Pyrido [3, 2-d] pyrimidines as HPK1 inhibitors

Abstract

Provided are pyrido [3, 2-d] pyrimidine compounds that are potent HPK1 inhibitors, which are useful for the treatment or prevention of cancer and / or inflammatory and / or autoimmune diseases or symptoms thereof in mammals, particularly humans. Compounds disclosed herein have the chemical structures of general formulae (I) and (II) or prodrugs or pharmaceutically acceptable salts of any of the foregoing, including mixtures of all ratios thereof.

Description

background CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 377,900, filed on September 30, 2022, and U.S. Provisional Application No. 63 / 362,803, filed on April 11, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0002] Disclosed herein are pyrido[3,2-d]pyrimidine compounds that are potent HPK1 inhibitors and are useful for treating or preventing cancer and / or inflammatory and / or autoimmune diseases or their symptoms in mammals, particularly humans. The compounds disclosed herein have a chemical structure of formula (I) or (II), or a prodrug or pharmaceutically acceptable salt of any of the foregoing, including mixtures thereof in all ratios. Related technical description

[0003] Hematopoietic progenitor kinase 1 (HPK1) is a serine / threonine kinase expressed in T cells, B cells, and dendritic cells (Nature Immunology, 2006, 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, lowering of the 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 dendritic cell activation and antigen presentation. (Hernandez S. et al., Cell Reports, 2018, Vol. 25, pp. 80-94). HPK1 kinase activity is thought to be crucial for conferring HPK1 inhibitory function to regulatory T cells (Treg) in a variety of immune cells (such as CD8+, CD4+, DCs, and NK cells). Inactivation of the kinase domain of HPK1 is sufficient to trigger a powerful anti-tumor immune response (Liu et al., PLoS One, March 26, 2019). HPK1 knockout (KO) and kinase-dead (KD) mice show enhanced T cell function and anti-tumor efficacy (You D. et al., J. Immunother. Cancer 2021). Therefore, pharmacological inhibition of HPK1 has the potential to enhance effector T cell function and anti-tumor activity. Summary of the Invention

[0004] In one embodiment, a compound of formula (I) is provided: in: R1, R2, R3 and R4 are each independently selected from H and halogen; R5 is selected from the group consisting of H, halogen, -O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, and -CN; X is selected from the group consisting of N and CR6 Y is selected from the group consisting of N and CR7 R6 and R7 are each independently selected from H, halogen and C1-C6 alkyl; A is absent or selected from (-CH2-) n 、-O-(-CH2-) o -, -O- and n is selected from the group consisting of 1, 2, 3, and 4; o Selected from the group consisting of 1, 2, 3, and 4; B is absent or selected from H, CN, halogen, optionally substituted C6-C 14 Aryl, optionally substituted C2-C 14 Heteroaryl, optionally substituted C1-C 14 heterocycle, optionally substituted C1-C8 alkyl, C1-C8 haloalkyl, optionally substituted C1-C8 alkyl interrupted by 1-4 heteroatoms, and optionally substituted C3-C 14 Cycloalkyl; or a pharmaceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer or mixture of diastereomers.

[0005] In another embodiment, a compound having Formula Ia is provided.

[0006] In another embodiment, a compound having Formula Ib is provided.

[0007] In another embodiment, a compound having Formula Ic is provided.

[0008] In another embodiment, a compound having Formula Id is provided.

[0009] In another embodiment, a compound having Formula Ie is provided.

[0010] In another embodiment, a compound having formula If is provided.

[0011] In another embodiment, a compound having Formula Ig is provided.

[0012] In another embodiment, a compound having Formula Ih is provided.

[0013] In another embodiment, a compound having Formula Ii is provided.

[0014] In another embodiment, a compound having Formula Ij is provided.

[0015] In another embodiment, a compound having Formula Ik is provided.

[0016] In one embodiment, a compound of Formula I is provided, wherein R1, R2, R3, and R4 are each H.

[0017] In one embodiment, a compound of Formula I is provided wherein R1, R3 and R4 are H and R2 is halogen.

[0018] In one embodiment, a compound of Formula I is provided, wherein R2 is F.

[0019] In one embodiment, a compound of Formula I is provided wherein R1, R2, and R3 are H and R4 is halogen.

[0020] In one embodiment, a compound of Formula I is provided wherein R4 is F.

[0021] In one embodiment, a compound of Formula I is provided wherein R1 and R2 are halogen and R3 and R4 are H.

[0022] In one embodiment, a compound of Formula I is provided, wherein R1 and R2 are F.

[0023] In one embodiment, a compound of Formula I is provided wherein R1 and R2 are H and R3 and R4 are halogen.

[0024] In one embodiment, a compound of Formula I is provided wherein R3 and R4 are F.

[0025] In one embodiment, a compound of Formula I is provided, wherein R5 is selected from the group consisting of H, -CN, and -CF3.

[0026] In one embodiment, a compound of Formula I is provided, wherein R5 is -CN.

[0027] In one embodiment, a compound of Formula I is provided, wherein -AB is selected from the group consisting of: wherein R8 and R9 are each independently selected from H and C1-C6 alkyl; wherein R8 and R9 together with the carbon to which they are attached may form a ring having 3-6 carbon atoms; wherein R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 and R 17 Each is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, halogen and -CN. Preferably, R8 and R9 are hydrogen. Preferably, R8 and R9 together with the carbon to which they are attached form a cyclopropyl ring. Preferably, R 10 、R 11 、R 16 and R 17 are each independently selected from H and -CH3; and R 12 、R 13 、R 14 and R 15 is H. Preferably, R 12 and R 13 Both F and R 10 、R 11 、R 14 、R 15 、R 16 and R 17 It’s H.

[0028] Preferably, R 10 and R 11 are each independently selected from H and -CN; and R 12 、R 13 、R 14 、R 15 、R 16 and R 17 is H. Preferably, R 10 and R 11 are each independently selected from H and -CF3 and R 12 、R 13 、R 14 、R 15 、R 16 and R 17 is H. Preferably, R 12 and R 13 are each independently selected from H and -CN; and R10 、R 11 、R 14 、R 15 、R 16 and R 17 is H. Preferably, R 12 and R 13 are each independently selected from H and -CF3; and R 10 、R 11 、R 14 、R 15 、R 16 and R 17 is H. Preferably, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 and R 17 is H. Preferably, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 and R 17 is H. Preferably, R 12 and R 13 are each independently selected from H and -CH3; and R 10 、R 11 、R 14 、R 15 、R 16 and R 17 It’s H.

[0029] In one embodiment, a compound of Formula I is provided, wherein -AB is selected from the group consisting of:

[0030] In one embodiment, a compound of Formula I is provided, wherein -AB is selected from the group consisting of where R 18 Selected from the group consisting of H, -OH, halogen, C1-C6 alkyl, -O-(C1-C6 alkyl) and C1-C6 haloalkyl.

[0031] In one embodiment, a compound of Formula I is provided, wherein -AB is selected from the group consisting of where R 19and R 20 Each is independently selected from H, -OH, halogen, C1-C6 alkyl, -O-(C1-C6 alkyl) and C1-C6 haloalkyl.

[0032] In one embodiment, a compound of Formula I is provided, wherein -AB is selected from the group consisting of where R 21 Selected from the group consisting of H and C1-C6 alkyl.

[0033] In one embodiment, a compound of formula I is provided, wherein -AB is selected from the group consisting of: -OCH3, -CN, -CH2SO2CH3, -OCF3, -CF3, -CHF2,

[0034] In one embodiment, there is provided a compound of formula II in: R 21 、R 22 、R 23 and R 24 are each independently selected from H and halogen; W is selected from the group consisting of an optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms, an optionally substituted 5-6 membered heterocycle containing 1-4 heteroatoms, a C1-C6 alkenyl (an optionally substituted 5-6 membered heterocycle containing 1-4 heteroatoms), a C1-C6 alkyl (an optionally substituted 5-6 membered heterocycle containing 1-4 heteroatoms) and an optionally substituted cyclohexene, or a pharmaceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer or mixture of diastereomers.

[0035] In one embodiment, a compound having Formula IIa is provided.

[0036] In one embodiment, a compound having Formula lib is provided.

[0037] In one embodiment, a compound having Formula IIc is provided.

[0038] In one embodiment, a compound having Formula IId is provided.

[0039] In another embodiment, a compound having Formula IIe is provided.

[0040] In another embodiment, a compound having Formula IIf is provided.

[0041] In another embodiment, a compound having Formula IIg is provided.

[0042] In another embodiment, a compound having Formula IIh is provided.

[0043] In another embodiment, a compound having Formula III is provided.

[0044] In another embodiment, a compound having Formula IIj is provided.

[0045] In another embodiment, a compound having Formula IIk is provided.

[0046] In another embodiment, a compound is provided wherein R 21 、R 22 、R 23 and R 24 Each is H.

[0047] In another embodiment, a compound is provided wherein R 21 、R 23 and R 24 is H and R 22 It's a halogen.

[0048] In another embodiment, a compound is provided wherein R 22 It's F.

[0049] In another embodiment, a compound is provided wherein R 21 、R 22 and R 23 is H and R 24 It's a halogen.

[0050] In another embodiment, a compound is provided wherein R 24 It's F.

[0051] In another embodiment, a compound is provided wherein R 21 and R 22 is a halogen and R 23 and R 24 It’s H.

[0052] In another embodiment, a compound is provided wherein R 21 and R 22 It's F.

[0053] In another embodiment, a compound is provided wherein R 21 and R 22 is H and R 23 and R 24 It's a halogen.

[0054] In another embodiment, a compound is provided wherein R 23 and R 24 It's F.

[0055] In another embodiment, a compound is provided, wherein W is selected from the group consisting of: where R 25 and R 26 independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, halogen, -CN, -CH2-O-CH3, -CH2CH2-O-CH3, tetrahydropyranyl, morpholino, R 27 Selected from the following group: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, R 28 Selected from the group consisting of H, halogen, -O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, and -CN; R 29 Selected from the group consisting of H and C1-C6 alkyl.

[0056] In one embodiment, the compound of formula (I) is one of the following compounds: or a pharmaceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer or mixture of diastereomers.

[0057] In one embodiment, the compound of formula (II) is one of the following compounds: and or a pharmaceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer or mixture of diastereomers.

[0058] In one embodiment, a pharmaceutical composition comprises a compound of formula (I) or (II) as defined above, and a pharmaceutically acceptable adjuvant, carrier or vehicle.

[0059] In one embodiment, a method is provided wherein a therapeutically effective amount of a compound having the structure of Formula (I) or (II) as defined above, or a physiologically acceptable salt thereof, is administered to a patient suffering from an HPK1-mediated disorder. The HPK-1-mediated disorder may be cancer. The cancer may be one or more of the following: breast cancer, bladder cancer, bone cancer, brain cancer, central and peripheral nervous system cancer, colon cancer, endocrine cancer, esophageal cancer, endometrial cancer, germ cell cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, laryngeal 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, ureteral cancer, vaginal cancer, and vulvar cancer. The therapeutically effective amount of a compound can be one of 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, 10 to 20 mg / kg, 10-50 mg / kg patient body weight, or 10-100 mg / kg patient body weight, or any other dosage range disclosed herein. Compounds can be administered to patients continuously, multiple times a day, once a day, every other day, weekly, every two weeks, monthly, or every two months. The compound can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or by implanted reservoirs. The compound can be administered subcutaneously, intravenously, intramuscularly, intraarticularly, intrasynovially, intrasternally, intrathecally, intrahepatically, intralesionally, and by intracranial injection or infusion techniques.

[0060] In one embodiment, a method is provided wherein a therapeutically effective amount of a pharmaceutical composition, or a physiologically acceptable salt thereof, is administered to a patient suffering from an HPK1-mediated disorder. The HPK-1-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 cancer, esophageal cancer, endometrial cancer, germ cell cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, laryngeal 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, ureteral cancer, vaginal cancer, and vulvar cancer. The therapeutically effective amount of the pharmaceutical composition can be in the range of 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, 10 to 20 mg / kg patient body weight, or any other dosage range disclosed herein. The pharmaceutical composition can be administered to the patient continuously, multiple times daily, once daily, every other day, weekly, biweekly, monthly, or bimonthly. The pharmaceutical composition can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The pharmaceutical composition can be administered subcutaneously, intravenously, intramuscularly, intraarticularly, intrasynovially, intrasternally, intrathecally, intrahepatically, intralesionally, and by intracranial injection or infusion techniques.

[0061] In one embodiment, a kit is provided, comprising a therapeutically effective amount of a compound of formula (I) or (II) as defined above, or a physiologically acceptable salt or prodrug thereof; and instructions for use of the compound.

[0062] 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 intended to provide further explanation without limiting the scope of the claims. DETAILED DESCRIPTION

[0063] Provided herein are chemical structures of formula (I) and (II) or prodrugs or pharmaceutically acceptable salts thereof, including mixtures thereof in all ratios, which are preferably used to treat and / or prevent cancer and inflammatory and / or autoimmune diseases or symptoms thereof. The compounds disclosed herein can inhibit HPK1 activity. The compounds disclosed herein have the general formula (I) and (II): in: R1, R2, R3 and R4 are each independently selected from H and halogen; R5 is selected from the group consisting of H, halogen, -O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, and -CN; X is selected from the group consisting of N and CR6 Y is selected from the group consisting of N and CR7 R6 and R7 are each independently selected from H, halogen and C1-C6 alkyl; A is absent or selected from (-CH2-) n 、-O-(-CH2-) o -, -O- and n is selected from the group consisting of 1, 2, 3, and 4; o Selected from the group consisting of 1, 2, 3, and 4; B is absent or selected from H, CN, halogen, optionally substituted C6-C 14 Aryl, optionally substituted C2-C 14 Heteroaryl, optionally substituted C1-C 14 heterocycle, optionally substituted C1-C8 alkyl, C1-C8 haloalkyl, optionally substituted C1-C8 alkyl interrupted by 1-4 heteroatoms, and optionally substituted C3-C 14 Cycloalkyl; or a pharmaceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer or mixture of diastereomers, and in: R 21 、R 22 、R 23 and R 24 are each independently selected from H and halogen; W is selected from the group consisting of an optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms, an optionally substituted 5-6 membered heterocycle containing 1-4 heteroatoms, a C1-C6 alkenyl (an optionally substituted 5-6 membered heterocycle containing 1-4 heteroatoms), a C1-C6 alkyl (an optionally substituted 5-6 membered heterocycle containing 1-4 heteroatoms) and an optionally substituted cyclohexene; or a pharmaceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer or mixture of diastereomers.

[0064] 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.

[0065] Halogen may refer to F, Cl, Br or I.

[0066] A heterocyclic group is a monovalent group formed by removing a hydrogen atom from any ring atom of a heterocyclic compound. It may include one or more heteroatoms. The heteroatom may refer to one or more of oxygen, sulfur, nitrogen, phosphorus, or any oxidized form thereof. Heterocycle, heterocyclyl, and heterocyclyl ring are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 6- to 14-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and, in addition to carbon atoms, has one or more, preferably 1 to 4, heteroatoms as defined above. The heterocycle may be attached to its side group at any heteroatom or carbon atom to obtain a stable structure, and any ring atom may be optionally substituted. Examples of saturated or partially unsaturated heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, oxazepinyl, thiazepinyl, and morpholinyl. A heterocyclyl group may include a radical in a heterocyclyl ring fused to one or more aryl, heteroaryl, or cycloaliphatic rings, wherein the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be monocyclic or bicyclic.

[0067] 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.

[0068] Aryl can refer to a single aromatic group or a larger moiety, such as an aralkyl, an aralkyloxy and / or an aryloxyalkyl group. It can refer to a monocyclic or bicyclic ring. At least one ring in the system can be aromatic. Each ring in the system can contain 3-7 members. Exemplary aryl groups include, but are 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, phthalimido, naphthalenediimide, phenanthridinyl, tetrahydronaphthyl, etc.

[0069] Heteroaryl 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. Except 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 (indolizinyl), purinyl, naphthyridinyl and pteridinyl. Heteroaryl can also include a group in which heteroaromatic rings are fused to one or more aryl, cycloaliphatic and / or heterocyclic rings, wherein the group or point connected are located on the heteroaromatic rings. 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. Heterocyclyl is optionally monocyclic or bicyclic. Heteroaralkyl may refer to an alkyl substituted with a heteroaryl, wherein the alkyl and heteroaryl moieties are independently optionally substituted.

[0070] The term optionally substituted can refer to the replacement of one or more hydrogens of a designated moiety by a suitable substituent. Unless otherwise indicated, 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 by more than one substituent selected from a designated group, the substituent may be the same or different at each position.

[0071] The term stable can 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. A pharmaceutically acceptable salt can refer to a salt that is suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, and is 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 the 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.

[0072] Salts can be derived from suitable bases, including alkali metal salts, alkaline earth metal salts, and ammonium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium salts, quaternary ammonium salts, and amine cation salts formed using counterions such as halides, hydroxides, carboxylations, sulfates, phosphates, nitrates, alkylsulfonates, and arylsulfonates.

[0073] Unless otherwise indicated, structures described herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure. For example, R and S configurations for 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 indicated, all tautomeric forms of the compounds disclosed herein are within the scope of the present invention. Since the pharmaceutical activity of racemates or stereoisomers of the compounds described herein may differ, it may be desirable to use enantiomers. In some cases, the final product can be separated or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to those skilled in the art, or even can be used as is in the synthesis.

[0074] If the compounds disclosed herein or their prodrugs can undergo tautomerism (e.g., keto-enol tautomerism), the individual forms, such as the keto or enol forms, are protected separately and together as a mixture of any proportion. The same applies to stereoisomers, such as enantiomers, cis / trans isomers, conformers, etc. If desired, isomers can be separated by methods well known in the art, such as 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.

[0075] 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 that of the atom (as typically occurs naturally). Examples of isotopes that are readily commercially available and can be incorporated into compounds of formula (I) or (II) 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) or (II), prodrugs thereof, or pharmaceutically acceptable salts thereof containing one or more of 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) or (II) 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) or (II) 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 isotopically labeled compounds have greater metabolic stability. Greater metabolic stability translates directly into extended in vivo half-life or lower dosage. Isotopically labeled compounds of formula (I) or (II) can be adapted to the procedures disclosed in the synthetic schemes and related descriptions, the Examples section, and the Preparation section disclosed herein by replacing non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0076] The 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 performed enzymatically or in the absence of enzymes. 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 into 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 can be produced by compounds disclosed herein according to known methods. Other examples of prodrugs are compounds in which the carboxylate / ester 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.

[0077] 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 thereof. The patient or subject can refer to an animal, preferably a mammal, and even more preferably a human. The biological sample can refer to, but is not limited to, a cell culture or an extract thereof; a biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0078] Pharmaceutically acceptable carriers, adjuvants, or vehicles may refer to non-toxic carriers, adjuvants, or vehicles that do not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants, or vehicles 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 salt, ester, salt of an ester or other derivative of a compound disclosed herein that, upon administration to a recipient, is capable of providing a compound disclosed herein directly or indirectly.

[0079] 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 compositions can be administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions disclosed herein include aqueous or oily suspensions. These suspensions are formulated 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 formulated in parenterally acceptable non-toxic 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, fixed oils can be conventionally used as solvents or suspending media.

[0080] 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 typically 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, flavorings, and / or coloring agents can optionally be added. Most preferably, the pharmaceutically acceptable compositions disclosed herein are formulated for oral administration. Such formulations can be administered with or without food.

[0081] 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 host being treated, the specific mode of administration. Preferably, the composition provided can be formulated so that a dosage of 0.01-100 mg / kg body weight / day can be given to the patient receiving these compositions. In some cases, the dosage is 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 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, 10-50 mg / kg patient body weight, or 10-100 mg / kg patient body weight, or any other dosage range disclosed herein. In some cases, the compound or composition herein can be given continuously, multiple times a day, once a day, 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 a dosage of 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 may 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, time of administration, excretion rate, drug combinations, 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 compound in the composition.

[0082] The compounds of formula (I) or (II) disclosed herein can be administered once or several times before or after the onset of the disease to achieve a therapeutic effect. The compounds and medical products of the present invention are particularly useful for therapeutic treatment. The therapeutic effect is to alleviate one or more symptoms of the disease to some extent, or to partially or completely restore one or more physiological or biochemical parameters associated with or causing the disease or pathological condition to normal. Monitoring is considered a form of treatment, provided that the compound is administered at different time intervals, for example, 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 related to HPK1 activity in advance or to treat emerging and persistent symptoms.

[0083] The host or patient can 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 research, providing models for treating human diseases.

[0084] 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, 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 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, ureteral 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 neoplasms, and paraneoplastic syndromes.

[0085] The sensitivity of a given cancer to HPK1 inhibition can be assessed by, but is not limited to, measuring a reduction in primary or metastatic tumor burden (mild, partial or complete regression), changes in blood counts, changes in blood hormone or cytokine concentrations, inhibition of further increase in tumor burden, stabilization of the patient's disease, assessment of disease-associated biomarkers or surrogate markers, prolonged overall survival of the patient, prolonged time to disease progression of the patient, prolonged progression-free survival of the patient, prolonged disease-free survival of the patient, improved quality of life of the patient, or modulation of disease comorbidities (such as, but not limited to, pain, cachexia, activity, hospitalization, blood count changes, weight loss, wound healing, fever). Significant improvements in the pharmacokinetic profile of the compound of formula (I) or (ii) can be achieved and can be quantitatively expressed as increases in in vivo half-life (t / 2), maximum therapeutic concentration (Cmax), and area under the dose-response curve (AUC).

[0086] In various embodiments, compounds of Formula (I) or (II) 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, compounds of Formula (I) and (II) and related formulae exhibit an IC50 of at least 1 nM, at least 10 nM, at least 100 nM, or at least 500 nM for inhibition of HPK1. 50 In some embodiments, the range is a combination of these values.

[0087] The compounds of formula (I) or (II) and / or physiologically acceptable salts thereof can be used as intermediates to prepare other pharmaceutical active ingredients. The medicaments are preferably prepared non-chemically, for example, by combining the active ingredient and 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.

[0088] Provided herein is a medicament that may include at least one compound disclosed herein, or a prodrug or 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) or (II) or a preparation thereof (e.g., a pharmaceutical composition or pharmaceutical preparation) and can be used to prevent diseases associated with HPK1 activity, or to treat, follow up, or provide post-hospital care for patients with diseases associated with HPK1 activity, in order to at least temporarily alter the overall condition of an organism or the condition of a specific region thereof in a pathogenic manner.

