Tetrahydropyrido [3, 4-d] pyrimidines as HPK1 inhibitors

Abstract

Provided is a tetrahydropyrido [3, 4-d] pyrimidine compound which is a potent HPK1 inhibitor. The compounds are useful in the treatment or prevention of cancer and / or inflammatory and / or autoimmune diseases or symptoms thereof in mammals, in particular humans. The compounds have chemical structures of general formulas (I), (II), (III), (IV) or (V) or enantiomers or diastereomers or mixtures thereof or pharmaceutically acceptable salts thereof. # imgabs0 #

Description

Background of the Invention CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to 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. Technical Field Related technical description

[0002] Hematopoietic progenitor kinase 1 (HPK1) is a serine / threonine kinase expressed in T cells, B cells, and dendritic cells (Jr-Wen Shui, Nature Immunology, 2007, Vol. 8, pp. 84-91). In T cells, HPK1 acts as a rheostat for T cell activation by regulating the molecular circuit of the T cell receptor (TCR) signaling pathway. HPK1 is recruited to the TCR complex and phosphorylates the SLP76 protein, causing its degradation and downregulating the TCR signal intensity. Genetic elimination of HPK1 leads to T cell activation, reduced TCR threshold, increased proliferation, and increased levels of proinflammatory cytokines (such as IL-2, TNF-α, and IFN-γ). The loss of HPK1 expression enhances the activation and antigen presentation of dendritic cells. (Hernandez S. et al., Cell Reports, 2018, Vol. 25, pp. 80-94). HPK1 kinase activity is thought to be essential for conferring HPK1 inhibitory function in a variety of immune cells, such as CD8+, CD4+, DCs, and NK regulatory T cells (Tregs). Inactivation of the kinase domain of HPK1 is sufficient to elicit a robust antitumor immune response (Liu et al., PLoS One, March 26, 2019). HPK1 knockout (KO) and kinase-dead (KD) mice show enhanced T cell function and antitumor efficacy (You D. et al., J. Immunother. Cancer, 2021). Therefore, pharmacological inhibition of HPK1 has the potential to enhance effector T cell function and antitumor activity. Summary of the invention

[0003] In one embodiment, a compound of Formula I is provided: in: R 1 and R 2 are independently selected from the group consisting of hydrogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C6 Haloalkyl; R 1 and R 2 Together with the carbon to which they are attached, they can form C 3 -C 6 Carbon ring; R 3 Selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 4 Selected from the group consisting of hydrogen, halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 5 and R 6 Each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 7 Selected from the group consisting of hydrogen and C 1 -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; W is selected from the group consisting of N and CR 8 ; Z is selected from the group consisting of N and CH; R 8 and R 9 independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 6 Cycloalkyl, C 1 -C 6 haloalkyl, optionally substituted C 2 -C 8 Heterocyclic, optionally substituted heteroaryl, optionally substituted C 6 -C 14 Aryl, -(CH 2 ) m -NR'R",-NR'-(CH 2 ) m -NR'R",-(CH 2 ) n -OR11 ,-O-(CH 2 ) n -OR 11 ; R 10 Each occurrence is independently selected from the group consisting of: C 1 -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"; R' and R" are independently selected from the group consisting of hydrogen, C 1 -C 6 Alkyl and C 3 -C 6 Cycloalkyl; R 12 and R 13 Each occurrence is independently selected from hydrogen and C 1 -C 6 Alkyl; R 12 and R 13 Together with the carbon to which they are attached, they can form C 3 -C 6 Carbon ring; R 11 , R 14 , R 15 and R 16 Each occurrence is independently selected from the group consisting of hydrogen, C 1 -C 6 Alkyl, optionally substituted C 2 -C 8 Heterocyclic, optionally substituted heteroaryl, optionally substituted C 6 -C 14 Aryl; 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.

[0004] In one embodiment, a compound of Formula I is provided, wherein R 1 and R 2 It's hydrogen.

[0005] In one embodiment, a compound of Formula I is provided, wherein R 3 Selected from hydrogen and -CH 3 .

[0006] In one embodiment, a compound of Formula I is provided, wherein R 4 Selected from the group consisting of hydrogen, Cl, -CH 2 CH 3 and -CH 3 .

[0007] In one embodiment, a compound of Formula I is provided, wherein R 5 and R 6 It's hydrogen.

[0008] In one embodiment, a compound of Formula I is provided, wherein R 7 Selected from hydrogen and -CH 3 .

[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 CR 8 .

[0013] In one embodiment, a compound of Formula I is provided, wherein R 8 Select from the following group:

[0014] In one embodiment, a compound of Formula I is provided, wherein R 8 Select from the following group:

[0015] In one embodiment, a compound of Formula I is provided, wherein R 8 Select from the following group:

[0016] In one embodiment, a compound of Formula I is provided, wherein R 8 Select from the following group:

[0017] In one embodiment, a compound of Formula I is provided, wherein R 8 Select from the following group:

[0018] In one embodiment, a compound of Formula I is provided, wherein R 9 Selected from the following group: hydrogen, F, Cl, Br, I, -CF 3, -CH 3 ,-CH 2 CH 3 ,

[0019] In one embodiment, there is provided a compound of formula II in: B is selected from the following group: R 17 and R 18 are independently selected from the group consisting of hydrogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 17 and R 18 Together with the carbon to which they are attached, they can form C 3 -C 6 Carbon ring; R 19 Selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 20 Selected from the group consisting of hydrogen, halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 21 Selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 22 and R 23 Each independently selected from the group consisting of hydrogen, halogen, C 1 -C6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 24 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 hydrogen and C 1 -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.

[0020] In one embodiment, a compound of Formula II is provided, wherein R 17 and R 18 It's hydrogen.

[0021] In one embodiment, a compound of Formula II is provided, wherein R 19 Selected from hydrogen and -CH 3 .

[0022] In one embodiment, a compound of Formula II is provided, wherein R 20 Selected from the group consisting of hydrogen, Cl, -CH 2 CH 3 and -CH 3 .

[0023] In one embodiment, a compound of Formula II is provided, wherein R 22 and R 23 It's hydrogen.

[0024] In one embodiment, a compound of Formula II is provided, wherein R 21 Selected from hydrogen and -CH 3 .

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

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

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

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

[0029] In one embodiment, a compound of Formula II is provided, wherein R 25 , R 26 , R 27 and R 28 It's hydrogen.

[0030] In one embodiment, a compound of Formula II is provided, wherein R 25 and R 26 Yes-CH 3 And R 27 and R 28 It's hydrogen.

[0031] In one embodiment, a compound of Formula II is provided, wherein R 24 Selected from hydrogen, -CH 3 , -CF 3 , CH 2 F 2 and

[0032] In one embodiment, a compound of formula III is provided, in: A is selected from R 29 and R 30 are independently selected from the group consisting of hydrogen, 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, they can form C 3 -C 6 Carbon ring; R 31 Selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 32 Selected from the group consisting of hydrogen, halogen, C1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 33 Selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 34 and R 35 Each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 36 Selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 6 Cycloalkyl, -(CH 2 ) u -OR 37 and C 1 -C 6 Haloalkyl; R 37 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 an enantiomer or diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof.

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

[0034] In one embodiment, a compound of formula III is provided, wherein R 31 Selected from hydrogen and -CH 3 .

[0035] In one embodiment, a compound of formula III is provided, wherein R 32 Selected from the group consisting of hydrogen, Cl, -CH 2 CH 3 and -CH 3 .

[0036] In one embodiment, a compound of formula III is provided, wherein R 34 and R 35 It's hydrogen.

[0037] In one embodiment, a compound of formula III is provided, wherein R 33 Selected from hydrogen and -CH 3 .

[0038] In one embodiment, a compound of formula III is provided, wherein X" and Y" are CH.

[0039] In one embodiment, a compound of formula III is provided, wherein X" and Y" are N.

[0040] In one embodiment, a compound of formula III is provided wherein X" is N and Y" is CH.

[0041] In one embodiment, a compound of formula III is provided, wherein R 36 Selected from hydrogen, -CH 3 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 F 2 ,

[0042] In one embodiment, there is provided a compound of formula IV in: G is selected from the following group:

[0043] R 37 , R 38 , R 39 and R 40 Each occurrence is independently selected from the group consisting of hydrogen, C 1 -C 6 Alkyl and C 3 -C 6 Cycloalkyl;

[0044] R 41 For each substitutable position independently selected from the group consisting of hydrogen, halogen, -OC 1 -C 6Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkyl and C 3 -C 6 Cycloalkyl; or an enantiomer or diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

[0045] In one embodiment, a compound of formula IV is provided, wherein R 37 Yes-CH 3 .

[0046] In one embodiment, a compound of formula IV is provided, wherein R 38 Yes-CH 3 .

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

[0048] In one embodiment, a compound of formula IV is provided, wherein R 41 Selected from the group consisting of hydrogen, -OCH 3 and F.

[0049] In one embodiment, there is provided a compound of V in: J is selected from the following group: h is 1, 2, or 3 R 42 Select from the following group: C 1 -C 6 Alkyl and C 3 -C 6 Cycloalkyl; or an enantiomer or diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof.

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

[0051] In one embodiment, a compound of formula V is provided, wherein R 42 Yes-CH 3 .

[0052] In one embodiment, there is provided a compound of formula I selected from the group consisting of and pharmaceutically acceptable salts thereof.

[0053] In one embodiment, there is provided a compound of formula II selected from the group consisting of and pharmaceutically acceptable salts thereof.

[0054] In one embodiment, there is provided a compound of formula III selected from the group consisting of and pharmaceutically acceptable salts thereof.

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

[0056] In one embodiment, there is provided a compound of formula V selected from the group consisting of and pharmaceutically acceptable salts thereof.

[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 is provided wherein a therapeutically effective amount of a compound having the structure of Formula I, II, III, IV or V, or a pharmaceutically acceptable salt thereof, as defined above is administered to a patient suffering from an HPK1 -mediated disorder.

[0059] In one embodiment, a method is provided wherein a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, II, III, IV or V and a pharmaceutically acceptable adjuvant, carrier or vehicle is administered to a patient suffering from an HPK1-mediated disorder. The HPK1-mediated disorder may be cancer or an autoimmune and / or inflammatory disease.

[0060] The HPK1-mediated disorder can be cancer. The cancer can be one or more of the following: breast cancer, bladder cancer, bone cancer, brain cancer, central and peripheral nervous system cancer, colon cancer, endocrine gland cancer, esophageal cancer, endometrial cancer, germ cell cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, laryngeal cancer and hypopharyngeal cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, small intestine cancer, soft tissue cancer, testicular cancer, stomach cancer, skin cancer, ureter cancer, vaginal cancer and vulvar cancer.

[0061] HPK1-mediated disorders can be autoimmune diseases. The autoimmune disease can be one or more of the following: rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic lupus erythematosus (SLE), type I diabetes, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic arthritis, irritable bowel disease (IBD), scleroderma, Sjogren's disease, vitiligo, polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease (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 can also include, but are not limited to, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis and cryopathy.

[0062] The compound of formula I, II, III, IV or V or its pharmaceutical composition can be used to treat inflammatory diseases and / or immune responses associated with inflammatory diseases. The inflammatory disease can be one or more of non-rheumatoid arthritis, renal fibrosis and liver fibrosis. The inflammatory disease can be interface dermatitis. The inflammatory disease can be a skin disease, such as atopic dermatitis (eczema); sterile inflammation, such as drug-induced liver and / or pancreatic inflammation; inflammatory liver disease; and / or inflammatory pancreatic disease.

[0063] The therapeutically effective amount of a compound or pharmaceutical composition can be within the following range: 0.1 to 100 mg / kg patient weight, 0.1 to 50 mg / kg patient weight, 0.5 to 50 mg / kg patient weight, 1 to 20 mg / kg patient weight, 5 to 20 mg / kg patient weight, 10 to 20 mg / kg patient weight, 10 to 50 mg / kg patient weight, and 10 to 100 mg / kg patient 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 two weeks, monthly, or every two months. The compound or pharmaceutical composition can be administered orally, parenterally, by inhalation spray, locally, rectally, nasally, buccally, vaginally, or by an implanted reservoir. The compound can be administered subcutaneously, intravenously, intramuscularly, intraarticularly, intrasynovially, intrasternally, intrathecally, intrahepatically, intralesionally, and by intracranial injection or infusion techniques.

[0064] In one embodiment, a kit is provided, comprising 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 disclosed subject matter may be set forth or become apparent by considering the following detailed description and claims.In addition, it should be understood that the foregoing summary and the following detailed description are exemplary and are intended to provide further explanation without limiting the scope of the claims. DETAILED DESCRIPTION

[0066] Provided herein are chemical structures of Formula I, II, III, IV or V, or prodrugs or pharmaceutically acceptable salts of any of the foregoing, including mixtures thereof in all ratios, which are preferably used to treat and / or prevent cancer, inflammatory and / or autoimmune diseases. Compounds of Formula I, II, III, IV or V may inhibit HPK1 activity. Compounds disclosed herein may have the general formula (I): in: R 1 and R 2 are independently selected from the group consisting of hydrogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 1 and R 2 Together with the carbon to which they are attached, they can form C 3 -C 6 Carbon ring; R 3 Selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 4 Selected from the group consisting of hydrogen, halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 5 and R 6 Each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 7 Selected from the group consisting of hydrogen and C 1 -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; W is selected from the group consisting of N and CR 8 ; Z is selected from the group consisting of N and CH; R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 6 Cycloalkyl, C 1 -C 6 haloalkyl, optionally substituted C 2 -C 8 Heterocyclic, optionally substituted heteroaryl, optionally substituted C 6 -C 14 Aryl, -(CH 2 ) m -NR'R", -NR'-(CH 2 ) m -NR'R", -(CH 2 ) n -OR 11 ,-O-(CH 2 ) n -OR 11 ; R 10 Each occurrence is independently selected from the group consisting of: C 1 -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"; R' and R" are independently selected from the group consisting of hydrogen, C 1 -C 6 Alkyl and C 3 -C 6 Cycloalkyl; R 12 and R 13 Each occurrence is independently selected from hydrogen and C 1 -C 6 Alkyl; R 12 and R13 Together with the carbon to which they are attached, they can form C 3 -C 6 Carbon ring; R 11 , R 14 , R 15 and R 16 Each occurrence is independently selected from the group consisting of hydrogen, C 1 -C 6 Alkyl, optionally substituted C 2 -C 8 Heterocyclic, optionally substituted heteroaryl, optionally substituted C 6 -C 14 Aryl; m, n, o, p and q are each independently selected from the group consisting of 1, 2, 3, 4, 5 and 6; or an enantiomer or diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof; The compounds of the present disclosure may have the general formula II: in: B is selected from the following group: R 17 and R 18 are independently selected from the group consisting of hydrogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 17 and R 18 Together with the carbon to which they are attached, they can form C 3 -C 6 Carbon ring; R 19 Selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 20 Selected from the group consisting of hydrogen, halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 21 Selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 22 and R23 Each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 24 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 -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 1, 2 and 3, or an enantiomer or diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof; The compounds of the present disclosure may have the general formula III in: A is selected from R 29 and R 30 are independently selected from the group consisting of hydrogen, 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, they can form C 3 -C 6 Carbon ring; R 31 Selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 32 Selected from the group consisting of hydrogen, halogen, C 1 -C 6 Alkyl, C 3 -C6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 33 Selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 34 and R 35 Each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl and C 1 -C 6 Haloalkyl; R 36 Selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 6 Cycloalkyl, -(CH 2 ) u -OR 37 and C 1 -C 6 Haloalkyl; R 37 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 an enantiomer or diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof: The compounds of the present disclosure may have the general formula IV in: G is selected from the following group: R 37 , R 38 , R 39 and R 40 Each occurrence is independently selected from the group consisting of hydrogen, C 1 -C 6 Alkyl and C 3 -C 6 Cycloalkyl; R 41For each substitutable position independently selected from the group consisting of hydrogen, halogen, -OC 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkyl and C 3 -C 6 Cycloalkyl; or an enantiomer or diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof; And the compounds of the present disclosure may have the general formula V in: J is selected from the following group: h is 1, 2, or 3 R 42 Select from the following group: C 1 -C 6 Alkyl and C 3 -C 6 Cycloalkyl; or an enantiomer or diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

[0067] The alkyl group may be a straight chain or branched 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 group is not particularly limited. In some embodiments, the alkyl group may have a specified number of carbon atoms, such as 1-6.

[0068] Halogen may refer to F, Cl, Br or I. Haloalkyl may refer to an alkyl group to which one or more halogens are bonded. An example of a haloalkyl group may include CF 3 .

[0069] Heterocyclic group is a monovalent group formed by removing hydrogen atoms from any ring atom of a heterocyclic compound. It can include one or more heteroatoms. Heteroatoms can refer to one or more of oxygen, sulfur, nitrogen, phosphorus or any oxidized form thereof. Heterocycle, heterocyclic radical and heterocycle can be used interchangeably and refer to a stable 5 to 7-membered monocyclic or 6 to 14-membered bicyclic heterocyclic moiety, which is either saturated or partially unsaturated, and in addition to carbon atoms, has one or more, preferably 1 to 4 heteroatoms as defined above. Heterocycle can be connected to its side group at any heteroatom or carbon atom to obtain a stable structure, and any ring atom can be optionally substituted. Examples of saturated or partially unsaturated heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dioxanyl, oxazepine Thiazepine The heterocyclic radical may include a radical in a heterocyclic ring fused to one or more aryl, heteroaryl or cycloaliphatic rings, wherein the radical or point of attachment is located on the heterocyclic ring. The heterocyclic radical may be monocyclic or bicyclic.

[0070] Partially unsaturated can refer to a ring portion that includes at least one double bond or triple bond. It can include a ring with multiple unsaturated sites, but it is not intended to include aryl or heteroaryl moieties. The term unsaturated can refer to a portion having one or more unsaturated units.

[0071] Aryl (aromatic) can refer to a single aryl or a larger part, such as aralkyl, aralkyloxy and / or aryloxyalkyl. It can refer to a monocyclic and bicyclic ring. At least one ring in the system can be aromatic. Each ring in the system can contain 3-7 members. Exemplary aryl includes but is not limited to phenyl, biphenyl, naphthyl, anthracenyl, etc., which optionally include 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, such as indanyl, phthalimide, naphthalenediimide, phenanthridinyl, tetrahydronaphthyl, etc.

[0072] Heteroaryl (heteroaromatic) can refer to a part of a single heteroaryl or a larger part (such as heteroarylalkyl or heteroarylalkoxy). It can refer to a group with 5-14 ring atoms, preferably 5 or 6 ring atoms. In addition to carbon atoms, heteroaryl can also include 1 to 5 heteroatoms as provided above. Heteroaryl includes but is not limited to thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. Heteroaryl can also include a group in which a heteroaromatic ring is fused with one or more aryl, cycloaliphatic and / or heterocyclic rings, wherein the group or point connected is located 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, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido [2,3-b] -1, 4-oxazine -3 (4H) -one. Heterocyclic groups are optionally monocyclic or bicyclic. Heteroaralkyl groups may refer to alkyl groups substituted with heteroaryl groups, wherein the alkyl and heteroaryl moieties are independently and optionally substituted. The term optionally substituted may refer to the replacement of one or more hydrogens of a specified moiety with a suitable substituent. Unless otherwise specified, an optionally substituted group has a suitable substituent at each substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent may be the same or different at each position. Typical substituents include, but are not limited to: -F, -Cl, -Br, -I, deuterium, -OH, protected hydroxy, alkoxy, oxo, thioxo, -NO 2 、-CN、CF 3 、N 3 、-NH 2 , 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)-carbocyclyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocyclyl, -CONH 2 , -CONH-alkyl, -CONH-alkenyl, -CONH-alkynyl, -CONH-carbocyclyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocyclyl, -OCO 2 -alkyl, -OCO 2 -Alkenyl, -OCO 2 -Alkynyl, -OCO 2 -Carbocyclic group, -OCO 2 -Aryl, -OCO 2 -heteroaryl, -OCO 2 -heterocyclic group, -OCONH 2 , -OCONH-alkyl, -OCONH-alkenyl, -OCONH-alkynyl, -OCONH-carbocyclyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocyclyl, -NHC(O)-alkyl, -NHC(O)-alkenyl, -NHC(O)-alkynyl, -NHC(O)-carbocyclyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclyl, -NHC(O)-alkyl, -NHC(O)-alkenyl, -NHC(O)-alkynyl, -NHC(O)-carbocyclyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclyl, -NHC(O) 2 -alkyl, -NHCO 2 -Alkenyl, -NHCO 2 -Alkynyl, -NHCO 2 -Carbocyclic group, -NHCO 2 -Aryl, -NHCO 2 -heteroaryl, -NHCO2 -Heterocyclic group, -NHC(O)NH 2 , -NHC(O)NH-alkyl, -NHC(O)NH-alkenyl, -NHC(O)NH-alkenyl, -NHC(O)NH-carbocyclyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocyclyl, NHC(S)NH 2 , -NHC(S)NH-alkyl, -NHC(S)NH-alkenyl, -NHC(S)NH-alkynyl, -NHC(S)NH-carbocyclyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocyclyl, -NHC(NH)NH 2 , -NHC(NH)NH-alkyl, -NHC(NH)NH-alkenyl, -NHC(NH)NH-alkenyl, -NHC(NH)NH-carbocyclyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocyclyl, -NHC(NH)-alkyl, -NHC(NH)-alkenyl, -NHC(NH)-alkenyl, -NHC(NH)-carbocyclyl, -NHC(NH)-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocyclyl, -NHC(NH)-alkyl, -NHC(NH)-alkenyl, -NHC(NH)-alkenyl, -NHC(NH)-carbocyclyl, -NHC(NH)-aryl, -NHC(NH) -heteroaryl, -NHC(NH)-heterocyclyl, -C(NH)NH-alkyl, -C(NH)NH-alkenyl, -C(NH)NH-alkynyl, -C(NH)NH-carbocyclyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocyclyl, -S(O)-alkyl, -S(O)-alkenyl, -S(O)-alkynyl, -S(O)-carbocyclyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocyclyl-SO 2 NH 2 、-SO 2 NH-alkyl, -SO 2 NH-alkenyl, -SO 2 NH-alkynyl, -SO 2 NH-Carbocyclic group, -SO 2 NH-aryl, -SO 2 NH-heteroaryl, -SO 2 NH-heterocyclyl, -NHSO 2 -alkyl, -NHSO 2 -Alkenyl, -NHSO 2 -Alkynyl, -NHSO 2 -Carbocyclic group, -NHSO 2 -Aryl, -NHSO 2 -heteroaryl, -NHSO 2 -heterocyclic group, -CH 2 NH 2 、-CH2 SO 2 CH 3 , -mono-, di- or trialkylsilyl, -alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocycle, -heterocycle, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-alkyl, -S-alkenyl, -S-alkynyl, -S-carbocyclyl, -S-aryl, -S-heteroaryl, -S-heterocyclyl or methylthiomethyl.

