a yellow solid.

[0295] 1-(Methanesulfonylmethoxy)-4-nitrobenzene: To a stirred solution of 1-[(methylsulfanyl)methoxy]-4-nitrobenzene (570.00 mg, 2.80 mmol) in DCM (15.00 mL), m-CPBA (2541.00 mg, 13.99 mmol) was added portionwise at room temperature. The resulting mixture was then stirred at room temperature for an additional 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1), to give 1-(methanesulfonylmethoxy)-4-nitrobenzene (480.00 mg, 73.71%) as a white solid.

[0296] 4-(Methanesulfonylmethoxy)aniline: Palladium on activated carbon (27.00 mg, 0.03 mmol) was added to a solution of 1-(methanesulfonylmethoxy)-4-nitrobenzene (60.00 mg, 0.25 mmol) in MeOH (3.00 mL) in a pressure tank. The mixture was hydrogenated at room temperature for 2 hours under a hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered, and the filter cake was washed with 30 mL of EA. The filtrate was concentrated under reduced pressure to obtain 4-(methanesulfonylmethoxy)aniline (50.00 mg, 88.19%) as a yellow oil.

[0297] tert-Butyl 2-{[4-(methanesulfonylmethoxy)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: Cs2CO3 (890.00 mg, 2.59 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (57.00 mg, 0.06 mmol) were added to a solution of tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (350.00 mg, 1.30 mmol) and 4-(methanesulfonylmethoxy)aniline (299.00 mg, 1.30 mmol) in 1,4-dioxane (15.00 mL). The resulting mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (6:1), to obtain tert-butyl 2-{[4-(methanesulfonylmethoxy)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (300.00 mg, 52.94%) as a yellow solid.

[0298] N-[4-(Methanesulfonylmethoxy)phenyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine: To a stirred solution of tert-butyl 2-{[4-(methanesulfonylmethoxy)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (290.00 mg, 0.66 mmol) and DCM (5.00 mL) was added dropwise TFA (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was basified to pH = 7 with saturated NaHCO3 (aqueous solution) and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give N-[4-(methanesulfonylmethoxy)phenyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (300.00 mg, 133.66%) as a yellow solid.

[0299] tert-Butyl 7-(2-{[4-(Methanesulfonylmethoxy)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a solution of N-[4-(Methanesulfonylmethoxy)phenyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (163.00 mg, 0.48 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (170.00 mg, 0.48 mmol) in 1,4-dioxane (15.00 mL) were added Cs2CO3 (331.00 mg, 0.97 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (21.00 mg, 0.02 mmol). The resulting mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA:PE (10:1), to give tert-butyl 7-(2-{[4-(Methanesulfonylmethoxy)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (140.00 mg, 49.07%) as a yellow solid.

[0300] N-[4-(Methanesulfonylmethoxy)phenyl]-7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine: To a stirred solution of tert-butyl 7-(2-{[4-(methanesulfonylmethoxy)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (120.00 mg, 0.20 mmol) and DCM (5.00 mL) at room temperature, TFA (1.00 mL) was added dropwise. The resulting mixture was stirred at room temperature for 1 hour. The mixture was basified to pH = 7 with saturated NaHCO3 (aqueous solution) and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: from 25% B to 55% B in 8 minutes, 55% B; wavelength: 254 nm; RT1 (min): 7 to give N-[4-(methanesulfonylmethoxy)phenyl]-7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (21.80 mg, 22.15%) as a yellow solid.

[0301] HPLC: Purity 99.47%, RT = 3.24 min. MS: m / z = 483.20 [M+H] + . 11H NMR (300 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.23 (s, 1H), 7.73 - 7.49 (m, 2H), 7.21 (s, 1H), 7.06 - 6.88 (m, 2H), 5.45 (t, J = 2.7 Hz, 1H), 5.17 (s, 2H), 4.25 - 4.00 (m, 2H), 3.87 (s, 2H), 3.23 (d, J = 4.2 Hz, 2H), 3.04 (t, J = 5.6 Hz, 2H), 2.97 (s, 3H), 2.71 (t, J = 5.6 Hz, 2H), 1.97 (s, 3H). Example 26: Synthesis of Compound 26 N2-[2-(Dimethylamino)ethyl]-N5-(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)pyridine-2,5-diamine [Chemical formula]

[0302] N-[2-(Dimethylamino)ethyl]-5-nitropyridin-2-amine: To a solution of 2-fluoro-5-nitropyridine (1.00 g, 6.69 mmol) and K2CO3 (2.91 g, 20.06 mmol) in DMF (10.00 mL) was added dropwise (2-aminoethyl)dimethylamine (0.93 g, 10.03 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under a N2 atmosphere. The resulting mixture was filtered and the filter cake was washed with ACN. The filtrate was concentrated under reduced pressure. The residue was purified under the following conditions (column, C18 silica gel, mobile phase, MeCN in water (0.05% NH4HCO3), gradient from 100% to 100% in 30 min, detector, UV 254 nm) to give N-[2-(dimethylamino)ethyl]-5-nitropyridin-2-amine (1.30 g, 92.1%) as a green solid.

[0303] tert-Butyl N-[2-(dimethylamino)ethyl]-N-(5-nitropyridin-2-yl)carbamate: To a stirred solution of N-[2-(dimethylamino)ethyl]-5-nitropyridin-2-amine (1.28 g, 6.07 mmol) in DCM (3.00 mL) were added DMAP (0.14 g, 1.21 mmol), TEA (1.94 g, 18.20 mmol) and Boc2O (4.01 g, 18.20 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h under a N2 atmosphere. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (10:1) to afford tert-butyl N-[2-(dimethylamino)ethyl]-N-(5-nitropyridin-2-yl)carbamate (1.70 g, 89.4%) as a yellow oil.

[0304] tert-Butyl N-(5-aminopyridin-2-yl)-N-[2-(dimethylamino)ethyl]carbamate: To a stirred solution of tert-butyl N-[2-(dimethylamino)ethyl]-N-(5-nitropyridin-2-yl)carbamate (1.48 g, 4.72 mmol) in EtOH (15.00 mL) and water (5.00 mL) were added Fe (1.39 g, 23.61 mmol) and NH4Cl (1.59 g, 28.33 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 3 h under a H2 atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (3×3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (10:1) to afford tert-butyl N-(5-aminopyridin-2-yl)-N-[2-(dimethylamino)ethyl]carbamate (1.30 g, 94.8%) as a yellow solid.

[0305] tert-Butyl N-[2-(dimethylamino)ethyl]-N-{5-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}carbamate: To a stirred mixture of tert-butyl N-(5-aminopyridin-2-yl)-N-[2-(dimethylamino)ethyl]carbamate (500.00 mg, 1.72 mmol) and 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine (357.00 mg, 2.07 mmol) in 1,4-dioxane (5.00 mL) were added EPhos Pd G4 (166.00 mg, 0.17 mmol), Ephos (97.00 mg, 0.17 mmol) and Cs2CO3 (1771.00 mg, 5.16 mmol) portionwise at room temperature. The resulting mixture was stirred at 120 °C for 1 h under a N2 atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (3 × 2 mL). The filtrate was concentrated under reduced pressure. The residue was purified under the following conditions (column, C18 silica gel, mobile phase, ACN in water (0.05% NH3HCO3), gradient from 10% to 100% in 30 min, detector, UV 254 nm) to give tert-butyl N-[2-(dimethylamino)ethyl]-N-{5-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}carbamate (380.00 mg, 51.8%) as a brown solid.

[0306] tert-Butyl 7-{7-[(6-{[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino}pyridin-3-yl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of tert-butyl N-[2-(dimethylamino)ethyl]-N-{5-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}carbamate (360.00 mg, 0.85 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (339.00 mg, 1.02 mmol) in 1,4-dioxane (4.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (75.00 mg, 0.08 mmol) and Cs2CO3 (580.00 mg, 1.69 mmol) portionwise at room temperature. The resulting mixture was stirred at 100 °C overnight under a N2 atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na4SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (10:1) to give tert-butyl 7-{7-[(6-{[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino}pyridin-3-yl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (250.00 mg, 36.1%) as a yellow solid.

[0307] N2-[2-(Dimethylamino)ethyl]-N5-(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)pyridine-2,5-diamine: To a stirred mixture of tert-butyl 7-{7-[(6-{[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino}pyridin-3-yl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (230.00 mg, 0.28 mmol) in DCM (3.00 mL) was added dropwise TFA (1.00 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 hour under a N2 atmosphere. The resulting mixture was concentrated under vacuum. The crude product was purified under the following conditions (column: XBridge Shield RP18 OBD column, 30 * × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 22% - 50% over 9 minutes, wavelength: 254 nm; RT1 (min): 7) to give N2-[2-(dimethylamino)ethyl]-N5-(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)pyridine-2,5-diamine (49.00 mg, 37.4%) as a yellow solid.