[0089] 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) or (II) can be combined with at least one other formulation as an active ingredient, wherein the at least one other formulation is another compound of Formula (I) or (II) or a compound with a different structural scaffold. The active ingredients can be administered 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 the HPK1 inhibitor or additional therapeutic agent within about one minute, five minutes, 30 minutes, one hour, five hours, 24 hours, 48 ​​hours, or any time within 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 are administered by different routes of administration.

[0090] 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, mitobronol, apaziquinone, paliposphamide, 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.; anti-cancer antibodies such as bleomycin, mitomycin C, etc.; antimetabolites such as capecitabine, cladribine, etc.; hormones or antagonists such as tamoxifen, dexamethasone, etc.; cytokines such as interferon, etc.; antibodies such as pembrolizumab, nivolumab, ipilimumab, cetuximab, etc.

[0091] A method for inhibiting abnormal cell growth or treating cancer in a mammal, preferably a human, may comprise administering to the mammal an amount of a compound of Formula (I) or (II), or a prodrug or pharmaceutically acceptable salt thereof, in combination with radiation therapy, wherein the amount of the compound, salt, or prodrug is combined with radiation therapy effective for inhibiting abnormal cell growth or treating cancer or its symptoms in the mammal. Techniques for administering radiation therapy are known in the art and may be used in the combination therapy described herein.

[0092] As used herein, the terms "treat," "treat," and "therapeutic" may refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or condition or one or more of its symptoms. In some embodiments, treatment is administered after the onset of one or more symptoms. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible individual before symptoms develop (e.g., based on a history of symptoms and / or based on genetic or other predisposing factors). Treatment may also be continued after symptoms have resolved, for example, to prevent or delay recurrence of symptoms.

[0093] Disclosed herein is a kit comprising a separately packaged therapeutically effective amount of a compound disclosed herein or a physiologically acceptable salt or prodrug thereof, and optionally a therapeutically effective amount of a therapeutic agent. The kit may include a suitable container, such as a box, a separate bottle, a bag, or an ampoule, and instructions for use or application of the kit. For example, the kit may comprise separate ampoules, each ampoule comprising a therapeutically effective amount of a compound disclosed herein and / or its pharmaceutically acceptable derivatives, solvates, and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another therapeutic agent in dissolved or lyophilized form. Experimental procedures

[0094] As described in the examples below, in certain exemplary embodiments, compounds were 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.

[0095] 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.

[0096] Unless otherwise indicated, all temperatures are expressed in °C (degrees Celsius).

[0097] All solvents were 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).

[0098] 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 was set to d 0.00. 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).

[0099] LC-MS analysis was performed on either of the following two instruments: 1. SHIMADZU LC-MS machine, it is made up 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, in 2.2 minutes (min), start from 95% A (A: 0.05% trifluoroacetic acid (TFA) in water) and end at 100% B (B: 0.05% TFA in acetonitrile), total running time is 3.6 minutes.Column temperature is 40 DEG C and flow velocity 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 between 200 and 400 nm. The mass spectrometer scanned between m / z 90 and 900 with a scan time of 0.6 s. Column: XBridge C8, 3.5 μm, 4.6 x 50 mm; Solvent A: Water + 0.1% TFA; Solvent B: ACN [defined] + 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).

[0100] HPLC data were obtained from a Shimazu LC-MS instrument or an Agilent 1100 Series HPLC system 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 noted, 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.

[0101] In general, compounds according to formula (I) or (II) 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 synthetic techniques. In general, the synthetic route of any individual compound of formula (I) or (II) 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) or (II) and related formulas. The reaction conditions described in the following schemes, such as temperature, solvent or co-reagents, are given as examples only and are not restrictive. It should be understood that, unless otherwise stated, other experimental conditions may also be used when typical or preferred experimental conditions (i.e., reaction temperature, time, amount of reagent, solvent, etc.) are given. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions may be determined by those skilled in the art through conventional optimization procedures. For all protection and deprotection methods, see Philip J. Kocienski, “Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and Theodora W. Greene and Peter G.M. Wuts, “Protective Groups in Organic Synthesis”, Wiley Interscience, 3rd edition, 1999. Example 1: Synthesis of Compound 1: 6-(2-cyano-4-(2-hydroxy-2-methylpropyloxy)phenyl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0102] Ethyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate: To a stirred mixture of methyl 6-chloro-4-oxo-3H,4H-pyrido[3,2-d]pyrimidine-8-carboxylate (500.00 mg; 1.71 mmol) in SOCl2 (5.00 ml; 66.02 mmol) was added 3 drops of DMF (dimethylformamide) at room temperature. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 4 h (at which point the mixture was a clear solution). The resulting mixture was concentrated under reduced pressure and co-evaporated with DCM 4 times to provide methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (520.00 mg; crude product) as a brown solid. The residue was used directly in the next step without further purification.

[0103] Ethyl 4-(((3S,5S)-1-(tert-Butoxycarbonyl)-5-fluoropiperidin-3-yl)amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate: To a stirred mixture of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (500.00 mg; 1.55 mmol) and tert-butyl (3S,5S)-3-amino-5-fluoropiperidine-1-carboxylate (466.00 mg; 2.03 mmol) in MeCN (7.00 ml) was added dropwise DIEA [N,N-diisopropylethylamine] (1.01 ml; 5.53 mmol) at room temperature. The resulting mixture was stirred at 40°C under a nitrogen atmosphere for 1 h. To the resulting mixture was added 50 ml of water and extracted with EA [ethyl acetate] (3 x 30 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (3S,5S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (800.00 mg; crude product) as a brown solid.

[0104] tert-Butyl (3S,5S)-3-((8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluoropiperidine-1-carboxylate: A stirred mixture of tert-butyl (3S,5S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (750.00 mg; 1.45 mmol) in MeOH (10.00 ml) containing NH3 was stirred at 40°C for 1 h. The resulting mixture was concentrated under reduced pressure to provide tert-butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (740.00 mg; crude product) as a brown solid.

[0105] 2-Bromo-5-(2-hydroxy-2-methylpropoxy)benzonitrile: To a stirred mixture of 2-bromo-5-hydroxybenzonitrile (2.00 g; 9.90 mmol) and 1-chloro-2-methylpropan-2-ol (2.26 g; 19.80 mmol) in DMSO (15.00 ml) was added NaCO (2.25 g; 19.80 mmol) at room temperature. The resulting mixture was stirred at 140°C for 16 h. The resulting mixture was quenched with water (100 ml) and extracted with EtOAc (100 ml*3). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to provide 2-bromo-5-(2-hydroxy-2-methylpropoxy)benzonitrile (2.50 g, 84.15%) as a clear oil.

[0106] 5-(2-Hydroxy-2-methylpropoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile: To a stirred mixture of 2-bromo-5-(2-hydroxy-2-methylpropoxy)benzonitrile (1.50 g; 5.00 mmol) and BPD (2.67 g; 10.00 mmol) in 1,4-dioxane (25.00 ml) was added Pd(dppf)Cl2[(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride] (0.38 g; 0.50 mmol) and AcOK (1.49 g; 14.99 mmol) at room temperature. The resulting mixture was stirred at 100°C under argon for 2 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 5-(2-hydroxy-2-methylpropoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.60 g; 79.26%) as a brown oil.

[0107] tert-Butyl (3S,5S)-3-((8-carbamoyl-6-(2-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluoropiperidine-1-carboxylate: tert-Butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (120.00 mg; 0.22 mmol) and 5-fluoropiperidine were added to the mixture at room temperature. To a stirred mixture of 2-(2-hydroxy-2-methylpropoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (133.85 mg; 0.33 mmol) in 1,4-dioxane (12.00 ml) and H2O (2.40 ml) were added AMPHOS-PdCl2 (16.47 mg; 0.02 mmol) and K3PO4 (148.09 mg; 0.66 mmol). The resulting mixture was stirred at 100° C. under an argon atmosphere for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with DCM / MeOH [dichloromethane] (6:1) to afford tert-butyl (3S,5S)-3-({8-carbamoyl-6-[2-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (120.00 mg, 89.80%) as a yellow solid.

[0108] 6-(2-Cyano-4-(2-hydroxy-2-methylpropoxy)phenyl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide: A stirred mixture of tert-butyl (3S,5S)-3-({8-carbamoyl-6-[2-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (110.00 mg; 0.18 mmol) in DCM (6.00 ml) and TFA (1.00 ml) was stirred at room temperature. The resulting mixture was stirred 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 NH4HCO3+0.1% [28% NH3 aqueous solution]), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18% B to 48% B over 8 minutes, 48% B; wavelength: 254 nm; RT1 (min): 7; number of runs: 5) to provide 6-[2-cyano-4-(2-hydroxy-2-methylpropyloxy)phenyl]-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (46.00 mg, 51.99%).

[0109] HPLC: 98.94% purity, RT = 2.85 min. MS: m / z = 480.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6, ppm): δ9.92 (d, J=3.6Hz, 1H), 8.79 (s, 1H), 8.61 (s, 1H) ,8.29–8.17(m,2H),7.89(d,J=8.5Hz,1H),7.57(d,J=2.7Hz,1H),7.41(dd,J=8 .9,2.7Hz,1H),4.99–4.64(m,2H),4.50(s,1H),3.89(s,2H),3.17–2.81(m,2H ),2.75–2.53(m,2H),2.22(s,1H),1.95(dt,J=35.7,12.0Hz,1H),1.22(s,6H). Example 2: Synthesis of Compound 2: 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-(3-methyl-1,2-thiazol-5-yl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0110] (5-Cyanoquinolin-6-yl)boronic acid: To a stirred mixture of 6-bromoquinoline-5-carbonitrile (230.00 mg; 0.94 mmol) and BPD (794.00 mg; 2.81 mmol) in 1,4-dioxane (8.00 ml) at 25°C was added Pd(dppf)Cl2 (72.00 mg; 0.09 mmol) and 1,4-dioxane (8.00 ml) portionwise. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 h. The reaction was quenched with H2O at 25°C. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EA=80:20 to afford (5-cyanoquinolin-6-yl)boronic acid (200.00 mg; 94.9%) as a white solid.

[0111] tert-Butyl (3S,5S)-3-{[8-carbamoyl-6-(5-cyanoquinolin-6-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate: To a stirred mixture of (5-cyanoquinolin-6-yl)boronic acid (186.00 mg; 0.83 mmol) and (3S,5S)-tert-butyl 3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (150.00 mg; 0.28 mmol) in 1,4-dioxane (8.00 ml) at 25° C. were added AMPHOS-PdCl (21.00 mg; 0.03 mmol), K PO (185.00 mg; 0.83 mmol) and H O (2.00 ml) portionwise. The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with PE: EA = 20:80 to provide (3S, 5S) -3- { [8-carbamoyl-6- (5-cyanoquinolin-6-yl) pyrido [3,2-d] pyrimidin-4-yl] amino} -5-fluoropiperidine-1-carboxylic acid tert-butyl ester (120.00 mg; 67.3%) as a yellow solid.

[0112] 6-(5-Cyanoquinolin-6-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of (3S,5S)-tert-butyl 3-{[8-carbamoyl-6-(5-cyanoquinolin-6-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (100.00 mg; 0.15 mmol) in DCM (8.00 ml) was added TFA (2.00 ml) dropwise at 25° C. The resulting mixture was stirred at 25° C. under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions: column: Xselect CSH C18 OBD column 30*150mm 5μm,n; mobile phase A: water (0.1% FA [formic acid]), mobile phase B: ACN; flow rate: 60mL / min.; gradient: 5% B to 30% B over 8 minutes, 30% B; wavelength: 254 / 220nm; RT1 (min.): 7.22; number of runs: 2, thereby providing 6-(5-cyanoquinolin-6-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide; formic acid (51.30mg; 62.1%) as a yellow solid.

[0113] HPLC: 91.6% purity, RT = 2.6 min. MS: m / z = 443.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.90(d,J=3.5Hz,1H),9.17(dd,J=4.2,1.6Hz,1H),9.03(s,1H),8.75(s,1H),8.68(dd,J=8.8,1.6Hz,1H ),8.59(d,J=8.9Hz,1H),8.52(d,J=8.7Hz,2H),8.38(d,J=3.5Hz,1H),7.90(dd,J=8.6,4.2Hz,1H),5.31(d,J=45.0Hz,1H),5.01 -4.88(m,1H),3.60(t,J=12.7Hz,1H),3.53 -3.45(m,1H),3.22 -3.10(m,2),2.45(d,J=14.3Hz,2H),2.18(m,J=44.3,13.2Hz,1H). Example 3: Synthesis of Compound 3: 6-(1,3-dimethyl-1H-pyrazol-4-yl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0114] tert-Butyl (3S,5S)-3-((8-carbamoyl-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluoropiperidine-1-carboxylate: tert-Butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (120.00 mg; 0.22 mmol) and 1,3-dimethylpyrazol-4-yl To a stirred mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (58.87 mg, 0.27 mmol) in 1,4-dioxane (5.00 ml) and water (1.00 ml) was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (16.47 mg; 0.02 mmol) and K3PO4 (148.05 mg; 0.66 mmol). The mixture was stirred at 100°C under an argon atmosphere for 12 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EA (1:9) to afford tert-butyl (3S,5S)-3-{[8-carbamoyl-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate as a yellow solid (90.00 mg; 67.4%).

[0115] 6-(1,3-Dimethyl-1H-pyrazol-4-yl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide: To a solution of (3S,5S)-tert-butyl 3-{[8-carbamoyl-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (100.00 mg; 0.19 mmol) in DCM (4.00 ml) was added TFA (2.00 ml). After stirring at 25° C. for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 aqueous solution]), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 16% B to 43% B over 9 minutes, 43% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 1) to provide 6-(1,3-dimethyl-1H-pyrazol-4-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as an off-white solid (51.00 mg; 70.0%).

[0116] HPLC: 98.03% purity, RT = 2.04 min. MS: m / z = 385.10 [M+H] + . 1 H NMR (300MHz, DMSO-d6, ppm): δ10.43(d,1H),8.77(d,1H),8.63(d,1H),8.55(d,2H),8.24(d,1H),7.89(d,1H),7 .38(s,2H),4.88(d,1H),4.62(s,1H),3.13(s,1H),3.03(dd,2H),2.69-2.54(m,3H),2.29(s,3H),2.05(d,1H). Example 4: Synthesis of Compound 4: 4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0117] tert-Butyl (3S,5S)-3-((8-carbamoyl-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluoropiperidine-1-carboxylate: tert-Butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (120.00 mg; 0.22 mmol) and 1-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluoropiperidine-1-carboxylate were added to the mixture at room temperature. To a stirred mixture of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (94.06 mg; 0.33 mmol) in 1,4-dioxane (5.00 ml) and water (1.00 ml) was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (16.47 mg; 0.02 mmol) and K₃PO₄ (148.05 mg; 0.66 mmol). The resulting mixture was stirred at 100°C under an argon atmosphere for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:4) to afford tert-butyl (3S,5S)-3-({8-carbamoyl-6-[1-(tetrahydropyran-4-yl)-1H-pyrazol-4-yl]pyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate as a yellow solid (110.00 mg; 80.29%).

[0118]

[0266] 4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine-8-carboxamide: A stirred mixture of tert-butyl (3S,5S)-3-({8-carbamoyl-6-[1-(tetrahydropyran-4-yl)-1H-pyrazol-4-yl]pyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (110.00 mg; 0.18 mmol) and TFA (1.00 ml) in DCM (6.00 ml) was stirred at room temperature for 1 h, and then the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Xselect CSH C18 OBD column 30*150mm 5μm, n; mobile phase A: water (10mmol / L NH4HCO3+0.1% [28% NH3 aqueous solution]), mobile phase B: ACN; flow rate: 60mL / min.; gradient: 7% B to 37% B over 8 minutes, 37% B; wavelength: 254 / 220nm; RT1 (min.): 8.2; number of runs: 2) to afford 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-[1-(tetrahydropyran-4-yl)-1H-pyrazol-4-yl]pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (43.20mg; 55.14%).

[0119] HPLC: 99.74% purity, RT = 2.13 min. MS: m / z = 441.15 [M+H] + . 1 H NMR (300MHz, DMSO-d6, ppm): δ9.99(d,J=3.6Hz,1H),8.79(s,1H),8.57(d,J=17.0Hz,2H),8.44(s,1H),8.20(t,J=7.0Hz,2H),5.04 -4.88(s,1H),4.63(s,1H),4.49(tt,J=10.3,5.2Hz,1H),4.05-3.94(m,2H),3.51(td,J=11.3,3.4Hz,2H) ,3.13(t,J=13.7Hz,2H),2.94-2.71(m,2H),2.55(s,1H),2.24(dd,J=15.1,5.5Hz,1H),2.11-1.92(m,4H). Example 5: Synthesis of Compound 5: 6-(5-acetylthiophen-2-yl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0120] tert-Butyl (3S,5S)-3-((6-(5-acetylthiophen-2-yl)-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluoropiperidine-1-carboxylate: tert-Butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (120.00 mg; 0.22 mmol; 1.00 To a stirred mixture of 1,4-dioxane (5.00 ml) and (5-acetylthiophen-2-yl)boronic acid (57.49 mg; 0.33 mmol; 1.50 eq.) in 1,4-dioxane (5.00 ml) and water (1.00 ml) was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (16.47 mg; 0.02 mmol) and K3PO4 (148.05 mg; 0.66 mmol). The resulting mixture was stirred at 100°C under an argon atmosphere for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:4) to provide tert-butyl (3S,5S)-3-{[6-(5-acetylthiophen-2-yl)-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate as a yellow solid (90.00 mg, 64.79%).

[0121] 6-(5-Acetylthiophen-2-yl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide: A stirred mixture of tert-butyl (3S,5S)-3-{[6-(5-acetylthiophen-2-yl)-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (90.00 mg; 0.14 mmol) and TFA (1.00 ml) in DCM (6.00 ml) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3+0.1% [28% NH3 aqueous solution]), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 19% B to 45% B over 9 minutes, 45% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 2) to provide 6-(5-acetylthiophen-2-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (31.60 mg; 53.03%).

[0122] HPLC: 99.56% purity, RT = 2.57 min. MS: m / z = 415.15 [M+H] + . 1 H NMR (300MHz, DMSO-d6, ppm): δ9.92(d,J=3.6Hz,1H),8.78(s,1H),8.59(s,1H),8.25-8.12(m,3H),8.00(dd,J=4.0,1.2Hz,1H),4.96 -4.80(s,1H),4.62(dt,J=9.7,4.9Hz,1H),3.13-2.95(m,2H),2.93-2.70(m,2H),2.60(s,3H),2.36-2.17(m,2H). Example 6: Synthesis of Compound 6: 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-(3-methyl-1,2-thiazol-5-yl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0123] 3-Methyl-5-(tributylstannyl)-1,2-thiazole: To a stirred solution of 5-bromo-3-methyl-1,2-thiazole (500.00 mg; 2.67 mmol) in THF (5.00 ml) at -78°C under a nitrogen atmosphere was added n-BuLi (1.20 ml, 2.5 M in hexanes). The resulting mixture was stirred at -78°C under a nitrogen atmosphere for 1 hour. Tributyl(chloro)stannane (921.00 mg; 2.80 mmol) in THF (2.00 ml) was then added dropwise at -78°C. The resulting mixture was stirred at -78°C under a nitrogen atmosphere for 2 hours. The reaction was quenched by the addition of saturated NH4Cl (50 mL) at 0°C. The resulting mixture was extracted with EA (3 x 40 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 10% EA in PE to afford 3-methyl-5-(tributylstannyl)-1,2-thiazole (1.10 g; 2.63 mmol) as a yellow liquid.

[0124] tert-Butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate: To a stirred solution of tert-butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (200.00 mg; 0.37 mmol) and 3-methyl-5-(tributylstannyl)-1,2-thiazole (275.00 mg; 0.66 mmol) in 1,4-dioxane (3.00 ml) was added portionwise cataCXiumA Pd G3 (35.00 mg; 0.05 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 100°C under N2 for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 45% EA in PE to afford tert-butyl (3S,5S)-3-{[8-carbamoyl-6-(3-methyl-1,2-thiazol-5-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (190.00 mg; 98.2%) as a yellow solid.

[0125] 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-(3-methyl-1,2-thiazol-5-yl)pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of (3S,5S)-tert-butyl 3-{[8-carbamoyl-6-(3-methyl-1,2-thiazol-5-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (170.00 mg; 0.32 mmol) in DCM (3.00 ml) was added TFA (1.00 ml) dropwise at 0°C. The resulting mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: (column: XBridge ShieldRP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3+0.1% [28% NH3 aqueous solution]), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 18% B to 44% B over 9 minutes, 44% B; wavelength: 254 nm; RT1 (min): 7) to provide 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-(3-methyl-1,2-thiazol-5-yl)pyrido[3,2-d]pyrimidine-8-carboxamide (101.90 mg; 80.4%) as a yellow solid.

[0126] HPLC: 98.9% purity, RT = 2.39 min. MS: m / z = 388.2 [M+H] +. 1 H NMR (400MHz, DMSO-d6) δ9.94(d,J=3.5Hz,1H),8.71(s,1H),8.61(s,1H),8.27(d,J=3.4Hz,1H),8.19(d,J=8.8Hz,1H),8.1 0(s,1H),4.86(d,J=48.0Hz,1H),4.64–4.55(m,1H),3.09–2.93(m,2H),2.85–2.68(m,3H),2.52(m,3H),2.42–2.05(m,2H). Example 7: Synthesis of Compound 7 6-(5-cyano-1-methyl-1H-pyrrol-3-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide

[0127] 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carbonitrile: A solution of 4-bromo-1-methyl-1H-pyrrole-2-carbonitrile (1.00 g; 3.92 mmol), bis(pinacolato) boronate (2.60 g; 9.73 mmol), KOAc (608.00 mg; 5.89 mmol), and Pd(dppf)Cl2-CH2Cl2 (338.00 mg; 0.39 mmol) in 1,4-dioxane (20.00 ml) was stirred at 100°C under a nitrogen atmosphere for 16 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1x300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to provide 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carbonitrile (500.00 mg; 51.7%) as a yellow solid.

[0128] (3S,5S)-3-{[8-carbamoyl-6-(5-cyano-1-methyl-1H-pyrrol-3-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylic acid tert-butyl ester: (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylic acid tert-butyl ester (200.00 To a stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carbonitrile in 1,4-dioxane (2.50 ml) and water (0.25 ml) was added AMPHOS-PdCl2 (180.00 mg; 0.24 mmol) and tripotassium phosphate (31.00 mg; 0.14 mmol) portionwise. The resulting mixture was stirred at 100°C under N2 atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 55% EA in PE to afford tert-butyl (3S,5S)-3-{[8-carbamoyl-6-(5-cyano-1-methyl-1H-pyrrol-3-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (200.00 mg; 98.4%) as a yellow solid.