[0073] The term stable may refer to a compound that is substantially unchanged when subjected to conditions disclosed herein that allow its production or synthesis, detection, recovery, purification and / or use. Pharmaceutically acceptable salts may refer to salts that are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., within the scope of reasonable medical judgment, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the contents of which are incorporated herein by reference. Pharmaceutically acceptable salts of compounds disclosed herein include those derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids, such as 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, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydronaphthalenesulfonate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like.

[0074] Salts can be derived from suitable bases, including alkali metal salts, alkaline earth metal salts and ammonium salts. Representative alkali or alkaline earth salts include sodium, lithium, potassium, calcium, magnesium and the like. When appropriate, other pharmaceutically acceptable salts include: non-toxic ammonium salts, quaternary ammonium salts, and salts formed using counterions and amine cations, such as halide ions, hydroxide ions, carboxylates, sulfate ions, phosphate ions, nitrate ions, alkyl sulfonate ions and aryl sulfonate ions.

[0075] Unless otherwise stated, the structures described herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric and geometric (or conformational)) forms of the structures. For example, R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures 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 stated, all tautomeric forms of the compounds disclosed herein are within the scope of the present invention. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds described in the present invention may be different, it may be desirable to use enantiomers. In some cases, the final product may be separated or even the intermediate may be separated into enantiomeric compounds by chemical or physical measures known to those skilled in the art, or may even be used as is in the synthesis.

[0076] If the compounds disclosed herein or their prodrugs can undergo tautomerism (e.g., keto-enol tautomerism), separate forms, such as keto or enol forms, are protected separately and together as mixtures of any proportion. The same applies to stereoisomers, such as enantiomers, cis / trans isomers, conformers, etc. If desired, isomers can be separated by methods known in the art, separated by liquid chromatography. The same applies to enantiomers, for example, by using a chiral stationary phase. In addition, enantiomers can be separated by converting them into diastereomers, that is, coupling with an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of the compounds disclosed herein can be obtained by stereoselective synthesis using optically pure starting materials.

[0077] It is also contemplated that the compounds disclosed herein may include isotopically labeled forms thereof. Isotopically labeled forms of the compounds disclosed herein are identical to the compounds except that one or more atoms of the compound have been replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the atom. Examples of isotopes that are readily commercially available and can be incorporated into compounds of Formula I, II, III, IV or V by known methods include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, respectively 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds of Formula I, II, III, IV or V, prodrugs thereof, or pharmaceutically acceptable salts thereof containing the above-mentioned isotopes and / or other isotopes of other atoms are also contemplated as embodiments of the present disclosure. Isotopically labeled compounds of Formula I, II, III, IV or V can be used in a number of beneficial ways. For example, compounds containing, for example, radioactive isotopes (e.g. 3 H or 14 Compounds of Formula I, II, III, IV or V labeled with isotopes of formula (C) are suitable for drug and / or substrate tissue distribution assays. These radioactive isotopes are particularly preferred because of their ease of preparation and excellent detectability. Inclusion of heavier isotopes, such as deuterium ( 2 H) can have therapeutic advantages because such isotope-labeled compounds have higher metabolic stability. Higher metabolic stability directly translates into extended in vivo half-life or lower dosage. By replacing non-isotope-labeled reactants with readily available isotope-labeled reactants, isotope-labeled compounds of Formula I, II, III, IV or V can be adapted to the procedures disclosed in the synthetic schemes disclosed herein and the related descriptions, Examples section and Preparation section.

[0078] Compounds disclosed herein may be in the form of prodrug compounds. Prodrug compounds may refer to derivatives that are converted into biologically active compounds under physiological conditions of a living body, such as by oxidation, reduction, hydrolysis, etc., each of which is carried out enzymatically or without the participation of an enzyme. Examples of prodrugs are compounds in which the amino group in the compound is acylated, alkylated, or phosphorylated; wherein the hydroxyl group is acylated, alkylated, phosphorylated, or converted to a borate; wherein the carboxyl group is esterified or amidated; or wherein the sulfhydryl group forms a disulfide bridge with a carrier molecule (e.g., a peptide) that selectively delivers the drug to the target site and / or the cytoplasm of the cell. These compounds may be produced by compounds disclosed herein according to known methods. Other examples of prodrugs are compounds in which the carboxylate in the compound is converted into an alkyl ester, an aryl ester, a choline ester, an amino ester, an acyloxymethyl ester, or a linolenoyl ester.

[0079] According to one embodiment, a composition comprising 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 effectively and measurably inhibit HPK1, or a mutation thereof, in a biological sample or patient. A therapeutically effective amount of the compound can be administered to a patient in need. A patient or subject may refer to an animal, preferably a mammal, and even more preferably a human. A biological sample may refer to, but is not limited to, a cell culture or an extract thereof; a biopsy material or an extract thereof obtained from a mammal; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[0080] Pharmaceutically acceptable carriers, adjuvants or carriers may refer to non-toxic carriers, adjuvants or carriers that do not destroy the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants or carriers that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin. Pharmaceutically acceptable derivatives mean any non-toxic salts, esters, salts of esters or other derivatives of the compounds disclosed herein, which, after being administered to a receptor, can directly or indirectly provide the compounds disclosed herein.

[0081] The compositions disclosed herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or by implanted reservoirs. Parenteral administration can refer to subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition can be administered orally, intraperitoneally or intravenously. The sterile injectable form of the compositions disclosed herein includes aqueous or oily suspensions. These suspensions are prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions prepared in parenterally acceptable nontoxic diluents or solvents, such as, as solutions in 1,3-butanediol. Acceptable carriers and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oils can be conventionally used as solvents or suspension media.

[0082] The pharmaceutically acceptable compositions disclosed herein can be orally administered 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 usually added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an aqueous suspension is required for oral use, the active ingredient can be combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavoring agents and / or coloring agents can be optionally added. Most preferably, the pharmaceutically acceptable compositions disclosed herein are formulated for oral administration. Such preparations can be administered with or without food.

[0083] The amount of the compound disclosed herein that can be combined with a carrier material to produce a single-dose composition can vary according to the treated host, the specific mode of administration. Preferably, the composition provided can be formulated so that the patient receiving these compositions can be given a compound dosage of 0.01-100 mg / kg body weight / day. In some cases, the dosage is 0.1 to 100 mg / kg patient weight, 0.1 to 50 mg / kg patient weight, 0.5 to 50 mg / kg patient weight, 1 to 50 mg / kg patient weight, 1 to 20 mg / kg patient weight, 5 to 20 mg / kg patient weight, 10 to 20 mg / kg patient weight, 10-50 mg / kg patient weight, or 10-100 mg / kg patient weight, or any other dosage range disclosed herein. In some cases, the compound or composition herein can be continuously, multiple times a day, once a day, once every other day, weekly, every two weeks, monthly or every two months. The therapeutically effective amount of the compound or composition herein can vary according to factors known in the art, but about 0.1 to 100 mg / kg patient body weight, 0.1 to 50 mg / kg patient body weight, 0.5-50 mg / kg patient body weight, 1 to 50 mg / kg patient body weight, 1 to 20 mg / kg patient body weight, 5 to 20 mg / kg patient body weight, 10 to 20 mg / kg patient body weight, or 10-50 mg / kg patient body weight, or 10-100 mg / kg patient body weight, or any other dosage disclosed herein can be therapeutically effective. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, excretion rate, drug combination, the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound disclosed herein in the composition will also depend on the specific active compound in the composition.

[0084] The compounds of Formula I, II, III, IV or V disclosed herein can be administered once or several times before or after the onset of the disease to achieve a therapeutic effect. The aforementioned compounds and medical products of the present invention are particularly useful for therapeutic treatment. The therapeutic differential effect alleviates one or more symptoms of the disease to a certain extent, or partially or completely restores one or more physiological or biochemical parameters associated with or causing the disease or pathological condition to normal. Monitoring is considered a treatment, provided that the compound is administered at different time intervals, for example, in order to enhance the response and completely eliminate the symptoms of the disease. The same or different compounds can be administered. The methods disclosed herein can also be used to reduce the likelihood of illness or even prevent the occurrence of conditions associated with HPK1 activity in advance or to treat symptoms that occur and persist.

[0085] The host or patient may be of any mammalian species, such as primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental studies, which provide models for treating human diseases.

[0086] The compounds disclosed herein can be used as anticancer agents for cancers that respond to HPK1 inhibition. In certain embodiments, the cancer can include, but is not limited to, the following cancers: breast cancer, bladder cancer, bone cancer, brain cancer, central and peripheral nervous system cancer, colon cancer, endocrine gland cancer, esophageal cancer, endometrial cancer, germ cell cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, laryngeal cancer and hypopharyngeal cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, small intestine cancer, soft tissue cancer, testicular cancer, gastric cancer, skin cancer, ureter cancer, vaginal cancer, and vulvar cancer. In some cases, the cancer is mesothelioma, sarcoma, retinoblastoma, Wilms' tumor, leukemia, lymphoma, non-Hodgkin's disease, chronic and acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin's disease, multiple myeloma, T-cell lymphoma, myelodysplastic syndrome, plasma cell tumors, and paraneoplastic syndromes.

[0087] The compounds of Formula I, II, III, IV or V disclosed herein can be used in methods for alleviating symptoms associated with undesirable immunoactivity and / or treating undesirable immunoactivity, including but not limited to being used in methods for alleviating symptoms associated with autoimmunity and / or its treatment. The disclosed compounds can be used to suppress immune responses and thus prevent or delay the development of autoimmune diseases. Autoimmune diseases can be characterized by joint pain, antinuclear antibody positivity, butterfly erythema or discoid erythema. Autoimmune diseases can be associated with skin, muscle tissue and / or connective tissue. In some embodiments, autoimmune diseases are not followed by individual skin, muscle tissue and / or connective tissue symptoms. 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, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic arthritis, irritable bowel disease (IBD), scleroderma, Sjogren's disease, vitiligo, polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease (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 may also include, but are not limited to, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cryopathy.

[0088] In some embodiments, the disclosed compounds can be used to treat inflammatory diseases and / or immune responses associated with inflammatory diseases. The term "inflammatory conditions" used herein can encompass autoimmune diseases, and inflammatory conditions without known autoimmune components (e.g., atherosclerosis, asthma, etc.). In other aspects, suppressing the immune response can alleviate or mitigate one or more symptoms of inflammatory diseases. Suppressing the immune response can be used to treat inflammatory diseases and / or prevent or delay the development of inflammatory diseases. Inflammatory diseases can include, but are not limited to, non-rheumatoid arthritis, renal fibrosis, and liver fibrosis. Inflammatory diseases can be interface dermatitis. Interface dermatitis can be one or more of the following: lichen planus, lichenoid eruption, lichen planus keratosis, lichen linearis, chronic lichenoid keratosis, erythema multiforme, fixed drug eruption, pityriasis lichenoides, phototoxic dermatitis, radiation dermatitis, viral dermatitis, dermatomyositis, secondary syphilis, atrophic lichen sclerosus, mycosis fungoides, bullous pemphigoid, lichen aureus, porokeratosis, acrodermatitis chronicus atrophicus, and regressive melanoma. Inflammatory diseases can be skin diseases, such as atopic dermatitis (eczema); sterile inflammation, such as drug-induced liver and / or pancreatic inflammation; inflammatory liver disease; and / or inflammatory pancreatic disease.

[0089] The sensitivity of a given cancer to HPK1 inhibition can be assessed by, but not limited to, measuring a reduction in primary or metastatic tumor burden (mild, partial or complete regression), changes in blood counts, changes in hormone or cytokine concentrations in the blood, inhibition of further increases in tumor burden, stabilization of the patient's disease, assessment of disease-related biomarkers or surrogate markers, prolongation of the patient's overall survival, prolongation of the patient's time to disease progression, prolongation of the patient's progression-free survival, prolongation of the patient's disease-free survival, improvement in the patient's quality of life, or modulation of disease comorbidities (e.g., but not limited to, pain, cachexia, activity, hospitalization, changes in blood counts, weight loss, wound healing, fever). Significant improvements in the pharmacokinetic profile of a compound of Formula I, II, III, IV or V can thus be obtained and can be quantitatively expressed as increases in in vivo half-life (t / 2), maximum therapeutic effect concentration (Cmax) and area under the dose-response curve (AUC).

[0090] In various embodiments, compounds of Formula I, II, III, IV or V and related formulae exhibit 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 formulae exhibit an IC of at least 1 nM, at least 10 nM, at least 100 nM, or at least 500 nM for inhibiting HPK1. 50In 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 to prepare further active pharmaceutical ingredients. The medicament 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 in a suitable dosage form, and optionally in combination with one or more other active substances.

[0092] Provided herein is a medicament that may include at least one compound disclosed herein or a prodrug or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios. A medicament may refer to any preparation in the medical field that contains one or more compounds of Formula I, II, III, IV or V or a preparation thereof (e.g., a pharmaceutical composition or a pharmaceutical preparation) and can be used to prevent diseases associated with HPK1 activity, treat, follow up or post-hospitalize patients with diseases associated with HPK1 activity, so as to at least temporarily change the overall condition of an organism or the condition of a specific area in terms of pathogenicity.

[0093] In various embodiments, the active ingredients can be administered alone or in combination with other treatments. A synergistic effect can be achieved by using more than one compound in a pharmaceutical composition, i.e., a compound of Formula I, II, III, IV, or V can be combined with at least one other formulation as an active ingredient, the at least one other formulation being another compound of Formula I, II, III, IV, or V or a compound of a different structural scaffold. The active ingredients can be used simultaneously or sequentially. In some embodiments, the HPK1 inhibitor disclosed herein is administered simultaneously with one or more additional therapeutic agents. In some embodiments, sequential administration includes administering an HPK1 inhibitor or an additional therapeutic agent followed by administration of the HPK1 inhibitor or the additional therapeutic agent within about one minute, five minutes, 30 minutes, one hour, five hours, 24 hours, 48 ​​hours, or any time during a week. In some embodiments, the HPK1 inhibitor and the additional therapeutic agent are administered by the same route of administration. In some embodiments, the HPK1 inhibitor and the additional therapeutic agent can be administered by different routes of administration.

[0094] Therapeutic agents may include, but are not limited to, one or more anti-tumor agents and / or anti-inflammatory drugs conventionally used in chemotherapy or targeted therapy.The compounds or compositions disclosed herein may be used as a monotherapy or may be combined with a therapeutic agent. Examples of anti-tumor agents include, but are not limited to, platinum compounds such as carboplatin, cisplatin, picoplatin, etc.; alkylating agents such as altretamine, carmustine, chlorambucil, mitobrolol, apaziquinone, palifostamide, etc.; DNA altering agents such as bisantrene, decitabine, mitoxantrone, procarbazine, etc.; microtubule regulators such as docetaxel, eribulin, paclitaxel, vinblastine, etc.; topoisomerase inhibitors such as etoposide, razoxane, topotecan, etc.; anticancer 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.

[0095] A method for inhibiting abnormal cell growth in a mammal, preferably a human, or treating cancer, the method may include: administering to the mammal a certain amount of a compound of Formula I, II, III, IV, or V disclosed herein, or a prodrug or a pharmaceutically acceptable salt thereof, and combining with radiation therapy, wherein the amount of the compound, salt, or prodrug is combined with radiation therapy effective for inhibiting abnormal cell growth in the mammal or treating cancer or its symptoms. Techniques for administering radiation therapy are known in the art and may be used in the combination therapy described herein.

[0096] As used herein, the terms "treat," "treat," and "therapeutic" may refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or condition or one or more symptoms thereof. In some embodiments, treatment is administered after one or more symptoms have appeared. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible individual before symptoms appear (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment is continued after symptoms have been alleviated, for example, to prevent or delay the recurrence of symptoms.

[0097] A kit is disclosed herein, comprising a separately packaged therapeutically effective amount of a compound disclosed herein or a physiologically acceptable salt or prodrug thereof, and an optional therapeutically effective amount of a therapeutic agent. The kit may include a suitable container, such as a box, a separate bottle, a bag or an ampoule, and instructions for using or applying the kit. For example, the kit may include separate ampoules, each of which contains a therapeutically effective amount of a compound disclosed herein and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures of all proportions thereof, and an effective amount of another therapeutic agent in dissolved or lyophilized form. Experimental Procedure

[0098] As described in the following examples, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It should be understood that although the general methods describe the synthesis of certain compounds, the following general methods and other methods known to those of ordinary skill in the art are applicable to all compounds as described herein and subclasses and species of each of these compounds.

[0099] The symbols and conventions used in the following procedures, schemes, and example descriptions are consistent with those used in contemporary 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 are commercially available and used without further purification. Reactions were typically run under an inert atmosphere of nitrogen using anhydrous solvents. Flash column chromatography was typically performed using silica gel 60 (0.035-0.070 mm particle size).

[0102] All NMR experiments were performed at 400 MHz on a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400BBFO probe for proton NMR, or at 300 MHz on a Bruker Mercury Plus 300 NMR spectrometer equipped with a Bruker 300BBFO probe for proton NMR, or at 400 MHz on a Bruker Avance III 400 NMR spectrometer equipped with a Bruker PABBO BB-1H / DZ GRD probe for proton NMR. Most deuterated solvents typically contain 0.03% to 0.05% (vol / vol) tetramethylsilane, which was used as a reference signal ( 1 H and 13 C were all set to d0.00). In the case where the deuterated solvent did not contain tetramethylsilane, the residual non-deuterated solvent peak was used as the reference signal according to published guidelines (J. Org. Chem., Vol. 62, No. 21, 1997). LC-MS analysis was performed on either of the following two instruments: 1. SHIMADZU LC-MS machine, it is composed of UFLC 20-AD system and LCMS2020MS detector.The column used is Shim-pack XR-ODS, 2.2 μm, 3.0x 50mm.Adopt linear gradient, start from 95% A (A: water containing 0.05% trifluoroacetic acid (TFA)) in 2.2 minutes (min) and terminate at 100% B (B: acetonitrile (CAN) containing 0.05% TFA), total running time is 3.6 minutes.Column temperature is 40 ℃ and flow rate is 1.0mL / min.Diode array detector scans at 200-400nm.Mass spectrometer is equipped with electrospray ion source (ES) operated in positive or negative mode.Mass spectrometer scans between m / z 90-900 and scan time is 0.6s. 2. Agilent Technologies' Agilent 1200 series mass spectrometer using atmospheric pressure chemical ionization (APCI) or electrospray ionization (ESI). The diode array detector scanned at 200-400 nm. The mass spectrometer scanned between m / z 90-900 and the scan time was 0.6 s. Column: XBridge C8, 3.5 μm, 4.6 x 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 were obtained from a SHIMAZU LC-MS machine or using an Agilent 1100 series HPLC from Agilent Technologies using a column (XBridge C8, 3.5 μm, 4.6 x 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. Unless otherwise specified, 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.

[0104] In general, compounds according to formula I, II, III, IV or V and related formulas as described herein can be prepared from readily available starting materials. If such starting materials are not commercially available, they can be prepared by standard synthesis techniques. In general, the synthetic route of any individual compound of formula I, II, III, IV or V and related formulas will depend on the specific substituents of each molecule, and such factors are understood by those of ordinary skill in the art. The following general methods and procedures described in the examples below can be used to prepare compounds of formula I, II, III, IV or V and related formulas. The reaction conditions described in the following schemes, such as temperature, solvent or co-reagents are given only as examples and are not restrictive. It should be understood that, unless otherwise stated, other experimental conditions may also be used in the case of typical or preferred experimental conditions (i.e., reaction temperature, time, amount of substance of reagent, solvent, etc.). Preferred reaction conditions may vary with the specific reactants or solvents used, but the conditions may be determined by conventional optimization procedures by those skilled in the art. 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 GM 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

[0105] N-[2-(Dimethylamino)ethyl]-2-fluoro-4-nitroaniline: A solution of 1,2-difluoro-4-nitrobenzene (3.00 g; 17.91 mmol) and (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. under a nitrogen atmosphere overnight. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (PE {petroleum ether}:AcOEt=7:3) to provide N-[2-(dimethylamino)ethyl]-2-fluoro-4-nitroaniline (3.77 g; 90.9%) as a yellow oil.