[0308] HPLC: purity 98.89%, RT = 2.51 min. MS: m / z = 461.30 [M + H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.08 (d, J = 2.7 Hz, 1H), 7.87 (s, 1H), 7.53 (dd, J = 8.8, 2.7 Hz, 1H), 7.24 (s, 1H), 6.47 (d, J = 8.9 Hz, 1H), 6.37 (s, 1H), 5.96 (t, J = 5.6 Hz, 1H), 5.49 (s, 1H), 4.18 (t, J = 4.4 Hz, 2H), 3.93 (s, 2H), 3.29 (d, J = 5.9 Hz, 4H), 3.06 (s, 2H), 2.77 (s, 2H), 2.39 (t, J = 6.6 Hz, 2H), 2.17 (s, 6H), 2.02 (s, 3H). Example 27: Synthesis of Compound 27 2-Methyl-4-[(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-N-[2-(morpholin-4-yl)ethyl]benzamide [Chemical Structure]

[0309] tert-Butyl 7-{[4-(methoxycarbonyl)-3-methylphenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate: To a stirred mixture of tert-butyl 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (400.00 mg, 1.21 mmol) and methyl 4-amino-2-methylbenzoate (400.28 mg, 2.42 mmol) in 1,4-dioxane (12.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (107.15 mg, 0.12 mmol) and Cs2CO3 (831.07 mg, 2.42 mmol) at room temperature. The mixture was stirred at 100 °C for 2 hours. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give tert-butyl 7-{[4-(methoxycarbonyl)-3-methylphenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (450.00 mg, 91.9%) as a yellow solid.

[0310] Methyl 2-methyl-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]benzoate: To a stirred mixture of tert-butyl 7-{[4-(methoxycarbonyl)-3-methylphenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (530.00 mg, 1.18 mmol) and TFA (3.00 mL) in DCM (15.00 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was basified to pH = 9 with saturated NaHCO3 (aqueous solution). The resulting mixture was quenched with ice / water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave methyl 2-methyl-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]benzoate (420.00 mg, crude product) as a yellow solid.

[0311] tert-Butyl 7-(7-{[4-(methoxycarbonyl)-3-methylphenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of methyl 2-methyl-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]benzoate (410.00 mg, 1.12 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (738.95 mg, 2.24 mmol) in 1,4-dioxane (10.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (99.26 mg, 0.11 mmol) and Cs2CO3 (769.88 mg, 2.24 mmol) at room temperature. The mixture was stirred at 100 °C for 2 hours. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to afford tert-butyl 7-(7-{[4-(methoxycarbonyl)-3-methylphenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (270.00 mg, 43.1%) as a yellow solid.

[0312] 4-[(6-{1-[(tert-Butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-2-methylbenzoic acid: To a stirred mixture of tert-butyl 7-(7-{[4-(methoxycarbonyl)-3-methylphenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (260.00 mg, 0.34 mmol) in MeOH (6.00 mL) and H2O (3.00 mL) was added NaOH (42.91 mg, 1.02 mmol) at room temperature. The mixture was stirred at 50 °C for 3 hours. The mixture was acidified to pH = 7 with HCl (4N). The resulting mixture was quenched with ice / water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 4-[(6-{1-[(tert-Butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-2-methylbenzoic acid (150.00 mg, crude product) as a yellow solid.

[0313] tert-Butyl 8-methyl-7-{7-[(3-methyl-4-{[2-(morpholin-4-yl)ethyl]carbamoyl}phenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of 4-[(6-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-2-methylbenzoic acid (180.00 mg, 0.28 mmol) and 2-(morpholin-4-yl)ethan-1-amine (71.76 mg, 0.55 mmol) in DMF (12.00 mL) were added HATU (330.94 mg, 0.83 mmol) and DIEA (74.97 mg, 0.55 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with ice / water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give tert-butyl 8-methyl-7-{7-[(3-methyl-4-{[2-(morpholin-4-yl)ethyl]carbamoyl}phenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (120.00 mg, 62.9%) as a brown solid.

[0314] 2-Methyl-4-[(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-N-[2-(morpholin-4-yl)ethyl]benzamide: A mixture of tert-butyl 8-methyl-7-{7-[(3-methyl-4-{[2-(morpholin-4-yl)ethyl]carbamoyl}phenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (110.00 mg, 0.15 mmol) and TFA (1.00 mL) in DCM (5.00 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X Bridge Prep OBD C18 column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 22% B - 50% B in 9 min, 50% B, wavelength: 254 nm; RT1 (min): 7) to give 2-methyl-4-[(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-N-[2-(morpholin-4-yl)ethyl]benzamide (53.80 mg, 65.4%) as a yellow solid.

[0315] HPLC: Purity 99.57%, RT = 2.93 min. MS: m / z = 544.25 [M+H] + 。 11H NMR (300 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.04 (s, 1H), 7.91 (t, J = 5.7 Hz, 1H), 7.54 (dd, J = 8.4, 2.2 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.30 - 7.21 (m, 2H), 6.62 (s, 1H), 5.52 (s, 1H), 4.19 (t, J = 4.4 Hz, 2H), 4.00 (s, 2H), 3.58 (t, J = 4.6 Hz, 4H), 3.26 (s, 2H), 3.32 (s, 2H), 3.10 (s, 2H), 2.83 (s, 2H), 2.50 - 2.31 (m, 9H), 2.04 (s, 3H). Example 28: Synthesis of Compound 28 N2-[2-(Dimethylamino)ethyl]-3-methyl-N5-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridine-2,5-diamine [Chemical formula]

[0316] N-[2-(Dimethylamino)ethyl]-3-methyl-5-nitropyridin-2-amine: To a stirred mixture of 2-fluoro-3-methyl-5-nitropyridine (1.00 g, 6.28 mmol) and 2-(dimethylamino)ethylamine (864.64 mg, 9.42 mmol) in DMF (15.00 mL), Cs2CO3 (6197.91 mg, 18.83 mmol) was added portionwise at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give N-[2-(dimethylamino)ethyl]-3-methyl-5-nitropyridin-2-amine (3.0 g, crude product) as an orange-yellow solid.

[0317] tert-Butyl N-[2-(dimethylamino)ethyl]-N-(3-methyl-5-nitropyridin-2-yl)carbamate: To a stirred mixture of N-[2-(dimethylamino)ethyl]-3-methyl-5-nitropyridin-2-amine (1.00 g, 4.46 mmol) and (Boc)2O (3.14 mL, 13.38 mmol) in DCM (20.00 mL), TEA (1424.90 mg, 13.38 mmol) and DMAP (114.69 mg, 0.89 mmol) were added portionwise at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH = 95:5 to give tert-butyl N-[2-(dimethylamino)ethyl]-N-(3-methyl-5-nitropyridin-2-yl)carbamate (1.10 g, 72.95%) as an orange-yellow solid.

[0318] tert-Butyl N-(5-amino-3-methylpyridin-2-yl)-N-[2-(dimethylamino)ethyl]carbamate: To a stirred mixture of tert-butyl N-[2-(dimethylamino)ethyl]-N-(3-methyl-5-nitropyridin-2-yl)carbamate (1.00 g, 2.96 mmol) and NH4Cl (806.94 mg, 14.78 mmol) in EtOH (12.00 mL) and water (8.00 mL), Fe (733.93 mg, 11.83 mmol) was added portionwise at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH = 83:17 to give tert-butyl N-(5-amino-3-methylpyridin-2-yl)-N-[2-(dimethylamino)ethyl]carbamate (915 mg, 97.75%) as an orange-yellow solid.

[0319] tert-Butyl N-[2-(dimethylamino)ethyl]-N-[3-methyl-5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)pyridin-2-yl]carbamate: To a stirred solution of 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine hydrochloride (400.00 mg, 1.94 mmol) in 1,4-dioxane (8.00 mL) was added cesium carbonate (2662.90 mg, 7.76 mmol) portionwise at room temperature under a N2 atmosphere. The mixture was stirred at room temperature for 20 minutes. To the above mixture were added tert-butyl N-(5-amino-3-methylpyridin-2-yl)-N-[2-(dimethylamino)ethyl]carbamate (601.51 mg, 1.94 mmol), Ephos (109.27 mg, 0.19 mmol) and EPhos Pd G4 (187.68 mg, 0.19 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 hours under a N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with EA to give tert-butyl N-[2-(dimethylamino)ethyl]-N-[3-methyl-5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)pyridin-2-yl]carbamate (280.00 mg, 25.68%) as a yellow solid.

[0320] tert-Butyl 7-{2-[(6-{[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino}-5-methylpyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of tert-butyl N-[2-(dimethylamino)ethyl]-N-[3-methyl-5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)pyridin-2-yl]carbamate (250.00 mg, 0.53 mmol) in 1,4-dioxane (5.00 mL) were added tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (200.59 mg, 0.58 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (46.54 mg, 0.05 mmol), and Cs2CO3 (541.47 mg, 1.58 mmol) portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 120 °C overnight under a N2 atmosphere. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with 16% MeOH in DCM to afford tert-butyl 7-{2-[(6-{[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino}-5-methylpyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (230.00 mg, 58.7%) as a brownish orange solid.

[0321] N2-[2-(Dimethylamino)ethyl]-3-methyl-N5-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridine-2,5-diamine: To a stirred solution of tert-butyl 7-{2-[(6-{[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino}-5-methylpyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (210.00 mg, 0.30 mmol) in DCM (3.00 mL) was added TFA (0.60 mL) portionwise at 0 °C under N2 atmosphere. The resulting mixture was stirred at room temperature for 1 h under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X Bridge Prep OBD C18 column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 25% B - 55% B in 9 min, 55% B, wavelength: 254 nm; RT1 (min): 7) to give N2-[2-(dimethylamino)ethyl]-3-methyl-N5-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridine-2,5-diamine (23.80 mg, 16.6%) as a yellow solid.