[0129] 6-(5-Cyano-1-methyl-1H-pyrrol-3-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of (3S,5S)-tert-butyl 3-{[8-carbamoyl-6-(5-cyano-1-methyl-1H-pyrrol-3-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (180.00 mg; 0.33 mmol) in DCM (3.00 ml) was added TFA (1.00 ml) dropwise at 0°C. The resulting mixture was stirred at room temperature under nitrogen for 1 hour. 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 NH4HCO3+0.1% [28% NH3 aqueous solution]), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 19% B to 44% B over 9 minutes, 44% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 2) to provide 6-(5-cyano-1-methyl-1H-pyrrol-3-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (89.60 mg; 68.5%) as a yellow solid.

[0130] HPLC: 98.3% purity, RT = 2.36 min. MS: m / z = 395.0 [M+H] + . 1 H NMR (400MHz, DMSO, ppm) δ10.02(d,J=3.6Hz,1H),8.53(d,J=10.5Hz,2H),8.24(d,J=1.7Hz,1H),8.22–8.15(m,2H),7.96(d,J=1.8H z,1H),4.89(d,J=48.0Hz,1H),4.58(m,J=9.9,5.3,4.6Hz,1H),3.85(s,3H),3.14–2.61(m,4H),2.51(p,J=1.8Hz,1H),2.13(m,2H). Example 8: Synthesis of Compound 8: 6-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0131] 1-Ethyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole: To a stirred mixture of 4-bromo-1-ethyl-5-methyl-1H-pyrazole (200.00 mg; 1.04 mmol) and BPD [bis(boronic acid)pinacolatoyl] (554.25 mg; 2.07 mmol) in 1,4-dioxane (15.00 ml) was added Pd(dppf)Cl2 (79.85 mg; 0.10 mmol) and AcOK (308.32 mg; 3.11 mmol) at room temperature. After stirring at 100°C under argon atmosphere for 2 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (4:1) to provide 1-ethyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a brown solid (340.00 mg; 97.22%).

[0132] tert-Butyl (3S,5S)-3-((8-carbamoyl-6-(1-ethyl-5-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluoropiperidine-1-carboxylate: tert-Butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (120.00 mg; 0.22 mmol) was added to the mixture at room temperature. To a stirred mixture of 1-ethyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (111.78 mg; 0.33 mmol) in DME (10.00 ml) and H₂O (2.00 ml) was added Pd(PPh₃)₄ (26.87 mg; 0.02 mmol) and Na₂CO₃ (73.95 mg; 0.66 mmol). The resulting mixture was stirred at 100° C. under an argon atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (14:1) to provide tert-butyl (3S,5S)-3-{[8-carbamoyl-6-(1-ethyl-5-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate as a yellow solid (110.00 mg; 85.52%).

[0133] 6-(1-Ethyl-5-methyl-1H-pyrazol-4-yl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide: A stirred mixture of (3S,5S)-tert-butyl 3-{[8-carbamoyl-6-(1-ethyl-5-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (140.00 mg; 0.27 mmol) and TFA (1.00 ml) in DCM (6.00 ml) was stirred at room temperature for 1 h, and then the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 aqueous solution]), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 17% B to 44% B over 9 minutes, 44% B; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) to provide 6-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (12.40 mg; 11.33%).

[0134] HPLC: 98.92% purity, 2.21 min. MS: m / z = 399.2 [M+H] + . 1 H NMR (400MHz, DMSO, ppm): δ1.36 (t, J=7.2Hz, 3H), 2.18 (dt, J=13.4, 4.1Hz, 2H), 2.68 (s, 3H ),2.72(ddd,J=12.3,8.3,1.9Hz,2H),2.81(dd,J=13.3,2.6Hz,1H),3.03(dd,J=12.3,3.8 Hz,1H),4.20(q,J=7.2Hz,2H),4.53(dq,J=9.4,5.2,4.8Hz,1H),4.88(d,J=4.6Hz,1H),7. 86(d,J=8.7Hz,1H), 8.20(d,J=7.9Hz,2H), 8.54(d,J=11.8Hz,2H), 10.01(d,J=3.7Hz,1H). Example 9: Synthesis of Compound 9: 6-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0135] tert-Butyl (3S,5S)-3-((8-carbamoyl-6-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluoropiperidine-1-carboxylate: tert-Butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (120.00 mg; 0.22 To a stirred mixture of 1-ethyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (111.78 mg; 0.33 mmol) in DME (10.00 ml) and H₂O (2.00 ml) was added P4 (26.87 mg; 0.02 mmol) and Na₂CO₃ (73.95 mg; 0.66 mmol). The resulting mixture was stirred at 100° C. under an argon atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (14:1) to afford tert-butyl (3S,5S)-3-{[8-carbamoyl-6-(1-ethyl-5-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate as a yellow solid (100 mg; 71.42%).

[0136] 6-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide: A stirred mixture of (3S,5S)-tert-butyl 3-{[8-carbamoyl-6-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (100.00 mg; 0.19 mmol) in DCM (6.00 ml) and TFA (1.00 ml) was stirred at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: XBridge Shield RP18OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3+0.1% [28% NH3 aqueous solution]), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 17% B to 44% B over 9 minutes, 44% B; wavelength: 254 nm; RT1 (min.): 7) to provide 6-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (24.20 mg; 30.76%).

[0137] HPLC: 97.51% purity, RT = 4.97 min. MS: m / z = 399.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6, ppm): δ9.91(d,J=3.8Hz,1H),8.49(d,J=2.3Hz,1H),8.42(s,2H),8.08(d,J=3.8Hz,1H),7.66(d,J=8.6Hz,1H),4 .87-4.53(m,1H),4.37(s,1H),4.01(q,J=7.3Hz,2H),3.01-2.53(m,4H),2.43(s,3H),2.05(s,1H),1.99(s,1H),1.30(t,J=7.3Hz,3H). Example 10: Synthesis of Compound 10 (S)-6-(2-cyano-4-(difluoromethyl)phenyl)-4-((5,5-difluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0138] 2-Bromo-5-(difluoromethyl)benzonitrile: To a stirred mixture of 2-bromo-5-formylbenzonitrile (1.00 g; 4.52 mmol) in DCM (40.00 ml) at 0°C was added DAST (1.19 ml; 11.08 mmol) dropwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched with saturated NaHCO at 0°C and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to afford 2-bromo-5-(difluoromethyl)benzonitrile as a light yellow solid (1.11 g; crude).

[0139] 5-(Difluoromethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile: To a stirred mixture of 2-bromo-5-(difluoromethyl)benzonitrile (180.00 mg; 0.73 mmol) and BPD (582.29 mg; 2.18 mmol) in 1,4-dioxane (5.00 ml) at room temperature were added KOAc (237.54 mg; 2.18 mmol) and Pd(dppf)Cl2 (55.93 mg; 0.07 mmol). After stirring at 100°C under argon for 2 h, the resulting mixture was filtered; the filter cake was washed with dioxane. After filtration, the filtrate was concentrated under reduced pressure. This afforded 5-(difluoromethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile as a brown solid (240 mg; crude).

[0140] Methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate: A mixture of methyl 6-chloro-4-hydroxypyrido[3,2-d]pyrimidine-8-carboxylate (2.18 g; 8.07 mmol) in SOCl (20.00 ml; 264.07 mmol) was stirred at room temperature. The resulting mixture was stirred at 80°C for 4 h. The filtrate was concentrated under reduced pressure. This afforded methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate as a yellow solid (2.30 g; crude), which was used in the next step without purification.

[0141] (S)-methyl 4-((1-(tert-Butoxycarbonyl)-5,5-difluoropiperidin-3-yl)amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate: To a stirred mixture of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (700.00 mg; 1.81 mmol) and tert-butyl (5S)-5-amino-3,3-difluoropiperidine-1-carboxylate (676.95 mg; 2.72 mmol) in ACN (15.00 ml) was added DIEA (987.19 mg; 7.26 mmol) at room temperature. The resulting mixture was stirred at 75°C for 2 h. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (1:19) to provide tert-butyl (5S)-5-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-3,3-difluoropiperidine-1-carboxylate as a yellow solid (380 mg 40.67%).

[0142] (S)-tert-Butyl 5-((8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylate: A stirred mixture of (5S)-tert-butyl 5-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-3,3-difluoropiperidine-1-carboxylate (380.00 mg; 0.74 mmol; 1.00 eq.) in MeOH (5.00 ml) containing NH3(g) was stirred at room temperature. After stirring at 40 °C for 2 h, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (1:6) to provide (5S)-tert-butyl 5-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-3,3-difluoropiperidine-1-carboxylate (320.00 mg; 0.64 mmol; 86.76%; yellow solid; purified product).

[0143] (S)-tert-Butyl 5-((8-carbamoyl-6-(2-cyano-4-(difluoromethyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylate: (5S)-tert-Butyl 5-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-3,3-difluoropiperidine-1-carboxylate (160.00 mg; 0.32 mmol) and To a stirred mixture of 5-(difluoromethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (223.10 mg; 0.48 mmol) in 1,4-dioxane (5.00 ml) and water (1.00 ml) were added Pd(dtbpf)Cl2 (21.94 mg; 0.03 mmol) and K3PO4 (214.33 mg; 0.96 mmol). After stirring at 80° C. under argon atmosphere for 2 h, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with EtOAc / MeOH (13:1) to provide (5S)-tert-butyl 5-({8-carbamoyl-6-[2-cyano-4-(difluoromethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-3,3-difluoropiperidine-1-carboxylate as a brown solid (190 mg, 93.88%).

[0144] (S)-6-(2-cyano-4-(difluoromethyl)phenyl)-4-((5,5-difluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide: To a solution of (5S)-tert-butyl 5-({8-carbamoyl-6-[2-cyano-4-(difluoromethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-3,3-difluoropiperidine-1-carboxylate (180 mg; 0.28 mmol) in DCM (9.00 ml) was added TFA (3.00 ml) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3+0.1% [28% NH3 aqueous solution]), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 25% B to 55% B over 8 minutes, 55% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 2) to provide 6-[2-cyano-4-(difluoromethyl)phenyl]-4-{[(3S)-5,5-difluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (49.40 mg; 37.61%).

[0145] HPLC 99.48% purity, RT = 3.62 min. MS: m / z = 460.15 [M+H] + . 1 H NMR (400MHz, DMSO-d6, ppm): δ9.91(s,1H),8.91(s,1H),8.71(s,1H),8.46(d,J=8.2Hz,1H),8.33(d,J=13.3Hz,2H),8.22(d,J=8.5Hz,1H) ,8.11(d,J=8.3Hz,1H),7.23(s,1H),4.53(d,J=10.4Hz,1H),3.07(dd,J=24.6,11.5Hz,2H),2.82(s,2H),2.65(s,1H),2.28-2.15(m,1H). Example 11: Synthesis of Compound 11: (S)-4-((5,5-difluoropiperidin-3-yl)amino)-6-(4-methoxyphenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0146] (S)-tert-Butyl 5-((8-carbamoyl-6-(4-methoxyphenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylate: To a stirred mixture of (5S)-tert-butyl 5-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-3,3-difluoropiperidine-1-carboxylate (120.00 mg; 0.21 mmol) and (4-methoxyphenyl)boronic acid (40.99 mg; 0.26 mmol) in 1,4-dioxane (0.50 ml) and water (0.10 ml) was added Pd(dtbpf)Cl2 (14.65 mg; 0.02 mmol) and K3PO4 (143.13 mg; 0.64 mmol) at room temperature. The resulting mixture was stirred at 80°C under argon for 2 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (12:1) to afford tert-butyl (5S)-5-{[8-carbamoyl-6-(4-methoxyphenyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-3,3-difluoropiperidine-1-carboxylate as a yellow solid (100 mg; 77.6%).

[0147] (S)-4-((5,5-difluoropiperidin-3-yl)amino)-6-(4-methoxyphenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: To a solution of (5S)-5-{[8-carbamoyl-6-(4-methoxyphenyl)-1,5-naphthyridin-4-yl]amino}-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester (100 mg; 0.18 mmol) in DCM (2 ml) was added TFA (1 ml). The resulting mixture was stirred at 25 °C for 12 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 8-{[(3S)-5,5-difluoropiperidin-3-yl]amino}-2-(4-methoxyphenyl)-1,5-naphthyridin-4-carboxamide as a yellow solid (55.20 mg, 74.7%).

[0148] HPLC 99.16% purity, RT = 3.26 min. MS: m / z = 415.05 [M+H] + . 1 H NMR (300MHz, DMSO-d6, ppm): δ10.01(d,1H),8.82(s,1H),8.59(s,1H),8.44(d,1H),8.40-8.31(m,2H), 8.25(d,1H),7.18-7.07(m,2H),4.60(s,1H),3.87(s,3H),3.34(s,2H),3.06(d,3H),2.49-2.35(m,1H). Example 12: Synthesis of Compound 12 (4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)-6-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide)

[0149] 1-(4-Bromophenoxy)-2-methylpropan-2-ol: To a solution of 4-bromophenol (20.00 g; 109.82 mmol; 1.00 eq.) and 2,2-dimethyloxirane (12.50 g; 164.73 mmol) in DMF (100.00 ml) was added portionwise KCO (47.93 g; 329.47 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 140° C. under a nitrogen atmosphere overnight. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous NaSO. The resulting mixture was concentrated under reduced pressure to provide 1-(4-bromophenoxy)-2-methylpropan-2-ol (32.00 g, crude product) as a yellow oil.

[0150] 2-Methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol: To a stirred mixture of 1-(4-bromophenoxy)-2-methylpropan-2-ol (30.00 g; 122.39 mmol) and BPD (32.72 g; 122.39 mmol) in 1,4-dioxane (600.00 ml) was added portionwise KOAc (37.93 g; 367.18 mmol; 3.00 eq.) and Pd(dppf)Cl2 (4.71 g; 6.12 mmol; 0.05 eq.) at room temperature. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 1 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 dried over anhydrous NaSO. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with EtOAc:PE = 1:6 to provide 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol (30.00 g; 83.89%) as a white solid.

[0151] Ethyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate: To a stirred mixture of methyl 6-chloro-4-oxo-3H,4H-pyrido[3,2-d]pyrimidine-8-carboxylate (500.00 mg; 1.71 mmol) in SOCl2 (5.00 ml; 66.02 mmol) was added DMF (3 drops) at room temperature. The resulting mixture was stirred at 80°C under nitrogen atmosphere for 4 h (at which point the mixture was a clear solution). The resulting mixture was concentrated under reduced pressure and co-evaporated with DCM 4 times to provide methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (520.00 mg; crude product) as a brown solid. The residue was used directly in the next step without further purification.

[0152] Ethyl 4-(((3S,5S)-1-(tert-Butoxycarbonyl)-5-fluoropiperidin-3-yl)amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate: To a stirred mixture of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (500.00 mg; 1.55 mmol) and tert-butyl (3S,5S)-3-amino-5-fluoropiperidine-1-carboxylate (466.00 mg; 2.03 mmol) in MeCN (7.00 ml) was added dropwise DIEA (1.01 ml; 5.53 mmol) at room temperature. The resulting mixture was stirred at 40°C under nitrogen atmosphere for 1 h. To the resulting mixture was added 50 ml of water and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (3S,5S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (800.00 mg; crude product) as a brown solid.

[0153] tert-Butyl (3S,5S)-3-((8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluoropiperidine-1-carboxylate: A stirred mixture of tert-butyl (3S,5S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (750.00 mg; 1.45 mmol) in MeOH (10.00 ml) containing NH3 was stirred at 40°C for 1 h. The resulting mixture was concentrated under reduced pressure to provide tert-butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (740.00 mg; crude product) as a brown solid.

[0154] tert-Butyl (3S,5S)-3-((8-carbamoyl-6-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluoropiperidine-1-carboxylate: tert-Butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (200.00 mg; 0.39 mmol) and 2- To a stirred mixture of methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol (290.00 mg; 0.94 mmol) in 1,4-dioxane (5.00 ml) and H2O (0.50 ml) were added portionwise K3PO4 (200.00 mg; 0.90 mmol) and AMPHOS-PdCl2 (34.00 mg; 0.05 mmol). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 63% EA in PE to afford tert-butyl (3S,5S)-3-({8-carbamoyl-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (180.00 mg; 63.0%) as a yellow solid.

[0155] 4-(((3S,5S)-5-Fluoropiperidin-3-yl)amino)-6-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of (3S,5S)-tert-butyl 3-({8-carbamoyl-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (160.00 mg; 0.22 mmol; 1.00 eq.) in DCM (3.00 ml) at 0°C was added TFA (1.00 ml) dropwise. The resulting mixture was stirred at room temperature under nitrogen 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 Prep OBD C18 column, 30*150 mm; mobile phase A: water (10 mmol / L NH4HCO3+0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 20% B to 45% B over 9 minutes, 45% B; wavelength: 254 nm; RT1 (min.): 7; number of runs: 4) to provide 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-[4-(2-hydroxy-2-methylpropyloxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (71.00 mg; 70.3%) as a yellow solid.

[0156] HPLC: 98.3% purity, RT = 2.94 min. MS: m / z = 455.05 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.06(d,J=3.7Hz,1H),8.81(s,1H),8.56(s,1H),8.4 3–8.30(m,3H),8.22(d,J=3.8Hz,1H),7.11(d,J=8.4Hz,2H),4.87(d,J=48.1Hz ,1H),4.70(s,1H),4.60(d,J=10.4Hz,1H),3.83(s,2H),3.34(s,1H),3.13–2.9 2(m,2H),2.74(td,J=20.4,19.4,10.9Hz,2H),2.35–2.12(m,2H),1.24(s,6H). Example 13: Synthesis of Compound 13 (S)-6-(3-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0157] (S)-methyl 4-((1-(tert-Butoxycarbonyl)piperidin-3-yl)amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate: To a mixture of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (3.10 g; 9.87 mmol) and tert-butyl (3S)-3-aminopiperidine-1-carboxylate (2.29 g; 10.86 mmol) in ACN (30.00 ml) was added ethylbis(propan-2-yl)amine (4.03 g; 29.61 mmol). After stirring at 40°C under nitrogen for 2 h, the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (70:30) to afford tert-butyl (3S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}piperidine-1-carboxylate (2.80 g, 64.6%) as a yellow solid.

[0158] Tert-butyl (S)-3-((8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate: A mixture of tert-butyl (3S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}piperidine-1-carboxylate (2.80 g; 6.37 mmol) in MeOH (20.00 ml) containing NH3(g) was stirred at 40°C under nitrogen for 2 h. The resulting mixture was concentrated under reduced pressure. This afforded tert-butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (2.30 g, crude) as a light yellow solid, which was used in the next step without purification.

[0159] tert-Butyl (S)-3-((8-carbamoyl-6-cyanopyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate: To a stirred mixture of tert-butyl (S)-3-((8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (800 mg; 1.97 mmol) in 1,4-dioxane (15 ml) was added CuCN (355 mg; 3.94 mmol), tris(dibenzylideneacetone)dipalladium (180 mg; 0.197 mmol), and dppf (218 mg; 0.39 mmol) at room temperature. The resulting mixture was stirred at 100°C under argon for 5 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:8) to afford (S)-tert-butyl 3-((8-carbamoyl-6-cyanopyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate as a yellow solid (397 mg, 50.76%).

[0160] (S)-tert-Butyl 3-((8-carbamoyl-6-cyanopyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate: A mixture of tert-butyl (3S)-3-({8-carbamoyl-6-cyanopyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (320.00 mg; 0.70 mmol) and diazine hydrate (0.17 ml; 2.81 mmol) in EtOH (20.00 ml) was stirred at 80° C. for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to provide tert-butyl (3S)-3-{[6-(N-aminocarbamimidoyl)-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl]amino}piperidine-1-carboxylate as a yellow solid (230.00 mg, 68.7%).

[0161] (S)-methyl 4-((1-(tert-Butoxycarbonyl)piperidin-3-yl)amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate: To a stirred solution of (3S)-tert-butyl 3-{[6-(N-aminocarbamimidoyl)-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl]amino}piperidine-1-carboxylate (230.00 mg; 0.49 mmol) in DMA (10.00 ml) and THF (2.00 ml) was added NaCO (54.44 mg; 0.49 mmol). The mixture was cooled to 0°C. To the above mixture was then added 2-methoxyacetyl chloride (55.73 mg; 0.49 mmol) in DMA (3.00 ml) dropwise. The resulting mixture was stirred at 50°C for an additional 1 h. The reaction was quenched with water / ice. The organic layer was extracted with EtOAc (3x100 mL), washed with 1x100 mL of brine, and dried over Na2SO4. The resulting mixture was concentrated under reduced pressure. Diphenyl ether (20.00 ml) was added to the resulting mixture. After stirring the resulting mixture for another 2 h at 180 ° C, the residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (9: 1) to provide (3S)-3-({8-carbamoyl-6-[3-(methoxymethyl)-1H-1,2,4-triazol-5-yl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylic acid tert-butyl ester as a yellow solid (150.00 mg; 39.3%).

[0162]

[0146] (S)-tert-Butyl 3-((8-carbamoyl-6-(3-(methoxymethyl)-1H-1,2,4-triazol-5-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate: A stirred mixture of tert-butyl (3S)-3-({8-carbamoyl-6-[3-(methoxymethyl)-1H-1,2,4-triazol-5-yl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (120.00 mg; 0.15 mmol) and TFA (2 ml) in DCM (5 ml) was stirred at room temperature. The resulting 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 NH4HCO3 + 0.1% [28% NH3 aqueous solution]), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 10% B to 40% B over 8 minutes, 40% B; wavelength: 254 nm; RT1 (min.): 6; number of runs: 1) to provide 6-[3-(methoxymethyl)-1H-1,2,4-triazol-5-yl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a pale yellow solid (6.60 mg, 11.0%).