[0106] N-[2-(Dimethylamino)ethyl]-N-(2-fluoro-4-nitrophenyl)carbamic acid tert-butyl ester: N-[2-(dimethylamino)ethyl]-2-fluoro-4-nitroaniline (3.67 g; 15.85 mmol) and (Boc) were stirred at room temperature under nitrogen atmosphere. 2 To the mixture was added 4-(4-(2-fluoro-4-nitrophenyl)-1 ...

[0107] N-(4-amino-2-fluorophenyl)-N-[2-(dimethylamino)ethyl]carbamic acid tert-butyl ester: N-[2-(dimethylamino)ethyl]-N-(2-fluoro-4-nitrophenyl)carbamic acid tert-butyl ester (4.90 g; 14.97 mmol) and NH 4 Cl (4.00 g; 74.03 mmol) and Fe (4.00 g; 70.19 mmol) in water (32.00 mL) and EtOH (48.00 mL) were added for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (PE: EtOAc = 1: 99) to provide 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] 2-Chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester: Zn (22.00 g; 319.67 mmol) and NH 4 OH (24.00 mL). At 90 °C, N 2The resulting mixture was stirred for 15 h under a 4% sodium hydroxide 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 and eluted with ethyl acetate (EA): PE = 1:3 to provide 2-chloro-5H, 6H, 7H, 8H-pyrido [3, 4-d] pyrimidine-7-carboxylic acid tert-butyl ester (13.00 g; 77.2%) as a light yellow oil.

[0109] 2-Chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine hydrochloride: 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) in EA (10.00 mL; 40.00 mmol) containing HCl (g) and EtOAc (10.00 mL) was stirred. The resulting mixture was stirred at 25 °C under nitrogen atmosphere for 2 h. The resulting mixture was extracted with EA (3 x 50 mL). The filtrate was concentrated under reduced pressure to provide 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine hydrochloride (700 mg; 98%) as a red 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: tert-Butyl N-(4-amino-2-fluorophenyl)-N-[2-(dimethylamino)ethyl]carbamate (300.00 mg; 0.98 mmol) and 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine hydrochloride (252.00 mg; 1.20 mmol) and Ephos (46.00 mg; 0.08 mmol) were stirred at 120°C under a nitrogen atmosphere. 4 (54.00 mg; 0.06 mmol) and Cs 2 CO 3 (980.00 mg; 2.86 mmol) in DMF{N,N-dimethylformamide} (6.00 mL) solution for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (PE:EtOAc=7:3) to provide 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: 3-amino-5-bromo-4-methylpyridin-2-ol (100.00 g, 467.90, 1.0 equivalent) and K 2 CO 3 To a stirred mixture of 7-bromo-8-methyl-1H,3H-pyrido[2,3-b][1,4]oxazine-2-one (110 g, crude product) was added chloroacetyl chloride (1.22 g, 10.294 mmol) (205.00 g, 1409.19 mmol) in N,N-dimethylformamide (DMF) (600.00 mL). 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 min. The solid was filtered and dried in vacuo to provide 7-bromo-8-methyl-1H,3H-pyrido[2,3-b][1,4]oxazine-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: 7-Bromo-8-methyl-1H,3H-pyrido[2,3-b][1,4]oxazine-2-one (110.00 g, 424.19 mmol) and BH 3 -tetrahydrofuran (THF) (550.00 mL, 550.00 mmol, 1 Mol / L) and continued for 4 h. The resulting mixture was quenched with MeOH (~550 mL) at 0°C. HCl (2M, 550 mL) was added to the mixture under stirring. The solution was stirred at room temperature for about 30 min. The resulting mixture was concentrated to half volume and Na 2 CO 3 (aq.) to adjust pH = 7-8. The final solution was extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 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 dropwise Boc in DCM (150.00 mL) at 0°C. 2The resulting mixture was stirred at 30°C under nitrogen atmosphere overnight (~70% conversion, LCMS), and then TEA (53.915 mL, 368.47 mmol) and Boc 2 O (84.65 g, 368.47 mmol). The resulting mixture was stirred for 7 h at 30 ° C under nitrogen atmosphere. Water was added to the resulting mixture. The resulting mixture was extracted with DCM. 2 SO 4 The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 15% EtOAc in PE to provide 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] 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-carboxylic acid tert-butyl ester: N-[2-(dimethylamino)ethyl]-N-[2 tert-butyl-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]carbamate (200.00 mg; 0.37 mmol) and tert-butyl-7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (305.00 mg; 0.88 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (40.00 mg; 0.05 mmol) and Cs 2 CO 3 (450.00 mg; 1.31 mmol) in 1,4-dioxane (5.00 mL) for 4 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (PE: EtOAc = 7: 3) to provide 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-carboxylic acid tert-butyl ester (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: 7-{2-[(4-{[(tert-butyloxy)carbonyl][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 was stirred at room temperature under nitrogen atmosphere. =Toluene was added tert-butyl ester (130.00 mg; 0.16 mmol) and TFA (2.00 mL) in DCM (6.0 mL) for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by X Bridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 25% B to 55% B over 9 min, 55% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 4, thereby providing 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: 95.03% purity, RT = 2.21 min. MS: m / z = 479.25 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.30(s,1H),8.28(s,1H),7.60(dd,J=14.5,2.4Hz,1H),7.27(s,1H),7.26(s,1H),6.69(t,J=9.4Hz,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

[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) was added portionwise Xphos (146.44 mg; 0.29 mmol), Xphos Pd G 3 (130.01 mg; 0.15 mmol) and K 2 CO 3 (423.63 mg; 2.92 mmol). The resulting mixture was stirred at 100 ° C under nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (6:1) to provide 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-naphthyridin-2-carboxylate (330.00 mg; 0.86 mmol; 1.00 eq.) in DCM (15.00 mL) was added TFA (3.00 mL) in portions at room temperature. After stirring at room temperature for 1 h, the mixture was heated to 40°C with saturated NaHCO 3 (aq.) to alkalize the mixture to pH [7]. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 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-nitropyridine-2-ol: To a stirred solution of 4-chloro-3-nitropyridine-2-ol (75.00 g; 408.21 mmol) in THF (700.00 mL) was added N-bromosuccinimide (NBS) (89.88 g; 489.85 mmol) in portions 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 x 100 mL). The combined organic layers were washed with brine (150 mL) and purified by anhydrous Na 2 SO 4 The resulting mixture was concentrated under reduced pressure. The residue was purified by slurrying with PE:EA=3:1. The solid was collected to provide 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: 5-bromo-4-chloro-3-nitropyridine-2-ol (75.00 g; 270.15 mmol) and NH 4 To a stirred solution of Cl (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) in portions. The resulting mixture was stirred at 70 °C for 1 h. 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 purified by anhydrous Na 2 SO 4 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: 3-amino-5-bromo-4-chloropyridin-2-ol (60.00 g; 228.34 mmol) and K were added under 0°C and argon atmosphere. 2 CO 3A stirred solution of 7-bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-2-one (40.00 g; crude product) was added in portions to 2-chloroacetyl chloride (47.79 mL; 570.85 mmol). The resulting mixture was stirred at room temperature for 6 h and at 40 ° C for 1 h. 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 provide 7-bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-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: at 40°C, N 2 Stir in BH 3 7-bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-2-one (35.00 g; 130.59 mmol) in THF (350.00 mL; 350.00 mmol) was added for 2 h. The resulting 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 and eluted with PE / EtOAc (3:1) to provide 7-bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine (26.00 g; 71.34%) as a white solid.

[0123] 7-Bromo-8-chloro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester: room temperature, N 2 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) was added triethylamine (0.57 mL; 3.91 mmol) and N,N-dimethylpyridin-4-amine (34.00 mg; 0.26 mmol) in portions under N atmosphere. 2 The resulting mixture was stirred under a 4% CO atmosphere for 4 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with 15% EtOAc in PE to provide 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] 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-carboxylic acid tert-butyl ester: 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) was added portionwise Pd-PEPPSI-IPentCl at room temperature. 2-Methylpyridine (o-picoline) (153.49 mg; 0.17 mmol) and Cs 2 CO 3 (1190.50 mg; 3.47 mmol). The resulting mixture was stirred at 110 ° C. under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to provide 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-carboxylic acid tert-butyl ester (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: Raney Ni (20.04 mg; 0.22 mmol) was added 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) at room temperature. After stirring at room temperature under hydrogen atmosphere for 1 h, the resulting mixture was filtered. The filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to provide 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] 7-[7-({4-[2-(azetidin-1-yl)acetylamino]-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-carboxylic acid tert-butyl ester: At room temperature, 7-{7-[(4-amino-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-chloro To a stirred solution of tert-butyl-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) was added HATU (93.11 mg; 0.23 mmol) and DIEA (47.46 mg; 0.35 mmol) in portions. The resulting mixture was stirred at 40° C. under nitrogen atmosphere for 6 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to provide tert-butyl 7-[7-({4-[2-(azetidin-1-yl)acetylamino]-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)acetylamino]-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 portionwise with BBr 3 The resulting mixture was stirred at -78 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 55% B to 85% B over 9 min, 85% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 2, thereby providing 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: 99.59% purity, RT = 2.14 min. MS: m / z = 520.15 [M+H] + . 1 H NMR (300MHz, DMSO-d6): δ9.03(s,1H),8.74(s,1H),7.99(s,1H),7.40(d,J=9.5Hz,2H),7.31(d,J=17.1Hz,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=16.2Hz,4H),3.10(s,2H),2.83(s,2H),2.16(s,3H),2.06(q,J=6.9Hz,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

[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) was added portionwise X-PHOS (290.00 mg; 0.58 mmol), K 2 CO 3 (1261.00 mg; 8.67 mmol) and XPhos Pd G 3 (257.00 mg; 0.29 mmol). The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography and eluted with PE:EA=70:30 to provide 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 under nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by drying with NaHCO at 25°C. 3 The reaction was diluted with 1% (aq.). The resulting mixture was extracted with EA (3 x 80 mL). The combined organic layers were washed with brine and purified by anhydrous MgSO 4 After filtration, the filtrate was concentrated under reduced pressure to provide 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] 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-carboxylic acid tert-butyl ester: 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) was added portionwise Cs(2-[(3-methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[2,3-b][1,4]oxazine-1-carboxylate at 25 °C. 2 CO 3 (1.90 g; 5.54 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (130.00 mg; 0.15 mmol). The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere for 12 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with PE:EA=1:1 to provide 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-carboxylic acid tert-butyl ester (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 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-carboxylic acid tert-butyl ester (680.00 mg; 1.27 mmol) and Fe (225.00 mg; 3.83 mmol) in EtOH (9.00 mL) was added portionwise a mixture of NH 4 Cl (276.00 mg; 5.11 mmol) 2O (6.00 mL). The resulting mixture was stirred at 80 ° C under nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography and eluted with EA to provide 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-carboxylic acid tert-butyl ester (600.00 mg, 93.5%) as a yellow solid.

[0133] 7-[2-({4-[2-(azetidin-1-yl)acetylamino]-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-carboxylic acid tert-butyl ester: At room temperature, 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-carboxylic acid tert-butyl ester was added to the mixture. To a stirred mixture of tert-butyl}-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) was added HATU (349.35 mg; 0.87 mmol) and DIEA (79.14 mg; 0.58 mmol). The mixture was stirred at room temperature for 1 h. The resulting mixture was quenched by ice / water and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to provide 7-[2-({4-[2-(azetidin-1-yl)acetylamino]-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-carboxylic acid tert-butyl ester (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 7-[2-({4-[2-(azetidin-1-yl)acetylamino]-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-carboxylic acid tert-butyl ester (190.00 mg; 0.28 mmol) in DCM (5.00 mL) was added dropwise a mixture of BBr 3 DCM (1.00 mL; 1.00 mmol). The reaction mixture was stirred at -20 °C with NaHCO 3 The resulting mixture was quenched with 4-(4-(2-nitro-4-pyridin-1-yl)-4-(2-nitro-4-pyridin-2-yl)-5-(2-nitro-4-pyridin-1-yl)-4-(2-nitro-4-pyridin-2-yl)-5-(2-nitro-4-pyridin-2-yl)-6-(2-nitro-4-pyridin-2-yl)-7-nitro ...

[0135] HPLC: 97.34% purity, RT = 2.29 min. MS: m / z = 501.30 [M+H] + . 1 H NMR (300MHz, DMSO-d6): δ9.40(s,1H),9.05(s,1H),8.30(s,1H),7.58-7.49(m,2H),7.34(d,J=9.3Hz,1H),7.27(s,1H),5.51(s,1H),4.1 7(t,J=4.3Hz,2H),3.93(s,2H),3.30(s,6H),3.13(d,J=14.3Hz,4H),2.77(t,J=5.3Hz,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

[0136] 2-Fluoro-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline: At room temperature, N 2 To a stirred solution of 1-bromo-2-fluoro-4-nitrobenzene (6.40 g; 29.09 mmol; 1.00 eq.) and 2-(morpholin-4-yl)ethan-1-amine (3.80 g; 29.19 mmol) in toluene (100.00 mL) was added Pd 2 (dba) 3 (2.70 g; 2.65 mmol), Xantphos (3.40 g; 5.82 mmol) and t-BuONa (8.40 g; 78.67 mmol). 2 The resulting mixture was stirred under a C atmosphere for 2 h. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (500 mL) and purified by anhydrous Na 2 SO 4 The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with 80% EtOAc in PE to provide 2-fluoro-N-[2-(morpholin-4-yl)ethyl]-4-nitroaniline (6.40 g; 78.3%) as a yellow solid.

[0137] N-(2-Fluoro-4-nitrophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamic acid tert-butyl ester: At room temperature, N 2 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) was added triethylamine (9.62 mL; 65.72 mmol) and N,N-dimethylpyridin-4-amine (563.00 mg; 4.38 mmol) in portions under N atmosphere. 2 The resulting mixture was stirred under a C atmosphere for 4 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and purified by anhydrous Na 2 SO 4The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with 30% EtOAc in PE to afford tert-butyl N-(2-fluoro-4-nitrophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamate (7.20 g; 87.7%) as a yellow solid.

[0138] N-(4-amino-2-fluorophenyl)-N-[2-(morpholin-4-yl)ethyl]carbamic acid tert-butyl ester: at room temperature, N 2 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) was added NH 4 Cl (4.00 g; 74.03 mmol) and Fe (5.30 g; 89.91 mmol). The solid was filtered off. The filtrate was diluted with water (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL) and purified by anhydrous Na 2 SO 4 The resulting mixture was concentrated under reduced pressure to provide 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: A stirred solution of tert-butyl 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (800.00 mg; 2.83 mmol) in EA (16.00 mL; 64.00 mmol) containing 4N HCl was stirred at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to provide 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine hydrochloride (560.00 mg; crude product) as a white solid.

[0140] N-{2-fluoro-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}-N-[2-(morpholin-4-yl)ethyl]carbamic acid tert-butyl ester: at room temperature, N 2 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) was added Ephos Pd G 4(210.00 mg; 0.22 mmol), Ephos (126.00 mg; 0.22 mmol) and Cs 2 CO 3 (1477.00 mg; 4.49 mmol). 2 The resulting mixture was stirred under a 4% CO atmosphere for 16 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and purified by anhydrous Na 2 SO 4 The mixture was stirred for 2 hours at 4 ℃ for 1 h.Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (4:1) to provide 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] 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-carboxylic acid tert-butyl ester: N-{2-fluoro-4-[(5,6,7,8- Tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}-N-[2-(morpholin-4-yl)ethyl]carbamic acid tert-butyl ester (250.00 mg; 0.52 mmol) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (285.00 mg; 0.78 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (46.00 mg; 0.05 mmol) and Cs 2 CO 3 (356.00 mg; 1.04 mmol) in 1,4-dioxane (10.00 mL) for 4 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (DCM: MeOH = 6: 1) to provide 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-carboxylic acid tert-butyl ester (100.00 mg; 0.13 mmol; 25.7%) as a yellow solid.

[0142]

[0266] 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: To a stirred solution of 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-carboxylic acid tert-butyl ester (90.00 mg; 0.12 mmol) in DCM (3.00 mL) was added TFA (1.00 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 26% B to 56% B over 9 min, 56% B; wavelength: 254 nm; RT1 (min.): 7). This gave 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%) as a yellow solid.

[0143] HPLC: 99.51% purity, RT = 3.26 min. MS: m / z = 520.20 [M+H] + . 1H NMR (300 MHz, methanol-d4) δ7.86 (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=6.4Hz,2H),3.16(t,J=5.8Hz,2H ), 2.86 (t, J = 5.8Hz, 2H), 2.65 (t, J = 6.4Hz, 2H), 2.53 (dd, J = 5.5, 3.6Hz, 4H), 2.12 (s, 3H). Example 5: Synthesis of Compound 5: 5-Chloro-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

[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 dropwise PBr at -78 °C. 3 (0.51 mL; 5.15 mmol). 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 purified by anhydrous Na 2 SO 4 The mixture was concentrated under reduced pressure and purified by silica gel column chromatography and eluted with PE / EtOAc (1:1) to provide 5-bromo-2-(bromomethyl)-3-chloropyridine (446.00 mg; 38.1%) as a yellow oil.

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

[0146] tert-Butyl N-[5-chloro-6-(methylsulfonylmethyl)pyridin-3-yl]carbamate: To a stirred mixture of 5-bromo-3-chloro-2-(methylsulfonylmethyl)pyridine (370.00 mg; 1.14 mmol) and tert-butyl carbamate (210.75 mg; 1.71 mmol; 1.50 eq.) in 1,4-dioxane (15.00 mL) was added Pd 2 (dba) 3 (109.83 mg; 0.11 mmol), Xantphos (133.19 mg; 0.23 mmol) and Cs 2 CO 3 (781.56 mg; 2.28 mmol). After stirring at 90 °C under argon atmosphere for 16 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (19:1) to provide tert-butyl N-[5-chloro-6-(methylsulfonylmethyl)pyridin-3-yl]carbamate (420.00 mg; 90.3%) as a yellow solid.

[0147] 5-Chloro-6-(methylsulfonylmethyl)pyridin-3-amine: A mixture of tert-butyl N-[5-chloro-6-(methylsulfonylmethyl)pyridin-3-yl]carbamate (410.00 mg; 1.28 mmol) in MeOH (20.00 mL; 4 M) containing HCl was prepared at 25°C. The resulting mixture was stirred at 25°C under nitrogen atmosphere for 12 h. The resulting mixture was quenched by ice / water and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 5-chloro-6-(methylsulfonylmethyl)pyridin-3-amine (360.00 mg; crude product) as a brown solid.

[0148] tert-Butyl 2-{[5-chloro-6-(methylsulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a solution of 5-chloro-6-(methylsulfonylmethyl)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), Cs 2 CO3 (925.00 mg; 2.70 mmol) and EPhos PdG 4 (131.00 mg; 0.14 mmol). The resulting mixture was stirred at 90 ° C under nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (24: 1) to provide tert-butyl 2-{[5-chloro-6-(methylsulfonylmethyl)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-(methylsulfonylmethyl)-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-(methylsulfonylmethyl)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) in portions at room temperature. The resulting mixture was stirred at 25 °C under nitrogen for 4 h. The mixture was treated with saturated NaHCO 3 (aq.) to alkalize the mixture to pH [7]. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to provide 5-chloro-6-(methylsulfonylmethyl)-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] 7-(2-{[5-chloro-6-(methylsulfonylmethyl)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-carboxylic acid tert-butyl ester: To 5-chloro-6-(methylsulfonylmethyl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester To a solution of 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) was added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (23.00 mg; 0.03 mmol) and Cs 2 CO 3(169.00 mg; 0.51 mmol). The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (6: 1) to provide 7-(2-{[5-chloro-6-(methylsulfonylmethyl)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-carboxylic acid tert-butyl ester (45.00 mg; 21.8%) as a yellow solid.

[0151]

[0136] 5-Chloro-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: To a stirred solution of tert-butyl 7-(2-{[5-chloro-6-(methylsulfonylmethyl)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 under nitrogen for 4 h. The mixture was washed with saturated NaHCO 3 (aq.) was basified to pH = 7. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions (column: XBridgeShield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 18% B to 48% B over 9 min, 48% B; wavelength: 254 nm; RT1 (min.): 7) to provide 5-chloro-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 (4.60 mg; 18.1%) as a white solid.