[0322] HPLC: Purity 97.93%, RT = 2.05 min. MS: m / z = 476.25 [M + H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.19 (d, J = 17.8 Hz, 2H), 7.47 (s, 2H), 7.27 (s, 2H), 5.51 (s, 2H), 5.39 (s, 2H), 4.19 (s, 2H), 3.90 (s, 2H), 3.09 (s, 2H), 2.74 (s, 2H), 2.43 (s, 2H), 2.18 (s, 6H), 2.03 (s, 6H). Example 29: Synthesis of Compound 29 N{4-[(7-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-2-(trifluoromethyl)phenyl}-2-(morpholin-4-yl)acetamide [Chemical formula]

[0323] 2-(Morpholin-4-yl)-N-[4-nitro-2-(trifluoromethyl)phenyl]acetamide: A mixture of 2-(morpholin-4-yl)acetic acid (4358.77 mg, 28.53 mmol) and BTFFH (5932.26 mg, 17.83 mmol) in DMF (10.00 mL) was stirred for 30 minutes, then 4-nitro-2-(trifluoromethyl)aniline (1.50 g, 7.13 mmol) and DIEA (7.85 mL, 42.79 mmol) were added portionwise at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 5 hours under a nitrogen atmosphere. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA:PE = 21:79, to give 2-(morpholin-4-yl)-N-[4-nitro-2-(trifluoromethyl)phenyl]acetamide (4.20 g, 176.7%) as an off-white solid.

[0324] N-[4-Amino-2-(trifluoromethyl)phenyl]-2-(morpholin-4-yl)acetamide: To a stirred mixture of 2-(morpholin-4-yl)-N-[4-nitro-2-(trifluoromethyl)phenyl]acetamide (1.00 g, 3.00 mmol) and NH4Cl (844.76 mg, 15.00 mmol) in EtOH (6.00 mL) and water (4.00 mL), Fe (707.52 mg, 12.00 mmol) was added portionwise at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 4 h under a nitrogen atmosphere. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH = 92:8 to give N-[4-amino-2-(trifluoromethyl)phenyl]-2-(morpholin-4-yl)acetamide (1.60 g, 175.8%) as a yellow solid.

[0325] tert-Butyl 2-({4-[2-(morpholin-4-yl)acetamido]-3-(trifluoromethyl)phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a stirred mixture of N-[4-amino-2-(trifluoromethyl)phenyl]-2-(morpholin-4-yl)acetamide (400.00 mg, 1.32 mmol) and tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (540.00 mg, 2.00 mmol) in DMF (10.00 mL), Xphos Pd G3 (120.00 mg, 0.13 mmol), X-PHOS (60.00 mg, 0.12 mmol) and K2CO3 (560.00 mg, 3.85 mmol) were added portionwise at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 7:3) to give tert-butyl 2-({4-[2-(morpholin-4-yl)acetamido]-3-(trifluoromethyl)phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (650.00 mg, 90.7%) as a yellow solid.

[0326] 2-(Morpholin-4-yl)-N-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)-2-(trifluoromethyl)phenyl]acetamide: A solution of tert-butyl 2-({4-[2-(morpholin-4-yl)acetamido]-3-(trifluoromethyl)phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (600.00 mg, 1.10 mmol) and TFA (2.00 mL) in DCM (6.0 mL) was stirred at 30 °C for 1 h under a nitrogen atmosphere. The mixture was basified to pH 12 with NaOH (4N). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This afforded 2-(morpholin-4-yl)-N-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)-2-(trifluoromethyl)phenyl]acetamide (540.00 mg, 96.0%) as a yellow solid.

[0327] tert-Butyl 8-methyl-7-[2-({4-[2-(morpholin-4-yl)acetamido]-3-(trifluoromethyl)phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: A solution of 2-(morpholin-4-yl)-N-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)-2-(trifluoromethyl)phenyl]acetamide (300.00 mg, 0.59 mmol), tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (340.00 mg, 0.98 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (60.00 mg, 0.07 mmol), and Cs2CO3 (674.00 mg, 1.97 mmol) in 1,4-dioxane (4.00 mL) was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 7:3) to give tert-butyl 8-methyl-7-[2-({4-[2-(morpholin-4-yl)acetamido]-3-(trifluoromethyl)phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (188.00 mg, 46.6%) as a yellow solid.

[0328] N-{4-[(7-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-2-(trifluoromethyl)phenyl}-2-(morpholin-4-yl)acetamide: A solution of tert-butyl 8-methyl-7-[2-({4-[2-(morpholin-4-yl)acetamido]-3-(trifluoromethyl)phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (178.00 mg, 0.24 mmol) and TFA (2.00 mL) in DCM (6.00 mL) was stirred at room temperature for 2 h under a nitrogen atmosphere. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 29% B - 59% B in 9 min, 59% B, wavelength: 254 nm; RT1 (min): 7. Thereby, N-{4-[(7-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-2-(trifluoromethyl)phenyl}-2-(morpholin-4-yl)acetamide (40.00 mg, 27.2%) was obtained as an off-white solid.

[0329] HPLC: Purity 95.03%, RT = 2.85 min. MS: m / z = 585.20 [M + H] + 。 1 H NMR (400 MHz, DMSO-d6) 9.88 (s, 1H), 9.61 (s, 1H), 8.39 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.90 (s, 1H), 7.29 (s, 1H), 5.54 (s, 1H), 4.19 (t, J = 4.3 Hz, 2H), 3.97 (s, 2H), 3.65 (s, 6H), 3.16 - 3.11 (m, 4H), 2.81 (s, 2H), 2.26 (s, 4H), 2.04 (s, 3H). Example 30: Synthesis of a Compound 2-Methyl-1-{5-[(7-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-2,3-dihydro-1H-isoindol-2-yl}propan-2-ol

Chem.

[0330] 2-Methyl-1-(5-nitro-2,3-dihydro-1H-isoindol-2-yl)propan-2-ol: To a stirred solution of 5-nitro-2,3-dihydro-1H-isoindole hydrochloride (320.00 mg, 1.52 mmol) and TEA (0.89 mL, 6.06 mmol) in EtOH (15.00 mL) was added 2,2-dimethyloxirane (345.00 mg, 4.55 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The mixture was cooled to room temperature. After filtration, the filtrate was concentrated under reduced pressure. Thereby, 2-methyl-1-(5-nitro-2,3-dihydro-1H-isoindol-2-yl)propan-2-ol (350.00 mg, 97.8%) was obtained as a yellow solid.

[0331] 1-(5-Amino-2,3-dihydro-1H-isoindol-2-yl)-2-methylpropan-2-ol: To a stirred mixture of 2-methyl-1-(5-nitro-2,3-dihydro-1H-isoindol-2-yl)propan-2-ol (350.00 mg, 1.48 mmol), NH4Cl (404.00 mg, 7.40 mmol) in EtOH (10.00 mL) and water (5.00 mL) was added Fe (422.00 mg, 7.40 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 3 h. The mixture was cooled to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (3:1) to give 1-(5-amino-2,3-dihydro-1H-isoindol-2-yl)-2-methylpropan-2-ol (300.00 mg, 90.5%) as a yellowish brown solid.

[0332] tert-Butyl 2-{[2-(2-hydroxy-2-methylpropyl)-2,3-dihydro-1H-isoindol-5-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a stirred solution of 1-(5-amino-2,3-dihydro-1H-isoindol-2-yl)-2-methylpropan-2-ol (300.00 mg, 1.26 mmol) and tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (428.00 mg, 1.51 mmol) in 1,4-dioxane (15.00 mL), Cs2CO3 (862.00 mg, 2.51 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (111.00 mg, 0.13 mmol) were added portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 100 °C for 16 h under a N2 atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (4:1) to afford tert-butyl 2-{[2-(2-hydroxy-2-methylpropyl)-2,3-dihydro-1H-isoindol-5-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (380.00 mg, 68.8%) as a yellowish brown solid.

[0333] 2-Methyl-1-[5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)-2,3-dihydro-1H-isoindol-2-yl]propan-2-ol: To a stirred solution of tert-butyl 2-{[2-(2-hydroxy-2-methylpropyl)-2,3-dihydro-1H-isoindol-5-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (380.00 mg, 0.86 mmol) in DCM (9.00 mL) was added dropwise TFA (3.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluting with H2O / MeCN (1:4) to afford 2-methyl-1-[5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)-2,3-dihydro-1H-isoindol-2-yl]propan-2-ol (320.00 mg, 90.9%) as a brown solid.

[0334] tert-Butyl 7-(2-{[2-(2-Hydroxy-2-methylpropyl)-2,3-dihydro-1H-isoindol-5-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of 2-methyl-1-[5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)-2,3-dihydro-1H-isoindol-2-yl]propan-2-ol (300.00 mg, 0.74 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (306.00 mg, 0.88 mmol) in 1,4-dioxane (15.00 mL) were added Cs2CO3 (505.00 mg, 1.47 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (65.00 mg, 0.07 mmol) portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 100 °C for 16 h under a N2 atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (4:1) to afford tert-butyl 7-(2-{[2-(2-hydroxy-2-methylpropyl)-2,3-dihydro-1H-isoindol-5-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (260.00 mg, 60.0%) as a yellow solid.

[0335] 2-Methyl-1-{5-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-2,3-dihydro-1H-isoindol-2-yl}propan-2-ol: To a stirred solution of tert-butyl 7-(2-{[2-(2-hydroxy-2-methylpropyl)-2,3-dihydro-1H-isoindol-5-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (240.00 mg, 0.41 mmol) in DCM (9.00 mL) was added dropwise TFA (3.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: Xselect CSH C18 OBD column 30×150 mm 5 μm, n, mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 5% B - 23% B in 8 minutes, 23% B, wavelength: 254 / 220 nm, RT1 (min): 6.3 to give 2-methyl-1-{5-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-2,3-dihydro-1H-isoindol-2-yl}propan-2-ol (21.20 mg, 10.4%) as a yellow solid.