[0163] HPLC 98.09% purity, RT = 2.88 min. MS: m / z = 348.10 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm): δ 9.14-9.07 (m, 1H), 8.55-8.48 (m, 1H), 4.71 (d, 2H), 4.33 (s, 1H), 3.51 (s, 3H), 3.45-3.35 (m, 1H), 3.09 (dt, 1H), 2.80 (td, 2H), 2.22 (d, 1H), 1.99-1.91 (m, 1H), 1.86-1.68 (m, 2H). Example 14: Synthesis of Compound 14: 6-(4-(((S)-3-cyanomorpholino)methyl)phenyl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide and 6-(4-(((R)-3-cyanomorpholino)methyl)phenyl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0164] 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine-3-carbonitrile: To a stirred mixture of morpholine-3-carbonitrile hydrochloride (0.50 g; 4.24 mmol) and 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.99 g; 6.35 mmol) in CHCN (20.00 ml) was added KCO (1.23 g; 8.47 mmol) at room temperature. The resulting mixture was stirred at 50°C for 2 h. The residue was directly purified by silica gel column chromatography eluting with CHCl / MeOH (9:1). This gave 4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}morpholine-3-carbonitrile as a light brown solid (1.30 g; 70.03%).

[0165] tert-Butyl (3S)-3-((8-carbamoyl-6-(4-((3-cyanomorpholino)methyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate: tert-Butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (100.00 mg; 0.23 mmol) and 4-{[4-(4,4, To a stirred mixture of 1,4-dioxane (5 ml) and water (1 ml) were added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (17.32 mg; 0.02 mmol) and K3PO4 (155.68 mg; 0.70 mmol). The resulting mixture was stirred at 100° C. under an argon atmosphere for 2 h. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to afford tert-butyl (3S)-3-[(8-carbamoyl-6-{4-[(3-cyanomorpholin-4-yl)methyl]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate as a yellow solid (180 mg; 90.43%).

[0166] 6-(4-((3-Cyanomorpholino)methyl)phenyl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide: A stirred mixture of (3S)-tert-butyl 3-[(8-carbamoyl-6-{4-[(3-cyanomorpholin-4-yl)methyl]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (180.00 mg; 0.21 mmol) and TFA (2 ml) in DCM (6 ml) was stirred at room temperature. The resulting mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography, eluting with CHCl / MeOH (4:1). The crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30×150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in water]), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 30B to 60B over 8 minutes; 254 nm; RT1: 6.5; RT2: 7.2; injection volume: 1 ml; number of runs: 2) to provide 6-{4-[(3-cyanomorpholin-4-yl)methyl]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (24.00 mg, 23.23%).

[0167] 6-(4-(((S)-3-cyanomorpholino)methyl)phenyl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide and 6-(4-(((R)-3-cyanomorpholino)methyl)phenyl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide: 6-{4-[(3-cyanomorpholin-4-yl)methyl]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (44.00 mg; 0.09 mmol) were purified by preparative chiral HPLC (column: CHIRALPAK IC, 3*25 cm, 5 μm; mobile phase A: Hex:DCM=1:1 (0.5% 2M 3-[[(3S)-3-cyanomorpholin-4-yl]methyl}phenyl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (15.30 mg) and 6-(4-{[(3R)-3-cyanomorpholin-4-yl]methyl}phenyl)-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (14.00 mg).

[0168] Isomer 1: HPLC 93.42% purity, 4.02 min. MS: m / z = 473.20 [M+H] + . 11H NMR (400 MHz, DMSO-d6, ppm): δ 10.04 (d, J = 3.8 Hz, 1H), 8.84 (s, 1H), 8.58 (s, 1H), 8.37 (dd, J = 11.9, 8.5 Hz, 3H), 8.24 (d, J = 3.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 4.31 (s, 1H), 4.00 - 3.90 (m, 2H), 3.86 - 3.78 (m, 1H), 3.72 (s, 2H), 3.64 (dd, J = 11.7, 2.6 Hz, 1H), 3.51 (td, J = 11.5, 2.7 Hz, 1H), 3.05 (d, J = 11.9 Hz, 1H), 2.83 (d, J = 10.9 Hz, 1H), 2.74 (t, J = 10.3 Hz, 1H), 2.66 - 2.52 (m, 2H), 2.45 (dd, J = 11.9, 3.4 Hz, 1H), 1.90 (s, 1H), 1.82 (d, J = 9.8 Hz, 1H), 1.68 (s, 1H), 1.50 (d, J = 12.9 Hz, 1H).

[0169] Isomer 2: HPLC purity 92.36%, 3.99 min. MS: m / z = 473.15 [M + H] + . 1 1H NMR (400 MHz, DMSO-d6, ppm): δ 10.04 (d, J = 3.6 Hz, 1H), 8.85 (s, 1H), 8.58 (s, 1H), 8.37 (dd, J = 14.2, 8.5 Hz, 3H), 8.24 (d, J = 3.8 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 4.32 (s, 1H), 4.00 - 3.91 (m, 2H), 3.82 (d, J = 10.9 Hz, 1H), 3.72 (s, 2H), 3.64 (dd, J = 11.7, 2.6 Hz, 1H), 3.51 (td, J = 11.5, 2.7 Hz, 1H), 3.07 (d, J = 12.2 Hz, 1H), 2.84 (s, 1H), 2.76 (t, J = 10.2 Hz, 1H), 2.66 - 2.52 (m, 2H), 2.51 - 2.41 (m, 1H), 1.91 (s, 1H), 1.82 (d, J = 10.1 Hz, 1H), 1.69 (s, 1H), 1.52 (s, 1H). Example 15: Synthesis of Compound 15 4-(((S)-piperidin-3-yl)amino)-6-(4-(((S)-3-(trifluoromethyl)morpholino)methyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide and 4-(((S)-piperidin-3-yl)amino)-6-(4-(((R)-3-(trifluoromethyl)morpholino)methyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0170] 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-(trifluoromethyl)morpholine: To a stirred mixture of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-(trifluoromethyl)morpholine; 4-methylbenzene-1-sulfonic acid (661.26 mg; 1.92 mmol) in CHCN (10.00 ml) was added KCO (698.02 mg; 4.80 mmol). The resulting mixture was stirred at 80°C for 2 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This afforded 4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-3-(trifluoromethyl)morpholine as a yellow solid (450.00 mg, 62.38%).

[0171] tert-Butyl (3S)-3-((8-carbamoyl-6-(4-((3-(trifluoromethyl)morpholino)methyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate: Under argon atmosphere, tert-butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (390.00 mg; 0.91 mmol) and 4-{[4-(4,4,5 To a stirred mixture of 1,4-dioxane (15 ml) and water (3 ml) was added K 3 PO 4 (610.64 mg; 2.73 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (67.92 mg; 0.09 mmol). The resulting mixture was stirred at 100° C. for 2 h. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:9) to afford tert-butyl (3S)-3-{[8-carbamoyl-6-(4-{[3-(trifluoromethyl)morpholin-4-yl]methyl}phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino}piperidine-1-carboxylate as a yellow solid (387.00 mg; 57.1%).

[0172] 4-(((S)-Piperidin-3-yl)amino)-6-(4-((3-(trifluoromethyl)morpholino)methyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: To a solution of tert-butyl (3S)-3-{[8-carbamoyl-6-(4-{[3-(trifluoromethyl)morpholin-4-yl]methyl}phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino}piperidine-1-carboxylate (377.00 mg; 0.51 mmol) in DCM (15 ml) was added TFA (5 ml) at room temperature. After stirring for 1 h, the solvent was removed in vacuo and the crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30×150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in water]), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 20B to 50B over 8 minutes; 254 nm; RT1: 6.4; RT2: 7.8) to provide 4-{[(3S)-piperidin-3-yl]amino}-6-(4-{[3-(trifluoromethyl)morpholin-4-yl]methyl}phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (120.00 mg; 45.46%).

[0173] 4-(((S)-Piperidin-3-yl)amino)-6-(4-(((S)-3-(trifluoromethyl)morpholino)methyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide and 4-(((S)-piperidin-3-yl)amino)-6-(4-(((R)-3-(trifluoromethyl)morpholino)methyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: The product 4-{[(3S)-piperidin-3-yl]amino}-6-(4-{[(3S)-3-(trifluoromethyl)morpholin-4-yl]methyl}phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide (120.00 mg; 0.23 mmol) was determined by preparative chiral HPLC (column: CHIRAL ART®). Cellulose-SC, 2*25cm, 5um; mobile phase A: Hex: DCM = 3:1 (0.5% 2M 3-(trifluoromethyl)morpholin-4-yl]methyl}phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (68.40 mg) and 4-{[(3S)-piperidin-3-yl]amino}-6-(4-{[(3R)-3-(trifluoromethyl)morpholin-4-yl]methyl}phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (64.80 mg).

[0174] Isomer 1: HPLC 98.92% purity, 3.78 min. MS: m / z = 516.20 [M+H] + . 1H NMR (300MHz, DMSO-d6, ppm): δ10.03(d,J=3.7Hz,1H),8.82(s,1H),8.55(s,1H),8.33(dd,J=15.1,8.5Hz ,3H),8.23(d,J=3.7Hz,1H),7.53(d,J=8.1Hz,2H),4.05(d,J=14.1Hz,1H),4.00-3.85(m,3H),3.81-3.6 6(m,2H),3.54(dd,J=11.2,8.1Hz,2H),3.09-2.99(m,1H),2.92(d,J=12.6Hz,1H),2.87-2.66(m,2H),2. 57(d,J=9.7Hz,1H),2.40(d,J=12.2Hz,1H),1.88(s,2H),1.79(d,J=9.6Hz,1H),1.67(d,J=12.1Hz,1H).

[0175] Isomer 2: HPLC 99.08% purity, 3.77 min. MS: m / z = 516.20 [M+H] + .

[0176] 1 H NMR (300MHz, DMSO-d6, ppm): δ10.03(d,J=3.8Hz,1H),8.82(s,1H),8.55(s,1H),8.34(dd,J=15.6,8.4Hz,3H) ,8.22(d,J=3.7Hz,1H),7.53(d,J=8.1Hz,2H),4.05(d,J=14.1Hz,1H),4.00-3.85(m,1H),3.76(d,J=12.1Hz, 2H),3.76-3.65(m,2H),3.54(dd,J=10.8,7.8Hz,2H),3.04(dd,J=11.5,3.8Hz,1H),2.97-2.66(m,3H),2.55( t,J=10.0Hz,1H),2.40(d,J=12.3Hz,1H),1.83(dd,J=22.4,7.4Hz,2H),1.66(s,1H),1.49(d,J=11.2Hz,1H). Example 16: Synthesis of Compound 16 ((R)-4-((4,4-difluoropiperidin-3-yl)amino)-6-(4-((1-hydroxycyclopropyl)methoxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide)

[0177] Methyl 2-(4-bromophenoxy)acetate: To a stirred solution of 4-bromophenol (9.50 g; 52.17 mmol) and methyl 2-bromoacetate (10.08 g; 62.60 mmol) in DMF (40.00 ml) was added portionwise KCO (11.38 g; 78.25 mmol; 1.50 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere overnight. 500 ml of water was added to the reaction. The mixture was extracted with EA (3×250 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to provide methyl 2-(4-bromophenoxy)acetate (11.32 g; 45.66 mmol; 87.5%; brown liquid; crude product).

[0178] 1-((4-bromophenoxy)methyl)cyclopropan-1-ol: To a stirred mixture of methyl 2-(4-bromophenoxy)acetate (8.30 g; 32.85 mmol; 1.00 eq.) in THF (80.00 ml) at 0° C., tetraisopropyl titanate (9.67 g; 32.32 mmol; 0.98 eq.) and (ethyl)magnesium bromide (30.60 ml) were added dropwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was quenched with 100 ml of water at 0° C. and extracted with EA (3×80 mL). The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE containing 5% EA to provide 1-[(4-bromophenoxy)methyl]cyclopropan-1-ol (3.10 g; 32.5%) as a white solid.

[0179] 1-((4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)cyclopropan-1-ol: To a stirred mixture of 1-[(4-bromophenoxy)methyl]cyclopropan-1-ol (3.00 g; 10.32 mmol) and BPD (9.41 g; 35.20 mmol) in 1,4-dioxane (20.00 ml) was added portionwise KOAc (3.65 g; 35.33 mmol; 3.42 eq.) and Pd(dppf)Cl (0.91 g; 1.18 mmol; 0.11 eq.) at room temperature. The resulting mixture was stirred at 100° C. under nitrogen for 1 hour. The residue was purified by silica gel column chromatography, eluting with 10% EA in PE. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 45% to 55% gradient over 10 minutes; detector, UV 254 nm to provide 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopropan-1-ol (650.00 mg 21.7%) as a yellow oil.

[0180] (R)-tert-Butyl 3-((8-carbamoyl-6-(4-((1-hydroxycyclopropyl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-4,4-difluoropiperidine-1-carboxylate: (3R)-tert-Butyl 3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-4,4-difluoropiperidine-1-carboxylate (280.00 mg; 0.61 mmol) and To a stirred mixture of 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopropan-1-ol (460.00 mg; 1.59 mmol) in DME (3.00 ml) and H₂O (1.00 ml) were added portionwise Na₂CO₃ (269.00 mg; 2.41 mmol) and Pd(PPh₃)₄ (74.00 mg; 0.06 mmol). The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 45% EA in PE to afford tert-butyl (3R)-3-[(8-carbamoyl-6-{4-[(1-hydroxycyclopropyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-4,4-difluoropiperidine-1-carboxylate (200.00 mg; 51.7%) as a yellow solid.

[0181] (R)-4-((4,4-difluoropiperidin-3-yl)amino)-6-(4-((1-hydroxycyclopropyl)methoxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of (3R)-tert-butyl 3-[(8-carbamoyl-6-{4-[(1-hydroxycyclopropyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-4,4-difluoropiperidine-1-carboxylate (190.00 mg; 0.30 mmol; 1.00 eq.) in DCM (3.00 ml) at 0°C was added TFA (1.00 ml) dropwise. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture 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, 20% to 25% gradient over 10 minutes; detector, UV 220 nm. The 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 NH4HCO3 + 0.1% [28% NH3 in water]), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 18B to 48B over 8 minutes) to provide 4-{[(3R)-4,4-difluoropiperidin-3-yl]amino}-6-{4-[(1-hydroxycyclopropyl)methoxy]phenyl}pyrido[3,2-d]pyrimidine-8-carboxamide (35.40 mg; 0.07 mmol; 23.7%) as a yellow solid.

[0182] HPLC: 93.7% purity, RT = 3.20 min. MS: m / z = 471.10 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ9.90(s,1H),8.82(s,1H),8.62(s,1H),8.30(d,J=8.4Hz,2H),8.22(s,1H),8.16(d,J=9.8Hz,1H),7.13(d,J=8.4Hz,2H),5.6 3(s,1H),4.88(s,1H),4.07(s,2H),3.07(s,1H),2.97(d,J=11.2Hz,2H),2 .73(s,1H),2.62(s,1H),2.14(s,1H),1.96(s,1H),0.68(d,J=13.6Hz,4H). Example 17: Synthesis of Compound 17 6-(4-morpholinocyclohex-1-en-1-yl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0183] tert-Butyl (3S)-3-((8-carbamoyl-6-(4-morpholinocyclohex-1-en-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate: Under argon atmosphere, tert-butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (300.00 mg; 0.70 mmol) and 4-[4-(4,4,5,5 To a stirred mixture of [-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]morpholine (259.54 mg; 0.84 mmol) in 1,4-dioxane (15 ml) and H2O (3 ml) were added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (52.24 mg; 0.07 mmol) and K3PO4 (469.74 mg; 2.10 mmol). After stirring at 100 °C for 2 h, the residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (7:3) to afford tert-butyl (3S)-3-({8-carbamoyl-6-[4-(morpholin-4-yl)cyclohex-1-en-1-yl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate as a yellow solid (390.00 mg, 92.0%).

[0184] 6-(4-Morpholinocyclohex-1-en-1-yl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide: To a solution of tert-butyl (3S)-3-({8-carbamoyl-6-[4-(morpholin-4-yl)cyclohex-1-en-1-yl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (380.00 mg; 0.63 mmol) in DCM (15 ml) was added TFA (5 ml). The resulting mixture was stirred at room temperature for 1 h. 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 + 0.1% [28% NH 3 in water]), mobile phase B: ACN; flow rate: 60 mL / min.; gradient: 10B to 40B over 8 minutes) to provide 6-[4-(morpholin-4-yl)cyclohex-1-en-1-yl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (107.20 mg, 38.8%).

[0185] HPLC 99.4% purity, RT = 2.42 min. MS: m / z = 438.25 [M+H] + . 1H NMR (400MHz, DMSO, ppm): δ10.04(d,J=3.8Hz,1H),8.51(d,J=8.9Hz,2H),8.18(d,J=3.8Hz,1H ),8.10(d,J=8.6Hz,1H),6.93(d,J=4.3Hz,1H),4.25(d,J=8.5,4.3Hz,1H),3.60(t,J=4.6Hz,4 H),3.05-2.90(m,2H),2.83-2.67(m,2H),2.60-2.52(m,4H),2.47(d,J=6.0Hz,4H),2.35-2.2 0(m,1H),2.11(d,J=12.4Hz,1H),1.87-1.74(m,2H),1.64(s,1H),1.49(d,J=13.6,5.0Hz,2H). Example 18: Synthesis of Compound 18: ((R)-3-amino-1-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazin-8-yl)piperidin-3-yl)pyrrolidin-2-one)

[0186] 4-nitro-4-phenylbutyric acid ethyl ester: At 0 ° C, under a nitrogen atmosphere, to a stirred solution of (nitromethyl) benzene (7.00g, 48.491mmol) and ethyl acrylate (5.11g, 48.491mmol) in 1,4-dioxane (70.00mL, 826.286mmol) was added Amberlyst A-21 (21g). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere, filtered, and the filtrate was dried over sodium sulfate and concentrated in vacuo. The crude product was purified on silica gel by flash column chromatography (eluent: heptane / ethyl acetate 0 to 10%) to provide 4-nitro-4-phenylbutyric acid ethyl ester (8g, 65.99%) as a colorless oil.

[0187] 5-nitro-5-phenylpiperidin-2-one: To a stirred mixture of NH4OAc (5.19 g, 63.999 mmol) in EtOH (15 mL) was added formaldehyde solution (2.60 g, 31.999 mmol) at room temperature under a nitrogen atmosphere. To the above mixture was added ethyl 4-nitro-4-phenylbutyrate (8.00 g, 31.999 mmol) in EtOH (5.00 mL) at room temperature. The resulting mixture was stirred at 70 ° C for another 18 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with water and then triturated with Et2O to provide 5-nitro-5-phenylpiperidin-2-one (5 g, 70.95%) as a white solid.

[0188] 5-amino-5-phenylpiperidin-2-one: Under N2 atmosphere, to a stirred solution of 5-nitro-5-phenylpiperidin-2-one (5.00 g; 21.57 mmol) in tetrahydrofuran (30.00 ml) was added Raney Ni (2.00 g) in portions. The resulting mixture was stirred overnight under H2 atmosphere. The mixture was filtered and concentrated under reduced pressure to provide 5-amino-5-phenylpiperidin-2-one (4.10 g; 18.32 mmol) as a white solid.

[0189] 3-Phenylpiperidin-3-amine: To a solution of lithium aluminum hydride (5.45 g; 43.10 mmol) in THF was added dropwise a solution of 5-amino-5-phenylpiperidin-2-one (4.10 g; 21.55 mmol) in tetrahydrofuran (50.00 ml) at room temperature. The mixture was refluxed for 30 minutes. The resulting mixture was cooled in an ice bath and carefully quenched with 5.17 mL of water, 5.17 mL of NaOH (5N), and finally 15.51 mL of water. Ethyl acetate was added. The mixture was filtered and the filtrate was concentrated in vacuo to provide 3-phenylpiperidin-3-amine (2.80 g; 13.11 mmol; 60.82%; yellow oil; crude product).

[0190] 3-amino-3-phenylpiperidine-1-carboxylic acid tert-butyl ester: at 0 ℃, N2 atmosphere, to 3-phenylpiperidin-3-amine (2.80g; 13.11mmol) and triethylamine (2.09g; 19.66mmol) in DCM (30.00ml) stirred solution was added di-tert-butyl dicarbonate (3.61g; 15.73mmol) in DCM. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was quenched with Na2CO3 (aq.). The solution was extracted with DCM and concentrated under reduced pressure. The residue was purified by C18 flash column (30% water containing ACN) to provide 3-amino-3-phenylpiperidine-1-carboxylic acid tert-butyl ester (2.50g; 57.69%) as a colorless oil.

[0191] 3-{[6-Chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-3-phenylpiperidine-1-carboxylate: To a stirred mixture of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (800.00 mg; 1.86 mmol) and tert-butyl 3-amino-3-phenylpiperidine-1-carboxylate (603.00 mg; 1.86 mmol) in ACN (20.00 ml) was added DIEA (0.93 ml; 5.58 mmol) at room temperature. The resulting mixture was stirred at 65°C under a nitrogen atmosphere overnight. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE:EA=7:3 to provide tert-butyl 3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-3-phenylpiperidine-1-carboxylate (700.00 mg; 1.41 mmol) as a yellow solid.

[0192] tert-Butyl 3-({8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-3-phenylpiperidine-1-carboxylate: A mixture of tert-butyl 3-{[6-chloro-8-(methoxycarbonyl)pyridine]-tert-butyl 3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-3-phenylpiperidine-1-carboxylate[3,2-d]pyrimidin-4-yl]amino}-3-phenylpiperidine-1-carboxylate (680.00 mg; 1.37 mmol) in MeOH (15.00 ml, 13%) containing NH3(g) was stirred at room temperature. The resulting mixture was stirred at 40°C under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. This afforded tert-butyl 3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-3-phenylpiperidine-1-carboxylate (600.00 mg; crude product) as a yellow solid.

[0193] tert-Butyl 3-[(8-carbamoyl-6-{4-[(morpholin-4-yl)methyl]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-3-phenylpiperidine-1-carboxylate: tert-Butyl 3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-3-phenylpiperidine-1-carboxylate (300.00 mg; 0.62 mmol) and 4-{[ To a stirred mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}morpholine (396.00 mg; 1.30 mmol) in DME (12.00 ml) was added Pd(PPh3)4 (76.00 mg, 0.062 mmol), Na2CO3 (208.00 mg, 1.96 mmol), and water (4.00 ml). The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography eluting with PE:EA = 4:6 to provide tert-butyl 3-[(8-carbamoyl-6-{4-[(morpholin-4-yl)methyl]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-3-phenylpiperidine-1-carboxylate (300.00 mg; 77.4%) as a yellow solid.