[0152] HPLC: 97.69% purity, RT = 2.63 min. MS: m / z = 502.00 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ10.15(s,1H),8.87(d,J=2.3Hz,1H),8.50(d,J=2.3Hz,1H),8.46(s,1H),7.30(s,1H),5.53(s,1H),4.6 7(s,2H),4.30–4.11(m,2H),4.02(s,2H),3.32(s,2H),3.13(d,J=5.5Hz,2H),3.06(s,3H),2.85(d,J=5.8Hz,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

[0153] N-[2-Fluoro-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]-N-[2-(morpholin-4-yl)ethyl]carbamic acid tert-butyl ester: at room temperature, N 2 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) was added EPhos Pd G 4 (76.00 mg; 0.08 mmol), Ephos (63.00 mg; 0.11 mmol) and Cs 2 CO 3 (1.20 g; 3.50 mmol). 2 The resulting mixture was stirred under a C atmosphere for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4The residue was purified by silica gel column and eluted with 15% MeOH in DCM to provide 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] 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-carboxylic acid tert-butyl ester: at room temperature, N 2 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) was added portionwise Pd-PEPPSI-IPentCl 2-methylpyridine(o-picoline) (57.00 mg; 0.06 mmol) and Cs(II)-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) under atmospheric pressure. 2 CO 3 (664.00 mg; 1.94 mmol; 3.25 eq.). 2 The resulting mixture was stirred overnight under a C atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4 The resulting mixture was dried. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with 100% EtOAc to provide 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-carboxylic acid tert-butyl ester (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: 0℃, N 2 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) was added TFA (1.00 mL) dropwise under N atmosphere at room temperature. 2 The resulting mixture was stirred for 2 h under a 4% CO atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 26% B to 56% B over 9 min, 56% B; wavelength: 254 nm; RT1 (min.): 7) to provide 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: 90.02% purity, RT = 2.17 min. MS: m / z = 521.15 [M+H] + . 1H NMR (300MHz, DMSO-d6) δ9.28 (s, 1H), 8.27 (s, 1H), 7.59 (dd, J = 14.5, 2.4Hz, 1H),7.26(d,J=9.0Hz,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=4.6Hz,4H),3.30(s,2H),3.14(dd,J=12. 6, 6.3Hz, 4H), 2.76 (s, 2H), 2.54 (s, 2H), 2.40 (t, J = 4.6Hz, 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]diazepine -7-Keto

[0157] 2-(3-Bromo-5-methyl-1H-pyrazol-1-yl)acetic acid methyl ester: at room temperature, N 2 Under atmosphere, 3-bromo-5-methyl-1H-pyrazole (20.00 g; 118.01 mmol), tetra-n-butylammonium iodide (TBAI) (2.40 g; 6.17 mmol) and K 2 CO 3 A stirred solution of methyl 2-chloroacetate (31.10 g; 213.78 mmol) in DMF (200.00 mL) was added dropwise with methyl 2-chloroacetate (20.30 g; 177.70 mmol). 2 The resulting mixture was stirred overnight under a C atmosphere. The resulting mixture was diluted with water (1.5 L) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (1 L) and purified by anhydrous Na 2 SO 4 The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with 30% EA in PE to provide methyl 2-(3-bromo-5-methyl-1H-pyrazol-1-yl)acetate (29.00 g; 98.5%).

[0158] 2-[3-Bromo-5-(bromomethyl)-1H-pyrazol-1-yl]acetic acid methyl ester: at room temperature, N 2Under atmosphere, 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) were added to a solution of PhCF 3 2-[(1Z)-2-(1-cyano-1-methylethyl)diazen-1-yl]-2-methylpropionitrile (18.54 g; 107.27 mmol) was added portionwise to a stirred solution in 105°C, N 2 The resulting mixture was stirred for 3 h under a 4% CO atmosphere. The reaction mixture was washed with water (1 L) and extracted with DCM (3 x 400 mL). The combined organic layers were washed with brine (500 mL) and purified by anhydrous Na 2 SO 4 Dried and concentrated under reduced pressure.The residue was purified by silica gel column and eluted with EtOAc:PE=8:1 to provide methyl 2-[3-bromo-5-(bromomethyl)-1H-pyrazol-1-yl]acetate (22.00 g; 46.85%).

[0159] 2-[3-Bromo-5-(cyanomethyl)-1H-pyrazol-1-yl]acetic acid methyl ester: at room temperature, N 2 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) was added sodium cyanide (3.77 g; 75.38 mmol) and water (4.00 mL; 219.76 mmol) in portions under N atmosphere. 2 The resulting mixture was stirred under atmosphere for 1 h. 4 The resulting mixture was quenched with 1% (aq.) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (15 mL) and purified by anhydrous Na 2 SO 4 The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with PE:EA=7:1, and concentrated to provide 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) at room temperature under nitrogen was added platinum dioxide (6.00 g; 25.10 mmol) and AcOH (60.00 mg; 0.99 mmol) was added dropwise. The resulting mixture was stirred at room temperature under an atmosphere of hydrogen (11.71 g; 5807.68 mmol) for 1.5 h. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column and eluted with DCM:MeOH=20:1 to afford 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) was added dropwise LiOH (5.13 g; 116.14 mmol) in water (200.00 mL) at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was adjusted to pH=5-6 with HCl (6N) and concentrated under reduced pressure to provide 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]diazepine -7-Keto: at room temperature, N 2 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) was added TEA (16.29 mL; 111.35 mmol) portionwise under N atmosphere. 2 The resulting mixture was stirred under a C atmosphere for 1 h. The resulting mixture was diluted with water (1 L) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (500 mL) and purified by anhydrous Na 2 SO4 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 provide 2-bromo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -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]diazepine -7-one: to 2-bromo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -7-ketone (1.00 g; 3.46 mmol) and NH 3 -H 2 To a stirred solution of 2-nitropropene (2.00 mL; 759.13 mmol) in DMSO (10.00 mL) was added CuI (139.00 mg; 0.69 mmol), L-proline (168.00 mg; 1.39 mmol) and K 2 CO 3 (1008.00 mg; 6.93 mmol). The resulting mixture was stirred overnight at 110°C under nitrogen atmosphere with a sealed tube. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, water containing MeCN, 10% to 50% gradient over 10 min; detector, UV 254 nm. This gave 2-amino-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -7-one (380.00 mg; 52.7%) as a yellow solid.

[0164] 7-{[7-oxo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -2-yl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylic acid tert-butyl ester: at room temperature, N 2 Under atmosphere, 2-amino-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine was added. A stirred solution of -7-ketone (330.00 mg; 1.51 mmol) in 1,4-dioxane (6.00 mL) was added portionwise with 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 Cs 2 CO 3 (1548.84 mg; 4.52 mmol). 2 The resulting mixture was stirred for 3 h under 4% CO atmosphere. The residue was purified by silica gel column and eluted with 91% EtOAc in PE to provide 7-{[7-oxo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -2-yl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylic acid tert-butyl ester (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]diazepine -7-Keto: at 0℃, N 2 Under atmosphere, 7-{[7-oxo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine To a stirred solution of tert-butyl]-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (190.00 mg; 1.00 eq.) in DCM (2.40 mL) was added TFA (0.80 mL) portionwise. 2 The resulting mixture was stirred under atmosphere for 1 h. 3 The resulting mixture was adjusted to pH 10 with 4% paraformaldehyde (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (15 mL) and purified by anhydrous Na 2 SO 4 The resulting mixture was concentrated under reduced pressure to provide 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]diazepine -7-one (140.00 mg; crude product) as a brown solid.

[0166] 8-methyl-7-(7-{[7-oxo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -2-yl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester: at room temperature, N 2 Under atmosphere, 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]diazepine was added. To a stirred solution of 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (221.70 mg; 0.64 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (28.29 mg; 0.03 mmol) and Cs-1-hydroxy-7-one (110.00 mg; 0.32 mmol) in 1,4-dioxane (3.00 mL) were added portionwise. 2 CO 3 (329.14 mg; 0.96 mmol). The residue was purified by silica gel column and eluted with 75% EtOAc in PE to provide the crude product. The crude product was purified again by C18 flash column and eluted with 55% ACN in water to provide 8-methyl-7-(7-{[7-oxo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -2-yl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (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]diazepine -7-Keto: 0℃, N 2 Under atmosphere, 8-methyl-7-(7-{[7-oxo-6-(propan-2-yl)-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine A stirred solution of tert-butyl 1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (115.00 mg; 0.195 mmol) in DCM (1.50 mL) was added with TFA (0.50 mL) in portions. The mixture was heated at room temperature under N2 The resulting mixture was stirred for 1 h under a 4% CO atmosphere. The residue was purified by Pre-HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B over 9 min, 55% B; wavelength: 254 nm; RT1 (min): 7), thereby providing 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]diazepine -7-one (24.30 mg; 24.70%) as a white solid.

[0168] HPLC: 96.17% purity, RT = 2.445 min. MS: m / z = 489.30 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.99(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=6.8Hz,1H),4.21-4 .15(m,2H),3.97(s,2H),3.76(d,J=11.7Hz,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

[0169] At room temperature, N 2To 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) was added PEPPSI in portions under an atmosphere of 4% paraformaldehyde. TM -IPr (269.00 mg; 0.31 mmol) and Cs 2 CO 3 (2150.00mg; 6.27mmol). 100℃, N 2 The resulting mixture was stirred for 4 h under a 3-H- atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (MeOH:DCM=1:9) to provide tert-butyl 2-[(6-acetylaminopyridin-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-acetylaminopyridin-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 under nitrogen atmosphere for 1 h. The mixture was adjusted to pH with NaOH (aq.) and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. This gave N-[5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)pyridin-2-yl]acetamide (280.00 mg; 52.6%) as a yellow solid.

[0171] 7-{2-[(6-acetylaminopyridin-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-carboxylic acid tert-butyl ester: N-[5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)pyridin-2-yl]acetamide (260.00 mg; 0.91 mmol) and 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (402.00 mg; 1.10 mmol) and Pd-PEPPSI-IPentCl were stirred at 100°C under nitrogen atmosphere. 2-Methylpyridine (o-picoline) (81.00 mg; 0.09 mmol) and Cs 2 CO 3 (627.00 mg; 1.83 mmol) in 1,4-dioxane (13.00 mL) for 4 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (DCM: MeOH = 8: 2) to provide 7-{2-[(6-acetylaminopyridin-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-carboxylic acid tert-butyl ester (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-acetylaminopyridin-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. under nitrogen atmosphere for 10 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, H 2O / MeCN in water, 10% to 50% gradient over 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] 8-Methyl-7-(2-{[6-(3-methyloxetane-3-ylamino)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-carboxylic acid tert-butyl ester: at room temperature, N 2 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), 3-methyloxetane-3-carboxylic acid (33.00 mg; 0.27 mmol) in DMF (7.00 mL) was added azobenzotriazolium tetramethyluronium hexafluorophosphate (HATU) (355.00 mg; 0.89 mmol) under 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 x 100 mL). The combined organic layers were washed with brine (1 x 50 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (3: 1) to provide 8-methyl-7-(2-{[6-(3-methyloxetane-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-carboxylic acid tert-butyl ester (200.00 mg; 61.5%) as a yellow solid.

[0174]

[0136] 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 8-methyl-7-(2-{[6-(3-methyloxetane-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-carboxylic acid tert-butyl ester (180.00 mg; 0.29 mmol) in DCM (9.00 mL) was added TFA (3.00 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was purified by Prep-HPLC using 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: 3% B to 25% B over 8 min, 25% B; wavelength: 254 / 220 nm; RT1 (min.): 7.4). This gave 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%) as a yellow solid.

[0175] HPLC: 98.38% purity, RT = 2.47 min. MS: m / z = 489.10 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ9.84 (s, 1H), 8.66 (d, J = 2.4Hz, 1H), 8.39 (s, 1H), 8.23 ​​( s,1H),7.91(dd,J=9.5,2.4Hz,1H),7.30(s,1H),6.92(d,J=9.5Hz,1H),5.55(s, 1H),4.36(d,J=14.0Hz,1H),4.23-4.11(m,3H),4.01(s,2H),3.46(d,J=10.8Hz, 2H), 3.33 (d, J = 7.9Hz, 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

[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) was added portionwise X-PHOS (292.88 mg; 0.58 mmol), Xphos Pd G 3 (260.01 mg; 0.29 mmol) and K 2 CO 3 (847.27 mg; 5.84 mmol). The resulting mixture was stirred at 100 ° C under nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to provide 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-naphthyridin-2-carboxylate (580.00 mg; 1.49 mmol) in DCM (15.00 mL) was added TFA (3.00 mL) in portions at room temperature. After stirring at room temperature for 1 h, the mixture was heated to 40°C with saturated NaHCO 3 The mixture was basified to pH = 7 with EtOAc. The combined organic layers were washed with NaCl (aq.) and purified by anhydrous Na 2 SO 4 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] 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-carboxylic acid tert-butyl ester: 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) was added portionwise Pd-PEPPSI-IPentCl at room temperature. 2-Methylpyridine (o-picoline) (54.48 mg; 0.06 mmol) and Cs 2 CO 3 (422.54 mg; 1.23 mmol). The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:100) to provide 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-carboxylic acid tert-butyl ester (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: 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) were added to a solution of EtOH (6.00 mL) and H 2 O (4.00 mL) was added portionwise to NH 4 Cl (43.36 mg; 0.77 mmol). After stirring at 80°C for 2 h, the resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaCl (aq.) and purified by anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure to provide 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] 7-[7-({4-[2-(azetidin-1-yl)acetylamino]-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-carboxylic acid tert-butyl ester: At room temperature, 7-{7-[(4-amino-3-methylphenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl To a stirred solution of tert-butyl-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) was added HATU (125.50 mg; 0.31 mmol) and DIEA (63.97 mg; 0.47 mmol) in portions. The resulting mixture was stirred at 40° C. under nitrogen atmosphere for 6 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to provide tert-butyl 7-[7-({4-[2-(azetidin-1-yl)acetylamino]-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)acetylamino]-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 portionwise with BBr 3The resulting mixture was stirred at -78 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 20% B to 50% B over 9 min, 50% B; wavelength: 254 nm; RT1 (min.): 7, thereby providing 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: 99.4% purity, RT = 2.91 min, MS: m / z = 500.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6): δ9.03(s,1H),8.73(s,1H),7.99(s,1H),7.40(d,J=7.9Hz,2H),7.32(d,J=8.5Hz,1H),7.27(s,1H),6.57(s,1H),5.50(s,1 H),4.19(s,2H),3.98(s,2H),3.45(s,2H),3.34(d,J=7.0Hz,4H),3.17(s ,2H),3.08(d,J=6.0Hz,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

[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) was added portionwise X-PHOS (290.00 mg; 0.58 mmol), K 2 CO 3 (1261.00 mg; 8.67 mmol) and XPhos Pd G 3 (257.00 mg; 0.29 mmol). The resulting mixture was stirred at 100 ° C. under nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with PE:EA=70:30 to provide 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 under nitrogen atmosphere for 2 h. The reaction mixture was heated to 40°C with NaHCO 3 The reaction was diluted with 1% (aq.). The resulting mixture was extracted with EA (3 x 80 mL). The combined organic layers were washed with brine and purified by anhydrous MgSO 4 After filtration, the filtrate was concentrated under reduced pressure to provide 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] 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-carboxylic acid tert-butyl ester: 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) was added portionwise Cs(2-[(3-methyl-4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[2,3-b][1,4]oxazine-1-carboxylate at 25 °C. 2 CO 3 (1.90 g; 5.54 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (130.00 mg; 0.15 mmol). The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere for 12 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with PE:EA=1:1 to provide 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-carboxylic acid tert-butyl ester (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 portionwise NH 4 Cl (276.00 mg; 5.11 mmol) and H 2O (6.00 mL). The resulting mixture was stirred at 80 ° C under nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with EA to provide 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-carboxylic acid tert-butyl ester (600.00 mg; 93.5%) as a yellow oil.

[0187] 8-Methyl-7-[2-({3-methyl-4-[2-(pyrrolidin-1-yl)acetylamino]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester: At room temperature, 7-{2-[(4-amino-3-methylphenyl)amino]-5H,6H,7H,8 To a stirred mixture of tert-butyl 1H,2H,3H-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) in DMF (8.00 mL) was added HATU (388.16 mg; 0.97 mmol) and DIEA (87.93 mg; 0.65 mmol). The mixture was stirred at room temperature for 1 h. The resulting mixture was quenched by ice / water and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography and by CH 2 Cl 2 / MeOH (10:1) to provide 8-methyl-7-[2-({3-methyl-4-[2-(pyrrolidin-1-yl)acetylamino]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (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 8-methyl-7-[2-({3-methyl-4-[2-(pyrrolidin-1-yl)acetylamino]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (80.00 mg; 0.11 mmol) in DCM (4.00 mL) was added dropwise a mixture of BBr 3 The mixture was stirred at -78°C for 1 h. 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 to 27% B over 8 min, 27% B; wavelength: 254 / 220 nm; RT1 (min.): 6.7) to afford 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: 95.2% purity, RT = 2.39 min. MS: m / z = 515.25 [M+H] + . 1 H NMR (300MHz, DMSO-d6): δ9.43(s,1H),9.21(s,1H),8.32(s,1H),7.59(d,J=2. 4Hz,2H),7.42(d,J=8.4Hz,1H),7.29(s,1H),5.53(s,1H),4.19(t,J=4.2Hz,2H ),3.95(s,2H),3.28(d,J=17.6Hz,4H),3.12(t,J=5.6Hz,2H),2.79(d,J=5.7H z, 2H), 2.65 (p, J = 3.6Hz, 4H), 2.15 (s, 3H), 2.04 (s, 3H), 1.77 (p, J = 3.1Hz, 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

[0190] 7-{[4-(Methoxycarbonyl)phenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylic acid tert-butyl ester: at room temperature, N 2 To a stirred solution 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) was added Cs 2 CO 3 (970.00 mg; 2.83 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (125.00 mg; 0.14 mmol). The resulting mixture was stirred at 90°C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with 90% EtOAc in PE to provide 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) and DCM (5.00 mL) was added TFA (1.00 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was washed with saturated NaHCO 3 (aq.) was basified and extracted with EA. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted 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) was added portionwise Cs 2 CO 3 (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 under nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM: MeOH (10: 1) to provide 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-carboxylic acid tert-butyl ester (40.00 mg; 25.08%) as a yellow solid.

[0193] 4-[(6-{1-[(tert-Butyloxy)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 heated to 40 °C with saturated NaHCO 3 (aq.) to alkalize the mixture to pH [7]. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaCl (aq.) and purified by anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure to provide 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] 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-carboxylic acid tert-butyl ester: 4-[(6-{1-[(tert-butyloxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-7 To a stirred mixture of (5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]benzoic acid (80.00 mg; 0.14 mmol) and (3R)-N,N-dimethylpyrrolidin-3-amine dihydrochloride (43.00 mg; 0.22 mmol) in DMF (10.00 mL) was added HATU (112.00 mg; 0.28 mmol) and DIEA (0.08 mL; 0.42 mmol). The resulting mixture was stirred for 16 h. The mixture was extracted with EtOAc. The combined organic layers were washed with NaCl (aq.) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with C18 to provide 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-carboxylic acid tert-butyl ester (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) was added dropwise TFA (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was washed with concentrated saturated NaHCO 3 (aq.) to pH [7] and extracted with EA. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / LNH 4 HCO 3 +0.1% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 25% B to 55% B over 8 min, 55% B; wavelength: 254 nm; RT1 (min.): 7) to provide 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%) as a yellow solid.

[0196] HPLC: 99.7% purity, RT = 4.54 min. MS: m / z = 514.4 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ9.15(s,1H),8.05(s,1H),7.68(d,J=8.4Hz,2H),7.46(d,J=8.1Hz,2H),7.28(s,1H),6.65(s,1H),5.52(s,1 H), 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 = 18.4Hz, 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

[0197] 2-[(4-nitrophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester: A solution of 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (600.00 mg; 2.22 mmol) and 4-nitroaniline (383.00 mg; 2.67 mmol) in 1,4-dioxane (15.00 mL) was added to Cs 2 CO 3 (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. under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (6: 1) to provide 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: TFA (1.00 mL) was added dropwise 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) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was heated to 40°C with saturated NaHCO 3 The mixture was basified to pH = 7 with EA (aq.). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EA to provide N-(4-nitrophenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (470.00 mg; 91.85%) as a yellow solid.

[0199] 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-carboxylic acid tert-butyl ester: 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) was added Cs 2 CO 3 (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. under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM: MeOH (10: 1) to provide 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-carboxylic acid tert-butyl ester (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: 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) was added palladium on carbon (17.00 mg; 0.02 mmol) in a pressure vessel. The mixture was hydrogenated at room temperature for 2 h under 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 provide 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] 8-Methyl-7-[2-({4-[2-(morpholin-4-yl)acetylamino]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester: At room temperature, 7-{2-[(4-aminophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}- To a stirred mixture of tert-butyl 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) was added HATU (126.44 mg; 0.32 mmol) and DIEA (0.09 mL; 0.47 mmol). 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 (aq.) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted by C18 to provide 8-methyl-7-[2-({4-[2-(morpholin-4-yl)acetylamino]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (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 8-methyl-7-[2-({4-[2-(morpholin-4-yl)acetylamino]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (75.00 mg; 0.12 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 h. The mixture was washed with saturated NaHCO 3 The mixture was basified to pH = 7 with EA (aq.). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.1% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 25% B to 55% B over 8 min, 55% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 2) to provide 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: 96.0% purity, RT = 1.97 min. MS: m / z = 517.15 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ9.60(s,1H),9.45(s,1H),8.31(s,1H),7.67(d,J=8.0Hz,2H),7.49(d,J=8.0Hz,2H),7.28(s, 1H), 5.53 (s, 1H), 4.19 (s, 2H), 3.95 (s, 2H), 3.61 (d, J = 19.3Hz, 8H), 3.12 (d, J = 9.7Hz, 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

[0204] 3,3-Dimethyl-2,3-dihydro-1H-isoindol-1-one: -78℃, N 2 To a stirred solution of 2-cyanobenzoic acid (6.00 g; 38.74 mmol) in THF (200.00 mL) was added CH 3 Li (250.00 mL; 400.00 mmol). 2Atmosphere, the resulting mixture was stirred overnight. The reaction was quenched with saline and then extracted twice with ethyl acetate. The combined organics were washed with 1N HCl, saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography to obtain the desired product 3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (2.80 g; 44.8%), which was a yellow solid.