[0336] HPLC: Purity 97.59%, RT = 2.44 min. MS: m / z = 488.30 [M+H] + 。 1 H NMR (300 MHz, methanol-d4) δ 8.22 (s, 1H), 7.60 (s, 1H), 7.42 (dd, J = 8.2, 2.0 Hz, 1H), 7.27 (s, 1H), 7.11 (d, J = 8.2 Hz, 1H), 4.35 - 4.26 (m, 2H), 4.07 - 3.95 (m, 6H), 3.46 - 3.37 (m, 2H), 3.19 (t, J = 5.7 Hz, 2H), 2.84 (t, J = 5.7 Hz, 2H), 2.75 (s, 2H), 2.14 (s, 3H), 1.26 (s, 6H). Example 31: Synthesis of Compound 31 2-(Dimethylamino)-N-{5-[(6-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}acetamide

Chemical formula

[0337] 2-(Dimethylamino)-N-(5-nitropyridin-2-yl)acetamide: To a stirred solution of 5-nitropyridin-2-amine (1.00 g, 6.97 mmol) in DMF (10.00 mL) were added BTFFH (3.48 g, 10.46 mmol), DIEA (4.74 g, 34.86 mmol) and 2-(dimethylamino)acetic acid (2.42 g, 20.92 mmol) at 0 °C under a N2 atmosphere. The resulting mixture was allowed to cool to room temperature. The residue was purified under the following conditions (column, C18 silica gel, mobile phase, MeCN in water (0.05% NH4HCO3), gradient from 70% to 80% in 10 minutes, detector, UV 254 nm) to give 2-(dimethylamino)-N-(5-nitropyridin-2-yl)acetamide (800.00 mg, 48.5%) as a yellow solid.

[0338] N-(5-Aminopyridin-2-yl)-2-(dimethylamino)acetamide: To a solution of 2-(dimethylamino)-N-(5-nitropyridin-2-yl)acetamide (780.00 mg, 3.30 mmol) in MeOH (10.00 mL) was added Raney Ni (500.00 mg, 5.54 mmol) at room temperature. The resulting mixture was stirred for 1 hour at room temperature under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (3 × 20 mL). The filtrate was concentrated under reduced pressure. Thereby, N-(5-aminopyridin-2-yl)-2-(dimethylamino)acetamide (600.00 mg, 92.6%) was obtained as a red oil.

[0339] tert-Butyl 7-({6-[2-(dimethylamino)acetamido]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate: To a stirred solution of N-(5-aminopyridin-2-yl)-2-(dimethylamino)acetamide (258.00 mg, 1.31 mmol) and tert-butyl 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (300.00 mg, 1.09 mmol) in 1,4-dioxane (5.00 mL), EPhos Pd G4 (106.00 mg, 0.11 mmol), Cs2CO3 (1.08 g, 3.28 mmol) and Ephos (62.00 mg, 0.11 mmol) were added under N2 atmosphere at room temperature. The resulting mixture was stirred at 100 °C for 1 h under N2 atmosphere. The resulting mixture was allowed to cool to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified under the following conditions (column, C18 silica gel, mobile phase, MeCN in water (0.05% NH4HCO3), gradient from 70% to 80% in 10 min, detector, UV 254 nm) to give tert-butyl 7-({6-[2-(dimethylamino)acetamido]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (400.00 mg, 85.5%) as a brown solid.

[0340] 2-(Dimethylamino)-N-{5-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}acetamide: To a stirred solution of tert-butyl 7-({6-[2-(dimethylamino)acetamido]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (380.00 mg, 0.89 mmol) in DCM (3.00 mL) was added dropwise TFA (1.00 mL) at room temperature under a N2 atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a N2 atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions (column, C18 silica gel, mobile phase, MeCN in water (0.05% NH4HCO3), gradient 10% - 20% over 30 minutes, detector, UV 254 nm). This gave 2-(dimethylamino)-N-{5-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}acetamide (280.00 mg, 96.1%) as a pale brown oil.

[0341] tert-Butyl 7-[7-({6-[2-(dimethylamino)acetamido]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of 2-(dimethylamino)-N-{5-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}acetamide (130.00 mg, 0.40 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (157.00 mg, 0.48 mmol) in 1,4-dioxane (2.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (35.00 mg, 0.04 mmol) and Cs2CO3 (408.00 mg, 1.19 mmol) portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 120 °C for 24 h under a N2 atmosphere. The resulting mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with MeOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH 20:1) to give tert-butyl 7-[7-({6-[2-(dimethylamino)acetamido]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (50.00 mg, 20.6%) as a yellow solid.

[0342] 2-(Dimethylamino)-N-{5-[(6-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}acetamide: To a stirred solution of tert-butyl 7-[7-({6-[2-(dimethylamino)acetamido]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (50.00 mg, 0.08 mmol) in DCM (1.50 mL) was added TFA (0.50 mL) at 0 °C under a N2 atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a N2 atmosphere. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: MeOH-HPLC, flow rate: 60 mL / min; gradient: 48% - 78% over 8 minutes, wavelength: 254 nm; RT1 (min): 7) to give 2-(dimethylamino)-N-{5-[(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}acetamide (13.00 mg, 33.3%) as a white solid.

[0343] HPLC: Purity 99.35%, RT = 4.63 min. MS: m / z = 475.25 [M + H] + 。 1 1H NMR (300 MHz, methanol-d4) δ 8.49 (dd, J = 2.3, 1.2 Hz, 1H), 8.09 - 7.96 (m, 2H), 7.97 (s, 1H), 7.26 (s, 1H), 6.56 (s, 1H), 4.30 (t, J = 4.4 Hz, 2H), 4.03 (s, 2H), 3.41 (t, J = 4.4 Hz, 2H), 3.17 (d, J = 5.9 Hz, 4H), 2.90 (t, J = 5.7 Hz, 2H), 2.40 (s, 6H), 2.13 (s, 3H). Example 32: Synthesis of Compound 32 N2-[2-(Dimethylamino)ethyl]-3-methyl-N5-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)pyridine-2,5-diamine

Chem.

[0344] 2-(Morpholin-4-yl)-N-(5-nitropyridin-2-yl)acetamide: To a stirred solution of 2-(morpholin-4-yl)acetic acid (3.20 g, 20.92 mmol) in DMF (20.00 mL) were added DMAP (0.36 g, 2.79 mmol), 5-nitropyridin-2-amine (2.00 g, 13.95 mmol), and DCC (4.54 g, 20.92 mmol) portionwise at 0 °C under a N2 atmosphere. The resulting mixture was stirred at 30 °C for 3 h under a N2 atmosphere. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with 90% EtOAc in PE to give 2-(morpholin-4-yl)-N-(5-nitropyridin-2-yl)acetamide (2.55 g, 68.7%) as a pale yellow solid.

[0345] N-(5-Aminopyridin-2-yl)-2-(morpholin-4-yl)acetamide: To a stirred solution of 2N-(morpholin-4-yl)-N-(5-nitropyridin-2-yl)acetamide (2.48 g, 8.38 mmol) in EtOH (15.00 mL), Fe (2.47 g, 41.92 mmol) and NH4Cl (2.36 g, 41.92 mmol (dissolved in H2O (10.00 mL))) were added portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 80 °C for 1.5 h under a N2 atmosphere. The residue was purified by silica gel column, eluting with 35% DCM in MeOH to give N-(5-aminopyridin-2-yl)-2-(morpholin-4-yl)acetamide (2.00 g, 99.0%) as a yellow oil.

[0346] tert-Butyl 7-({6-[2-(morpholin-4-yl)acetamido]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate: To a stirred solution of N-(5-aminopyridin-2-yl)-2-(morpholin-4-yl)acetamide (280.00 mg, 1.07 mmol) in 1,4-dioxane (5.00 mL), tert-butyl 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (331.89 mg, 1.17 mmol), EPhos Pd G4 (103.13 mg, 0.11 mmol), Ephos (120.08 mg, 0.21 mmol) and cesium carbonate (1097.40 mg, 3.20 mmol) were added portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 120 °C for 1 h under a N2 atmosphere. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column, eluting with 7% MeOH in DCM to give tert-butyl 7-({6-[2-(morpholin-4-yl)acetamido]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (600.00 mg, 100%) as a yellow solid.

[0347] 2-(Morpholin-4-yl)-N-{5-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}acetamide: To a stirred solution of tert-butyl 7-({6-[2-(morpholin-4-yl)acetamido]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (630.00 mg, 1.34 mmol) in DCM (5.00 mL) was added TFA (1.00 mL) portionwise at 0 °C under a N2 atmosphere. The resulting mixture was stirred at room temperature for 1 h under a N2 atmosphere. The resulting mixture was adjusted to pH = 12 with NaOH (4N) and then extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure to give 2-(morpholin-4-yl)-N-{5-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}acetamide (550.00 mg, crude product) as a pale yellow solid.

[0348] tert-Butyl 8-methyl-7-[7-({6-[2-(morpholin-4-yl)acetamido]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of 2-(morpholin-4-yl)-N-{5-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}acetamide (280.00 mg, 0.66 mmol) in 1,4-dioxane (5.00 mL) were added tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (252.02 mg, 0.73 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (58.47 mg, 0.07 mmol), and Cs2CO3 (680.29 mg, 1.98 mmol) portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 100 °C for 1 h under a N2 atmosphere. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with 4% MeOH in DCM to give tert-butyl 8-methyl-7-[7-({6-[2-(morpholin-4-yl)acetamido]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (120.00 mg, 27.5%) as a yellow solid.