[0194] 6-{4-[(morpholin-4-yl)methyl]phenyl}-4-[(3-phenylpiperidin-3-yl)amino]pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of tert-butyl 3-[(8-carbamoyl-6-{4-[(morpholin-4-yl)methyl]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-3-phenylpiperidine-1-carboxylate (280.00 mg; 0.45 mmol) in DCM (8.00 ml) was added TFA (2.00 ml) at room temperature. The resulting mixture was stirred at room temperature under nitrogen for 2 h. The reaction was quenched with NaHCO (aq.) at room temperature. The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo. This afforded 6-{4-[(morpholin-4-yl)methyl]phenyl}-4-[(3-phenylpiperidin-3-yl)amino]pyrido[3,2-d]pyrimidine-8-carboxamide (200.00 mg; crude product) as a yellow solid.

[0195] 6-{4-[(Morpholin-4-yl)methyl]phenyl}-4-{[(3R)-3-phenylpiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide & 6-{4-[(Morpholin-4-yl)methyl]phenyl}-4-{[(3S)-3-phenylpiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: 6-{4-[(Morpholin-4-yl)methyl]phenyl}-4-[(3-phenylpiperidin-3-yl)amino]pyrido[3,2-d]pyrimidine-8-carboxamide (200.00 mg; 0.37 mmol) was purified by the following: Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; Mobile phase A: Hex (0.5% 2M 3-PhenyIpiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (41.50 mg; 41.8%) as a yellow solid and 6-{4-[(morpholin-4-yl)methyl]phenyl}-4-{[(3S)-3-phenylpiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (40.80 mg; 40.8%) as a yellow solid.

[0196] Isomer 1: 6-{4-[(morpholin-4-yl)methyl]phenyl}-4-{[(3R)-3-phenylpiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide. HPLC: 98.08% purity, RT = 4.38 min. MS: m / z = 524.25 [M+H] + . 1HNMR(400MHz, DMSO-d6)δ9.92(d,J=3.6Hz,1H),8.86(d,J=3.0Hz,2H),8.32(s,1H),8.31-8.25( m,2H),8.25-8.19(m,1H),7.58-7.52(m,2H),7.52-7.45(m,2H),7.31(t,J=7.7Hz,2H),7.27-7.1 8(m,1H),3.60(dd,J=10.0,5.3Hz,6H),3.25(d,J=11.7Hz,1H),2.95(d,J=11.4Hz,2H),2.69(d, J=11.9Hz,1H),2.59(s,1H),2.42(t,J=4.6Hz,4H),2.18-2.06(m,1H),1.53(s,2H),1.24(s,1H).

[0197] Isomer 2: 6-{4-[(morpholin-4-yl)methyl]phenyl}-4-{[(3S)-3-phenylpiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide. HPLC: 97.3% purity, RT = 4.37 min. MS: m / z = 524.25 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ9.92(d,J=3.6Hz,1H),8.87(s,1H),8.83(s,1H),8.33(s,1H),8.31-8.25(m ,2H),8.22(d,J=3.6Hz,1H),7.58-7.51(m,2H),7.53-7.45(m,2H),7.31(dd,J=8.4,6.9Hz,2H),7.27- 7.18(m,1H),3.60(dd,J=10.4,5.7Hz,6H),2.97(t,J=15.6Hz,2H),2.74(d,J=11.9Hz,1H),2.61(d,J= 9.4Hz, 1H), 2.41 (t, J = 4.7Hz, 4H), 2.12 (dt, J = 13.2, 8.7Hz, 1H), 1.56 (s, 2H), 1.24 (d, J = 13.0Hz, 2H). Example 19: Synthesis of Compound 19 (S)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0198] (S)-tert-Butyl 3-((8-carbamoyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate: To a stirred mixture of 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (150 mg, 0.507 mmol) and tert-butyl 3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (325 mg, 0.760 mmol) in 1,4-dioxane and H2O (3 mL) at 25°C were added K3PO4 (339 mg, 1.521 mmol) and AMPHOS-PdCl2 (37 mg, 0.051 mmol). The resulting mixture was stirred under argon atmosphere for 2 h at 100° C. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography eluting with CH 2 Cl 2 / MeOH (6:1) to provide (3S)-tert-butyl 3-([8-carbamoyl-6-[1-(2-methoxyethyl)pyrazol-4-yl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (120 mg, 38.09%) as a yellow oil.

[0199] (S)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of tert-butyl (3S)-3-([8-carbamoyl-6-[1-(2-methoxyethyl)pyrazol-4-yl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (110 mg, 0.177 mmol) in DCM at 25° C. was added TFA (4 mL, 51.160 mmol). The resulting mixture was stirred at 25° C. for 1 h. The solvent was removed in vacuo and the crude product was purified by preparative HPLC using the following conditions: (#2 SHIMADZU (HPLC-01)): Column, XBridge Prep OBD C18 column, 30 x 150 mm 5 μm; Mobile phase, water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in water]) and ACN (20% phase B up to 50% over 8 minutes); Detector, UV 254 nm. This gave 6-[1-(2-methoxyethyl)pyrazol-4-yl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide (50.8 mg, 71.82%) as a yellow solid.

[0200] HPLC 99.2% purity, 1.987 min. MS: m / z = 397.4 [M+H] + .1 H NMR (300MHz, DMSO-d6, ppm): δ10.04(d,J=3.6Hz,1H),8.79-8.65(m,1H),8.55(s,1H),8.51(s,1H),8.40(d,J=0.7Hz,1H),8.17(d ,J=8.6Hz,2H),4.40-4.14(m,3H),3.77(t,J=5.2Hz,2H),3.31(s,2H),3.07(dd,J=11.5,3.8Hz,1H),2.84(d,J=12.2Hz,1H),2.76 -2.55(m,2H),1.93(s,1H),1.86-1.64(m,2H),1.49(d,J=11.6Hz,1H). Example 20: Synthesis of Compound 20 4-((3-azabicyclo[3.1.0]hex-1-yl)amino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0201] Methyl 4-((3-(tert-Butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate: To a mixture of 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (200 mg, 0.660 mmol) and tert-butyl 1-aminobicyclo[3.1.0]hexane-3-carboxylate (274.24 mg, 1.321 mmol) in MeCN (5 mL) was added DIEA (0.36 mL, 2.810 mmol). The resulting mixture was stirred at 40 °C under nitrogen for 16 h. The solvent was removed and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:17) to afford methyl 4-[[3-(tert-butoxycarbonyl)bicyclo[3.1.0]hexan-1-yl]amino]-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate (142 mg, 47.54%) as a yellow solid.

[0202] tert-Butyl 1-((8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate: A solution of tert-butyl 1-[[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (142.00 mg, 0.313 mmol) in MeOH (3 mL) containing NH3(g) was stirred at 40°C under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. This afforded tert-butyl 1-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (130 mg, crude) as a pale yellow solid which was used in the next step without purification.

[0203] tert-Butyl 1-((8-carbamoyl-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate: To tert-butyl 1-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (120 mg, 0.250 mmol) and To a solution of 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (95.58 mg, 0.299 mmol) in 1,4-dioxane (5 mL) and H2O (1 ml) were added K3PO4 (167.29 mg, 0.749 mmol) and AMPHOS-PdCl2 (18.60 mg, 0.025 mmol). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 h and then concentrated under reduced pressure. The residue was purified by preparative TLC / silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to afford tert-butyl 1-([8-carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 57.87%) as a yellow solid.

[0204] 4-((3-Azabicyclo[3.1.0]hexan-1-yl)amino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: A stirred solution of tert-butyl 1-([8-carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (90 mg, 0.130 mmol) and HCl (g) in MeOH (5 mL) was stirred under air. The resulting mixture was concentrated in vacuo. The crude product (85 mg) was purified by preparative HPLC using the following conditions: (#2 SHIMADZU (HPLC-01)): Column, XBridge Prep OBD C18 column, 150 mm 5 μm; Mobile phase, water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in water]) and ACN (26% Phase B up to 56% over 8 minutes); Detector, UV 254 nm. The product was obtained. This afforded 4-[3-azabicyclo[3.1.0]hexan-1-ylamino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (35.8 mg, 60.46%) as a light yellow solid.

[0205] HPLC 97.8% purity, RT = 2.11 min. MS: m / z = 446.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6, ppm): δ10.03 (d, J = 3.7Hz, 1H), 9.17 (s, 1H), 8.83 (s, 1H), 8.59 (s, 1H),8.42-8.33(m,2H),8.22(d,J=3.7Hz,1H),7.47(d,J=8.1Hz,2H),3.57(dd,J=10.1,5. 5Hz, 6H), 3.20-3.04 (m, 2H), 2.84 (d, J = 10.5Hz, 1H), 2.76 (d, J = 11.2Hz, 1H), 2.37 (t, J = 4. 7Hz, 4H), 1.73 (dt, J = 8.3, 4.3Hz, 1H), 1.10 (t, J = 5.1Hz, 1H), 0.95 (dd, J = 8.4, 5.3Hz, 1H).

[0206] 4-({3-azabicyclo[3.1.0]hexan-1-yl}amino)-6-{4-[(morpholin-4-yl)methyl]phenyl}pyrido[3,2-d]pyrimidine-8-carboxamide (35.1 mg; 0.079 mmol) was dissolved in a minimal amount of DMSO and purified using supercritical fluid chromatography. The purification was run on a Waters SFC Prep 200 (Phenomenex Cellulose-3, 250 x 21 mm, 5 μm particle size, 1000 Å pore size) with a column temperature of 40°C and a mobile phase of A: methanol + 20 mM NH4OH B: CO2. The desired enantiomer was separated at an isocratic flow rate of 100 g / min using 45% solvent A and 55% solvent B. The product-containing fractions were combined and concentrated in vacuo. Enantiomeric excess was determined on an Agilent 1100 (Phenomenex Cellulose-3, 4.6 x 150 mm, particle size 5 μm, pore size 1000 Å) equipped with an Aurora Fusion A5 SFC column temperature of 40° C. with a mobile phase of A: CO 2 B: methanol + 20 mM NH 4 OH). Enantiomers were chromatographed using the following gradient: 95% solvent A + 5% solvent B to 40% solvent A + 60% solvent B over 3.5 minutes, isocratic 40% solvent A + 60% solvent B for 3.5-5 minutes, isocratic 95% solvent A + 5% solvent B for 5-6 minutes, with a flow rate of 3 mL / min. Chirality was arbitrarily assigned, with the first peak being 4-{[(1R,5S)-3-azabicyclo[3.1.0]hexan-1-yl]amino}-6-{4-[(morpholin-4-yl)methyl]phenyl}pyrido[3,2-d]pyrimidine-8-carboxamide (5.2 mg, 98% enantiopure) with an RT of 3.251 min, and the second peak being 4-{[(1S,5R)-3-azabicyclo[3.1.0]hexan-1-yl]amino}-6-{4-[(morpholin-4-yl)methyl]phenyl}pyrido[3,2-d]pyrimidine-8-carboxamide (4.7 mg, 89% enantiopure) with an RT of 3.579 min. Example 21: Synthesis of Compound 21 (S)-4-(Azepan-3-ylamino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide and (R)-4-(Azepan-3-ylamino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0207] Methyl 4-((1-(tert-Butoxycarbonyl)azepan-3-yl)amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate: To a stirred mixture of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (300.00 mg, 0.958 mmol) and tert-butyl 3-aminoazepan-1-carboxylate (172.88 mg, 0.766 mmol) in ACN (3 ml) was added DIEA (360.12 mg, 2.647 mmol). The resulting mixture was stirred at 40° C. under nitrogen for 4 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to provide tert-butyl 3-[[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino]azepane-1-carboxylate (140 mg, 33.53%) as a yellow solid.

[0208] tert-Butyl 3-((8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)azepane-1-carboxylate: A mixture of tert-butyl 3-[[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino]azepane-1-carboxylate (130.00 mg, 0.298 mmol) in MeOH (8 mL) containing NH3(g) was stirred at 40°C under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. This gave tert-butyl 3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)azepane-1-carboxylate (120 mg, 77.63%) as a yellow solid, which was used directly in the next step.

[0209] tert-Butyl 3-((8-carbamoyl-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)azepane-1-carboxylate: To a solution of tert-butyl 3-[(8-carbamoyl-6-chloroquinazolin-4-yl)amino]azepane-1-carboxylate (110 mg, 0.213 mmol) and 4-[[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl]methyl]morpholine (82.06 mg, 0.255 mmol) in 1,4-dioxane (5 mL) and H2O (1.00 mL) were added K3PO4 (142.58 mg, 0.638 mmol) and AMPHOS-PdCl2 (15.85 mg, 0.021 mmol). The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH 2 Cl 2 / MeOH (9:1) to provide tert-butyl 3-([8-carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)azepane-1-carboxylate (180 mg, 97.70%) as a yellow solid.

[0210] 4-(Azepan-3-ylamino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: A solution of tert-butyl 3-([8-carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)azepane-1-carboxylate (170 mg, 0.196 mmol) in MeOH (8 mL) containing HCl (g) was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. The crude product (140 mg) was purified by preparative HPLC using the following conditions: (#2 SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 aqueous solution]) and ACN (20% phase B up to 40% over 8 minutes); detector, UV 254 nm. This yielded 4-(azepan-3-ylamino)-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (40 mg, 42.66%) as a light yellow solid.

[0211] (S)-4-(Azacycloheptan-3-ylamino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide and (R)-4-(Azacycloheptan-3-ylamino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: The products (40 mg) were chirally separated by chiral preparative HPLC using the following conditions: (Prep-HPLC-032): column, CHIRALPAK ID, 2*25 cm (5 μm); mobile phase, MTBE (10 mM NH3-MEOH) and EtOH (maintaining 50% EtOH within 14 minutes); detector, UV 254 nm. This afforded 4-[(3S)-azepan-3-ylamino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (4.3 mg, 10.62%) as a yellow solid and 4-[(3R)-azepan-3-ylamino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (3.6 mg, 9.04%) as a yellow solid.

[0212] Isomer 1: HPLC 96.8% purity, RT = 2.351 min. MS: m / z = 462.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6, ppm): δ10.04(d,J=3.8Hz,1H),8.81(s,1H),8.57-8.46(m,2H),8.36-8.19(m,3H),7.49(d,J=7.9Hz,2 H), 4.39 (s, 1H), 3.57 (dd, J = 10.3, 5.7Hz, 7H), 3.06-2.74 (m, 3H), 2.38 (t, J = 4.7Hz, 4H), 2.0-1.90 (m, 2H), 1.88-1.56 (m, 4H).

[0213] Isomer 2: HPLC 95.2% purity, RT = 2.359 min. MS: m / z = 462.2 [M+H] + . 1H NMR (300MHz, DMSO-d6, ppm): δ10.04(d,J=3.8Hz,1H),8.81(s,1H),8.57-8.46(m,2H),8.36-8.19(m,3H),7.49(d,J=7.9Hz,2 H), 4.39 (s, 1H), 3.57 (dd, J = 10.3, 5.7Hz, 7H), 3.06-2.74 (m, 3H), 2.38 (t, J = 4.7Hz, 4H), 2.0-1.90 (m, 2H), 1.88-1.56 (m, 4H). Example 22: Synthesis of Compound 22: 4-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide, 4-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide, 4-((3S,4S)-3-amino-4-fluoropiperidin-1-yl)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide and 4-((3S,4R)-3-amino-4-fluoropiperidin-1-yl)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0214] Methyl 4-(3-((tert-Butoxycarbonyl)amino)-4-fluoropiperidin-1-yl)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate: To a stirred mixture of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (580 mg, 1.33 mmol) and tert-butyl N-(4-fluoropiperidin-3-yl)carbamate (250 mg, 1.06 mmol) in ACN (10 mL) was added DIEA (544 mg, 4 mmol). The resulting mixture was stirred at 40° C. under nitrogen for 4 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to afford methyl 4-[3-[(tert-butoxycarbonyl)amino]-4-fluoropiperidin-1-yl]-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate (500 mg, 85.29%) as a yellow solid.

[0215] Tert-Butyl (1-(8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl)-4-fluoropiperidin-3-yl)carbamate: A mixture of methyl 4-[3-[(tert-butoxycarbonyl)amino]-4-fluoropiperidin-1-yl]-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate (500 mg, 1.18 mmol) in MeOH (10 mL) containing NH3(g) was stirred at 40°C under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. This afforded tert-butyl N-(1-[8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]-4-fluoropiperidin-3-yl)carbamate (460 mg, 99.81%) as a light yellow solid.

[0216] tert-Butyl (1-(8-carbamoyl-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)-4-fluoropiperidin-3-yl)carbamate: To a mixture of tert-butyl N-(1-[8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]-4-fluoropiperidin-3-yl)carbamate (460 mg, 1 mmol) and 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (400 mg, 0.626 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) were added AMPHOS-PdCl2 (78 mg, 0.1 mmol) and K3PO4 (690 mg, 3.2 mmol). After stirring 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 eluting with CH 2 Cl 2 / MeOH (9:1) to provide tert-butyl N-(1-[8-carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]-4-fluoropiperidin-3-yl)carbamate (290 mg, 47%) as a yellow solid.

[0217] 4-(3-Amino-4-fluoropiperidin-1-yl)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: A solution of tert-butyl N-(1-[8-carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]-4-fluoropiperidin-3-yl)carbamate (290.00 mg, 0.431 mmol) in MeOH (8 mL) containing HCl (g) was stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated in vacuo. The crude product (250 mg) was purified by preparative HPLC using the following conditions: (2# SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in water]) and ACN (15% phase B up to 40% over 8 minutes). This gave 4-(3-amino-4-fluoropiperidin-1-yl)-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (170 mg, 77.41%) as a yellow-green solid.

[0218] 4-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide, 4-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide, 4-((3S,4S)-3-amino-4-fluoropiperidin-1-yl)-6- (4-(Morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide and 4-((3S,4R)-3-amino-4-fluoropiperidin-1-yl)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: The product (170 mg) was chirally separated by chiral preparative HPLC using the following conditions: (Prep-HPLC-083): column, CHIRALPAK IG, 3*25 cm, 5 um; mobile phase, MTBE (10 mM NH3-MEOH)- and MeOH- (maintaining 50% MeOH- within 18 minutes); detector, UV 254 nm. This gave 4-[(3S,4S)-3-amino-4-fluoropiperidin-1-yl]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (43.7 mg, 27.98%) as a yellow solid and 4-[(3S,4S)-3-amino-4-fluoropiperidin-1-yl]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (43.7 mg, 27.98%) as a yellow solid. , 4-[(3S,4R)-3-amino-4-fluoropiperidin-1-yl]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (22.7 mg, 14.39%) as a light yellow solid and 4-[(3R,4S)-3-amino-4-fluoropiperidin-1-yl]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (21.1 mg, 13.44%) as a light yellow solid.

[0219] Isomer 1: HPLC 97.6% purity, RT = 2.13 min. MS: m / z = 462.2 [M+H] + .

[0220] 1 H NMR (300MHz, DMSO-d6, ppm): δ10.02 (d, J = 3.7Hz, 1H), 8.80 (s, 1H), 8.56 (s, 1H), 8.20(d,J=3.7Hz,1H),8.13(d,J=8.0Hz,2H),7.49(d,J=8.1Hz,2H),5.54-5.01( m,1H),4.96-4.80(m,1H),3.68(s,1H),3.64-3.51(m,6H),3.33(s,2H),3.12-3. 02(m,1H),2.39(t,J=4.7Hz,4H),2.18(q,J=9.6,8.3Hz,1H),2.18-1.87(m,3H).

[0221] Isomer 2: HPLC 99.5% purity, RT = 2.13 min. MS: m / z = 462.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6, ppm): δ10.02 (d, J = 3.7Hz, 1H), 8.80 (s, 1H), 8.56 (s, 1H), 8.20(d,J=3.7Hz,1H),8.13(d,J=8.0Hz,2H),7.49(d,J=8.1Hz,2H),5.54-5.01( m,1H),4.96-4.80(m,1H),3.68(s,1H),3.64-3.51(m,6H),3.33(s,2H),3.12-3. 02(m,1H),2.39(t,J=4.7Hz,4H),2.18(q,J=9.6,8.3Hz,1H),2.18-1.87(m,3H).

[0222] Isomer 3: HPLC 98.5% purity, RT = 2.07 min. MS: m / z = 462.2 [M+H] + . 1H NMR (300MHz, DMSO-d6, ppm): δ10.02 (d, J = 3.7Hz, 1H), 8.80 (s, 1H), 8.56 (s, 1H), 8.20(d,J=3.7Hz,1H),8.13(d,J=8.0Hz,2H),7.49(d,J=8.1Hz,2H),5.54-5.01( m,1H),4.96-4.80(m,1H),3.68(s,1H),3.64-3.51(m,6H),3.33(s,2H),3.12-3. 02(m,1H),2.39(t,J=4.7Hz,4H),2.18(q,J=9.6,8.3Hz,1H),2.18-1.87(m,3H).

[0223] Isomer 4: HPLC 99.0% purity, RT = 2.07 min. MS: m / z = 462.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6, ppm): δ10.02 (d, J = 3.7Hz, 1H), 8.80 (s, 1H), 8.56 (s, 1H), 8.20(d,J=3.7Hz,1H),8.13(d,J=8.0Hz,2H),7.49(d,J=8.1Hz,2H),5.54-5.01( m,1H),4.96-4.80(m,1H),3.68(s,1H),3.64-3.51(m,6H),3.33(s,2H),3.12-3. 02(m,1H),2.39(t,J=4.7Hz,4H),2.18(q,J=9.6,8.3Hz,1H),2.18-1.87(m,3H). Example 23: Synthesis of Compound 23: 4-((2-aminoethyl)amino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0224] Methyl 4-((2-((tert-Butoxycarbonyl)amino)ethyl)amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate: To a stirred mixture of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (200 mg, 0.369 mmol) and tert-butyl N-(2-aminoethyl)carbamate (49.77 mg, 0.295 mmol) in ACN (10 mL) was added DIEA (150.56 mg, 1.107 mmol). The resulting mixture was stirred at 50° C. under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:7) to afford methyl 4-([2-[(tert-butoxycarbonyl)amino]ethyl]amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate (140 mg, 54.67%) as a light yellow solid.

[0225] Tert-Butyl (2-((8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)ethyl)carbamate: A mixture of methyl 4-([2-[(tert-butoxycarbonyl)amino]ethyl]amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate (140 mg, 0.202 mmol) in MeOH (5 mL) containing NH3(g) was stirred at 40°C under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. This afforded tert-butyl N-[2-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)ethyl]carbamate (93 mg, 98.31%) as a light yellow solid.