[0205] 3,3-Dimethyl-6-nitro-2,3-dihydro-1H-isoindol-1-one: To a stirred solution of 3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (2.80 g; 17.37 mmol) in sulfuric acid (42.00 mL) was added KNO in portions at 0 °C. 3 The mixture was stirred overnight at room temperature. The reaction solution was poured into ice water and then extracted with ethyl acetate. The extract was washed with water, saturated sodium bicarbonate aqueous solution 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: 3,3-dimethyl-6-nitro-2,3-dihydro-1H-isoindole-1-one (3.15 g; 15.28 mmol) was stirred in a solution containing BH 3 The product was stirred overnight in THF (20.00 mL; 20.00 mmol). NaOH (aq.) and MeOH were added to the mixture and refluxed for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (PE: EtOAc = 7: 3) to provide 1,1-dimethyl-5-nitro-2,3-dihydro-1H-isoindole (2.60 g; 83.1%) as a yellow solid.

[0207] 1,1-Dimethyl-5-nitro-2,3-dihydro-1H-isoindole-2-carboxylic acid tert-butyl ester: 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 h. (Boc) was added 2O (4.41mL; 19.59mmol) and the mixture was warmed to room temperature and stirred for 1h. The reaction was then quenched by adding 20mL of water and extracted with ethyl acetate. The organic phase was concentrated in vacuo. The residue was purified by flash chromatography on silica gel using petroleum ether / ethyl acetate (1 / 1) to provide tert-butyl 1,1-dimethyl-5-nitro-2,3-dihydro-1H-isoindole-2-carboxylate (1.80g; 91.0%) as a yellow solid.

[0208] 5-Amino-1,1-dimethyl-2,3-dihydro-1H-isoindole-2-carboxylic acid tert-butyl ester: 1,1-dimethyl-5-nitro-2,3-dihydro-1H-isoindole-2-carboxylic acid tert-butyl ester (2.00 g; 6.84 mmol) and NH 4 A solution of Cl (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 added for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (PE:EtOAc=7:3) to provide 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] 1,1-Dimethyl-5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)-2,3-dihydro-1H-isoindole-2-carboxylic acid tert-butyl ester: 5-amino-1,1-dimethyl-2,3-dihydro-1H-isoindole-2-carboxylic acid tert-butyl ester (500.00 mg; 1.91 mmol) and 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine hydrochloride (511.00 mg; 2.41 mmol) were stirred at 100°C under nitrogen atmosphere. 2 CO 3 (1.85g; 5.39mmol),Ephos(200.00mg; 0.36mmol),EPhos PdG 4 (200.00 mg; 0.21 mmol) in 1,4-dioxane (10.00 mL) was stirred for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (PE: EtOAc = 7: 3) to provide 1,1-dimethyl-5-({5H, 6H, 7H, 8H-pyrido [3, 4-d] pyrimidin-2-yl}amino)-2,3-dihydro-1H-isoindole-2-carboxylic acid tert-butyl ester (380.00 mg; 50.4%) as a yellow solid.

[0210] 5-[(7-{1-[(tert-Butyloxy)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-carboxylic acid tert-butyl ester: 1,1-dimethyl-5-({5H,6H ,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)-2,3-dihydro-1H-isoindole-2-carboxylic acid tert-butyl ester (340.00 mg; 0.86 mmol) and 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (560.00 mg; 1.58 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (75.00 mg; 0.08 mmol), Cs 2 CO 3 (837.00 mg; 2.44 mmol) in 1,4-dioxane (5.00 mL) and stirred for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (PE: EtOAc = 7: 3) to provide 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-carboxylic acid tert-butyl ester (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: 5-[(7-{1-[(tert-butyloxy)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)-2,3-dihydro-1H-isoindol-5-amine was added to 5-[(7-{1-[(tert-butyloxy)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}-2,3-dihydro-1H-isoindol-5-amine under nitrogen atmosphere at -78°C. A stirred solution of tert-butyl 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 dropwise with BBr 3 The resulting mixture was stirred at -78°C under nitrogen atmosphere for 2 h. 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 purified by anhydrous Na2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 20% B to 50% B over 8 min, 50% B; wavelength: 254 nm; RT1 (min.): 7; This gave 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: 97.0% purity, RT = 2.44 min. MS: m / z = 444.25 [M+H] + . 1 H NMR(400MHz, DMSO-d6)9.42(s,1H),8.31(s,1H),7.60(s,1H),7.49(d,J=8.4Hz,1H),7.28(s,1H),7.05(d,J=8.2Hz,1 H), 5.53 (s, 1H), 4.19 (t, J = 4.4Hz, 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 15N1-[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

[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 portionwise K 2 CO 3 (2.67g; 18.37mmol). 80℃, N2 The resulting mixture was stirred under a 4% CO atmosphere for 5 h. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 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) was added 4-dimethylaminopyridine (DMAP) (0.13 g; 1.11 mmol), TEA (1.78 g; 16.71 mmol) and Boc 2 O (3.68 g; 16.71 mmol). 2 The resulting mixture was stirred under a 4% CO atmosphere for 2 d. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM:MeOH (10:1) to provide 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) was added Fe (0.72 g; 12.21 mmol) and NH 4 Cl (0.82 g; 14.65 mmol). 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 and eluted with DCM: MeOH (10: 1) to provide 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) was added portionwise Ephos (37.00 mg; 0.07 mmol), Ephos Pd G 4 (63.00 mg; 0.07 mmol) and Cs 2 CO 3 (668.00 mg; 1.95 mmol). Using a microwave reaction tube, at 120 °C, N 2 The resulting mixture was stirred under a 4% carbonyl atmosphere for 1 h. The resulting mixture was extracted with EA. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM:MeOH (10:1) to provide 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] 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-carboxylic acid tert-butyl ester: At room temperature, N-[2-(dimethylamino)ethyl]-N-{2-methyl-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-2-yl}-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester was added to the mixture. To a stirred mixture of tert-butyl 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) was added portionwise Pd-PEPPSI-IPentCl 2-methylpyridine(o-picoline) (48.00 mg; 0.05 mmol) and Cs 2 CO 3 (563.00 mg; 1.64 mmol). 2The resulting mixture was stirred overnight under a 3% CO atmosphere. The resulting mixture was extracted with EA. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 The residue was purified by preparative TLC (DCM:MeOH 30:1) to afford 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 room temperature under N 2 The resulting mixture was stirred for 1 h under a 4% 4-H-pyrido[2,3-b][1,4]oxazine-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: 99.8% purity, RT = 2.13 min. MS: m / z = 474.3 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ8.18(d,J=6.9Hz,2H),7.88(s,1H),7.26-7.16(m,2H),7.08( d,J=2.5Hz,1H),6.50(d,J=8.6Hz,1H),6.40(s,1H),5.49(d,J=3.5Hz,1H),4.21-4.14 (m,2H),3.92(s,2H),3.30(d,J=4.7Hz,2H),3.15(t,J=6.5Hz,2H),3.06(t,J=5.7Hz,2 H), 2.77 (t, J = 5.7Hz, 2H), 2.62 (t, J = 6.4Hz, 2H), 2.30 (s, 6H), 2.04 (d, J = 15.2Hz, 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

[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) was added Pd in ​​portions at 25 °C. 2 (dba) 3 (0.87 g; 0.91 mmol), BINAP (1.19 g; 1.81 mmol) and Cs 2 CO 3 (6.22 g; 18.15 mmol). The resulting mixture was stirred at 100 ° C under argon atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (3:1) to provide 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) was added portionwise N,N-dimethylpyridin-4-amine (0.12 g; 0.94 mmol) and TEA (2.06 mL; 14.05 mmol) at room temperature under argon atmosphere. The resulting mixture was stirred at 50°C under argon atmosphere for 1 d. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with 15% EtOAc in PE to afford 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: Raney Ni (190.30 mg; 0.22 mmol) was added 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) at room temperature. 2 At 40 ℃, stir the mixture at room temperature for 2 h. Filter the resulting mixture, wash the filter cake with MeOH (50 mL), and concentrate the filtrate under reduced pressure to provide 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-naphthyridin-3-yl)amino]phenyl}-N-[2-(morpholin-4-yl)ethyl]carbamate (15.00 mL) was added Cs 2 CO 3 (512.60 mg; 1.49 mmol), Ephos (56.09 mg; 0.10 mmol) and EPhos Pd G 4 (48.17 mg; 0.05 mmol). The resulting mixture was stirred at 100°C under nitrogen atmosphere for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH2 Cl 2 / MeOH (11:1) to provide 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] 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-carboxylic acid tert-butyl ester: To N-{2-methyl-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-2-yl} A solution of 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) was added to Cs 2 CO 3 (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 under nitrogen atmosphere for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (12: 1) to provide 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-carboxylic acid tert-butyl ester (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 h, 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 NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 25% B to 55% B over 8 min, 55% B; wavelength: 254 nm; RT1 (min.): 7) to provide 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: 98.9% purity, RT = 3.58 min. MS: m / z = 516.35 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ8.19(s,1H),7.88(s,1H),7.24(s,1H),7.18(dd,J=8.5,2.6Hz,1H),7.08 (d,J=2.5Hz,1H),6.50(d,J=8.6Hz,1H),6.40(s,1H),5.50(t,J=2.7Hz,1H),4.43(s,1H),4.18(dd, J=5.1,3.5Hz,2H),3.92(s,2H),3.59(q,J=4.8Hz,4H),3.29(dt,J=6.8,3.3Hz,2H),3.13(s,2H),3 .05(t,J=5.4Hz,2H),2.77(t,J=5.6Hz,2H),2.56(t,J=6.5Hz,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

[0227] 7-[2-({4-[2-(dimethylamino)acetylamino]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-carboxylic acid tert-butyl ester: At room temperature, 7-{2-[(4-aminophenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl}- To a stirred mixture of tert-butyl 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) was added HATU (85.84 mg; 0.21 mmol) and DIEA (0.06 mL; 0.32 mmol). 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 (aq.) and purified by anhydrous Na 2 SO 4The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (6:1) to provide 7-[2-({4-[2-(dimethylamino)acetylamino]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-carboxylic acid tert-butyl ester (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)acetylamino]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) was added dropwise TFA (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was treated with saturated NaHCO 3 (aq.) was basified to pH = 7 and extracted with EA. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 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 NH 4 HCO 3 +0.1% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 25% B to 55% B over 8 min, 55% B; wavelength: 254 nm; RT1 (min.): 7) to provide 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%) as a yellow solid.

[0229] HPLC: 96.0% purity, RT = 2.23 min. MS: m / z = 475.15 [M+H] + . 1H NMR (300MHz, DMSO-d6) δ9.60(s,1H),9.44(s,1H),8.23(d,J=49.4Hz,1H),7.66(d,J=9.0Hz,2H),7.52(d,J=9.0Hz,2H),7.29(s,1 H), 5.52 (d, J = 3.3Hz, 1H), 4.34-4.11 (m, 2H), 3.95 (s, 2H), 3.11 (d, J = 6.9Hz, 6H), 2.79 (t, J = 5.5Hz, 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

[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 (6.00 mL) was added K 2 CO 3 (586.28 mg; 4.03 mmol). 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 and eluted with PE / EtOAc (1:1) to provide 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 at room temperature for 2 h 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. This gave N1,2-dimethyl-N1-[2-(morpholin-4-yl)ethyl]benzene-1,4-diamine (190.00 mg; 69.8%) 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: 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 eq.) in 1,4-dioxane (13.00 mL) was added Pd-PEPPSI-IPentCl2-methylpyridine(o-picoline) (103.56 mg; 0.12 mmol) and Cs(III) at room temperature. 2 CO 3 (803.26 mg; 2.34 mmol). The mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated under reduced pressure, purified by silica gel column chromatography and eluted with PE / EtOAc (1:1) to provide 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: 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) was prepared at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was washed with saturated NaHCO 3 The mixture was basified to pH = 9 with EtOAc (aq.). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 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] 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-carboxylic acid tert-butyl ester: At room temperature, N1,2-dimethyl-N1-[2-(morpholin-4-yl)ethyl]-N4-{5H,6H,7 To a stirred mixture of 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) was added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (77.16 mg; 0.09 mmol) and Cs 2 CO 3 (598.49 mg; 1.75 mmol). The mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography and eluted with PE / EtOAc (1:1) to provide 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-carboxylic acid tert-butyl ester (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: 8-methyl-7-{2-[(3-methyl-4-{methyl A stirred mixture of [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-carboxylic acid tert-butyl ester (150.00 mg) and TFA (1.00 mL; 12.79 mmol) in DCM (5.00 mL). The mixture 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 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 over 8 min, 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] + . 1 H NMR (300MHz, DMSO-d6): δ9.46(s,1H),9.35(s,1H),8.29(s,1H),7.62-7.53(m,1H),7.49(d,J=2.5Hz,1H),7.27(s,1H),7.05(d,J=8.7Hz,1H ), 4.19 (d, J = 1.3Hz, 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 = 9.9Hz, 3H), 2.22 (s, 3H), 2.03 (s, 3H). Example 18: Synthesis of Compound 18 6-(1-methylsulfonylcyclopropyl)-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

[0237] 2-(Bromomethyl)-5-nitropyridine: 2-Methyl-5-nitropyridine (10.00 g; 70.95 mmol) was dissolved in CCl at room temperature. 4 To a stirred solution in 4% paraformaldehyde (100.00 mL) was added NBS (38.66 g; 212.85 mmol) and AIBN (4.76 g; 28.38 mmol). 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 and eluted with PE / EA (6:1) to provide 2-(bromomethyl)-5-nitropyridine (6.20 g; 38.58%) as a yellow solid.

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

[0239] 2-(1-Methanesulfonylcyclopropyl)-5-nitropyridine: To a solution of 2-(methylsulfonylmethyl)-5-nitropyridine (696.00 mg; 3.16 mmol) in DMF (10.00 mL) was 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 and eluted with PE / EtOAc (3:1) to provide 2-(1-methylsulfonylcyclopropyl)-5-nitropyridine (155.00 mg; 19.77%) as a yellow oil.

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

[0241] tert-Butyl 2-{[6-(1-methylsulfonylcyclopropyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a stirred solution of 6-(1-methylsulfonylcyclopropyl)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) was added Pd-PEPPSI-IPentCl 2-methylpyridine(o-picoline) (107.67 mg; 0.12 mmol) and Cs 2 CO 3 (835.08 mg; 2.43 mmol). The resulting mixture was stirred at 100 ° C under nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (1:100) to provide tert-butyl 2-{[6-(1-methylsulfonylcyclopropyl)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-methylsulfonylcyclopropyl)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 provide 6-(1-methylsulfonylcyclopropyl)-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] 7-(2-{[6-(1-methylsulfonylcyclopropyl)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-carboxylic acid tert-butyl ester: To 6-(1-methylsulfonylcyclopropyl)-N-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester 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 Cs 2 CO 3 (253.07 mg; 0.74 mmol). The resulting mixture was stirred at 100°C under nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to provide 7-(2-{[6-(1-methylsulfonylcyclopropyl)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-carboxylic acid tert-butyl ester (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-methylsulfonylcyclopropyl)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 portionwise TFA (2.00 mL) 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 using the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 18% B to 48% B over 9 min, 48% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 2, thereby providing 6-(1-methylsulfonylcyclopropyl)-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] + . 1 H NMR (300MHz, DMSO-d6): δ9.90 (s, 1H), 8.91 (d, J = 2.6Hz, 1H), 8.40 (s, 1H), 8 .25(dd,J=8.6,2.7Hz,1H),7.51(d,J=8.6Hz,1H),7.29(s,1H),5.54(s,1H), 4.19(d,J=4.9Hz,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, 4.3Hz, 2H), 1.38 (t, J = 3.7Hz, 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

[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 PBr at -20 °C. 3 (0.61 mL; 6.12 mmol). The resulting mixture was stirred at room temperature for 2 h. At 0 °C, saturated NaHCO 3 The reaction was quenched with DCM (3 x 30 mL). 2 SO 4The combined organic layers were dried.After filtration, the filtrate was concentrated under reduced pressure to provide 5-bromo-2-(bromomethyl)-3-fluoropyridine (670.00 mg; 51.5%).

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

[0248] tert-Butyl N-[5-fluoro-6-(methylsulfonylmethyl)pyridin-3-yl]carbamate: To a stirred mixture of 5-bromo-3-fluoro-2-(methylsulfonylmethyl)pyridine (775.00 mg; 2.53 mmol) and tert-butyl carbamate (469.00 mg; 3.80 mmol) in 1,4-dioxane (20.00 mL) was added Pd 2 (dba) 3 (245.00 mg; 0.25 mmol), Xantphos (297.00 mg; 0.51 mmol) and Cs 2 CO 3 (1738.00 mg; 5.07 mmol). After stirring at 90 °C under argon atmosphere for 16 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (19:1) to provide tert-butyl N-[5-fluoro-6-(methylsulfonylmethyl)pyridin-3-yl]carbamate (770.00 mg; 87.5%) as a yellow solid.

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

[14] with saturated NaOH (aq.). The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (6:1) to provide 5-fluoro-6-(methylsulfonylmethyl)pyridin-3-amine (310.00 mg; 67.8%) as a yellow solid.

[0250] tert-Butyl 2-{[5-fluoro-6-(methylsulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a solution of 5-fluoro-6-(methylsulfonylmethyl)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) was added Ephos (164.00 mg; 0.29 mmol), Cs 2 CO 3 (999.00 mg; 2.91 mmol) and EPhosPd G 4 (141.00 mg; 0.15 mmol). The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (24: 1) to provide 2-{[5-fluoro-6-(methylsulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (610.00 mg; 84.8%) as a yellow solid.

[0251] 5-Fluoro-6-(methylsulfonylmethyl)-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-(methylsulfonylmethyl)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) at room temperature. The resulting mixture was stirred at 25 °C under nitrogen for 4 h. The mixture was basified to pH

[14] and the filter cake was treated with H 2 O (2 x 50 mL) and dried under reduced pressure to afford 5-fluoro-6-(methylsulfonylmethyl)-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-(methylsulfonylmethyl)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-(methylsulfonylmethyl)-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) was added portionwise Cs(2-H-{[5-fluoro-6-(methylsulfonylmethyl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[2,3-b][1,4]oxazine-1-carboxylate 2 CO 3 (638.00 mg; 1.86 mmol) and Pd-PEPPSI-IPentCl2-methylpyridine (o-picoline) (93.00 mg; 0.11 mmol). The resulting mixture was stirred overnight at 90 ° C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (10: 1) to provide 7-(2-{[5-fluoro-6-(methylsulfonylmethyl)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-carboxylic acid tert-butyl ester (60.00 mg; 9.9%) as a yellow oil.

[0253] 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: To a stirred solution of tert-butyl 7-(2-{[5-fluoro-6-(methylsulfonylmethyl)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). The mixture was heated to 4 ℃ with saturated NaHCO 3 (aq.) to alkalize the mixture to pH [7]. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions (column: X Bridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 18% B to 48% B over 9 min, 48% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 2) to provide 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 (20.90 mg; 50.7%) as a yellow solid.

[0254] HPLC: 99.5% purity, RT = 3.17 min. MS: m / z = 486.0 [M+H] + . 1 HNMR (300MHz, DMSO-d6) δ10.19(d,J=1.4Hz,1H),8.68(dd,J=2.2,1.2Hz,1H),8.43(s,1H),8.35(dd,J=12.6,2.1Hz,1H),7.29(s,1H),5.52(s,1H) ,4.61–4.52(m,2H),4.18(t,J=4.4Hz,2H),4.01(s,2H),3.30–3.23(m,2H ), 3.11 (d, J = 5.8Hz, 2H), 3.02 (s, 3H), 2.82 (t, J = 5.6Hz, 2H), 2.03 (s, 3H). Example 20: Synthesis of Compound 20: 6-(2-methylsulfonylpropan-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

[0255] 2-(Bromomethyl)-5-nitropyridine: 2-Methyl-5-nitropyridine (10.00 g; 70.95 mmol) was added to CCl at room temperature. 4To a stirred solution in 4% paraformaldehyde (100.00 mL) was added NBS (38.66 g; 212.85 mmol) and AIBN (4.76 g; 28.38 mmol) in portions. 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 and eluted with PE / EA (6:1) to provide 2-(bromomethyl)-5-nitropyridine (6.20 g; 31.65%) as a yellow solid.