[0349] N-{5-[(6-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}-2-(morpholin-4-yl)acetamide: To a stirred solution of tert-butyl 8-methyl-7-[7-({6-[2-(morpholin-4-yl)acetamido]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (100.00 mg, 1.62 mmol) in DCM (4.00 mL) was added TFA (0.80 mL) portionwise at 100 °C under a N2 atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X Bridge Prep OBD C18 column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 25% B - 55% B over 9 minutes, 55% B, wavelength: 254 nm; RT1 (min): 7) to give N-{5-[(6-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]pyridin-2-yl}-2-(morpholin-4-yl)acetamide (35.50 mg, 42.3%) as a white solid.

[0350] HPLC: Purity 95.26%, RT = 1.94 min. MS: m / z = 517.30 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.97 (s, 1H), 8.56 (d, J = 2.7 Hz, 1H), 8.07 (dd, J = 8.9, 2.7 Hz, 1H), 8.02 - 7.94 (m, 2H), 7.26 (s, 1H), 6.57 (s, 1H), 5.50 (t, J = 2.7 Hz, 1H), 4.18 (t, J = 4.4 Hz, 2H), 3.99 (s, 2H), 3.63 (t, J = 4.6 Hz, 4H), 3.33 - 3.26 (m, 2H), 3.16 (s, 2H), 3.09 (t, J = 5.7 Hz, 2H), 2.82 (t, J = 5.7 Hz, 2H), 2.54 (d, J = 4.6 Hz, 4H), 2.05 (d, J = 18.0 Hz, 3H). Example 33: Synthesis of Compound 33 2-(Dimethylamino)-N-{2-methyl-4-[(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}acetamide

Chemical Structure

[0351] tert-Butyl 7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate: To a stirred mixture of 3-methyl-4-nitroaniline (499.81 mg, 3.28 mmol, 1.50 equiv) and tert-butyl 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (600.00 mg, 2.19 mmol) in 1,4-dioxane (18.00 mL) were added PEPPSI-IPr (142.44 mg, 0.22 mmol) and Cs2CO3 (1500.83 mg, 4.38 mmol) portionwise at 25 °C. The resulting mixture was stirred at 100 °C for 2 h under an argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give tert-butyl 7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (530.00 mg, 62.92%) as a pale yellow solid.

[0352] N-(3-Methyl-4-nitrophenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine: To a stirred mixture of tert-butyl 7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (520.00 mg, 1.35 mmol) in DCM (10.00 mL) was added TFA (2.00 mL) at room temperature. After stirring at room temperature for 1 h, the mixture was concentrated under reduced pressure. The resulting mixture was quenched with water. The mixture was acidified / basified to pH = 8 with Na2CO3 (aqueous solution). The resulting mixture was filtered and the filter cake was washed with water. The filter cake was concentrated under reduced pressure to give N-(3-methyl-4-nitrophenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine (290.00 mg, 75.37%) as a yellow solid.

[0353] tert-Butyl 8-methyl-7-{7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a solution of N-(3-methyl-4-nitrophenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine (280.00 mg, 0.98 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (490.92 mg, 1.47 mmol) in 1,4-dioxane (15.00 mL) were added Cs2CO3 (1011.37 mg, 2.95 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (86.93 mg, 0.10 mmol). The resulting mixture was stirred at 100 °C for 24 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:2), to give tert-butyl 8-methyl-7-{7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (430.00 mg, 75.69%) as a yellow solid.

[0354] tert-Butyl 7-{7-[(4-amino-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a solution of tert-butyl 8-methyl-7-{7-[(3-methyl-4-nitrophenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (420.00 mg, 0.73 mmol) in MeOH (10.00 mL) was added Raney Ni (186.79 mg, 0.22 mmol) at room temperature. The mixture was stirred at room temperature for 2 h under a H2 atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (50 mL), and the filtrate was concentrated under reduced pressure to give tert-butyl 7-{7-[(4-amino-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (330.00 mg, 86.84%) as a pale yellow solid.

[0355] tert-Butyl 7-[7-({4-[2-(dimethylamino)acetamido]-3-methylphenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of tert-butyl 7-{7-[(4-amino-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (150.00 mg, 0.29 mmol) and 2N-(dimethylamino)acetic acid (37.36 mg, 0.34 mmol) in DMF (15.00 mL) was added DIEA (0.16 mL, 0.86 mmol) at room temperature. The mixture was then cooled to 0 °C and HATU (229.61 mg, 0.57 mmol) was slowly added at 0 °C. After stirring at room temperature for 4 h, the resulting mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give tert-butyl 7-[7-({4-[2-(dimethylamino)acetamido]-3-methylphenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (120.00 mg, 70.34%) as a yellow solid.

[0356] 2-(Dimethylamino)-N-{2-methyl-4-[(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}acetamide: To a stirred mixture of tert-butyl 7-[7-({4-[2-(dimethylamino)acetamido]-3-methylphenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (120.00 mg, 0.20 mmol) in DCM (5.00 mL) was added TFA (1.00 mL) at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 ExRS, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: from 25% B to 55% B in 8 minutes, 55% B; wavelength: 254 nm; RT1 (min): 7, number of runs: 2) to give 2-(dimethylamino)-N-{2-methyl-4-[(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}acetamide (36.40 mg, 36.84%) as an off-white solid.

[0357] HPLC: 99.5% purity, RT = 2.17 min. MS: m / z = 488.30 [M+H] + 11H NMR (300 MHz, methanol-d4): δ 7.86 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.27 (dd, J = 8.5, 2.5 Hz, 1H), 6.95 (s, 1H), 4.43 (t, J = 4.4 Hz, 2H), 4.20 (s, 2H), 4.01 (t, J = 3.3 Hz, 2H), 3.98 - 3.90 (m, 4H), 3.51 (t, J = 4.4 Hz, 2H), 3.25 (dd, J = 11.4, 5.5 Hz, 6H), 2.98 (t, J = 5.8 Hz, 2H), 2.35 (s, 3H), 2.22 (s, 3H). Example 34: Synthesis of Compound 34 N-{2-Methyl-4-[(6-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}-2-(morpholin-4-yl)acetamide [Chemical Structure]

[0358] tert-Butyl 8-methyl-7-[7-({3-methyl-4-[2-(morpholin-4-yl)acetamido]phenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of tert-butyl 7-{7-[(4-amino-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (120.00 mg, 0.23 mmol) and 2-(morpholin-4-yl)acetic acid (42.07 mg, 0.28 mmol) in DMF (12.00 mL) was added DIEA (0.13 mL, 0.69 mmol) at room temperature. The mixture was then cooled to 0 °C and HATU (183.68 mg, 0.46 mmol) was slowly added at 0 °C. After stirring at room temperature for 4 h, the resulting mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give tert-butyl 8-methyl-7-[7-({3-methyl-4-[2-(morpholin-4-yl)acetamido]phenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (140.00 mg, 94.85%) as a yellow solid.

[0359] N-{2-Methyl-4-[(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}-2-(morpholin-4-yl)acetamide: To a stirred mixture of tert-butyl 8-methyl-7-[7-({3-methyl-4-[2-(morpholin-4-yl)acetamido]phenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (130.00 mg, 0.20 mmol) in DCM (5.00 mL) was added TFA (1.00 mL) at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 22% B to 52% B in 9 minutes, 52% B, wavelength: 254 nm; RT1 (min): 7) to give N-{2-methyl-4-[(6-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}-2-(morpholin-4-yl)acetamide (24.30 mg, 22.53%) as an off-white solid.

[0360] HPLC: 99.2% purity, RT = 2.29 min. MS: m / z = 530.25 [M+H] + 11H NMR (300 MHz, methanol-d4): δ 7.86 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.27 (dd, J = 8.5, 2.5 Hz, 1H), 6.95 (s, 1H), 4.43 (t, J = 4.4 Hz, 2H), 4.20 (s, 2H), 4.01 (t, J = 3.3 Hz, 2H), 3.98 - 3.90 (m, 4H), 3.51 (t, J = 4.4 Hz, 2H), 3.25 (dd, J = 11.4, 5.5 Hz, 6H), 2.98 (t, J = 5.8 Hz, 2H), 2.35 (s, 3H), 2.22 (s, 3H). Example 35: Synthesis of Compound 35 2-Methyl-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-N-(1-methylazetidin-3-yl)benzamide [Chemical Structure]

[0361] tert-Butyl 2-{[4-(methoxycarbonyl)-3-methylphenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a stirred mixture of tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (1.00 g, 3.02 mmol) and methyl 4-amino-2-methylbenzoate (1.00 g, 6.04 mmol) in 1,4-dioxane (25.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (0.27 g, 0.30 mmol) and Cs2CO3 (2.07 g, 6.04 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was stirred at 100 °C for 2 hours. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give tert-butyl 2-{[4-(methoxycarbonyl)-3-methylphenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (1.20 g, 98.6%) as a yellow solid.

[0362] Methyl 2-methyl-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)benzoate: To a stirred mixture of tert-butyl 2-{[4-(methoxycarbonyl)-3-methylphenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (1.26 g, 2.79 mmol, 1.00 equiv) and TFA (5.00 mL) in DCM (20.00 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was basified to pH = 9 with saturated NaHCO3 (aqueous solution). The resulting mixture was quenched with ice / water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This afforded methyl 2-methyl-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)benzoate (800.00 mg, 85.4%) as a yellow solid.