[0226] tert-Butyl (2-((8-carbamoyl-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)ethyl)carbamate: To a mixture of tert-butyl N-[2-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)ethyl]carbamate (93 mg, 0.198 mmol) and 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (75.94 mg, 0.238 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) were added K3PO4 (132.90 mg, 0.595 mmol) and AMPHOS-PdCl2 (14.78 mg, 0.020 mmol). The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 2 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH 2 Cl 2 / MeOH (9:1) to provide tert-butyl N-[2-([8-carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)ethyl]carbamate (80 mg, 76.07%) as a light yellow solid.

[0227] 4-((2-Aminoethyl)amino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: A solution of tert-butyl N-[2-([8-carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)ethyl]carbamate (80 mg, 0.151 mmol) in MeOH (5 mL) containing HCl (g) was stirred at room temperature under nitrogen for 1 h. The resulting mixture was concentrated in vacuo. The crude product (60 mg) was purified by preparative HPLC using the following conditions: (#2 SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (10% phase B up to 30% over 8 minutes); detector, UV 254 nm. This afforded 4-[(2-aminoethyl)amino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (26.3 mg, 41.94%) as a light yellow solid.

[0228] HPLC 98.0% purity, RT = 1.923 min. MS: m / z = 408.3 [M+H] + .

[0229] 1H NMR (300MHz, DMSO-d6, ppm): δ10.08(s,1H),8.83(s,1H),8.54(s,1H),8.35(t,J=7.2Hz,2H),8.24(s,1H),7.48(dd, J=8.3,3.3Hz,2H),3.64-3.62(m,6H),3.51(s,2H),3.43-3.28(m,1H),2.87(t,J=6.6Hz,1H),2.39(t,J=4.6Hz,4H). Example 24: Synthesis of Compound 24 (S)-6-(4-(2-methoxyethoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0230] (S)-tert-Butyl 3-((8-carbamoyl-6-(4-(2-methoxyethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate: To a solution of tert-butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (300 mg, 0.666 mmol) and 4-(2-methoxyethoxy)phenylboronic acid (431 mg, 2.089 mmol) in 1,4-dioxane (15.00 mL) and H2O (3.00 mL) was added K3PO4 (654 mg, 3.084 mmol) and AMPHOS-PdCl2 (89 mg, 0.119 mmol). The resulting mixture was stirred at 100°C under nitrogen for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford tert-butyl (3S)-3-([8-carbamoyl-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (200 mg, 71.27%) as a yellow solid.

[0231] (S)-6-(4-(2-methoxyethoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred solution of (3S)-tert-butyl 3-([8-carbamoyl-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (180 mg, 0.342 mmol) in DCM (8.00 mL) was added TFA (2.00 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: (#2 SHIMADZU (HPLC-01)): column, XBridgePrep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (18% phase B up to 48% over 8 minutes); detector, UV 254 nm. The product (S)-6-(4-(2-methoxyethoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide (112.7 mg, 76.20%) was obtained as a light yellow solid.

[0232] HPLC: 99.5% purity, RT = 8.98 min. MS: m / z = 423.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ10.04(d,J=3.4Hz,1H),8.78(s,1H),8.53(s,1H),8.31(dd,J=8.7,3.2Hz,3H),8.20(d,J=3.7Hz,1H),7.10(d,J=8.4Hz ,2H),4.51-4.05(m,3H),3.74-3.65(m,2H),3.33(s,2H),3.04(d,J=11. 7Hz, 1H), 2.87-2.67 (m, 2H), 2.58 (d, J = 10.6Hz, 2H), 2.01-1.31 (m, 4H). Example 25: Synthesis of Compound 25: (R)-4-((2-aminopropyl)amino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide and (S)-4-((2-aminopropyl)amino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0233] Methyl 4-((2-((tert-Butoxycarbonyl)amino)propyl)amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate: A solution of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (400 mg, 0.891 mmol), tert-butyl N-(1-aminopropan-2-yl)carbamate (539.46 mg, 2.941 mmol), and DIEA (606.26 mg, 4.456 mmol) in ACN (10 mL) was stirred at 40 °C under nitrogen for 16 h. The resulting mixture was concentrated in vacuo. This afforded methyl 4-([2-[(tert-Butoxycarbonyl)amino]propyl]amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate (150 mg, 23.26%) as a yellow solid.

[0234] Tert-Butyl (1-((8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)propan-2-yl)carbamate: A solution of methyl 4-([2-[(tert-butoxycarbonyl)amino]propyl]amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate (140 mg, 0.193 mmol) in MeOH (3 mL) containing NH3(g) was stirred at 40°C under nitrogen for 4 h. The resulting mixture was concentrated in vacuo. This afforded tert-butyl N-[1-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)propan-2-yl]carbamate (120 mg, 94.51%) as a yellow solid.

[0235] tert-Butyl (1-((8-carbamoyl-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)propan-2-yl)carbamate: At 100°C under nitrogen atmosphere, tert-butyl N-[1-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)propan-2-yl]carbamate (120 mg, 0.199 mmol) and 4-[[ A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (115.23 mg, 0.361 mmol), AMPHOS-PdCl2 (22.30 mg, 0.030 mmol), and K3PO4 (200.10 mg, 0.896 mmol) in 1,4-dioxane (10 mL) and H2O (3 mL) was added for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to provide tert-butyl N-[1-([8-carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)propan-2-yl]carbamate (100 mg, 67.95%) as a yellow solid.

[0236]

[0266] 4-((2-aminopropyl)amino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: A solution of tert-butyl N-[(2R)-1-([8-carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)propan-2-yl]carbamate (100 mg) in 1,4-dioxane (6 mL) with HCl(g) was stirred at 25°C under nitrogen for 2 h. The solvent was removed and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (8:1) to afford 4-[(2-aminopropyl)amino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (50 mg, 97.18%) as an off-white solid.

[0237] (R)-4-((2-aminopropyl)amino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide and (S)-4-((2-aminopropyl)amino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: 4-[(2-aminopropyl)amino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (50 mg) was purified by preparative HPLC using the following conditions: (2#SHIMADZU(HPLC-01)): column, XBridge PrepOBD C18 column, 30x150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% [28% aqueous NH3]) and ACN (28% phase B up to 58% over 8 minutes); detector, UV 254 nm. The products were chirally separated by chiral preparative HPLC (Agela High Pressure Fast): column, CHIRALPAK IC, 3 x 25 cm, 5 μm; mobile phase, MTBE (10 mM NH3-MEOH) and EtOH (maintained at 10% EtOH over 20 minutes); detector, UV 254 nm. This afforded 4-[[(2R)-2-aminopropyl]amino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (10.1 mg, 19.31%) as an off-white solid and 4-[[(2S)-2-aminopropyl]amino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (10.8 mg, 21.07%) as an off-white solid.

[0238] Isomer 1: HPLC 94.8% purity, RT = 2.472 min. MS: m / z = 422.2 [M+H] + .

[0239] 1 H NMR (300MHz, DMSO-d6, ppm): δ10.08(d,1H),8.86(d,2H),8.56(s,1H),8.45-8.30(m,2H ),8.25(d,1H),7.50(m,2H),3.59(m,8H),3.54-3.42(m,1H),2.40(t,4H),1.09(d,3H).

[0240] Isomer 2: HPLC 95.8% purity, RT = 2.472 min. MS: m / z = 422.2 [M+H] + .

[0241] 1 H NMR (300MHz, DMSO-d6, ppm): δ10.08(d,1H),8.86(d,2H),8.56(s,1H),8.45-8.30(m,2H ),8.25(d,1H),7.50(m,2H),3.59(m,8H),3.54-3.42(m,1H),2.40(t,4H),1.09(d,3H). Example 26: Synthesis of Compound 26: 4-[[(3S,5S)-5-fluoropiperidin-3-yl]amino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide

[0242] tert-Butyl 3-[[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino]-5-fluoropiperidine-1-carboxylate: To a stirred solution of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (600.00 mg, 0.997 mmol) and tert-butyl 3-amino-5-fluoropiperidine-1-carboxylate (270.00 mg, 1.175 mmol) in CH3CN (10.00 mL, 243.588 mmol) was added DIEA (240.00 μL, 1764.115 mmol) at room temperature. The resulting mixture was stirred at 60°C for 4 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford tert-butyl 3-[[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino]-5-fluoropiperidine-1-carboxylate (500 mg, 80.80%) as a brown solid.

[0243] tert-Butyl 3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)-5-fluoropiperidine-1-carboxylate: A solution of tert-butyl 3-[[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino]-5-fluoropiperidine-1-carboxylate (450.00 mg, 0.725 mmol) in MeOH (10.00 mL, 45.800 mmol) containing NH3(g) was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo to afford tert-butyl 3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)-5-fluoropiperidine-1-carboxylate (300 mg, 97.35%) as a yellow solid.

[0244] tert-Butyl 3-([8-Carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)-5-fluoropiperidine-1-carboxylate: tert-Butyl 3-([8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)-5-fluoropiperidine-1-carboxylate (280.00 mg, 0.659 mmol) and 4-[[4-(4,4,5,5-tetramethyl-1,3 To a solution of [1,4-dioxaborolan-2-yl]phenyl]methyl]morpholine (300.00 mg, 0.940 mmol) in 1,4-dioxane (9.00 mL, 106.237 mmol) and H2O (1.71 mL, 94.919 mmol) were added K3PO4 (420.00 mg, 1.880 mmol) and AMPHOS-PdCl2 (48.00 mg, 0.064 mmol). After stirring at 100°C under a nitrogen atmosphere for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to afford tert-butyl 3-([8-carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)-5-fluoropiperidine-1-carboxylate (310 mg, 38.25%) as a brown solid.

[0245] 4-[[(3S,5R)-5-fluoropiperidin-3-yl]amino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide: The crude product (4-[(5-fluoropiperidin-3-yl)amino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (135.00 mg, 0.290 mmol) was purified by chiral preparative HPLC using the following conditions: (Agela high pressure fast): column, CHIRALPAK IG, 3*25 cm, 5 μm; mobile phase, MTBE (10 mM NH3-MEOH) and EtOH (maintained at 50% EtOH within 30 minutes); detector, UV 254nm; to provide 4-[[(3S,5R)-5-fluoropiperidin-3-yl]amino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (24.1mg, 17.25%, white solid), 4-[[(3S,5S)-5-fluoropiperidin-3-yl]amino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (16.4mg, 11.41%, white solid) [3,2-d]pyrimidine-8-carboxamide (7.8 mg, 17.7%; white solid), 4-[[(3R,5R)-5-fluoropiperidin-3-yl]amino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (11.4 mg, 7.72%; white solid), and 4-[[(3R,5S)-5-fluoropiperidin-3-yl]amino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (23.5 mg, 17.29%; white solid).

[0246] Isomer 1: HPLC: 96.6% purity, RT = 2.37 min. MS: m / z = 466.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6,ppm)10.02(d,J=3.7Hz,1H),8.85(s,1H),8.59(s,1H),8.53(d ,J=8.8Hz,1H),8.34-8.29(m,2H),8.23(d,J=3.6Hz,1H),7.52(d,J=8.1Hz,2H),4.83 -4.58(m,1H),4.41(d,J=7.6Hz,1H),3.60(dd,J=9.4,4.8Hz,6H),3.14-2.95(m,2H), 2.77-2.64(m,2H),2.41(t,J=4.7Hz,4H),2.30(d,J=19.3Hz,1H),2.16-2.03(m,1H).

[0247] Isomer 2: HPLC: 93.9% purity, RT = 2.92 min. MS: m / z = 466.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6,ppm)10.01(d,J=3.7Hz,1H),8.82(s,1H),8.57(s,1H),8.33(dd,J=12.2,8.6Hz, 3H),8.20(d,J=3.9Hz,1H),7.49(d,J=8.1Hz,2H),4.94-4.55(m,2H),3.57(dd,J=9.5,4.8Hz,7H),3.10 -2.91(m,2H),2.81-2.71(m,1H),2.66(d,J=15.8Hz,1H),2.38(dd,J=5.6,3.7Hz,4H),2.25-2.09(m,2H).

[0248] Isomer 3: HPLC: 91.3% purity, RT = 2.67 min. MS: m / z = 466.3 [M+H] + . 1 H NMR(300MHz,DMSO-d6,ppm)10.04(d,J=3.7Hz,1H),8.85(s,1H),8.59(s,1H) ,8.36(dd,J=14.4,8.5Hz,3H),8.23(d,J=3.7Hz,1H),7.51(d,J=8.0Hz,2H),4 .87(d,J=48.0Hz,1H),4.61(d,J=10.2Hz,1H),3.60(dd,J=9.7,5.0Hz,6H),3. 09-2.96(m,2H),2.83-2.69(m,2H),2.40(t,J=4.7Hz,4H),2.25-2.09(m,2H).

[0249] Isomer 4: HPLC: 99.3% purity, RT = 3.32 min. MS: m / z = 466.2 [M+H] + . 1H NMR(300MHz,DMSO-d6,ppm)10.02(d,J=3.5Hz,1H),8.85(s,1H),8.65-8.49(m,2H),8.35-8.21(m,3H),7.52(d,J=8.2Hz,2H),4.83-4.60(m,1 H),4.47-4.36(m,1H),3.60(dd,J=9.5,4.8Hz,6H),3.15-2.94(m,2H),2.77-2.64(m,2H),2.41(dd,J=5.7,3.5Hz,5H),2.09(t,J=10.3Hz,1H). Example 27: Synthesis of Compound 27: 6-(4-[[(2S)-2-methylmorpholin-4-yl]methyl]phenyl)-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide dihydrochloride

[0250] tert-Butyl (3S)-3-([8-carbamoyl-6-[4-(hydroxymethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate: To a solution of tert-butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (500.00 mg, 0.880 mmol) and 4-(hydroxymethyl)phenylboronic acid (224.00 mg, 1.400 mmol) in 1,4-dioxane (8.00 mL) and H2O (1.60 mL) were added K3PO4 (781.00 mg, 3.495 mmol, 3.97 equiv, 95.0%) and AMPHOS-PdCl2 (87.00 mg, 0.117 mmol). After stirring 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 eluting with CH 2 Cl 2 / MeOH (10:1) to provide (3S)-tert-butyl 3-([8-carbamoyl-6-[4-(hydroxymethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (420 mg, 98.25%) as a yellow solid.

[0251] Tert-Butyl (3S)-3-([8-carbamoyl-6-[4-(chloromethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate: A solution of tert-butyl (3S)-3-([8-carbamoyl-6-[4-(hydroxymethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (300.00 mg, 0.275 mmol), MsCl (109.19 mg, 0.906 mmol), and TEA (128.61 mg, 1.207 mmol) in DCM (4.00 mL, 47.098 mmol) was stirred at 100° C. under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. This afforded tert-butyl (3S)-3-([8-carbamoyl-6-[4-(chloromethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (250 mg, 56.08%) as a yellow solid.

[0252] tert-Butyl (3S)-3-[[8-carbamoyl-6-(4-[[(2S)-2-methylmorpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylate: A solution of tert-butyl (3S)-3-([8-carbamoyl-6-[4-(chloromethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (100.00 mg, 0.095 mmol), (2S)-2-methylmorpholine (40.04 mg, 0.376 mmol), and TEA (80.02 mg, 0.751 mmol) in DCM (2.00 mL, 23.548 mmol) was stirred at 40° C. under nitrogen for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (1:1) to afford (3S)-tert-butyl 3-[[8-carbamoyl-6-(4-[[(2S)-2-methylmorpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylate (50 mg, 93.73%) as a yellow oil.

[0253] 6-(4-[[(2S)-2-methylmorpholin-4-yl]methyl]phenyl)-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide dihydrochloride: A solution of (3S)-tert-butyl 3-[[8-carbamoyl-6-(4-[[(2S)-2-methylmorpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylate (45.00 mg, 0.080 mmol) in HCl (g) in 1,4-dioxane (1.00 mL, 12%) was stirred at 25° C. under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions: (#2 SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase, water (0.05% HCl) and ACN (35% phase B up to 55% over 8 minutes); detector, UV 254 nm. This yielded 6-(4-[[(2S)-2-methylmorpholin-4-yl]methyl]phenyl)-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide dihydrochloride (5.9 mg, 12.40%) as a yellow solid.

[0254] HPLC: 95.0% purity, RT = 4.52 min. MS: m / z = 462.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.95(s,1H),8.69(s,1H),8.55(d,J=8.0Hz,2H),7.84(d,J=8.1Hz,2H),4.74(d,J=10.6Hz,1H),4.54-4.28(m,2H ),4.05-3.76(m,3H),3.35-3.16(m,5H),3.06(t,J=11.2Hz,1H),2.82(q,J=13.2,12.0Hz,2H),2.09-1.64(m,4H),1.11(d,J=6.3Hz,3H). Example 28: Synthesis of Compound 29: 6-[4-[1-(morpholin-4-yl)cyclopropyl]phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide

[0255] 4-[1-(4-Bromophenyl)cyclopropyl]morpholine: In a 30 mL sealed tube was placed 1-(4-bromophenyl)cyclopropan-1-amine (1 g, 4.479 mmol), MeCN (20.00 mL, 462.835 mmol), DIEA (3.05 g, 22.419 mmol), and 1-bromo-2-(2-bromoethoxy)ethane (1.31 g, 5.366 mmol). The resulting solution was stirred in an oil bath at 120°C for 4 h. The resulting mixture was concentrated. The residue was applied to a silica gel column and purified by ethyl acetate / petroleum ether (1:10-1:4). This afforded 4-[1-(4-bromophenyl)cyclopropyl]morpholine (800 mg, 63.23%) as an off-white solid.

[0256] 4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]morpholine: In a 30 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 4-[1-(4-bromophenyl)cyclopropyl]morpholine (800 mg, 2.832 mmol), 1,4-dioxane (15.00 mL, 161.736 mmol), BPD (1135.60 mg, 4.248 mmol), KOAc (877.77 mg, 8.497 mmol), and Pd(dppf)Cl2.CHCl2 (243.46 mg, 0.283 mmol). The mixture was stirred overnight at 100°C in an oil bath. The resulting mixture was concentrated. The residue was applied to a silica gel column and purified by ethyl acetate / petroleum ether (1:10-1:4). This afforded 4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]morpholine (700 mg, 71.01%) as a light brown solid.

[0257] (3S)-3-[(8-Carbamoyl-6-[4-[1-(morpholin-4-yl)cyclopropyl]phenyl]pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester: To (3S)-3-([8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylic acid tert-butyl ester (80.00 mg, 0.138 mmol) and 4-[1-[4-(4,4,5,5-tetramethyl To a solution of [1,3,2-dioxaborolan-2-yl]phenyl]cyclopropyl]morpholine (150.00 mg, 0.431 mmol) in 1,4-dioxane (8.00 mL, 94.433 mmol) and H2O (1.43 mL, 79.377 mmol) was added K3PO4 (120.00 mg, 0.537 mmol) and AMPHOS-PdCl2 (16.00 mg, 0.021 mmol). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (12:1) to afford tert-butyl (3S)-3-[(8-carbamoyl-6-[4-[1-(morpholin-4-yl)cyclopropyl]phenyl]pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (50 mg, 63.05%) as a brown solid.

[0258] 6-[4-[1-(morpholin-4-yl)cyclopropyl]phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide: A solution of (3S)-tert-butyl 3-[(8-carbamoyl-6-[4-[1-(morpholin-4-yl)cyclopropyl]phenyl]pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1 carboxylate (40.00 mg, 0.044 mmol) in HCl (g) in 1,4-dioxane (5.00 mL, 16.456 mmol) was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions: (#2 SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD column, 5 μm, 19*150 mm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in water]) and ACN (25% phase B up to 55% over 8 minutes); detector, UV 254 nm. 6-[4-[1-(morpholin-4-yl)cyclopropyl]phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide (10 mg, 44.95%) was obtained as a yellow solid.

[0259] HPLC: 93.5% purity, RT = 4.03 min. MS: m / z = 474.3 [M+H] + . 1 H NMR (300MHz, methanol-d4, ppm) 8.96 (d, J=0.8Hz, 1H), 8.56 (d, J=0.7Hz, 1H), 8.28 (d, J= 8.2Hz,2H),7.51(d,J=8.3Hz,2H),4.45-4.37(m,1H),3.64(t,J=4.6Hz,4H),3.27 (d,J=3.9Hz,1H),2.99(d,J=12.7Hz,1H),2.86-2.71(m,2H),2.61(t,J=4.7Hz,4H ), 2.14 (s, 1H), 1.92-1.68 (m, 3H), 1.06 (q, J = 4.1, 3.6Hz, 2H), 1.01-0.86 (m, 2H). Example 29: Synthesis of Compound 30 4-[[(3R)-4,4-difluoropiperidin-3-yl]amino]-6-(4-[[(3R,5S)-3,5-dimethylmorpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0260] tert-Butyl (3R)-3-[[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino]-4,4-difluoropiperidine-1-carboxylate: To a stirred solution of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (1.5 g, 5.150 mmol) and tert-butyl (3R)-3-amino-4,4-difluoropiperidine-1-carboxylate (1.536 mg, 6.180 mmol) in DMSO (15.00 mL) was added DIEA (2.802 g, 20.600 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 40°C under nitrogen for 3 h. The reaction was quenched by the addition of water (60 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (2x30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (7:3) to provide (3R)-3-[[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino]-4,4-difluoropiperidine-1-carboxylic acid tert-butyl ester (1.56 g, 65.70%) as a yellow solid.

[0261] tert-Butyl (3R)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)-4,4-difluoropiperidine-1-carboxylate: A solution of tert-butyl (3R)-3-[[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino]-4,4-difluoropiperidine-1-carboxylate (1.50 g, 1.727 mmol) in MeOH (30.00 mL) containing NH3(g) was stirred at 40°C for 1 h. The resulting mixture was concentrated in vacuo to afford tert-butyl (3R)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)-4,4-difluoropiperidine-1-carboxylate (1.0 g, crude, 54.80%) as a brown solid.

[0262] tert-Butyl (3R)-3-([8-Carbamoyl-6-[4-(hydroxymethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)-4,4-difluoropiperidine-1-carboxylate: A solution of tert-butyl (3R)-3-([8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)-4,4-difluoropiperidine-1-carboxylate (840.00 mg, 1.584 mmol) and 4-(hydroxymethyl)phenylboronic acid (435.00 mg, 2.719 mmol), AMPHOS-PdCl2 (134.00 mg, 0.180 mmol), K3PO4 (1.20 g, 5.369 mmol) in 1,4-dioxane (10.00 mL) and H2O (2.00 mL) was stirred at 100°C under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography using PE / EtOAc (1:1) as eluent to provide tert-butyl (3R)-3-([8-carbamoyl-6-[4-(hydroxymethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)-4,4-difluoropiperidine-1-carboxylate (830 mg, 99.91%) as a brown solid.