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

[0257] 2-(2-Methylsulfonylpropan-2-yl)-5-nitropyridine: To a solution of 2-(methylsulfonylmethyl)-5-nitropyridine (1.25 g; 5.68 mmol) in DMF (12.00 mL) was added NaH (0.27 g; 6.81 mmol) and CH 3 I (2.12 g; 14.20 mmol). 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 and eluted with PE / EtOAc (1:1) to provide 2-(2-methylsulfonylpropan-2-yl)-5-nitropyridine (270.00 mg; 19.44%) as a yellow solid.

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

[0259] tert-Butyl 2-{[6-(2-methylsulfonylpropan-2-yl)pyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a stirred solution of 6-(2-methylsulfonylpropan-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) was added Pd-PEPPSI-IPentCl 2-methylpyridine(o-picoline) (83.39 mg; 0.09 mmol) and Cs 2 CO 3 (646.81 mg; 1.89 mmol). The resulting mixture was stirred at 100 ° C under nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (1: 1) to provide tert-butyl 2-{[6-(2-methylsulfonylpropan-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 provide 6-(2-methylsulfonylpropan-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] 7-(2-{[6-(2-methylsulfonylpropan-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-carboxylic acid tert-butyl ester: tert-butyl 7-(2-{[6-(2-methylsulfonylpropan-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-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (114.78 mg; 0.33 mmol) in 1,4-dioxane (10.00 mL) was added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (29.32 mg; 0.03 mmol) and Cs 2 CO 3 (227.42 mg; 0.66 mmol). The resulting mixture was stirred at 100°C under nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to provide 7-(2-{[6-(2-methylsulfonylpropan-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-carboxylic acid tert-butyl ester (47.00 mg; 21.78%) as a yellow oil.

[0262]

[0136] 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 h, the resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: column: X Bridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3+0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 20% B to 50% B over 9 min, 50% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 2, thereby providing 6-(2-methylsulfonylpropan-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 H NMR (300MHz, DMSO-d6): 9.89(s,1H),8.95(d,J=2.7Hz,1H),8.40(s,1H),8.25(dd,J=8.8,2.7Hz,1H),7.58(d,J=8.8Hz,1H),7.29(s ,1H),5.54(s,1H),4.20(d,J=4.8Hz,2H),4.01(s,2H),3.43(s,2H),3.13(s,2H),2.80(d,J=14.5Hz,5H),2.05(s,3H),1.75(s,6H). Example 21: Synthesis of Compound 21: 6-(Methylsulfonylmethyl)-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

[0264] 3-Methyl-5-nitropyridine-2-carboxylic acid methyl ester: To a stirred solution of 3-methylpyridine-2-carboxylic acid methyl ester (5.00 g; 31.42 mmol) in DCM (10.00 mL) at 0°C under nitrogen atmosphere was added TFAA (13.20 g; 59.71 mmol) and tetrabutylammonium nitrate (nitro-3-oxidanide; tetrabutylazanium) (15.10 g; 47.11 mmol). The resulting mixture was then stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (1:7) to provide 3-methyl-5-nitropyridine-2-carboxylic acid methyl ester (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) was added diisobutylaluminum hydride (1.0 M in dichloromethane; 32.00 mL; 32.00 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The reaction was carried out by adding H 2 The mixture was quenched with 4-nitropyridine-2-yl)-2-ol (350.00 mg; 11.7%) and quenched with 4-nitropyridine-2-yl)-2-ol (30 mL). The resulting mixture was filtered and the filter cake was washed with EA (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (2: 1) to provide (3-methyl-5-nitropyridine-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 PBr at -20 °C. 3 (0.20 mL; 2.00 mmol). The resulting mixture was stirred at room temperature for 2 h. At 0 °C, saturated NaHCO 3 The reaction was quenched with DCM (3 x 30 mL). 2 SO 4 The combined organic layers were dried.After filtration, the filtrate was concentrated under reduced pressure to provide 2-(bromomethyl)-3-methyl-5-nitropyridine (440.00 mg; 1.61 mmol; 96.5%) as a red solid.

[0267] 2-(Methylsulfonylmethyl)-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 under nitrogen atmosphere for 4 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (1:1) to provide 2-(methylsulfonylmethyl)-3-methyl-5-nitropyridine (210.00 mg; 52.1%) as a yellow oil.

[0268] 6-(Methylsulfonylmethyl)-5-methylpyridin-3-amine: 2-(Methylsulfonylmethyl)-3-methyl-5-nitropyridine (300.00 mg; 1.17 mmol) and NH 4To a stirred solution of Cl (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) in portions. The resulting mixture was stirred at 80°C for 2 h. 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 purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to provide 6-(methylsulfonylmethyl)-5-methylpyridin-3-amine (240.00 mg; 96.0%) as a black oil.

[0269] 2-{[6-(methylsulfonylmethyl)-5-methylpyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester: To a solution of 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (278.00 mg; 1.03 mmol) and 6-(methylsulfonylmethyl)-5-methylpyridin-3-amine (220.00 mg; 1.03 mmol) in 1,4-dioxane (20.00 mL) was added Cs 2 CO 3 (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 at 90 ° C under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:9) to provide 2-{[6-(methylsulfonylmethyl)-5-methylpyridin-3-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (250.00 mg; 50.7%) as a yellow oil.

[0270] 6-(Methylsulfonylmethyl)-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-(methylsulfonylmethyl)-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 heated to 4 ℃ with saturated NaHCO 3The mixture was basified to pH [7] by (aq.). The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (4:1) to provide 6-(methylsulfonylmethyl)-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-(methylsulfonylmethyl)-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-(methylsulfonylmethyl)-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) was added portionwise Cs 2 CO 3 (309.00 mg; 0.90 mmol) and Pd-PEPPSI-IPentCl2-methylpyridine (o-picoline) (41.00 mg; 0.05 mmol). The resulting mixture was stirred overnight at 90 ° C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (10: 1) to provide 7-(2-{[6-(methylsulfonylmethyl)-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-carboxylic acid tert-butyl ester (120.00 mg; 36.4%) as a yellow oil.

[0272] 6-(Methylsulfonylmethyl)-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-(methylsulfonylmethyl)-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 portionwise TFA (2.00 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.1% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 18% B to 48% B over 9 min, 48% B; wavelength: 254 nm; RT1 (min.): 7) to provide 6-(methylsulfonylmethyl)-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: 99.8% purity, RT = 2.67 min. MS: m / z = 482.0 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ9.80(s,1H),8.79(d,J=2.5Hz,1H),8.40(s,1H),8.07(d,J=2.5Hz,1H),7.30(s,1H),5.53(t,J=2.5Hz,1H),4.55(s ,2H),4.20(t,J=4.2Hz,2H),4.00(s,2H),3.33(s,2H),3.13(t,J=5.6Hz,2H),2.98(s,3H),2.82(t,J=5.6Hz,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]diazepine -7-Keto

[0274] 2-Bromo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -7-Keto: 0℃, N 2 To a stirred solution of methyl 2-[3-bromo-5-(cyanomethyl)-1H-pyrazol-1-yl]acetate (1.50 g; 5.06 mmol) and cobalt chloride hexahydrate (2.46 g; 10.11 mmol) in MeOH (50.00 mL) was added NaBH4 (1.06 g; 25.28 mmol) in portions under N atmosphere at 25°C. 2 The resulting mixture was stirred under a 4 h 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 x 50 mL), and the combined organic layers were purified by anhydrous Na 2 SO 4 Drying and concentration under reduced pressure provided 2-bromo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -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]diazepine -7-Keto: at room temperature, N 2 Under atmosphere, 2-bromo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine To a stirred solution of -7-ketone (1.10 g; 3.07 mmol) and MeI (0.40 mL; 6.15 mmol) in THF (15.00 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (5.99 mL; 6.15 mmol). 25 °C, N 2 The resulting mixture was stirred for 3 h under a C atmosphere. The resulting mixture was diluted with water (50 mL). The solution was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4The residue was purified by C18 flash chromatography eluting with 67% ACN in water to provide 2-bromo-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -7-ketone (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]diazepine -7-Keto: at room temperature, N 2 Under atmosphere, 2-bromo-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine was added. -7-ketone (240.00 mg; 0.96 mmol) and potassium carboperoxoate (280.11 mg; 1.93 mmol) were dissolved in DMSO (3.00 mL) and NH 4 To a stirred solution in OH (0.6 mL) was added CuI (38.60 mg; 0.19 mmol) and L-proline (46.67 mg; 0.39 mmol) in portions. Using a sealed tube, the mixture was heated at 110 °C and N 2 The resulting mixture was stirred overnight under a 4% aqueous solution of 5% ethyl acetate. The residue was purified by C18 flash chromatography column and eluted with 30% ACN in water to provide a crude product. The crude product was purified again by silica gel column and eluted with 5% MeOH in DCM to provide 2-amino-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -7-one (50.00 mg; 27.67%) as a white solid.

[0277] 2-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -2-yl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester: at room temperature, N 2 Under atmosphere, 2-amino-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine was added. A stirred solution of 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (756.00 mg; 2.66 mmol) in N,N-dimethylformamide (5.00 mL) was added portionwise to XPhos Pd G 3(237.00 mg; 0.27 mmol) and X-PHOS (267.00 mg; 0.53 mmol) and potassium carbonate (1.16 g; 7.99 mmol). 2 The resulting mixture was stirred under a C atmosphere for 1 h. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (DCM:MeOH=10:1) to provide 2-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -2-yl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (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]diazepine -7-Keto: 0℃, N 2 Under atmosphere, 2-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine To a stirred solution of tert-butyl 5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (580.00 mg; 1.28 mmol) in dichloromethane (6.00 mL) was added TFA (2.00 mL) dropwise. 2 The resulting mixture was stirred for 30 min under a 4% CO atmosphere. The resulting mixture was concentrated under reduced pressure to provide 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]diazepine -7-ketone (400.00 mg; 97.1%) as a yellow oil.

[0279] 8-methyl-7-[2-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -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-carboxylic acid tert-butyl ester: at room temperature, N 2Under atmosphere, 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]diazepine was added. To a stirred solution of -7-one (150.00 mg; 0.45 mmol) in 1,4-dioxane (3.00 mL) was added portionwise 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 Cs 2 CO 3 (467.89 mg; 1.36 mmol). 2 The resulting mixture was stirred overnight under a 37° C. atmosphere. The residue was purified by silica gel column eluting with 8% MeOH in DCM to provide 8-methyl-7-[2-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -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-carboxylic acid tert-butyl ester (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]diazepine -7-Keto: -78℃, N 2 Under atmosphere, 8-methyl-7-[2-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine A stirred solution of tert-butyl 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 portionwise with BBr 3 DCM (0.22 mL; 0.22 mmol). -78 °C, N 2 The resulting mixture was stirred under atmosphere for 0.5 h. 3The resulting mixture was quenched and then diluted with water (15 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (15 mL) and purified by anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.1% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 25% B to 55% B over 8 min, 55% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 1) to provide 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]diazepine -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] + . 1 H NMR (400MHz, DMSO-d6) δ9.50(s,1H),8.26(s,1H),7.26(s,1H),6.53(s,1H),5.52(d,J=3.1Hz,1H),4.90(s,2H),4.19(t,J=4. 4Hz,2H),3.91(s,2H),3.86-3.78(m,2H),3.10(t,J=5.5Hz,2H),3.04(t,J=5.7Hz,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

[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) was added Pd in ​​portions at 25 °C. 2 (dba) 3 (0.87 g; 0.91 mmol), BINAP (1.19 g; 1.81 mmol) and Cs 2 CO 3 (6.22 g; 18.15 mmol). The resulting mixture was stirred at 100 ° C under argon atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (3:1) to provide 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 portionwise N,N-dimethylpyridin-4-amine (0.17 g; 1.30 mmol) at room temperature under argon atmosphere. The resulting mixture was stirred at 50°C under argon atmosphere for 2 days. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with 15% EtOAc in PE to afford 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. 2 The mixture was stirred at room temperature for 2 h under a 4% CO 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 provide 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) was added Cs 2 CO 3 (351.01mg; 1.02mmol), Ephos (38.41mg; 0.07mmol) and EPhos Pd G 4 (32.99 mg; 0.03 mmol). The resulting mixture was stirred at 100°C under nitrogen atmosphere for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (12: 1) to provide 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] 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-carboxylic acid tert-butyl ester: To N-[2-methyl-4-({5H,6H,7H,8H-pyrido[ A solution of 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) was added to Cs 2 CO 3(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. under nitrogen atmosphere for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (12: 1) to provide 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-carboxylic acid tert-butyl ester (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: 7-{2-[(4-{[(tert-butyloxy)carbonyl][2-(morpholin-4-yl)ethyl]]-1,4-diamine was added to the mixture at room temperature. To a stirred mixture of tert-butyl 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). After stirring at room temperature for 3 h, 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 NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 25% B to 52% B over 8 min, 52% B; wavelength: 254 nm; RT1 (min.): 7) to provide 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 H NMR (300MHz, DMSO-d6): 9.02 (s, 1H), 8.23 ​​(s, 1H), 7.43 (d, J = 8.4Hz, 1H), 7.28 (d, J = 6.1Hz, 2H), 6.58 (d, J = 8.7Hz, 1H), 5.57 (s, 1H), 4.20 (t, J = 4.4Hz, 2H), 3.89 (d, J = 8Hz, 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-methylsulfonylphenyl)-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

[0289] tert-Butyl 2-[(4-methylsulfonylphenyl)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) was added Pd-PEPPSI-IPentCl 2-methylpyridine(o-picoline) (97.25 mg; 0.11 mmol) and Cs 2 CO 3 (754.30 mg; 2.20 mmol). The resulting mixture was stirred at 100 ° C under nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (1: 1) to provide tert-butyl 2-[(4-methylsulfonylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (340.00 mg; 71.52%) as a yellow solid.

[0290] N-(4-methylsulfonylphenyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine: To a stirred solution of tert-butyl 2-[(4-methylsulfonylphenyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-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 h, the resulting mixture was concentrated under reduced pressure to provide N-(4-methylsulfonylphenyl)-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-methylsulfonylphenyl)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-methylsulfonylphenyl)-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) was added Pd-PEPPSI-IPentCl. 2-Methylpyridine (o-picoline) (34.99 mg; 0.04 mmol) and Cs 2 CO 3 (271.37 mg; 0.79 mmol). The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (1: 1) to provide 7-{2-[(4-methylsulfonylphenyl)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-carboxylic acid tert-butyl ester (57.00 mg; 25.32%) as a yellow oil.

[0292] N-(4-Methylsulfonylphenyl)-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-methylsulfonylphenyl)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) 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 using the following conditions: column: XBridgePrep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 22% B to 52% B over 8 min, 52% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 2 to provide N-(4-methylsulfonylphenyl)-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: 97.9% purity, RT = 3.25 min. MS: m / z = 453.1 [M+H] + . 1 H NMR(300MHz,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 = 5.0Hz, 2H), 4.02 (s, 2H), 3.17 (d, J = 5.4Hz, 2H), 3.14 (s, 5H), 2.83 (d, J = 6.0Hz, 2H), 2.05 (s, 3H). Example 25: Synthesis of Compound 25: N-[4-(methylsulfonylmethoxy)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

[0294] 1-[(Methylthio)methoxy]-4-nitrobenzene: To a stirred solution of 4-nitrophenol (1.00 g; 6.83 mmol) in DMF (15.00 mL) was added sodium hydride (683.00 mg; 17.08 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at 0°C under nitrogen atmosphere. After 10 min, chloro(methylthio)methane (1041.00 mg; 10.24 mmol) was added to the above solution at 0°C under nitrogen atmosphere. The resulting mixture was then stirred for another 2 h at room temperature. The reaction was terminated by adding H 2 O quenched and extracted by EA. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to provide 1-[(methylthio)methoxy]-4-nitrobenzene (500.00 mg; 35.93%) as a yellow solid.

[0295] 1-(Methylsulfonylmethoxy)-4-nitrobenzene: To a stirred solution of 1-[(methylthio)methoxy]-4-nitrobenzene (570.00 mg; 2.80 mmol) in DCM (15.00 mL) was added m-CPBA (2541.00 mg; 13.99 mmol) in portions at room temperature. The resulting mixture was then stirred at room temperature for another 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to provide 1-(methylsulfonylmethoxy)-4-nitrobenzene (480.00 mg; 73.71%) as a white solid.

[0296] 4-(Methylsulfonylmethoxy)aniline: To a solution of 1-(methylsulfonylmethoxy)-4-nitrobenzene (60.00 mg; 0.25 mmol) in MeOH (3.00 mL) was added palladium on carbon (27.00 mg; 0.03 mmol) in a pressure vessel. The mixture was hydrogenated at room temperature for 2 h using a hydrogen balloon under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with 30 mL of EA. The filtrate was concentrated under reduced pressure to provide 4-(methylsulfonylmethoxy)aniline (50.00 mg; 88.19%) as a yellow oil.

[0297] 2-{[4-(methylsulfonylmethoxy)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester: To a solution of 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (350.00 mg; 1.30 mmol) and 4-(methylsulfonylmethoxy)aniline (299.00 mg; 1.30 mmol) in 1,4-dioxane (15.00 mL) was added Cs 2 CO 3 (890.00 mg; 2.59 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (57.00 mg; 0.06 mmol). The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (6: 1) to provide tert-butyl 2-{[4-(methylsulfonylmethoxy)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-(Methylsulfonylmethoxy)phenyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine: TFA (1.00 mL) was added dropwise to a stirred solution of tert-butyl 2-{[4-(methylsulfonylmethoxy)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (290.00 mg; 0.66 mmol) and DCM (5.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was heated to 40°C with saturated NaHCO 3 The mixture was basified to pH = 7 with EA (aq.). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to provide N-[4-(methylsulfonylmethoxy)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-(methylsulfonylmethoxy)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-(methylsulfonylmethoxy)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) was added Cs 2 CO 3 (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. under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EA: PE (10: 1) to provide 7-(2-{[4-(methylsulfonylmethoxy)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-carboxylic acid tert-butyl ester (140.00 mg; 49.07%) as a yellow solid.

[0300] N-[4-(Methylsulfonylmethoxy)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-(methylsulfonylmethoxy)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) was added dropwise TFA (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was heated to 40°C with saturated NaHCO 3 The mixture was basified to pH = 7 with EA (aq.). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 25% B to 55% B over 8 min, 55% B; wavelength: 254 nm; RT1 (min.): 7, thereby providing N-[4-(methylsulfonylmethoxy)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: 99.47% purity, RT = 3.24 min. MS: m / z = 483.20 [M+H] + . 1 H NMR(300MHz, DMSO-d6)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=2.7Hz,1H),5.17(s, 2H), 4.25-4.00 (m, 2H), 3.87 (s, 2H), 3.23 (d, J = 4.2Hz, 2H), 3.04 (t, J = 5.6Hz, 2H), 2.97 (s, 3H), 2.71 (t, J = 5.6Hz, 2H), 1.97 (s, 3H). Example 26: Synthesis of Compound 26N2-[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

[0302] N-[2-(Dimethylamino)ethyl]-5-nitropyridine-2-amine: 2-Fluoro-5-nitropyridine (1.00 g; 6.69 mmol) and K 2 CO 3 A stirred solution of (2.91 g; 20.06 mmol) in DMF (10.00 mL) was added dropwise with (2-aminoethyl)dimethylamine (0.93 g; 10.03 mmol). 2 The resulting mixture was stirred for 2 h under an atmosphere of 40 °C. The resulting mixture was filtered and the filter cake was washed with ACN. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, water containing MeCN (0.05% NH 4 HCO3 ), 100% to 100% gradient over 30 min; detector, UV 254 nm, thereby providing 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) was added DMAP (0.14 g; 1.21 mmol), TEA (1.94 g; 18.20 mmol) and Boc 2 O (4.01 g; 18.20 mmol). 2 The resulting mixture was stirred under atmosphere for 1 h. The residue was purified by silica gel column chromatography and eluted with DCM:MeOH (10:1) to provide 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) was added Fe (1.39 g; 23.61 mmol) and NH 4 Cl (1.59 g; 28.33 mmol). 2 Atmosphere, stir the resulting mixture for 3h.Filter the resulting mixture, and the filter cake is washed with MeOH (3x 3mL).The filtrate is concentrated under reduced pressure.The residue is purified by silica gel column chromatography and eluted with DCM: MeOH (10: 1) to provide N- (5-aminopyridine-2-yl) -N- [2- (dimethylamino) ethyl] tert-butyl carbamate (1.30g; 94.8%), which is 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) was added portionwise EPhos Pd G 4 (166.00 mg; 0.17 mmol), Ephos (97.00 mg; 0.17 mmol) and Cs 2 CO 3 (1771.00mg; 5.16mmol). 120℃, N 2 The resulting mixture was stirred for 1 h under a 4% (2% by volume) atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 2 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, water containing ACN (0.05% NH 3 HCO 3 ), 10% to 100% gradient over 30 min; detector, UV 254 nm, thereby providing 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] 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-carboxylic acid tert-butyl ester: At room temperature, N-[2-(dimethylamino)ethyl]-N-{5-[(5,6,7,8-tetrahydro-2,6 To a stirred mixture of 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) was added Pd-PEPPSI-IPentCl 2-methylpyridine(o-picoline) (75.00 mg; 0.08 mmol) and Cs-1-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2- 2 CO 3 (580.00mg; 1.69mmol). 100℃, N2 The resulting mixture was stirred overnight under a 4% CO atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM:MeOH (10:1) to provide 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 room temperature under N 2 The resulting mixture was stirred for 1 h under a 4% CO atmosphere. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 22% to 50% over 9 min; wavelength: 254 nm; RT1 (min.): 7) to provide 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: 98.89% purity, RT = 2.51 min. MS: m / z = 461.30 [M+H] + .1 H NMR (400MHz, DMSO-d6)8.24(s,1H),8.08(d,J=2.7Hz,1H),7.87(s,1H),7.53(d d,J=8.8,2.7Hz,1H),7.24(s,1H),6.47(d,J=8.9Hz,1H),6.37(s,1H),5.96(t,J =5.6Hz,1H),5.49(s,1H),4.18(t,J=4.4Hz,2H),3.93(s,2H),3.29(d,J=5.9Hz, 4H), 3.06 (s, 2H), 2.77 (s, 2H), 2.39 (t, J = 6.6Hz, 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

[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) was added Pd-PEPPSI-IPentCl 2-methylpyridine(o-picoline) (107.15 mg; 0.12 mmol) and Cs 2 CO 3 (831.07 mg; 2.42 mmol). The mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography and eluted with PE / EtOAc (1:1) to provide 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) was added at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was washed with saturated NaHCO 3 The mixture was basified to pH = 9 with 4% (aq.). The resulting mixture was quenched by ice / water and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 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) was added Pd-PEPPSI-IPentCl at room temperature. 2-Methylpyridine (o-picoline) (99.26 mg; 0.11 mmol) and Cs 2 CO 3 (769.88 mg; 2.24 mmol). The mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography and eluted with PE / EtOAc (1:1) to provide 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-carboxylic acid tert-butyl ester (270.00 mg; 43.1%) as a yellow solid.