[0363] tert-Butyl 7-(2-{[4-(Methoxycarbonyl)-3-methylphenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of methyl 2-methyl-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)benzoate (1.00 g, 2.73 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (1.80 g, 5.46 mmol) in 1,4-dioxane (20.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (0.24 g, 0.27 mmol) and Cs2CO3 (1.87 g, 5.46 mmol) at room temperature. The mixture was stirred at 100 °C for 2 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give tert-butyl 7-(2-{[4-(Methoxycarbonyl)-3-methylphenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (1.33 g, 86.8%) as a yellow solid.

[0364] 4-[(7-{1-[(tert-Butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-2-methylbenzoic acid: To a stirred mixture of tert-butyl 7-(2-{[4-(methoxycarbonyl)-3-methylphenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (370.00 mg, 0.48 mmol, 1.00 equiv) and NaOH (60.96 mg, 1.45 mmol, 3.00 equiv) in MeOH (10.00 mL) and H2O (3.00 mL) at room temperature. The mixture was stirred at 50 °C for 3 hours. The mixture was acidified to pH = 7 with HCl (4 N) and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 4-[(7-{1-[(tert-Butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-2-methylbenzoic acid (980.00 mg, crude product) as a gray solid.

[0365] 8-Methyl-7-[2-({3-methyl-4-[(1-methylazetidin-3-yl)carbamoyl]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of 4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-2-methylbenzoic acid (150.00 mg, 0.23 mmol) and 1-methylazetidin-3-amine (39.49 mg, 0.46 mmol) in DMF (10.00 mL) were added HATU (275.27 mg, 0.69 mmol) and DIEA (62.36 mg, 0.46 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with ice / water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give tert-butyl 8-methyl-7-[2-({3-methyl-4-[(1-methylazetidin-3-yl)carbamoyl]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (80.00 mg, 52.1%) as a yellow solid.

[0366] 2-Methyl-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-N-(1-methylazetidin-3-yl)benzamide: A mixture of tert-butyl 8-methyl-7-[2-({3-methyl-4-[(1-methylazetidin-3-yl)carbamoyl]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (80.00 mg, 0.12 mmol) and TFA (1.00 mL) in DCM (5.00 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X Bridge Prep OBD C18 column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 22% B to 50% B in 9 minutes, 50% B, wavelength: 254 nm; RT1 (min): 7) to give 2-methyl-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-N-(1-methylazetidin-3-yl)benzamide (22.70 mg, 23.4%) as a white solid.

[0367] HPLC: 98.2% purity, RT = 2.45 min. MS: m / z = 501.25 [M+H] + 11H NMR (300 MHz, DMSO-d6): 9.63 (s, 1H), 8.46 (d, J = 7.2 Hz, 1H), 8.37 (s, 1H), 7.68 (dd, J = 8.4, 2.2 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.29 (t, J = 4.2 Hz, 2H), 5.54 (d, J = 2.7 Hz, 1H), 4.38 (h, J = 7.1 Hz, 1H), 4.20 (t, J = 4.2 Hz, 2H), 3.97 (s, 2H), 3.56 (t, J = 7.3 Hz, 2H), 3.31 (d, J = 3.6 Hz, 2H), 3.12 (d, J = 5.8 Hz, 2H), 2.97 - 2.86 (m, 2H), 2.81 (d, J = 5.6 Hz, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 2.04 (s, 3H). Example 36: Synthesis of Compound 36 3-Methyl-N5-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-N2-[2-(morpholin-4-yl)ethyl]pyridine-2,5-diamine

Chemical Structure

[0368] 3-Methyl-N-[2-(morpholin-4-yl)ethyl]-5-nitropyridin-2-amine: To a stirred solution of 2-fluoro-3-methyl-5-nitropyridine (2.50 g, 15.21 mmol) and Cs2CO3 (10.01 g, 30.43 mmol) in DMF (25.00 mL) was added 2-(morpholin-4-yl)ethan-1-amine (2.50 g, 18.26 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 3-methyl-N-[2-(morpholin-4-yl)ethyl]-5-nitropyridin-2-amine (3.00 g, crude) as a yellowish-brown solid.

[0369] tert-Butyl N-(3-methyl-5-nitropyridin-2-yl)-N-[2-(morpholin-4-yl)ethyl]carbamate: A solution of 3-methyl-N-[2-(morpholin-4-yl)ethyl]-5-nitropyridin-2-amine (2.10 g, 7.89 mmol), Boc2O (5.00 g, 22.68 mmol), DMAP (100.00 mg, 0.85 mmol) and TEA (3.43 mL, 23.47 mmol) in DCM (10.00 mL) was stirred at 30 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 7:3) to give tert-butyl N-(3-methyl-5-nitropyridin-2-yl)-N-[2-(morpholin-4-yl)ethyl]carbamate (1.10 g, 34.6%) as a yellow solid.

[0370] tert-Butyl N-(5-amino-3-methylpyridin-2-yl)-N-[2-(morpholin-4-yl)ethyl]carbamate: A solution of tert-butyl N-(3-methyl-5-nitropyridin-2-yl)-N-[2-(morpholin-4-yl)ethyl]carbamate (1.10 g, 3.00 mmol), NH4Cl (810.00 mg, 14.99 mmol) and Fe (810.00 mg, 14.21 mmol) in EtOH (12.00 mL) and water (6.00 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with water. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column, eluting with DCM / MeOH = 7:1 to give tert-butyl N-(5-amino-3-methylpyridin-2-yl)-N-[2-(morpholin-4-yl)ethyl]carbamate (1.00 g, 99.0%) as a yellow solid.

[0371] tert-Butyl N-[3-methyl-5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)pyridin-2-yl]-N-[2-(morpholin-4-yl)ethyl]carbamate: To a stirred solution of tert-butyl N-(5-amino-3-methylpyridin-2-yl)-N-[2-(morpholin-4-yl)ethyl]carbamate (300.00 mg, 0.89 mmol) and 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine hydrochloride (320.00 mg, 1.43 mmol) in 1,4-dioxane (5.00 mL) were added EPhos Pd G4 (80.00 mg, 0.08 mmol), Ephos (80.00 mg, 0.14 mmol, 0.16) and Cs2CO3 (900.00 mg, 2.62 mmol) at room temperature. The resulting mixture was stirred at 120 °C for 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 7:3) to give tert-butyl N-[3-methyl-5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)pyridin-2-yl]-N-[2-(morpholin-4-yl)ethyl]carbamate (370.00 mg, 68.4%) as a yellow solid.

[0372] tert-Butyl 7-{2-[(6-{[(tert-Butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-5-methylpyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: A solution of tert-butyl N-[3-methyl-5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)pyridin-2-yl]-N-[2-(morpholin-4-yl)ethyl]carboxylate (350.00 mg, 0.58 mmol), tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (220.00 mg, 0.63 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (63.00 mg, 0.07 mmol) and Cs2CO3 (732.00 mg, 2.13 mmol) in 1,4-dioxane (5.00 mL) was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 7:3) to give tert-butyl 7-{2-[(6-{[(tert-Butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-5-methylpyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (285.00 mg, 49.3%) as a yellow solid.

[0373] 3-Methyl-N5-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-N2-[2-(morpholin-4-yl)ethyl]pyridine-2,5-diamine: A solution of tert-butyl 7-{2-[(6-{[(tert-butoxy)carbonyl][2-(morpholin-4-yl)ethyl]amino}-5-methylpyridin-3-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (275.00 mg, 0.34 mmol) and TFA (2.00 mL) in DCM (6.00 mL) was stirred at room temperature for 6 hours under a nitrogen atmosphere. The crude product was purified by preparative HPLC under the following conditions: column: YMC-Actus Triart C18 ExRS, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 18% B - 48% B in 8 minutes, 48% B, wavelength: 254 nm; RT1 (min): 7). Thereby, 3-methyl-N5-(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)-N2-[2-(morpholin-4-yl)ethyl]pyridine-2,5-diamine (42.50 mg, 21.9%) was obtained as an orange solid.

[0374] HPLC: 90.98% purity, RT = 2.11 min. MS: m / z = 518.40 [M+H] + 11H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.22 (s, 1H), 8.16 (d, J = 2.5 Hz, 1H), 7.47 (d, J = 2.5 Hz, 1H), 7.26 (s, 1H), 5.53 - 5.42 (m, 2H), 4.18 (t, J = 4.4 Hz, 2H), 3.89 (s, 2H), 3.58 (t, J = 4.7 Hz, 5H), 3.42 (q, J = 6.4 Hz, 2H), 3.09 (d, J = 6.1 Hz, 2H), 2.74 (s, 2H), 2.41 (s, 5H), 2.03 (s, 6H). Example 37: Synthesis of Compound 37 2-[(6-{8-Chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one [Chemical formula]

[0375] tert-Butyl 8-chloro-7-[7-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred solution of tert-butyl 7-bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (200.00 mg, 0.53 mmol) and 6-methyl-2-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (182.67 mg, 0.53 mmol) in 1,4-dioxane (5.00 mL) were added Cs2CO3 (541.52 mg, 1.58 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (46.54 mg, 0.05 mmol) portionwise at room temperature under a N2 atmosphere. The resulting mixture was stirred at 100 °C overnight under a N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with 8% MeOH in DCM to afford the crude product. The crude product was re-purified by C18 flash column eluting with 45% ACN in water to give tert-butyl 8-chloro-7-[7-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (160.00 mg, 36.17%) as a yellow solid.