[0263]

[0148] tert-Butyl (3R)-3-([8-carbamoyl-6-[4-(chloromethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)-4,4-difluoropiperidine-1-carboxylate: To a stirred solution of tert-butyl (3R)-3-([8-carbamoyl-6-[4-(hydroxymethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)-4,4-difluoropiperidine-1-carboxylate (240.00 mg, 0.448 mmol) and TEA (0.13 mL, 0.889 mmol) in DCM (6.00 mL) at 0°C under argon was added MsCl (81.08 mg, 0.672 mmol) dropwise. The resulting mixture was stirred at room temperature under argon overnight. The resulting mixture was concentrated in vacuo. This afforded tert-butyl (3R)-3-([8-carbamoyl-6-[4-(chloromethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)-4,4-difluoropiperidine-1-carboxylate (210 mg, 58.72%) as a light yellow solid.

[0264] tert-Butyl (3R)-3-[[8-Carbamoyl-6-(4-[[(3R,5S)-3,5-dimethylmorpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino]-4,4-difluoropiperidine-1-carboxylate: A solution of tert-butyl (3R)-3-([8-Carbamoyl-6-[4-(chloromethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)-4,4-difluoropiperidine-1-carboxylate (150.00 mg, 0.134 mmol) and (3R,5S)-3,5-dimethylmorpholine (46.71 mg, 0.385 mmol) and K2CO3 (77.92 mg, 0.536 mmol) in ACN (2.00 mL) was stirred at 70 °C under nitrogen atmosphere for 32 h. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:10) to afford tert-butyl (3R)-3-[[8-carbamoyl-6-(4-[[(3R,5S)-3,5-dimethylmorpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino]-4,4-difluoropiperidine-1-carboxylate (60 mg, 70.29%) as a yellow oil.

[0265] 4-[[(3R)-4,4-difluoropiperidin-3-yl]amino]-6-(4-[[(3R,5S)-3,5-dimethylmorpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: A solution of tert-butyl (3R)-3-[[8-carbamoyl-6-(4-[[(3R,5S)-3,5-dimethylmorpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino]-4,4-difluoropiperidine-1-carboxylate (55.00 mg, 0.086 mmol) and HCl (g) in 1,4-dioxane (2.00 mL) was stirred at 25° C. under nitrogen for 2 h. The precipitated solid was collected by filtration and washed with 1,4-dioxane (3×10 mL). The crude solid was dissolved in water and basified with saturated NaHCO3 (aqueous solution) to pH = 9. The resulting mixture was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 4-[[(3R)-4,4-difluoropiperidin-3-yl]amino]-6-(4-[[(3R,5S)-3,5-dimethylmorpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide (19.6 mg, 43.85%) as a white solid.

[0266] HPLC: 99.0% purity, RT = 4.429 min. MS: m / z = 512.25 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ9.89(s,1H),8.85(s,1H),8.65(s,1H),8.32-8.15(m,4H),7.59(d,J=8.0Hz,2H),4.95-4.80(m,1H),3.84(s,2H) ,3.71-3.67(s,1H),3.63-3.61(m,1H),3.20-3.07(m,1H),2.98(d,J=11.4Hz,3H),2.83-2.63(m,2H),2.71(s,5H),0.88(d,J=6.2Hz,6H). Example 30: Synthesis of Compound 31 6-[4-(morpholin-4-ylmethyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide

[0267] 3-Amino-6-chloropyridine-2-carboxamide: To a mixture of 6-chloro-3-nitropyridine-2-carbonitrile (182.00 g, 793.244 mmol) in THF [tetrahydrofuran] (1800.11 mL) was added NH4Cl (210 g, 37391.034 mmol) and Fe (336.20 g, 5719.223 mmol) in water (2000 mL) at room temperature. The mixture was stirred at 50 ° C for 1 h. The resulting mixture was filtered and the filter cake was washed with EtOAc (2x2000 mL). The combined organic layer was washed with NaHCO3 (aqueous solution) and brine (2x3000 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 3-amino-6-chloropyridine-2-carboxamide (137 g, 79.82%) as a light reddish-brown solid.

[0268] 3-Amino-4-bromo-6-chloropyridine-2-carboxamide: To a stirred mixture of 3-amino-6-chloropyridine-2-carboxamide (50.00 g, 276.839 mmol) in DMF (500.00 mL, 6460.876 mmol) was added portionwise NBS (62.24 g, 332.207 mmol) at room temperature. The resulting mixture was stirred at 50°C under a nitrogen atmosphere for 3 h. The resulting mixture was filtered, and the filter cake was washed with PE (3 x 500 mL). The organic layer was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 1500 mL). The combined organic layers were washed with brine (4 x 1000 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to afford 3-amino-4-bromo-6-chloropyridine-2-carboxamide as a brown solid (47 g, 61.20%).

[0269] 8-Bromo-6-chloropyrido[3,2-d]pyrimidin-4(3H)-one: A solution of 3-amino-4-bromo-6-chloropyridine-2-carboxamide (65.00 g; 232.25 mmol) in triethyl orthoformate (600.00 ml) was stirred at 150°C under a nitrogen atmosphere for 16 hours. The precipitated solid was collected by filtration and washed with PE (3 x 1000 mL). The resulting solid was dried under reduced pressure in an oven. This gave 8-bromo-6-chloropyrido[3,2-d]pyrimidin-4(3H)-one (45.00 g, crude product) as a yellow solid.

[0270] 6-Chloro-4-oxo-3H,4H-pyrido[3,2-d]pyrimidine-8-carboxylic acid: To a flask was added AcO (100.00 ml) and HCOOH (20.71 ml; 521.51 mmol). The mixture was heated to 50°C for 30 min. The resulting mixture was slowly added to a flask containing 8-bromo-6-chloro-3H,4H-pyrido[3,2-d]pyrimidin-4-one (25.00 g; 86.92 mmol), Pd(AcO) (1.08 g; 4.35 mmol), XantPhos (5.29 g; 8.69 mmol), and DIEA (17.73 g; 130.38 mmol) in DMF (200.00 ml) at 75°C. The resulting mixture was heated to 100°C and stirred overnight. The mixture was allowed to cool to room temperature. The pH of the mixture was adjusted to 10-11 with NaOH (aqueous solution, 4N) at 0°C. The solid was removed by filtration. The filtrate was extracted with EtOAc (500mL x 3). The aqueous layer was then adjusted to pH 2 and extracted with EA. The organic layer was dried over Na2SO4 and concentrated in vacuo. This gave 6-chloro-4-oxo-3H, 4H-pyrido [3,2-d] pyrimidine-8-carboxylic acid (12.40g, crude product) as a brownish-black oil.

[0271] 6-chloro-4-oxo-3H-pyrido[3,2-d]pyrimidine-8-carboxylic acid methyl ester: To a stirred solution of 6-chloro-4-oxo-3H-pyrido[3,2-d]pyrimidine-8-carboxylic acid (7.30 g, 25.370 mmol) in MeOH (70.00 mL, 2184.685 mmol) was added H2SO4 (0.50 mL, 9.193 mmol) dropwise at room temperature. The mixture was stirred at 60 ° C for 4-8 h. When the reaction was complete, it was quenched by adding ice-cold water (200 mL). The precipitated solid was collected by filtration and dried to provide 6-chloro-4-oxo-3H-pyrido[3,2-d]pyrimidine-8-carboxylic acid methyl ester (6.5 g, 55.60%) as a yellow solid.

[0272] 4,6-Dichloropyrido[3,2-d]pyrimidine-8-carboxylic acid methyl ester: To a stirred solution of 6-chloro-4-oxo-3H-pyrido[3,2-d]pyrimidine-8-carboxylic acid methyl ester (7.30 g, 15.842 mmol) in SOCl2 (50.00 mL, 420.289 mmol) was added DMF (3 drops) at room temperature. The resulting mixture was stirred at 80 ° C for 3 h. The resulting mixture was concentrated in vacuo to provide 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylic acid methyl ester (6.5 g, 93.17%) as a yellow solid.

[0273] Tert-Butyl (3S)-3-[[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylate: A solution of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (5.30 g, 14.890 mmol), tert-butyl (3S)-3-aminopiperidine-1-carboxylate (4.90 g, 23.242 mmol), and DIEA (13.00 g, 95.556 mmol) in CHCN (50.00 mL) was stirred at 40° C. for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford tert-butyl (3S)-3-[[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylate (7.8 g, 96.73%) as a yellow solid.

[0274] tert-Butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate: A solution of tert-butyl (3S)-3-[[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylate (6.10 g, 11.264 mmol) in MeOH (20.00 mL, 152.622 mmol, 7 mol / L) containing NH3(g) was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo to afford tert-butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (6.5 g, 88.08%) as a yellow solid.

[0275] (3S)-3-([8-Carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylic acid tert-butyl ester: To the reaction mixture was added tert-butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (7.50 g, 17.198 mmol) and 4-[[4-(4,4,5,5-tetramethyl-1, To a solution of [3,2-dioxaborolan-2-yl]phenyl]methyl]morpholine (5.98 g, 18.736 mmol) in 1,4-dioxane (50.00 mL) and H₂O (10.00 mL, 555.084 mmol, 32.28 equivalents, 100%) was added K₃PO₄ (11.26 g, 50.391 mmol) and AMPHOS-PdCl₂ (1.54 g, 0.003 mmol). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 h. The resulting mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 400 mL) and dried over anhydrous Na₂SO₄. 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, ACN in water, 60% to 70% gradient over 10 minutes; detector, UV 254 nm. This afforded tert-butyl (3S)-3-([8-carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (6.5 g, 69.01%) as a yellow solid.

[0276] 6-[4-(Morpholin-4-ylmethyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide: A mixture of (3S)-tert-butyl 3-([8-carbamoyl-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (7.00 g, 12.782 mmol) in HCl(g) in 1,4-dioxane (50.00 mL, 12%) was stirred at room temperature for 2 h. The precipitated solid was collected by filtration and washed with 1,4-dioxane (3 x 100 mL). The crude solid was dissolved in water and basified with saturated NaHCO(aq) to pH 9. The resulting mixture was extracted with CHCl (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave 6-[4-(morpholin-4-ylmethyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide (5.5658 g, 96.91%) as a yellow solid.

[0277] HPLC: 99.6% purity, RT = 3.580 min. MS: m / z = 448.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6, ppm) δ10.06(d,J=3.7Hz,1H),8.83(s,1H),8.56(s,1H),8.36(d,J=8.6Hz,1H),8.27(dd,J= 16.1,5.8Hz,3H),7.50(d,J=7.9Hz,2H),4.30(m,J=8.8,4.8Hz,1H),3.60(t,J=4.6Hz,4H),3.56(s,2H),3.05(dd, J=12.0,3.8Hz,1H),2.82(m,J=12.6,4.2Hz,1H),2.74(dd,J=11.7,8.6Hz,1H),2.67(s,1H),2.58(t,J=10.3Hz,1H ), 2.39 (t, J = 4.6Hz, 4H), 1.94-1.88 (m, 1H), 1.82 (t, J = 8.9, 4.4Hz, 1H), 1.69 (d, J = 13.6Hz, 1H), 1.56-1.43 (m; 1H). Example 31: Synthesis of Compound 32 6-[4-(morpholin-4-ylmethyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide

[0278] tert-Butyl (3S)-3-([8-carbamoyl-6-[4-(trifluoromethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate: To a solution of tert-butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (5.00 g, 11.969 mmol) and 4-(trifluoromethoxy)phenylboronic acid (3113.51 mg, 14.363 mmol) in 1,4-dioxane (50.00 mL) and H2O (10.00 mL) were added K3PO4 (8023.28 mg, 35.908 mmol) and AMPHOS-PdCl2 (892.13 mg, 1.197 mmol). The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 h, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2:3) to provide (3S)-tert-butyl 3-([8-carbamoyl-6-[4-(trifluoromethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (3.5 g, 53.81%) as a yellow solid.

[0279] 4-[(3S)-Piperidin-3-ylamino]-6-[4-(trifluoromethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide: A solution of (3S)-tert-butyl 3-([8-carbamoyl-6-[4-(trifluoromethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (3.50 g, 6.099 mmol) in MeOH (35.00 mL, 12%) containing HCl (g) was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The crude product was recrystallized from EtOAc (30 mL) to afford 4-[(3S)-piperidin-3-ylamino]-6-[4-(trifluoromethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (1.9177 g, 68.03%) as a light yellow solid.

[0280] HPLC: 98.8% purity, RT = 5.54 min. MS: m / z = 433.2 [M+H] + . 1H NMR(300MHz,DMSO-d6,ppm)δ10.00(d,J=3.6Hz,1H),8.82(s,1H),8.55(s,1H),8.50-8.41(m,3H),8.37-8.22(m,1H),7.56-7.47(m,2H) ,4.26(m,J=8.9,4.8Hz,1H),3.03(dd,J=12.0,4.1Hz,1H),2.85-2.69(m,2H),2.60-2.50(m,1H),1.91-1.74(m,3H),1.74-1.61(m,1H). Example 32: 4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)-6-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0281] 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyrrolidin-3-ol: To a stirred mixture of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.20 g; 4.76 mmol) and pyrrolidin-3-ol (0.64 g; 7.14 mmol) in DMSO (20.00 ml) was added KCO (1.38 g; 9.52 mmol) at room temperature. After stirring at 90°C for 3 h, the resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (3:1) to provide 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyrrolidin-3-ol as a brown oil (700 mg; 44.68%).

[0282] Methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate: To a solution of methyl 6-chloro-4-oxo-3H,4H-pyrido[3,2-d]pyrimidine-8-carboxylate (10 g; 12.80 mmol) in thionyl chloride (80 mL) was added dropwise DMF (0.5 mL). The resulting mixture was stirred at 80°C for 4 h, at which point the mixture became a clear solution. The resulting mixture was concentrated under reduced pressure and co-evaporated four times with DCM. This afforded methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate as a light brown solid (8 g; 79.6%).

[0283] (3S,5S)-tert-Butyl 3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate: To a stirred solution of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (6.5 g; 22.67 mmol) and tert-butyl (3S,5S)-3-amino-5-fluoropiperidine-1-carboxylate (5.21 g; 22.67 mmol) in MeCN (60.00 ml) was added portionwise iPrNEt (12.17 ml; 68.01 mmol) at room temperature under N2. The resulting mixture was stirred at 40°C under N2 for 2 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (150 mL) and dried over anhydrous NaSO. The resulting mixture was concentrated under reduced pressure to provide tert-butyl (3S,5S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate as a brown solid (12.1 g; crude product).

[0284] tert-Butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate: A stirred solution of tert-butyl (3S,5S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (10 g; 18.26 mmol) in MeOH containing NH3 (50 ml; 350.00 mmol) was stirred at 40°C for 4 hours. The resulting mixture was concentrated under reduced pressure to afford tert-butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate as a brown solid (8.5 g; crude product).

[0285] tert-Butyl (3S,5S)-3-({8-carbamoyl-6-[6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl]pyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate: tert-Butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (150 mg; 0.28 mmol) and 1-[5 To a stirred mixture of -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyrrolidin-3-ol (136.4 mg; 0.41 mmol) in dioxane-1,4 (5 ml) and water (1 ml) were added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (20.58 mg; 0.03 mmol) and K3PO4 (185.06 mg; 0.83 mmol). After stirring at 100° C. under argon atmosphere for 2 h, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to provide (3S,5S)-3-({8-carbamoyl-6-[6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl]pyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylic acid tert-butyl ester as a yellow solid (130 mg; 64.11%).

[0286] 4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)-6-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)pyrido[3,2-d]pyrimidine-8-carboxamide: To a solution of tert-butyl (3S,5S)-3-({8-carbamoyl-6-[6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl]pyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (120.00 mg; 0.16 mmol) in DCM (5.00 ml) was added TFA (1.00 ml). After stirring at 25°C for 2 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; mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7% B to 37% B over 8 minutes, 37% B; wavelength: 254 / 220 nm; RT1 (min): 5.6; number of runs: 2) to afford 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-[6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl]pyrido[3,2-d]pyrimidine-8-carboxamide as an orange-yellow solid (28 mg; 35.2%).

[0287] HPLC 92% purity, 9.02 min. MS: m / z = 453.20 [M+H] + .

[0288] 1H NMR(400MHz,DMSO-d6):10.03(d,J=3.7Hz,1H),9.24(d,J=2.5Hz,1H),8.73(s,1H),8.5 3(s,1H),8.46(dd,J=9.0,2.5Hz,1H),8.36(d,J=9.0Hz,1H),8.20(d,J=3.9Hz,1H),6.57 (d,J=9.0Hz,1H),5.05(s,1H),4.98(s,1H),4.44(s,1H),3.62-3.54(m,3H),3.08(dt,J= 15.8,7.9Hz,2H),2.86-2.69(m,2H),2.27-2.19(m,2H),2.18-2.00(m,2H),1.93(s,1H). Example 33: 6-(3,5-difluoro-4-((1-hydroxycyclobutyl)methoxy)phenyl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0289] (1-Hydroxycyclobutyl)methyl 4-methylbenzene-1-sulfonate: To a stirred mixture of 1-(hydroxymethyl)cyclobutan-1-ol (1 g; 9.30 mmol) in DCM (5 ml) at 0°C were added portionwise TEA (4.09 ml; 27.98 mmol) and DMAP (0.12 g; 0.93 mmol). 4-Methylbenzene-1-sulfonyl chloride (2.06 g; 10.26 mmol) in DCM (5.00 ml) was then added dropwise to the mixture at 0°C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water at 0°C. The mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 15% EA in PE to afford (1-hydroxycyclobutyl)methyl 4-methylbenzene-1-sulfonate as a white solid (1.8 g; 69.1%).

[0290] 1-[(4-Bromo-2,6-difluorophenoxy)methyl]cyclobutan-1-ol: To a stirred solution of (1-hydroxycyclobutyl)methyl 4-methylbenzene-1-sulfonate (900 mg; 3.21 mmol) and 4-bromo-2,6-difluorophenol (560 mg; 2.55 mmol) in DMF (5 ml) was added portionwise potassium carbonate (1.07 g; 7.35 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C under a nitrogen atmosphere overnight. Water was added to the reaction. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. 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, ACN in water, 55% to 65% gradient over 10 minutes; detector, UV 220 nm to afford 1-[(4-bromo-2,6-difluorophenoxy)methyl]cyclobutan-1-ol as a yellow oil (550 mg; 55.6%).

[0291] 1-{[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclobutan-1-ol: To a stirred mixture of 1-[(4-bromo-2,6-difluorophenoxy)methyl]cyclobutan-1-ol (200 mg; 0.65 mmol) and BPD (245 mg; 0.92 mmol) in dioxane-1,4-dioxane (5 ml) was added portionwise KOAc (165 mg; 1.60 mmol) and Pd(dppf)Cl2 (50 mg; 0.06 mmol) at room temperature. The resulting mixture was stirred at 100°C under nitrogen for 1 h. The resulting mixture was concentrated to provide 1-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclobutan-1-ol as a brown solid (200 mg; crude product).

[0292] (3S,5S)-3-[(8-carbamoyl-6-{3,5-difluoro-4-[(1-hydroxycyclobutyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylic acid tert-butyl ester: At room temperature and N2 atmosphere, (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylic acid tert-butyl ester (140 mg; 0.26 To a stirred solution of 1-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclobutan-1-ol (176 mg; 0.25 mmol) in dioxane-1,4-dioxane (4.5 ml) and water (1.5 ml) were added portionwise Pd(AMPHOS)Cl2 (195 mg; 0.26 mmol) and tripotassium phosphate (22 mg; 0.10 mmol). The resulting mixture was stirred at 100°C under a N2 atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 40% EA in PE to afford tert-butyl (3S,5S)-3-[(8-carbamoyl-6-{3,5-difluoro-4-[(1-hydroxycyclobutyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylate as an orange solid (200 mg; 87.3%).

[0293] 6-{3,5-Difluoro-4-[(1-hydroxycyclobutyl)methoxy]phenyl}-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of (3S,5S)-tert-butyl 3-[(8-carbamoyl-6-{3,5-difluoro-4-[(1-hydroxycyclobutyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylate (180 mg; 0.20 mmol) in DCM (3 ml) was added TFA (1 ml) dropwise at 0°C. The resulting mixture was stirred at room temperature under nitrogen for 1 hour. 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 NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B over 8 minutes, 50% B; wavelength: 254 nm; RT1 (min): 7; number of runs: 4) to provide 6-{3,5-difluoro-4-[(1-hydroxycyclobutyl)methoxy]phenyl}-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (93.90 mg; 85.8%).

[0294] HPLC 93% purity, 3.35 min. MS: m / z = 503.00 [M+H] +1 H NMR (DMSO, 400MHz): δ9.93 (d, 1H, J = 3.6Hz), 8.82 (s, 1H), 8.58 (s, 1H), 8.50 (d, 1H, J = 8.8Hz), 8.24 (m, 3H), 5.27 (s, 1H), 4.8 9(d,1H,J=47.9Hz),4.63(dt,1H,J=10.1,5.1,5.1Hz),4.16(s,2H),2.89(m,4H),2.61(s,1H),2.12(m,6H),1.63(m,2H)ppm. Example 34: 4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)-6-(4-((1-hydroxycyclopropyl)methoxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0295] Methyl 2-(4-bromophenoxy)acetate: To a stirred solution of 4-bromophenol (9.50 g; 52.17 mmol) and methyl 2-bromoacetate (10.08 g; 62.60 mmol) in DMF (40 ml) was added portionwise potassium carbonate (11.38 g; 78.25 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere overnight. 500 ml of water was added to the reaction. The mixture was extracted with EA (3 x 250 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to provide methyl 2-(4-bromophenoxy)acetate as a brown liquid (11.32 g; crude product).

[0296] 1-[(4-Bromophenoxy)methyl]cyclopropan-1-ol: To a stirred mixture of methyl 2-(4-bromophenoxy)acetate (11.32 g; 45.68 mmol) in THF (110.00 ml) at 0°C were added dropwise Ti(Oi-Pr) (13.18 g; 44.05 mmol) and (ethyl)magnesium bromide (41.76 ml; 125.28 mmol). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water at 0°C. The resulting mixture was filtered, and the filter cake was washed with EA (3 x 20 ml). The filtrate was extracted with EA (3 x 60 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 13% EA in PE to afford 1-[(4-bromophenoxy)methyl]cyclopropan-1-ol as a white solid (4.67 g; 40.3%).