[0312] 4-[(6-{1-[(tert-Butyloxy)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 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) was added to a mixture of MeOH (6.00 mL) and H 2 To the stirred mixture in 2% CO (3.00 mL) was added NaOH (42.91 mg; 1.02 mmol). The mixture was stirred at 50°C for 3 h. 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 purified by anhydrous Na 2 SO 4 The mixture was dried. 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]oxazine-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] 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-carboxylic acid tert-butyl ester: At room temperature, 4-[(6-{1-[(tert-butyloxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine To a stirred mixture of 2-(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) was added HATU (330.94 mg; 0.83 mmol) and DIEA (74.97 mg; 0.55 mmol) in portions. The mixture was stirred at room temperature for 1 h. The resulting mixture was quenched by ice / water and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography and by CH 2 Cl2 / MeOH (10: 1) to provide 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-carboxylic acid tert-butyl ester (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: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22% B to 50% B over 9 min, 50% B; wavelength: 254 nm; RT1 (min.): 7) to provide 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: 99.57% purity, RT = 2.93 min. MS: m / z = 544.25 [M+H] + . 1H NMR (300MHz, DMSO-d6): 8.97 (s, 1H), 8.04 (s, 1H), 7.91 (t, J = 5.7Hz, 1H), 7.54 (dd,J=8.4,2.2Hz,1H),7.41(d,J=2.2Hz,1H),7.30-7.21(m,2H),6.62(s,1H), 5.52(s,1H),4.19(t,J=4.4Hz,2H),4.00(s,2H),3.58(t,J=4.6Hz,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

[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-aminoethyl)dimethylamine (864.64 mg; 9.42 mmol) in DMF (10.00 mL) was added portionwise Cs(2-(dimethylamino)ethyl)-3-methyl-5-nitropyridin-2-amine at 25°C under nitrogen atmosphere. 2 CO 3 (6197.91 mg; 18.83 mmol). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 h. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine and purified by anhydrous MgSO 4 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] N-[2-(Dimethylamino)ethyl]-N-(3-methyl-5-nitropyridin-2-yl)carbamic acid tert-butyl ester: At 25°C, under a nitrogen atmosphere, N-[2-(dimethylamino)ethyl]-3-methyl-5-nitropyridin-2-amine (1.00 g; 4.46 mmol) and (Boc 2To a stirred mixture of 1H-1H-2O (3.14 mL; 13.38 mmol) in DCM (20.00 mL) was added TEA (1424.90 mg; 13.38 mmol) and DMAP (114.69 mg; 0.89 mmol) portionwise. The resulting mixture was stirred at 25 °C under nitrogen atmosphere for 2 h. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine and purified by anhydrous MgSO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM:MEOH=95:5 to provide 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: At 25°C, under a nitrogen atmosphere, tert-butyl N-[2-(dimethylamino)ethyl]-N-(3-methyl-5-nitropyridin-2-yl)carbamate (1.00 g; 2.96 mmol) and NH 4 To a stirred mixture of Cl (806.94 mg; 14.78 mmol) in EtOH (12.00 mL) and water (8.00 mL) was added Fe (733.93 mg; 11.83 mmol) portionwise. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine and purified by anhydrous MgSO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM:MEOH=83:17 to provide tert-butyl N-(5-amino-3-methylpyridin-2-yl)-N-[2-(dimethylamino)ethyl]carbamate (915 mg; 97.75%) as an orange-yellow solid.

[0319] N-[2-(Dimethylamino)ethyl]-N-[3-methyl-5-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)pyridin-2-yl]carbamic acid tert-butyl ester: at room temperature, N 2To 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) in portions under a 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine hydrochloride atmosphere. The mixture was stirred at room temperature for 20 min. To the above mixture was 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 G 4 (187.68 mg; 0.19 mmol). 2 Atmosphere, the resulting mixture was stirred for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with EA to provide 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 (280.00mg; 25.68%) as a yellow solid.

[0320] 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-carboxylic acid tert-butyl ester: at room temperature, N 2 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) was added portionwise 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 Cs(III) under atmospheric pressure. 2 CO 3 (541.47 mg; 1.58 mmol). 2 The resulting mixture was stirred overnight under a C atmosphere. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (15 mL) and purified by anhydrous Na 2 SO 4The resulting mixture was dried. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with 16% MeOH in DCM to provide 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-carboxylic acid tert-butyl ester (230.00 mg; 58.7%) as a brown-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: 0°C, N 2 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 under N atmosphere at room temperature. 2 The resulting mixture was stirred for 1 h under a 4% atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions (column: X Bridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 25% B to 55% B over 9 min, 55% B; wavelength: 254 nm; RT1 (min.): 7) to provide 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: 97.93% purity, RT = 2.05 min. MS: m / z = 476.25 [M+H] + . 1H NMR (400MHz, DMSO-d6)8.95(s,1H),8.19(d,J=17.8Hz,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

[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 at 25°C under nitrogen for 30 min, then 4-nitro-2-(trifluoromethyl)aniline (1.50 g; 7.13 mmol) and DIEA (7.85 mL; 42.79 mmol) were added portionwise. The resulting mixture was stirred at 80°C under nitrogen for 5 h. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine and purified by anhydrous MgSO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EA:PE=21:79 to provide 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: 2-(morpholin-4-yl)-N-[4-nitro-2-(trifluoromethyl)phenyl]acetamide (1.00 g; 3.00 mmol) and NH 4 To a stirred mixture of Cl (844.76 mg; 15.00 mmol) in EtOH (6.00 mL) and water (4.00 mL) was added Fe (707.52 mg; 12.00 mmol) portionwise. The resulting mixture was stirred at 80°C under nitrogen atmosphere for 4 h. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine and purified by anhydrous MgSO4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM:MEOH=92:8 to provide 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)acetylamino]-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) was added portionwise Xphos Pd G 3 (120.00 mg; 0.13 mmol), X-PHOS (60.00 mg; 0.12 mmol) and K 2 CO 3 (560.00 mg; 3.85 mmol). The resulting mixture was stirred at 100 ° C. under nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (PE: EtOAc = 7: 3) to provide 2-({4-[2-(morpholin-4-yl)acetylamino]-3-(trifluoromethyl)phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (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)acetylamino]-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 (6.00 mL) was stirred at 30 °C under nitrogen for 1 h. 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 purified by anhydrous Na 2 SO 4The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. This gave 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] 8-Methyl-7-[2-({4-[2-(morpholin-4-yl)acetylamino]-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-carboxylic acid tert-butyl ester: 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) and tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (340.00 mg; 0.98 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (60.00 mg; 0.07 mmol) and Cs 2 CO 3 (674.00 mg; 1.97 mmol) in 1,4-dioxane (4.00 mL) solution and stirred for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (PE: EtOAc = 7: 3) to provide 8-methyl-7-[2-({4-[2-(morpholin-4-yl)acetylamino]-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-carboxylic acid tert-butyl ester (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: 8-methyl-7-[2-({4-[2-(morpholin-4 -yl)acetylamino]-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-carboxylic acid tert-butyl ester (178.00 mg; 0.24 mmol) and TFA (2.00 mL) in DCM (6.00 mL) were stirred for 2 h. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / LNH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 29% B to 59% B over 9 min, 59% B; wavelength: 254 nm; RT1 (min.): 7. This gave 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%) as an off-white solid.

[0329] HPLC: 95.03% purity, RT = 2.85 min. MS: m / z = 585.20 [M+H] + . 1 H NMR (400MHz, DMSO-d6)9.88(s,1H),9.61(s,1H),8.39(s,1H),8.23(d,J=2.4Hz,1H),8.01(d,J=9.2Hz,1H),7.90(s,1H),7.29( s,1H),5.54(s,1H),4.19(t,J=4.3Hz,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 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

[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), 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 reaction was cooled to room temperature. After filtration, the filtrate was concentrated under reduced pressure. This gave 2-methyl-1-(5-nitro-2,3-dihydro-1H-isoindol-2-yl)propan-2-ol (350.00 mg; 97.8%) as a yellow solid.

[0331] 1-(5-amino-2,3-dihydro-1H-isoindol-2-yl)-2-methylpropan-2-ol: 2-methyl-1-(5-nitro-2,3-dihydro-1H-isoindol-2-yl)propan-2-ol (350.00 mg; 1.48 mmol) and NH 4 To a stirred mixture of Cl (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). The resulting mixture was stirred at 80 °C for 3 h. The reaction was cooled to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (3:1) to provide 1-(5-amino-2,3-dihydro-1H-isoindol-2-yl)-2-methylpropan-2-ol (300.00 mg; 90.5%) as a yellow-brown solid.

[0332] 2-{[2-(2-hydroxy-2-methylpropyl)-2,3-dihydro-1H-isoindol-5-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester: at room temperature, N 2To 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) was added Cs-1 in portions under an atmosphere of 4% paraformaldehyde. 2 CO 3 (862.00 mg; 2.51 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (111.00 mg; 0.13 mmol). 2 The resulting mixture was stirred for 16 h under a 4% CO atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (4:1) to provide 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 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 TFA (3.00 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 3 h. The filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography and purified by H 2 O / MeCN (1:4) eluted 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] 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-carboxylic acid tert-butyl ester: at room temperature, N 2 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) was added Cs-1 in portions under a 4% CO atmosphere. 2 CO 3 (505.00 mg; 1.47 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (65.00 mg; 0.07 mmol). 2 The resulting mixture was stirred under a 4% CO atmosphere for 16 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (4:1) to provide 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-carboxylic acid tert-butyl ester (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: 7-(2-{[2-(2-hydroxy-2-methylpropyl)-2, To a stirred solution of tert-butyl 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 TFA (3.00 mL) dropwise. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using 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 to 23% B over 8 min, 23% B; Wavelength: 254 / 220 nm; RT1 (min.): 6.3, to provide 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: 97.59% purity, RT = 2.44 min. MS: m / z = 488.30 [M+H] + . 1 H NMR (300MHz, methanol-d4)8.22(s,1H),7.60(s,1H),7.42(dd,J=8.2,2.0Hz,1H),7.27(s,1H),7.11(d,J=8.2Hz,1H),4.35-4.26(m,2 H),4.07-3.95(m,6H),3.46-3.37(m,2H),3.19(t,J=5.7Hz,2H),2.84(t,J=5.7Hz,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

[0337] 2-(Dimethylamino)-N-(5-nitropyridin-2-yl)acetamide: at 0°C, N 2 To a stirred solution of 5-nitropyridin-2-amine (1.00 g; 6.97 mmol) in DMF (10.00 mL) was 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) in portions under atmosphere. The resulting mixture was cooled to room temperature. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% NH 4 HCO 3 ), 70% to 80% gradient over 10 min; detector, UV 254 nm, thereby providing 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: Raney Ni (500.00 mg; 5.54 mmol) was added to a solution of 2-(dimethylamino)-N-(5-nitropyridin-2-yl)acetamide (780.00 mg; 3.30 mmol) in MeOH (10.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated under reduced pressure. This gave N-(5-aminopyridin-2-yl)-2-(dimethylamino)acetamide (600.00 mg; 92.6%) as a red oil.

[0339] 7-({6-[2-(dimethylamino)acetylamino]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylic acid tert-butyl ester: at room temperature, N 2To 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) was added EPhos Pd G 4 (106.00 mg; 0.11 mmol), Cs 2 CO 3 (1.08 g; 3.28 mmol) and Ephos (62.00 mg; 0.11 mmol). 2 The resulting mixture was stirred under a 4% CO atmosphere for 1 h. The resulting mixture was cooled to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, water containing MeCN (0.05% NH 4 HCO 3 ), 70% to 80% gradient over 10 min; detector, UV 254 nm, thereby providing tert-butyl 7-({6-[2-(dimethylamino)acetylamino]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: at room temperature, N 2 To a stirred solution of tert-butyl 7-({6-[2-(dimethylamino)acetylamino]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 TFA (1.00 mL) dropwise under N atmosphere. 2 The resulting mixture was stirred under atmosphere for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, water containing MeCN (0.05% NH 4 HCO 3), 10% to 20% gradient over 30 min; 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 light brown oil.

[0341] 7-[7-({6-[2-(dimethylamino)acetylamino]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-carboxylic acid tert-butyl ester: at room temperature, N 2 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) was added Pd-PEPPSI-IPentCl2-methylpyridine(o-picoline) (35.00 mg; 0.04 mmol) and Cs(III) in a 1% argon atmosphere. 2 CO 3 (408.00 mg; 1.19 mmol). 2 Atmosphere, stir the obtained mixture 24h.The obtained mixture is cooled to room temperature.Filter the obtained mixture, and the filter cake is washed with MeOH (3x 5mL).The filtrate is concentrated under reduced pressure.The crude product is purified by preparative TLC (DCM: MeOH 20: 1) to provide 7- [7- ({ 6- [2- (dimethylamino) acetylamino] pyridine -3- base} amino) -1,2,3,4- tetrahydro -2,6- naphthyridine -2- base] -8- methyl -1H, 2H, 3H- pyrido [2,3-b] [1,4] oxazine -1- carboxylic acid tert-butyl ester (50.00mg; 20.6%), it is 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: at 0°C, N 2To a stirred solution of tert-butyl 7-[7-({6-[2-(dimethylamino)acetylamino]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). The mixture was stirred at room temperature under N atmosphere. 2 The resulting mixture was stirred for 1 h under a 4% CO atmosphere. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: MeOH-HPLC; flow rate: 60 mL / min.; gradient: 48% to 78% over 8 min; wavelength: 254 nm; RT1 (min.): 7) to provide 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: 99.35% purity, RT = 4.63 min. MS: m / z = 475.25 [M+H] + . 1 H NMR (300MHz, methanol-d4)8.49(dd,J=2.3,1.2Hz,1H),8.09-7.96(m,2H),7.97(s,1H),7.26(s,1H),6.56(s,1H),4.30(t,J= 4.4Hz, 2H), 4.03 (s, 2H), 3.41 (t, J = 4.4Hz, 2H), 3.17 (d, J = 5.9Hz, 4H), 2.90 (t, J = 5.7Hz, 2H), 2.40 (s, 6H), 2.13 (s, 3H). Example 32: Synthesis of Compound 32N2-[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

[0344] 2-(Morpholin-4-yl)-N-(5-nitropyridin-2-yl)acetamide: 0°C, N 2 To a stirred solution of 2-(morpholin-4-yl)acetic acid (3.20 g; 20.92 mmol) in DMF (20.00 mL) was 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) in portions under N atmosphere. 2 The resulting mixture was stirred under a C atmosphere for 3 days. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (15 mL) and purified by anhydrous Na 2 SO 4 The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with 90% EtOAc in PE to provide 2-(morpholin-4-yl)-N-(5-nitropyridin-2-yl)acetamide (2.55 g; 68.7%) as a light yellow solid.

[0345] N-(5-aminopyridin-2-yl)-2-(morpholin-4-yl)acetamide: at room temperature, N 2 To a stirred solution of 2-(morpholin-4-yl)-N-(5-nitropyridin-2-yl)acetamide (2.48 g; 8.38 mmol) in EtOH (15.00 mL) was added Fe (2.47 g; 41.92 mmol) and NH 4 Cl (2.36 g; 41.92 mmol (dissolved in H 2 O (10.00 mL)). 2 The resulting mixture was stirred under atmosphere for 1.5 h. The residue was purified by silica gel column and eluted with 35% DCM in MeOH to afford N-(5-aminopyridin-2-yl)-2-(morpholin-4-yl)acetamide (2.00 g; 99.0%) as a yellow oil.

[0346] 7-({6-[2-(morpholin-4-yl)acetylamino]pyridin-3-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylic acid tert-butyl ester: at room temperature, N 2 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) was added portionwise tert-butyl 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (331.89 mg; 1.17 mmol), EPhos Pd G 4(103.13 mg; 0.11 mmol), Ephos (120.08 mg; 0.21 mmol) and cesium carbonate (1097.40 mg; 3.20 mmol). 2 The resulting mixture was stirred under a C atmosphere for 1 h. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (15 mL) and purified by anhydrous Na 2 SO 4 The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with 7% MeOH in DCM to provide tert-butyl 7-({6-[2-(morpholin-4-yl)acetylamino]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: at 0°C, N 2 To a stirred solution of tert-butyl 7-({6-[2-(morpholin-4-yl)acetylamino]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) under N atmosphere. 2 The resulting mixture was stirred under a 4% atmosphere for 1 h. The resulting mixture was adjusted to pH = 12 with NaOH (4N) and then extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (15 mL) and purified by anhydrous Na 2 SO 4 The resulting mixture was concentrated under reduced pressure to provide 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] 8-Methyl-7-[7-({6-[2-(morpholin-4-yl)acetylamino]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-carboxylic acid tert-butyl ester: at room temperature, N 2To 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) was added portionwise 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-IPentCl2-methylpyridine(o-picoline) (58.47 mg; 0.07 mmol) and Cs(III) under atmospheric pressure. 2 CO 3 (680.29 mg; 1.98 mmol). 2 The resulting mixture was stirred under a C atmosphere for 1 h. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (15 mL) and purified by anhydrous Na 2 SO 4 The residue was purified by silica gel column and eluted with 4% MeOH in DCM to provide 8-methyl-7-[7-({6-[2-(morpholin-4-yl)acetylamino]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-carboxylic acid tert-butyl ester (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: at 100°C, N 2 To a stirred solution of tert-butyl 8-methyl-7-[7-({6-[2-(morpholin-4-yl)acetylamino]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) in portions under N atmosphere. The mixture was stirred at room temperature for 2 hours under N atmosphere. 2 The resulting mixture was stirred for 1 h under a 4% CO atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions (column: X Bridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3+0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 25% B to 55% B over 9 min, 55% B; wavelength: 254 nm; RT1 (min.): 7) to provide 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: 95.26% purity, RT = 1.94 min. MS: m / z = 517.30 [M+H] + . 1 H NMR (400MHz, DMSO-d6)9.74(s,1H),8.97(s,1H),8.56(d,J=2.7Hz,1H),8.07(dd,J=8.9 ,2.7Hz,1H),8.02-7.94(m,2H),7.26(s,1H),6.57(s,1H),5.50(t,J=2.7Hz,1H),4.18(t ,J=4.4Hz,2H),3.99(s,2H),3.63(t,J=4.6Hz,4H),3.33-3.26(m,2H),3.16(s,2H),3.0 9(t,J=5.7Hz,2H), 2.82(t,J=5.7Hz,2H), 2.54(d,J=4.6Hz,4H), 2.05(d,J=18.0Hz,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

[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 eq.) 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) was added portionwise PEPPSI-IPr (142.44 mg; 0.22 mmol) and Cs 2 CO3 (1500.83 mg; 4.38 mmol). The resulting mixture was stirred at 100°C under argon atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to provide 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 light 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-naphthyridin-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 residue was purified by evaporation with Na 2 CO 3 The mixture was acidified / basified to pH = 8 (aq.). The resulting mixture was filtered and the filter cake was washed with water. The filter cake was concentrated under reduced pressure to provide 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] 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-carboxylic acid tert-butyl ester: 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) was added Cs 2 CO 3(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. under nitrogen atmosphere for 24 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (1:2) to provide 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-carboxylic acid tert-butyl ester (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. 2 The mixture was stirred at room temperature for 2 h under a 4% argon atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (50 mL), and the filtrate was concentrated under reduced pressure to provide 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 light yellow solid).