[0376] 2-[(6-{8-Chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one: To a stirred solution of tert-butyl 8-chloro-7-[7-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (150.00 mg, 0.26 mmol) in DCM (3.00 mL) was added dropwise TFA (1.00 mL) at room temperature under a N2 atmosphere. The resulting mixture was stirred at 25 °C for 2 h under a N2 atmosphere. The residue was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 18% B to 48% B over 8 min, 48% B, wavelength: 254 nm; RT1 (min): 7) to give 2-[(6-{8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (33.80 mg, 26.73%) as an off-white solid.

[0377] HPLC: 98.23% purity, RT = 2.76 min. MS: m / z = 481.10 [M+H] + 1 1H NMR (300 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.94 (s, 1H), 7.28 (s, 1H), 7.01 (s, 1H), 6.18 (s, 1H), 6.08 (s, 1H), 4.91 (s, 2H), 4.23 (s, 2H), 4.09 (s, 2H), 3.81 (s, 2H), 3.20 (s, 3H), 3.02 (s, 2H), 2.92 (m, 2H), 2.77 (s, 3H), 2.51 (s, 1H). Example 38: Synthesis of Compound 38 N,N-Dimethyl-1-{2-methyl-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]benzoyl}azetidin-3-amine

Chemical Structure

[0378] tert-Butyl 7-[2-({4-[3-(dimethylamino)azetidine-1-carbonyl]-3-methylphenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of 4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-2-methylbenzoic acid (150.00 mg, 0.23 mmol) and N,N-dimethylazetidin-3-amine (45.93 mg, 0.46 mmol) in DMF (10.00 mL) were added HATU (275.27 mg, 0.69 mmol) and DIEA (62.36 mg, 0.46 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with ice / water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give tert-butyl 7-[2-({4-[3-(dimethylamino)azetidine-1-carbonyl]-3-methylphenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (100.00 mg, 67.9%) as a blue solid.

[0379] N,N-Dimethyl-1-{2-methyl-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]benzoyl}azetidin-3-amine: To a stirred mixture of tert-butyl 7-[2-({4-[3-(dimethylamino)azetidine-1-carbonyl]-3-methylphenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (160.00 mg, 0.23 mmol) and TFA (1.00 mL) in DCM (5.00 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X Bridge Prep OBD C18 column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN, flow rate: 60 mL / min; gradient: 22% B - 50% B in 9 minutes, 50% B, wavelength: 254 nm; RT1 (min): 7) to give N,N-dimethyl-1-{2-methyl-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]benzoyl}azetidin-3-amine (26.70 mg, 22.4%) as a green solid.

[0380] HPLC: 98.83% purity, RT = 2.33 min. MS: m / z = 515.25 [M+H] + 11H NMR (300 MHz, methanol-d4): δ 8.31 (s, 1H), 7.72 (dd, J = 8.3, 2.2 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.30 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.37 - 4.28 (m, 2H), 4.28 - 4.16 (m, 1H), 4.14 - 4.03 (m, 1H), 4.03 (s, 2H), 3.98 (dd, J = 10.6, 5.1 Hz, 1H), 3.86 (dd, J = 9.6, 5.1 Hz, 1H), 3.44 (t, J = 4.4 Hz, 2H), 3.21 (dt, J = 13.0, 6.4 Hz, 3H), 2.89 (t, J = 5.4 Hz, 2H), 2.38 (s, 3H), 2.19 (d, J = 13.1 Hz, 9H). Example 39: Synthesis of 2-Methyl-4-[(7-{8-Methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-N-[2-(morpholin-4-yl)ethyl]benzamide

Chemical Structure

[0381] tert-Butyl 8-methyl-7-{2-[(3-methyl-4-{[2-(morpholin-4-yl)ethyl]carbamoyl}phenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate: To a stirred mixture of 4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-2-methylbenzoic acid (150.00 mg, 0.23 mmol) and 2-(morpholin-4-yl)ethan-1-amine (59.69 mg, 0.46 mmol) in DMF (10.00 mL) were added HATU (275.27 mg, 0.69 mmol) and DIEA (62.36 mg, 0.46 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with ice / water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give tert-butyl 8-methyl-7-{2-[(3-methyl-4-{[2-(morpholin-4-yl)ethyl]carbamoyl}phenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (150.00 mg, 98.4%) as a yellow solid.

[0382] 2-Methyl-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-N-[2-(morpholin-4-yl)ethyl]benzamide: To a...

Claims

1. A compound of formula I: 【Chemical 1】 [wherein, R １ and R ２ each independently is selected from the group consisting of hydrogen and C １ to C ６ alkyl, C ３ to C ６ cycloalkyl and C １ to C ６ haloalkyl, R １ and R ２ together with the carbon to which they are attached form a C ３ -C ６ carbocyclic ring, R ３ is selected from the group consisting of hydrogen and C １ to C ６ alkyl, and R ４ is selected from the group consisting of hydrogen, halogen, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl and C １ to C ６ haloalkyl R ５ and R ６ each independently represents hydrogen, halogen, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl and C １ to C ６ haloalkyl, and is selected from the group consisting of: R ７ is selected from the group consisting of hydrogen and C １ to C ６ alkyl, and X is selected from the group consisting of N and CH, Y is selected from the group consisting of N and CH, W is selected from the group consisting of N and CR ８ and is selected from the group consisting of Z is selected from the group consisting of N and CH, R ８ and R ９ are each independently hydrogen, halogen, optionally substituted C １ to C ６ alkyl, optionally substituted C ３ to C ６ cycloalkyl, C １ to C ６ haloalkyl, optionally substituted C ２ to C ８ heterocycle, optionally substituted heteroaromatic, optionally substituted C ６ to C １４ aromatic, -(CH ２ ) ｍ -NR'R", -NR'-(CH ２ ) ｍ -NR'R", -(CH ２ ) ｎ -OR １１ , -O-(CH ２ ) ｎ -OR １１ , 【Chemical Formula 2】 is selected from the group consisting of, R １０ is, for each occurrence, independently, C １ to C ６ alkyl, -NR'R", -(CH ２ ) ｐ -OR １１ , -(CH ２ ) ｎ -O-(CH ２ ) ｎ -OR １１ and -(CH ２ ) ｍ -NR'R" selected from the group consisting of, R’ and R” are, independently for each occurrence, hydrogen, C １ -C ６ alkyl and C ３ -C ６ selected from the group consisting of cycloalkyl, R １２ and R １３ each occurrence of which, independently, is selected from the group consisting of hydrogen and C １ to C ６ alkyl, and R １２ and R １３ together with the carbon to which they are attached can form a C ３ to C ６ carbocyclic ring R １１ 、 R １４ 、 R １５ and R １６ for each occurrence, independently, is selected from the group consisting of hydrogen, C １ -C ６ alkyl, optionally substituted C ２ -C ８ heterocyclic ring, optionally substituted heteroaromatic, optionally substituted C ６ -C １４ aromatic, m, n, o, p and q are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6]], or an enantiomer or diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof.

2. R １ and R ２ is hydrogen, the compound according to claim 1.

3. R ３ is selected from the group consisting of hydrogen and -CH ３ The compound according to claim 1.

4. R ４ is hydrogen, 【Chemical 3】 Cl, -CH ２ CH ３ and -CH ３ The compound according to claim 1, selected from the group consisting of

5. R ５ and R ６ is hydrogen, the compound according to claim 1.

6. R ７ is selected from the group consisting of hydrogen and -CH ３ The compound according to claim 1

7. The compound according to claim 1, wherein X and Y are CH.

8. The compound according to claim 1, wherein X and Y are N.

9. The compound according to claim 1, wherein X is N and Y is CH.

10. W is CR ８ The compound according to claim 1, wherein

11. R ８ is 【Chemical Formula 4】 The compound according to claim 10, selected from the group consisting of.

12. R ８ is 【Chemical Formula 5】 The compound according to claim 10, selected from the group consisting of.

13. R ８ is 【Chemical Formula 6】 The compound according to claim 10, selected from the group consisting of.

14. R ８ is 【Chemical Formula 7】 The compound according to claim 10, selected from the group consisting of.

15. R ８ is 【Chemical 8】 The compound according to claim 10, selected from the group consisting of.

16. R ９ is Hydrogen, F, Cl, Br, I, -CF ３ , -CH ３ , -CH ２ CH ３ , 【Chemical Formula 9】 The compound according to claim 1, selected from the group consisting of.

17. A compound of formula II 【Chemical 10】 [wherein, B is 【Chemical Formula 11】 selected from the group consisting of, R １７ and R １８ each independently represents hydrogen and C １ to C ６ alkyl, C ３ to C ６ cycloalkyl and C １ to C ６ haloalkyl, and is selected from the group consisting of: R １７ and R １８ together with the carbon to which they are attached form a C ３ -C ６ carbon ring, R １９ is selected from the group consisting of hydrogen and C １ to C ６ alkyl, R ２０ is selected from the group consisting of hydrogen, halogen, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl and C １ to C ６ haloalkyl, R ２１ is selected from the group consisting of hydrogen and C １ to C ６ alkyl, and R ２２ and R ２３ each independently represents hydrogen, halogen, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl and C １ to C ６ haloalkyl, and is selected from the group consisting of R ２４ is selected from the group consisting of hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ６ cycloalkyl and C １ -C ６ haloalkyl R ２５ 、 R ２６ 、 R ２７ and R ２８ each occurrence is, independently, selected from the group consisting of hydrogen and C １ to C ６ alkyl, X' is selected from the group consisting of N and CH, Y' is selected from the group consisting of N and CH, E is selected from the group consisting of N and CH, s and r are independently selected from the group consisting of 1, 2 and 3]], or an enantiomer or diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof.