[0355] tert-Butyl 7-[7-({4-[2-(Dimethylamino)acetylamino]-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 2-(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 purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to provide tert-butyl 7-[7-({4-[2-(dimethylamino)acetylamino]-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 h, 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 NH 4 HCO3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 25% B to 55% B over 8 min, 55% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 2) to provide 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] +1 H NMR (300MHz, methanol-d4): 7.86 (s, 1H), 7.63 (d, J = 8.5Hz, 1H), 7.36-7.28 (m, 2H ),7.27(dd,J=8.5,2.5Hz,1H),6.95(s,1H),4.43(t,J=4.4Hz,2H),4.20(s ,2H),4.01(t,J=3.3Hz,2H),3.98-3.90(m,4H),3.51(t,J=4.4Hz,2H),3.2 5(dd,J=11.4,5.5Hz,6H),2.98(t,J=5.8Hz,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

[0358] tert-Butyl 8-methyl-7-[7-({3-methyl-4-[2-(morpholin-4-yl)acetylamino]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 purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by CH 2 Cl 2 / MeOH (10:1) to provide 8-methyl-7-[7-({3-methyl-4-[2-(morpholin-4-yl)acetylamino]phenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (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)acetylamino]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 h, 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 NH 4 HCO3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 22% B to 52% B over 9 min, 52% B; wavelength: 254 nm; RT1 (min.): 7) to provide 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] +1 H NMR (300MHz, methanol-d4): 7.86 (s, 1H), 7.63 (d, J = 8.5Hz, 1H), 7.36-7.28 (m, 2H ),7.27(dd,J=8.5,2.5Hz,1H),6.95(s,1H),4.43(t,J=4.4Hz,2H),4.20(s ,2H),4.01(t,J=3.3Hz,2H),3.98-3.90(m,4H),3.51(t,J=4.4Hz,2H),3.2 5(dd,J=11.4,5.5Hz,6H),2.98(t,J=5.8Hz,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

[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) was added Pd-PEPPSI-IPentCl 2-methylpyridine(o-picoline) (0.27 g; 0.30 mmol) and Cs(III) at room temperature. 2 CO 3(2.07 g; 6.04 mmol). The mixture was stirred at room temperature for 1 h. The mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography and eluted with PE / EtOAc (1:1) to provide 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: 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 eq.) and TFA (5.00 mL) in DCM (20.00 mL) was prepared at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was heated to 40°C with saturated NaHCO 3 The mixture was basified to pH = 9 with 4% (aq.). The resulting mixture was quenched by ice / water and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. This gave 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) was added Pd-PEPPSI-IPentCl at room temperature. 2-Methylpyridine (o-picoline) (0.24 g; 0.27 mmol) and Cs 2 CO 3(1.87 g; 5.46 mmol). The mixture was stirred at 100 ° C for 2 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (1: 1) to provide 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-carboxylic acid tert-butyl ester (1.33 g; 86.8%) as a yellow solid.

[0364] 4-[(7-{1-[(tert-butyloxy)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: Preparation of 7-(2-{[4-(methoxycarbonyl)-3-methylphenyl]amino}-5H,6H tert-butyl 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 eq.) and NaOH (60.96 mg; 1.45 mmol; 3.00 eq.) were dissolved in MeOH (10.00 mL) and H 2 O (3.00 mL). The mixture was stirred at 50 ° C for 3 h. The mixture was acidified to pH = 7 with HCl (4N) and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 The mixture was dried. 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]oxazine-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: 4-[(7-{1-[(tert-butyloxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate was added to the mixture at room temperature. To a stirred mixture of 1-methyl-1-oxazine-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) was added HATU (275.27 mg; 0.69 mmol) and DIEA (62.36 mg; 0.46 mmol). The mixture was stirred at room temperature for 1 h. The resulting mixture was quenched by ice / water and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography and by CH 2 Cl 2 / MeOH (10: 1) to provide 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-carboxylic acid tert-butyl ester (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 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 22% B to 50% B over 9 min, 50% B; wavelength: 254 nm; RT1 (min.): 7) to provide 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] +1H NMR(300MHz, DMSO-d6):9.63(s,1H),8.46(d,J=7.2Hz,1H),8.37(s,1H),7.68(dd,J=8.4,2.2H z,1H),7.56(d,J=2.2Hz,1H),7.29(t,J=4.2Hz,2H),5.54(d,J=2.7Hz,1H),4.38(h,J=7.1Hz,1 H),4.20(t,J=4.2Hz,2H),3.97(s,2H),3.56(t,J=7.3Hz,2H),3.31(d,J=3.6Hz,2H),3.12(d,J =5.8Hz,2H),2.97-2.86(m,2H),2.81(d,J=5.6Hz,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

[0368] 3-Methyl-N-[2-(morpholin-4-yl)ethyl]-5-nitropyridine-2-amine: 2-Fluoro-3-methyl-5-nitropyridine (2.50 g; 15.21 mmol), Cs 2 CO 3 To a stirred solution of 2-(morpholin-4-yl)ethan-1-amine (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). 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 x 50 mL). The combined organic layers were washed with brine (1 x 30 mL) and purified by anhydrous Na 2 SO 4 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 brownish yellow solid.

[0369] N-(3-Methyl-5-nitropyridin-2-yl)-N-[2-(morpholin-4-yl)ethyl]carbamic acid tert-butyl ester: 3-Methyl-N-[2-(morpholin-4-yl)ethyl]-5-nitropyridin-2-amine (2.10 g; 7.89 mmol), Boc 2=Toluene (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) overnight. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (PE: EtOAc = 7: 3) to provide 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] N-(5-amino-3-methylpyridin-2-yl)-N-[2-(morpholin-4-yl)ethyl]carbamic acid tert-butyl ester: N-(3-methyl-5-nitropyridin-2-yl)-N-[2-(morpholin-4-yl)ethyl]carbamic acid tert-butyl ester (1.10 g; 3.00 mmol) and NH 4 A solution of Cl (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 for 2 h. 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 and eluted with DCM / MeOH=7:1 to provide tert-butyl N-(5-amino-3-methylpyridin-2-yl)-N-[2-(morpholine-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) was added EPhos PdG 4 (80.00 mg; 0.08 mmol), Ephos (80.00 mg; 0.14 mmol; 0.16) and Cs 2 CO 3(900.00 mg; 2.62 mmol). The resulting mixture was stirred at 120 ° C. under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (PE: EtOAc = 7: 3) to provide 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] carbamic acid tert-butyl ester (370.00 mg; 68.4%), which is a yellow solid.

[0372] 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-carboxylic acid tert-butyl ester: 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]carbamic acid tert-butyl ester (350.00 mg; 0.58 mmol), 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (220.00 mg; 0.63 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picolin) (63.00 mg; 0.07 mmol) and Cs 2 CO 3 (732.00 mg; 2.13 mmol) in 1,4-dioxane (5.00 mL) for 4 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with (PE: EtOAc = 7: 3) to provide 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-carboxylic acid tert-butyl ester (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: 7-{2-[(6-{[(tert-butyloxy)carbonyl][2-(morpholin-4-yl)ethyl]]pyridine-2,5-diamine was stirred at room temperature under nitrogen atmosphere. -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-carboxylic acid tert-butyl ester (275.00 mg; 0.34 mmol) and TFA (2.00 mL) in DCM (6.00 mL) were stirred for 6 h. The crude product was purified by preparative HPLC using the following conditions: column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.1% NH 4 OH), 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). This gave 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%) as an orange solid.

[0374] HPLC: 90.98% purity, RT = 2.11 min. MS: m / z = 518.40 [M+H] +1 H NMR (400MHz, DMSO-d6)8.95(s,1H),8.22(s,1H),8.16(d,J=2.5Hz,1H),7.47(d,J=2.5Hz,1H),7.26(s,1H),5.53–5.42(m,2H),4.18(t, J=4.4Hz,2H),3.89(s,2H),3.58(t,J=4.7Hz,5H),3.42(q,J=6.4Hz,2H),3.09(d,J=6.1Hz,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]diazepine -7-Keto

[0375] 8-Chloro-7-[7-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -2-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester: at room temperature, N 2 Under atmosphere, 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]diazepine were added. A stirred solution of -7-ketone (182.67 mg; 0.53 mmol) in 1,4-dioxane (5.00 mL) was added portionwise with Cs 2 CO 3 (541.52 mg; 1.58 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (46.54 mg; 0.05 mmol). 2 The resulting mixture was stirred overnight under a 4% 4% 2-naphthene atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with DCM containing 8% MeOH to provide a crude product. The crude product was re-purified by C18 flash column and eluted with water containing 45% CAN to provide 8-chloro-7-[7-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -2-yl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (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]diazepine -7-Keto: at room temperature, N 2 Under atmosphere, 8-chloro-7-[7-({6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine A stirred solution of tert-butyl 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). The mixture was heated at 25 °C under N 2 The resulting mixture was stirred for 2 h under a 4% CO atmosphere. The residue was purified by preparative HPLC using the following conditions (column: XBridgePrep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), 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), thereby providing 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]diazepine -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 H NMR(300MHz,DMSO-d6)δ9.00(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-2yl)amino]benzoyl}azetidin-3-amine

[0378] 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-carboxylic acid tert-butyl ester: 4-[(7-{1-[(tert-butyloxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine] was added to the mixture at room temperature. To a stirred mixture of 1H,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) was added HATU (275.27 mg; 0.69 mmol) and DIEA (62.36 mg; 0.46 mmol). The mixture was stirred at room temperature for 1 h. The resulting mixture was quenched by ice / water and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography and by CH 2 Cl 2 / MeOH (10:1) to provide 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-carboxylic acid tert-butyl ester (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-2yl)amino]benzoyl}azetidin-3-amine: 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) was prepared at room temperature. The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 22% B to 50% B over 9 min, 50% B; wavelength: 254 nm; RT1 (min.): 7) to provide 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]pyrimidine-2yl)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] +1H NMR (300 MHz, methanol-d4): 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=10.6,5.1Hz,1H),3.86(dd,J=9.6,5.1Hz,1H),3.44(t,J=4.4Hz,2H) ,3.21(dt,J=13.0,6.4Hz,3H),2.89(t,J=5.4Hz,2H),2.38(s,3H),2.19(d,J=13.1Hz,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

[0381] 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-carboxylic acid tert-butyl ester: 4-[(7-{1-[(tert-butyloxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine] was added to the mixture at room temperature. To a stirred mixture of 2-(morpholin-4-yl)ethyl-1-amine (59.69 mg; 0.46 mmol) and 1-(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)ethyl-1-amine (59.69 mg; 0.46 mmol) in DMF (10.00 mL) was added HATU (275.27 mg; 0.69 mmol) and DIEA (62.36 mg; 0.46 mmol). The mixture was stirred at room temperature for 1 h. The resulting mixture was quenched by ice / water and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography and by CH 2 Cl 2 / MeOH (10: 1) to provide 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-carboxylic acid tert-butyl ester (150.00 mg; 98.4%) as a yellow solid.

[0382]

[0266] 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 stirred mixture of 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-carboxylic acid tert-butyl ester (190.00 mg; 0.26 mmol) in DCM (5.00 mL) was added TFA (1.00 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.05% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 22% B to 50% B over 9 min, 50% B; wavelength: 254 nm; RT1 (min.): 7), thereby providing 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 (25.50 mg; 17.7%) as a yellow solid.

[0383] HPLC: 98.02% purity, RT = 2.46 min. MS: m / z = 545.25 [M+H] +1H NMR (300MHz, DMSO-d6): 9.62 (s, 1H), 8.36 (s, 1H), 7.95 (t, J = 5.7Hz, 1H), 7.67 ( dd,J=8.5,2.2Hz,1H),7.56(d,J=2.2Hz,1H),7.32-7.21(m,2H),5.52(d,J=3.2 Hz,1H),4.19(t,J=4.3Hz,2H),3.97(s,2H),3.57(t,J=4.6Hz,4H),3....

Claims

1. Compounds of Formula I in: R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl; R1 and R2 together with the carbon to which they are attached may together form a C3-C6 carbocyclic ring; R3 is selected from the group consisting of hydrogen and C1-C6 alkyl; R4 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl; R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl; R7 is selected from the group consisting of hydrogen and C1-C6 alkyl; 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 CR8; Z is selected from the group consisting of N and CH; R8 and R9 are independently selected from the group consisting of hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, C1-C6 haloalkyl, optionally substituted C2-C8 heterocycle, optionally substituted heteroaryl, optionally substituted C6-C 14 Aryl, -(CH2) m -NR'R", -NR'-(CH2) m -NR'R", -(CH2) n -OR 11 、-O-(CH2) n -OR 11 ; R 10 Each occurrence is independently selected from the group consisting of C1-C6 alkyl, -NR'R", -(CH2) p -OR 11 、-(CH2) n -O-(CH2) n -OR 11 and -(CH2) m -NR'R"; R' and R" at each occurrence are independently selected from the group consisting of hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; R 12 and R 13 Each occurrence is independently selected from hydrogen and C1-C6 alkyl; R 12 and R 13 Together with the carbon to which they are attached, they can form a C3-C6 carbocyclic ring; R 11 , R 14 , R 15 and R 16 Each occurrence is independently selected from the group consisting of hydrogen, C1-C6 alkyl, optionally substituted C2-C8 heterocycle, optionally substituted heteroaryl, optionally substituted C6-C 14 Aryl; 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. The compound according to claim 1, wherein R1 and R2 are hydrogen.

3. The compound according to claim 1, wherein R3 is selected from the group consisting of: hydrogen and -CH3.

4. The compound according to claim 1, wherein R4 is selected from the group consisting of hydrogen, Cl, -CH2CH3 and -CH3.

5. The compound according to claim 1, wherein R5 and R6 are hydrogen.

6. The compound according to claim 1, wherein R7 is selected from the group consisting of: hydrogen and -CH3.

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. The compound according to claim 1, wherein W is CR8.

11. The compound according to claim 10, wherein R8 is selected from the group consisting of:

12. The compound according to claim 10, wherein R8 is selected from the group consisting of:

13. The compound according to claim 10, wherein R8 is selected from the group consisting of:

14. The compound according to claim 10, wherein R8 is selected from the group consisting of:

15. The compound according to claim 10, wherein R8 is selected from the group consisting of:

16. The compound according to claim 1, wherein R9 is selected from the group consisting of: Hydrogen, F, Cl, Br, I, -CF 3、 -CH3, -CH2CH3, 17. Compounds of formula II in: B is selected from the following group: R 17 and R 18 Each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl; R 17 and R 18 Together with the carbon to which they are attached, they can form a C3-C6 carbocyclic ring; R 19 Selected from the group consisting of hydrogen and C1-C6 alkyl; R 20 Selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl; R 21 Selected from the group consisting of hydrogen and C1-C6 alkyl; R 22 and R 23 Each is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl; R 24 is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, and C1-C6 haloalkyl; R 25 , R 26 , R 27 and R 28 Each occurrence is independently selected from the group consisting of hydrogen and C1-C6 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. The compound according to claim 17, wherein R 17 and R 18 It's hydrogen.

19. The compound according to claim 17, wherein R 19 Selected from: hydrogen and -CH3.

20. The compound according to claim 17, wherein R 20 Selected from the group consisting of hydrogen, Cl, -CH2CH3 and -CH3.

21. The compound according to claim 17, wherein R 22 and R 23 It's hydrogen.

22. The compound according to claim 17, wherein R 21 Selected from: hydrogen and -CH3.

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. The compound according to claim 17, wherein R 25 , R 26 , R 27 and R 28 It's hydrogen.

28. The compound according to claim 17, wherein R 25 and R 26 is -CH3 and R 27 and R 28 It's hydrogen.

29. The compound according to claim 17, wherein R 24 Selected from: hydrogen, -CH3, -CF3, CH2F2 and 30. Compounds of formula III in: A is selected from R 29 and R 30 Each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl; R 29 and R 30 Together with the carbon to which they are attached, they can form a C3-C6 carbocyclic ring; R 31 Selected from the group consisting of hydrogen and C1-C6 alkyl; R 32 Selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl; R 33 Selected from the group consisting of hydrogen and C1-C6 alkyl; R 34 and R 35 Each is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 haloalkyl; R 36 is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, -(CH2) u -OR 37 and C1-C6 haloalkyl; R 37 Selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 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 an enantiomer or diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof.

31. The compound according to claim 30, wherein R 29 and R 30 It's hydrogen.

32. The compound according to claim 30, wherein R 31 Selected from: hydrogen and -CH3.

33. The compound according to claim 30, wherein R 32 Selected from the group consisting of hydrogen, Cl, -CH2CH3 and -CH3.

34. The compound according to claim 30, wherein R 34 and R 35 It's hydrogen.

35. The compound according to claim 30, wherein R 33 Selected from: hydrogen and -CH3.

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. The compound according to claim 30, wherein R 36 Selected from: hydrogen, -CH3, -CH2CH2OCH3, -CH2CH2F2, 40. Compound of formula IV in: G is selected from the following group: R 37 , R 38 , R 39 and R 40 Each occurrence is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R 41 Each substitutable position is independently selected from the group consisting of hydrogen, halogen, -O-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl and C3-C6 cycloalkyl; or an enantiomer or diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

41. The compound according to claim 40, wherein R 37 It is -CH3.

42. The compound according to claim 40, wherein R 38 It is -CH3.

43. The compound according to claim 40, wherein R 39 and R 40 It's hydrogen.

44. The compound according to claim 40, wherein R 41 Selected from the group consisting of hydrogen, -OCH3 and F.

45. Compound of formula V in: J is selected from the following group: h is 1, 2, or 3; R 42 Selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl; or an enantiomer or diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof.

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

47. The compound according to claim 45, wherein R 42 It is -CH3.

48. The compound according to claim 1, selected from the group consisting of: and pharmaceutically acceptable salts thereof.

49. The compound according to claim 17, selected from the group consisting of: and pharmaceutically acceptable salts thereof.

50. The compound according to claim 30, selected from the group consisting of: and pharmaceutically acceptable salts thereof.

51. The compound according to claim 40, selected from the group consisting of: and pharmaceutically acceptable salts thereof.

52. The compound according to claim 45, selected from the group consisting of: and pharmaceutically acceptable salts thereof.

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

54. A method comprising: A therapeutically effective amount of a compound of claim 1, 17, 30, 40, 45, 48, 49, 50, 51 or 52, or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from an HPK1 -mediated disorder.

55. The method of claim 54, wherein: The HPK-1 mediated disorder is cancer, autoimmune disease and / or inflammatory disease.

56. The method of claim 55, wherein: The cancer is selected from the group consisting of breast cancer, bladder cancer, bone cancer, brain cancer, central and peripheral nervous system cancer, colon cancer, endocrine gland cancer, esophageal cancer, endometrial cancer, germ cell cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, laryngeal cancer and hypopharyngeal cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, small intestine cancer, soft tissue cancer, testicular cancer, stomach cancer, skin cancer, ureter cancer, vaginal cancer and vulvar cancer.

57. The method of 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, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic arthritis, irritable bowel disease (IBD), scleroderma, Sjogren's disease, vitiligo, polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), autoimmune hepatitis, hypopituitarism, graft-versus-host disease (GvHD), autoimmune skin diseases, uveitis, pernicious anemia and hypoparathyroidism, and the autoimmune disease may also include, but is not limited to, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis and cryosurgery.

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

59. The method of claim 55, wherein: The compound is administered to the patient continuously, multiple times daily, once daily, once every other day, weekly, biweekly, monthly, or bimonthly.

60. The method of claim 55, wherein: The compounds are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.

61. The method of claim 54, wherein: The compounds are administered subcutaneously, intravenously, intramuscularly, intra-articularly, intra-synovially, intrasternally, intrathecally, intrahepatically, intralesionally and by intracranial injection or infusion techniques.

62. A method comprising: A therapeutically effective amount of the pharmaceutical composition of claim 53 or a pharmaceutically acceptable salt thereof is administered to a patient suffering from an HPK1-mediated disorder.

63. The method of claim 62, wherein: The HPK-1 mediated disorder is selected from the group consisting of cancer, autoimmune disease and / or inflammatory disease.

64. The method of claim 63, wherein: The cancer is selected from the group consisting of breast cancer, bladder cancer, bone cancer, brain cancer, central and peripheral nervous system cancer, colon cancer, endocrine gland cancer, esophageal cancer, endometrial cancer, germ cell cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, laryngeal cancer and hypopharyngeal cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, small intestine cancer, soft tissue cancer, testicular cancer, stomach cancer, skin cancer, ureter cancer, vaginal cancer and vulvar cancer.

65. The method of 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, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic arthritis, irritable bowel disease (IBD), scleroderma, Sjogren's disease, vitiligo, polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), autoimmune hepatitis, hypopituitarism, graft-versus-host disease (GvHD), autoimmune skin diseases, uveitis, pernicious anemia and hypoparathyroidism, and the autoimmune disease may also include, but is not limited to, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis and cryosurgery.

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

67. The method of claim 63, wherein: The pharmaceutical composition is administered to the patient continuously, multiple times daily, once daily, once every other day, weekly, biweekly, monthly, or bimonthly.

68. The method of claim 63, wherein: The compounds are administered subcutaneously, intravenously, intramuscularly, intra-articularly, intra-synovially, intrasternally, intrathecally, intrahepatically, intralesionally and by intracranial injection or infusion techniques.

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

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