18. R １７ and R １８ is hydrogen, the compound according to claim 17.

19. R １９ is selected from the group consisting of hydrogen and -CH ３ the compound according to claim 17

20. R ２０ is hydrogen, 【Chemical Formula 12】 Cl, -CH ２ CH ３ and -CH ３ The compound according to claim 17, selected from the group consisting of

21. R ２２ and R ２３ The compound according to claim 17, wherein R and R are hydrogen.

22. R ２１ wherein R is selected from the group consisting of hydrogen and -CH ３ and the compound according to claim 17

23. The compound according to claim 17, wherein X' and Y' are CH.

24. The compound according to claim 17, wherein X' and Y' are N.

25. The compound according to claim 17, wherein X' is N and Y' is CH.

26. The compound according to claim 17, wherein r and s are 1.

27. R ２５ 、R ２６ 、R ２７ and R ２８ is hydrogen, the compound according to claim 17.

28. R ２５ and R ２６ are -CH ３ and R ２７ and R ２８ is hydrogen, the compound according to claim 17.

29. R ２４ is hydrogen, -CH ３ , -CF ３ , CH ２ F ２ and 【Chemical 13】 The compound according to claim 17, selected from.

30. A compound of formula III 【Chemical Formula 14】 [wherein, A is 【Chemical Formula 15】 selected from, R ２９ and R ３０ each independently is selected from the group consisting of hydrogen and C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl and C １ ~C ６ haloalkyl, R ２９ and R ３０ together with the carbon to which they are attached form a C ３ -C ６ carbon ring R ３１ is selected from the group consisting of hydrogen and C １ to C ６ alkyl, R ３２ is selected from the group consisting of hydrogen, halogen, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl and C １ to C ６ haloalkyl R ３３ is selected from the group consisting of hydrogen and C １ to C ６ alkyl, and R ３４ and R ３５ each independently represents hydrogen, halogen, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl and C １ to C ６ haloalkyl, and is selected from the group consisting of R ３６ is selected from the group consisting of hydrogen, optionally substituted C １ -C ６ -C alkyl, optionally substituted C ３ -C ６ -cycloalkyl, -(CH ２ ) ｕ -OR ３ and C １ -C ６ -haloalkyl R ３７ is selected from the group consisting of hydrogen, C １ -C ６ alkyl, C ３ -C ６ cycloalkyl and C １ -C ６ haloalkyl, u is selected from the group consisting of 1, 2, 3, 4, 5 and 6, X'' is selected from the group consisting of N and CH, Y'' is selected from the group consisting of N and CH]], or its enantiomer or diastereomer or mixture or its pharmaceutically acceptable salt.

31. R ２９ and R ３０ is hydrogen, the compound according to claim 30.

32. R ３１ is a compound according to claim 30, selected from the group consisting of hydrogen and -CH ３ ​

33. R ３２ is hydrogen, 【Chemical 16】 Cl, -CH ２ CH ３ and -CH ３ The compound according to claim 30, selected from the group consisting of

34. R ３４ and R ３５ is hydrogen, the compound according to claim 30.

35. R ３３ is a compound according to claim 30, selected from the group consisting of hydrogen and -CH ３ ​

36. The compound according to claim 30, wherein X” and Y” are CH.

37. The compound according to claim 30, wherein X” and Y” are N.

38. The compound according to claim 30, wherein X” is N and Y” is CH.

39. R ３６ is hydrogen, -CH ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH ２ F ２ , 【Chemical 17】 The compound according to claim 30, selected from the group consisting of

40. The compound of formula IV 【Chemical 18】 [wherein, G is 【Chemical Formula 19】 selected from the group consisting of R ３７ 、 R ３８ 、 R ３９ and R ４０ each occurrence of which, independently, is selected from the group consisting of hydrogen, C １ -C ６ alkyl and C ３ -C ６ cycloalkyl R ４１ is, for each replaceable position, independently, hydrogen, halogen, -O-C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, C １ ~C ６ alkyl and C ３ ~C ６ selected from the group consisting of cycloalkyl], or an enantiomer or diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof.

41. R ３７ is -CH ３ and is the compound according to claim 40.

42. R ３８ is -CH ３ and the compound according to claim 40.

43. R ３９ and R ４０ is hydrogen, the compound according to claim 40.

44. R ４１ is hydrogen, -OCH ３ and is selected from the group consisting of F, the compound according to claim 40.

45. The compound of formula V 【Chemical 20】 [wherein, J is 【Chemical 21】 selected from the group consisting of h is 1, 2 or 3, R ４２ is selected from the group consisting of C １ -C ６ alkyl and C ３ -C ６ cycloalkyl] or its enantiomer or diastereomer or mixture or its pharmaceutically acceptable salt.

46. The compound according to claim 45, wherein h is 1.

47. R ４２ is -CH ３ and the compound according to claim 45.

48. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 The compound according to claim 1, selected from the group consisting of, and its pharmaceutically acceptable salt.

49. 【Table 2-1】 【Table 2-2】 【Table 2-3】 The compound according to claim 17, selected from the group consisting of, and its pharmaceutically acceptable salt.

50. 【Table 3-1】 【Table 3-2】 The compound according to claim 30, selected from the group consisting of, and its pharmaceutically acceptable salt.

51. 【Table 4】 The compound according to claim 40, selected from the group consisting of, and its pharmaceutically acceptable salt.

52. 【Table 5-1】 【Table 5-2】 The compound according to claim 45, selected from the group consisting of, and its pharmaceutically acceptable salt.

53. A pharmaceutical composition comprising a compound according to claim 1, 17, 30, 40, 45, 48, 49, 50, 51 or 52 and a pharmaceutically acceptable adjuvant, carrier or vehicle.

54. A method comprising administering to a patient having an HPK-1 mediated disorder a therapeutically effective amount of a compound according to claim 1, 17, 30, 40, 45, 48, 49, 50, 51 or 52 or its pharmaceutically acceptable salt.

55. The method according to claim 54, wherein the HPK1 mediated disorder is cancer, an autoimmune disease and / or an inflammatory disease.

56. The method according to claim 55, wherein the cancer is selected from the group consisting of cancers of the breast, bladder, bone, brain, central and peripheral nervous systems, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, testis, stomach, skin, ureter, vagina, and vulva.

57. The method according to claim 55, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic lupus erythematosus (SLE), type I diabetes mellitus, multiple sclerosis (MS), antiphospholipid antibody syndrome (APS), sclerosing cholangitis, systemic-onset arthritis, inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft-versus-host disease (GvHD), autoimmune skin diseases, uveitis, pernicious anemia, and hypoparathyroidism. Autoimmune diseases include, but are not limited to, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cold urticaria.

58. The method according to claim 55, wherein the therapeutically effective amount of the compound is selected from the range consisting of 0.1 to 100 mg / kg of patient body weight, 0.1 to 50 mg / kg of patient body weight, 0.5 to 50 mg / kg of patient body weight, 1 to 20 mg / kg of patient body weight, 5 to 20 mg / kg of patient body weight, 10 to 20 mg / kg of patient body weight, 10 to 50 mg / kg of patient body weight, and 10 to 100 mg / kg of patient body weight.

59. The method according to claim 55, wherein the compound is administered to the patient continuously, multiple times a day, once a day, every other day, weekly, every other week, monthly, or every other month.

60. The method according to claim 55, wherein the compound is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, or via an implanted reservoir.

61. The method according to claim 54, wherein the compound is administered by injection or infusion techniques into the subcutaneous, intravenous, intramuscular, intra-articular, bursal, intrasternal, intramedullary, hepatic, intralesional, and intracranial sites.

62. A method comprising administering to a patient having an HPK-1-mediated disorder a therapeutically effective amount of the pharmaceutical composition according to claim 53 or a pharmaceutically acceptable salt thereof.

63. The method according to claim 62, wherein the HPK1-mediated disorder is selected from the group consisting of cancer, autoimmune diseases and / or inflammatory diseases.

64. The method according to claim 63, wherein the cancer is selected from the group consisting of cancers of the breast, bladder, bone, brain, central and peripheral nervous systems, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, testis, stomach, skin, ureter, vagina, and vulva.

65. The method according to claim 63, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic lupus erythematosus (SLE), type I diabetes mellitus, multiple sclerosis (MS), antiphospholipid antibody syndrome (APS), sclerosing cholangitis, systemic-onset arthritis, inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft-versus-host disease (GvHD), autoimmune skin diseases, uveitis, pernicious anemia, and hypoparathyroidism. Autoimmune diseases also include, but are not limited to, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cold intolerance.

66. The method according to claim 63, wherein the therapeutically effective amount of the pharmaceutical composition is selected from the range consisting of 0.1 to 100 mg / kg of patient body weight, 0.1 to 50 mg / kg of patient body weight, 0.5 to 50 mg / kg of patient body weight, 1 to 20 mg / kg of patient body weight, 5 to 20 mg / kg of patient body weight, 10 to 20 mg / kg of patient body weight, 10 to 50 mg / kg of patient body weight, and 10 to 100 mg / kg of patient body weight.

67. The method according to claim 63, wherein the pharmaceutical composition is administered to the patient continuously, multiple times a day, once a day, every other day, weekly, bi-weekly, monthly, or every other month.

68. The method according to claim 63, wherein the compound is administered by injection or infusion techniques into the subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intramedullary, intrahepatic, intralesional, and intracranial sites.

69. A kit comprising a therapeutically effective amount of the compound according to claim 1, 17, 30, 40, 45, 48, 49, 50, 51 or 52, or a pharmaceutically acceptable salt or prodrug thereof, and instructions for use of the compound.

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