[0297] 1-{[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopropan-1-ol: To a stirred mixture of 1-[(4-bromophenoxy)methyl]cyclopropan-1-ol (4.67 g; 18.40 mmol) and BPD (9.77 g; 36.55 mmol) in dioxane-1,4-dioxane (30 ml) was added portionwise KOAc (5.68 g; 54.98 mmol) and Pd(dppf)Cl2 (1.42 g; 1.84 mmol) at room temperature. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 15% EA in PE. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 45% to 50% gradient over 10 minutes; detector, UV 254 nm to provide 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopropan-1-ol as a white solid (1.70 g; 26.4%).

[0298] (3S,5S)-3-[(8-carbamoyl-6-{4-[(1-hydroxycyclopropyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylic acid tert-butyl ester: At room temperature under N2 atmosphere, (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylic acid tert-butyl ester (300 mg; 0. To a stirred solution of 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopropan-1-ol (513 mg; 1.47 mmol) in dioxane-1,4-dioxane (5 ml) and water (0.5 ml) were added K3PO4 (600 mg; 2.69 mmol) and Pd(dppf)Cl2 (47 mg; 0.07 mmol) portionwise. The resulting mixture was stirred at 80°C under N2 atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 80% EA in PE to afford tert-butyl (3S,5S)-3-[(8-carbamoyl-6-{4-[(1-hydroxycyclopropyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylate as a yellow solid (200 mg; 36.4%).

[0299] 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-{4-[(1-hydroxycyclopropyl)methoxy]phenyl}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of (3S,5S)-tert-butyl 3-[(8-carbamoyl-6-{4-[(1-hydroxycyclopropyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylate (180 mg; 0.18 mmol) in DCM (3 ml) was added TFA (1 ml) dropwise at 0°C. The resulting mixture was stirred at room temperature under nitrogen for 1 hour. 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 NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18% B to 44% B over 9 minutes, 44% B; wavelength: 254 nm; RT1 (min): 7; number of runs: 3) to provide 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-{4-[(1-hydroxycyclopropyl)methoxy]phenyl}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (42.7 mg; 50.1%).

[0300] HPLC 96% purity, 6.13 min. MS: m / z = 453.05 [M+H] + .

[0301] 1H NMR (400MHz, DMSO, 24℃) δ0.56–0.81(m,4H),1.96–2.39(m,2H),2.51(s,1H),2.65–3.17(m,4H),4.07(s,2H),4.60(dq,J=14.0,9.3,7.2Hz,1H),4. 87(d,J=48.1Hz,1H),5.64(s,1H),7.06–7.21(m,2H),8.21(d,J=3.8Hz,1 H), 8.28–8.49 (m, 3H), 8.55 (s, 1H), 8.80 (s, 1H), 10.05 (d, J = 3.7Hz, 1H). Example 35: 4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)-6-(4-((1-hydroxycyclopentyl)methoxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0302] 4-Methylbenzene-1-sulfonic acid (1-hydroxycyclopentyl)methyl ester: To a stirred mixture of 1-(hydroxymethyl)cyclopentan-1-ol (500.00 mg; 4.09 mmol) and TsCl (1230.97 mg; 6.13 mmol) in DCM (15.00 ml) at 25° C. was added DMAP (55.00 mg; 0.41 mmol) dropwise. The resulting mixture was stirred at 25° C. under a nitrogen atmosphere for 12 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE:EA=8:2 to provide 4-methylbenzene-1-sulfonic acid (1-hydroxycyclopentyl)methyl ester as a yellow oil (800 mg; 72.4%).

[0303] 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopentan-1-ol: To a stirred mixture of (1-hydroxycyclopentyl)methyl 4-methylbenzene-1-sulfonate (492 mg; 1.55 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (300 mg; 1.30 mmol) in DMF (15 ml) was added KCO (565 mg; 3.88 mmol) portionwise at 25° C. The resulting mixture was stirred at 25° C. under nitrogen for 12 h. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to provide 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopentan-1-ol as a yellow oil (300 mg; crude product).

[0304] tert-Butyl (3S,5S)-3-[(8-carbamoyl-6-{4-[(1-hydroxycyclopentyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylate: 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopentan-1-ol (250 mg; 0.50 mmol) and ( To a stirred mixture of tert-butyl 3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (270 mg; 0.50 mmol) in DMF (10 ml) was added portionwise Pd(AmPhos)Cl (37 mg; 0.05 mmol), KPO (333 mg; 1.49 mmol), and H O (2 ml). The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE:EA=1:1 to afford tert-butyl (3S,5S)-3-[(8-carbamoyl-6-{4-[(1-hydroxycyclopentyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylate as a yellow solid (200 mg; 55.6%).

[0305] 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-{4-[(1-hydroxycyclopentyl)methoxy]phenyl}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of (3S,5S)-tert-butyl 3-[(8-carbamoyl-6-{4-[(1-hydroxycyclopentyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylate (180 mg; 0.25 mmol) in DCM (8 ml) was added TFA (2 ml) portionwise at 25°C. The resulting mixture was stirred at 25°C under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions: column: YMC-Actus Triart C18 ExRS, 20*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B over 8 minutes, 55% B; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) to provide 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-{4-[(1-hydroxycyclopentyl)methoxy]phenyl}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (64.40 mg; 53.2%).

[0306] HPLC 98% purity, 2.98 min. MS: m / z = 481.05 [M+H] + .

[0307] 1 H NMR (400MHz, DMSO, 23℃) δ1.56-1.84(m,8H),2.06-2.27(m,2H),2.56-2.86(m,3H),2.94-3.14(m,2H),3.97(s,2H),4.61(d,J=11.9Hz,2H),4.87 (d,J=47.9Hz,1H),7.11(d,J=8.5Hz,2H),8.23(d,J=3.8Hz,1H),8.35(dd,J=8.5,5.5Hz,3H),8.56(s,1H),8.81(s,1H),10.06(d,J=3.7Hz,1H). Example 36: 6-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0308] tert-Butyl (3S,5S)-3-{[8-carbamoyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate: tert-Butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (120 mg; 0.22 mmol) was added to the mixture at room temperature. To a stirred mixture of 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (63.33 mg; 0.27 mmol) in dioxane-1,4-dioxane (10 ml) and H2O (2 ml) were added Pd(AmPhos)Cl2 (16.47 mg; 0.02 mmol) and K3PO4 (148.09 mg; 0.66 mmol). After stirring at 100°C under argon atmosphere for 2 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (12:1) to afford tert-butyl (3S,5S)-3-{[8-carbamoyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate as a yellow solid (110 mg; 90.38%).

[0309] 6-(1-Cyclopropyl-1H-pyrazol-4-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: A mixture of tert-butyl (3S,5S)-3-{[8-carbamoyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (140.00 mg; 0.25 mmol) and TFA (1.00 ml) in DCM (6.00 ml) was stirred at room temperature for 1 h, and then the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 ExRS, 20*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 45% B over 8 minutes, 45% B; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) to provide 6-(1-cyclopropyl-1H-pyrazol-4-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (38.5 mg; 38.06%).

[0310] HPLC 99% purity, 2.16 min. MS: m / z = 397.20 [M+H]+ .

[0311] 1 H NMR(400MHz,DMSO-d6):10.01(d,J=3.7Hz,1H),8.78(s,1H),8.55(d,J=17.5H z,2H),8.41(s,1H),8.23-8.16(m,2H),4.94-4.82(s,1H),4.58(dd,J=13.2,7. 6Hz, 1H), 3.83 (tt, J=7.5, 3.9Hz, 1H), 3.05 (ddd, J=25.9, 13.3, 7.6Hz, 2H), 2. 71(d,J=12.3Hz,2H),2.26-2.12(m,2H),1.20-1.12(m,2H),1.12-0.99(m,2H). Example 37: 6-(3,5-difluoro-4-((4-hydroxytetrahydro-2H-pyran-4-yl)methoxy)phenyl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0312] 4-[(4-Bromo-2,6-difluorophenoxy)methyl]oxan-4-ol: To a stirred mixture of 4-bromo-2,6-difluorophenol (1.00 g; 4.55 mmol) and 1,6-dioxaspiro[2.5]octane (1.64 g; 13.64 mmol) in DMF (15.00 ml) was added KCO (1.98 g; 13.64 mmol) at room temperature. After stirring at 80°C for 24 h, the resulting mixture was extracted with EtOAc and quenched with water. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with PE / EtOAc (7:3) to provide 4-[(4-bromo-2,6-difluorophenoxy)methyl]tetrahydropyran-4-ol as a light yellow oil (1.45 g; 33.94%).

[0313] 4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}tetrahydropyran-4-ol: To a stirred mixture of 4-[(4-bromo-2,6-difluorophenoxy)methyl]tetrahydropyran-4-ol (1.40 g; 1.51 mmol) and BPD (1.21 g; 4.53 mmol) in dioxane-1,4-ol (20.00 ml) was added KOAc (0.49 g; 4.53 mmol) and Pd(dppf)Cl2 (0.12 g; 0.15 mmol) at room temperature. After stirring at 100 °C under argon atmosphere for 3 h, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to afford 4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}tetrahydropyran-4-ol as a yellow solid (750 mg; 99.47%).

[0314] tert-Butyl (3S,5S)-3-[(8-carbamoyl-6-{3,5-difluoro-4-[(4-hydroxytetrahydropyran-4-yl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylate: tert-Butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (130.00 mg; 0.24 mmol) and 4-{[2, To a stirred mixture of 6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}tetrahydropyran-4-ol (155.20 mg; 0.31 mmol) in dioxane-1,4- (5.00 ml) and water (1.00 ml) were added K3PO4 (160.39 mg; 0.72 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (17.84 mg; 0.02 mmol). After stirring at 100° C. under argon atmosphere for 2 h, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (7:3) to provide (3S,5S)-3-[(8-carbamoyl-6-{3,5-difluoro-4-[(4-hydroxytetrahydropyran-4-yl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylic acid tert-butyl ester as a yellow solid (125.00 mg; 68.07%).

[0315] 6-{3,5-Difluoro-4-[(4-hydroxytetrahydropyran-4-yl)methoxy]phenyl}-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a solution of tert-butyl (3S,5S)-3-[(8-carbamoyl-6-{3,5-difluoro-4-[(4-hydroxytetrahydropyran-4-yl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylate (120.00 mg; 0.16 mmol) in DCM (3.00 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 and purified by preparative HPLC (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B over 8 minutes, 50% B; wavelength: 254 nm; RT1 (min): 7; number of runs: 3) to provide 6-{3,5-difluoro-4-[(4-hydroxytetrahydropyran-4-yl)methoxy]phenyl}-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (63.3 mg; 74.58%).

[0316] HPLC 98% purity, 2.72 min. MS: m / z = 533.25 [M+H] + .

[0317] 1 H NMR (300MHz, DMSO-d6): 9.90 (s, 1H), 8.82 (s, 1H), 8.57 (s, 1H), 8.49 (d, J = 8.8Hz, 1H), 8.32 -8.19(m,3H),4.94(s,1H),4.76(d,J=13.7Hz,1H),4.60(s,1H),4.01(s,2H),3.65(d,J=8.1Hz,4H),3.02 (t,J=14.8Hz,2H),2.71-2.57(m,2H),2.23(s,2H),1.77(dt,J=16.2,8.2Hz,2H),1.47(d,J=13.7Hz,2H). Example 38: 4-(((3R,4S)-4-fluoropiperidin-3-yl)amino)-6-(4-(2-hydroxy-2-methylpropyloxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0318] 1-(4-Bromophenoxy)-2-methylpropan-2-ol: To a solution of 4-bromophenol (10.00 g; 54.91 mmol) and 2,2-dimethyloxirane (6.25 g; 82.34 mmol) in DMF (100.00 ml) was added portionwise potassium carbonate (23.95 g; 164.63 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 140° C. under a nitrogen atmosphere for 3 h. Water (500 mL) was added to the resulting mixture. The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (1×500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to provide 1-(4-bromophenoxy)-2-methylpropan-2-ol as a yellow oil (13.40 g, crude product).

[0319] 2-Methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol: To a stirred mixture of 1-(4-bromophenoxy)-2-methylpropan-2-ol (13.00 g; 51.31 mmol) and BPD (27.43 g; 102.62 mmol) in dioxane-1,4-dioxane (130.00 ml) was added portionwise KOAc (15.90 g; 153.92 mmol) and PCl2 (3.95 g; 5.13 mmol) at room temperature. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 8% EA in PE to afford 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol as a yellow solid (9.32 g; 59.0%).

[0320] Tert-butyl (3R,4S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-4-fluoropiperidine-1-carboxylate: To a stirred mixture of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (520 mg; 1.61 mmol) and tert-butyl (3R,4S)-3-amino-4-fluoropiperidine-1-carboxylate (488.00 mg; 2.12 mmol) in MeCN (7 ml) was added dropwise DIEA (1.06 ml; 5.79 mmol) at room temperature. The resulting mixture was stirred at 40°C under a nitrogen atmosphere for 1 hour. 25 ml of water was added to the resulting mixture, and the mixture was extracted with EA (3 x 15 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20% EA in PE to afford tert-butyl (3R,4S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-4-fluoropiperidine-1-carboxylate as a yellow solid (600 mg; 54.4%).

[0321] tert-Butyl (3R,4S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate: A stirred mixture of tert-butyl (3R,4S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-4-fluoropiperidine-1-carboxylate (580 mg; 0.85 mmol) in MeOH (10 ml) containing NH3 was stirred at 40°C for 1 h. The resulting mixture was concentrated under reduced pressure to afford tert-butyl (3R,4S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate as an orange solid (440 mg; crude product).

[0322] tert-Butyl (3R,4S)-3-({8-carbamoyl-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate: tert-Butyl (3R,4S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate (150 mg; To a stirred solution of 1,4-dioxane (4 ml) and 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol (124 mg; 0.40 mmol) in dioxane (4 ml) and water (0.40 ml) was added PCl2 (26 mg; 0.03 mmol) and tripotassium phosphate (225 mg; 1.01 mmol) portionwise. The resulting mixture was stirred at 100°C under N2 atmosphere for 2 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 dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with 75% EtOAc in PE to afford tert-butyl (3R,4S)-3-({8-carbamoyl-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate as a yellow solid (140.00 mg 84.06%).

[0323] 4-{[(3R,4S)-4-Fluoropiperidin-3-yl]amino}-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred solution of tert-butyl (3R,4S)-3-({8-carbamoyl-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate (120 mg; 0.20 mmol) in dichloromethane (3 mL) was added dropwise TFA (1 mL) at 0°C under N2. The resulting mixture was stirred at room temperature under N2 for 30 minutes. The resulting mixture 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 NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B over 9 minutes, 50% B; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) to provide 4-{[(3R,4S)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-hydroxy-2-methylpropyloxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (56.70 mg; 60.22%).

[0324] HPLC 98%, 2.90min. M / S:m / z=455.15. 1 H-NMR (300MHz, DMSO-d6)9.98(d,J=3.8Hz,1H),8.82(s,1H),8.60(s,1H),8.27(d,J=8.4Hz,3H),8.11(d,J=8.7Hz,1H),7.14(d,J=8.4Hz,2H), 5.10(d,J=50.5Hz,1H),4.62(d,J=53.1Hz,2H),3.84(s,2H),3.35(s,1H ), 2.98 (s, 2H), 2.78 (d, J = 16.3Hz, 2H), 2.00-1.89 (m, 2H), 1.25 (s, 6H). Example 39: (S)-6-(3,5-difluoro-4-((1-hydroxycyclobutyl)methoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0325] tert-Butyl (3S)-3-[(8-carbamoyl-6-{3,5-difluoro-4-[(1-hydroxycyclobutyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate: tert-Butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (150 mg; 0.30 mmol) and To a stirred mixture of 1-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclobutan-1-ol (157 mg; 0.29 mmol) in H₂O (3 ml) and 1,4-dioxane (10 ml) was added portionwise K₃PO₄ (235 mg; 1.05 mmol) and PCl₂ (26 mg; 0.03 mmol). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 40% EA in PE to afford tert-butyl (3S)-3-[(8-carbamoyl-6-{3,5-difluoro-4-[(1-hydroxycyclobutyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate as a yellow solid (190 mg; 99.0%).

[0326] 6-{3,5-difluoro-4-[(1-hydroxycyclobutyl)methoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of (3S)-tert-butyl 3-[(8-carbamoyl-6-{3,5-difluoro-4-[(1-hydroxycyclobutyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (170 mg; 0.27 mmol) in DCM (3 ml) was added TFA (1 ml) dropwise at 0°C. The resulting mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: (column: Xselect CSH OBD column 30*150mm 5um; mobile phase A: water (10mmol / L NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60mL / min; gradient: 23% B to 53% B over 10 minutes, 53% B; wavelength: 254nm; RT1 (min): 7.58; number of runs: 2) to provide 6-{3,5-difluoro-4-[(1-hydroxycyclobutyl)methoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (79.70mg, 59.0%).

[0327] HPLC: 95%, 3.43min. M / S:m / z=455.15. 1 H NMR(400MHz, DMSO-d6)9.95(d,J=3.6Hz,1H),8.80(s,1H),8.56(s,1H),8.48(d,J=8.6Hz,1H),8.28-8.15( m,3H),5.28(s,1H),4.31(qt,J=9.1,3.9Hz,1H),4.15(s,2H),3.08(dd,J=11.9,4.0Hz,1H),2.88(dt,J=12 .6,3.7Hz,1H),2.74(dd,J=11.8,9.4Hz,1H),2.56(d,J=11.2Hz,1H),2.51(s,1H),2.17(tt,J=8.9,3.1Hz, 2H), 2.12-1.92 (m, 3H), 1.91-1.78 (m, 1H), 1.71 (qd, J=6.7, 4.7, 3.2Hz, 2H), 1.56 (dd, J=11.3, 8.8Hz, 2H). Example 40: 6-(4-(2-cyano-2-hydroxypropyloxy)phenyl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0328] 1-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-one: To a stirred mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5 g; 21.58 mmol) and 1-chloropropan-2-one (2.1 ml; 25.90 mmol) in acetone (40 ml) at 25°C was added KCO (9.42 g; 64.75 mmol) portionwise. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 12 h. The reaction was quenched with H2O at 25°C. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 column chromatography eluting with ACN:H2O=80:20 to afford 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-one as a yellow solid (2 g; 31.8%).

[0329] tert-Butyl (3S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}piperidine-1-carboxylate: To a mixture of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (3.1 g; 9.87 mmol) and tert-butyl (3S)-3-aminopiperidine-1-carboxylate (2.29 g; 10.86 mmol) in ACN (30 ml) was added ethylbis(propan-2-yl)amine (4.03 g; 29.61 mmol). After stirring at 40°C under nitrogen for 2 h, the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (70:30) to afford tert-butyl (3S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}piperidine-1-carboxylate as a yellow solid (2.8 g; 64.6%).

[0330] Tert-butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate: A mixture of tert-butyl (3S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl}amino}piperidine-1-carboxylate (2.80 g; 6.37 mmol) in MeOH (20 ml) containing NH3(g) was stirred at 40°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. This afforded tert-butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate as a light yellow solid (2.30 g; 85.9%).

[0331] tert-Butyl (3S)-3-({8-carbamoyl-6-[4-(2-oxopropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate: 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-one (220 mg; 0.76 mmol) and (3S)-3- To a stirred mixture of tert-butyl ({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (250 mg; 0.50 mmol) in dioxane-1,4-dioxane (8 ml) was added portionwise PCl (37.41 mg; 0.05 mmol), KPO (336.45 mg; 1.51 mmol), and H O (2 ml). The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE:EA = 4:6 to provide tert-butyl (3S)-3-({8-carbamoyl-6-[4-(2-oxopropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate as a yellow solid (250 mg; 92.5%).

[0332] 6-(4-{2-cyano-2-methyl-2-[(trimethylsilyl)oxy]ethoxy}phenyl)-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of tert-butyl (3S)-3-({8-carbamoyl-6-[4-(2-oxopropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (250 mg; 0.46 mmol) and TMSCN (97 mg; 0.93 mmol) in DCM (10 ml) was added ZnI (156 mg; 0.46 mmol) in portions at 25°C. The resulting mixture was stirred at 25°C under nitrogen for 12 h. The reaction was quenched with H2O at room temperature. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO 4. After filtration, the filtrate was concentrated under reduced pressure to provide 6-(4-{2-cyano-2-methyl-2-[(trimethylsilyl)oxy]ethoxy}phenyl)-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (200 mg; crude product).

[0333] 6-[4-(2-Cyano-2-hydroxy-2-methylethoxy)phenyl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide hydrochloride: To a stirred mixture of 6-(4-{2-cyano-2-methyl-2-[(trimethylsilyl)oxy]ethoxy}phenyl)-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (200 mg; 0.30 mmol) in THF (5.00 ml) was added dropwise HCl (5 ml; 10.00 mmol) at 25°C. The resulting mixture was stirred at 25°C under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by the following method: column: Xselect CSHOBD column 30*150mm 5um; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60mL / min; gradient: 5% B to 20% B over 10 minutes, 20% B; wavelength: 254nm; RT1 (min): 9.37; number of runs: 2) to provide 6-[4-(2-cyano-2-hydroxy-2-methylethoxy)phenyl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide hydrochloride as a yellow solid (52.50mg; 36.0%).

[0334] HPLC: 99%, 2.89min. M / S:m / z=448.2. 1 H NMR (400MHz, DMSO-d6): 9.72 (s, 2H), 9.51 (s, 2H), 8.98 (d, J = 3.1Hz, 1H), 8.76 (d, J = 1.9Hz, 1H),8.58(dd,J=9.0,3.0Hz,2H),8.43(s,1H),7.25-7.18(m,2H),4.86(s,1H),4.22(q,J=9 .8Hz,2H),3.40(d,J=11.0Hz,1H),3.28(d,J=14.1Hz,2H),2.82(d,J=11.4Hz,1H),2.51(p, J=1.9Hz,1H),2.08(s,1H),1.97(s,1H),1.93(td,J=26.4,23.8,10.9Hz,1H),1.64(s,3H). Example 41: (S)-6-(4-((1-hydroxycyclopentyl)methoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0335] tert-Butyl (3S)-3-[(8-carbamoyl-6-{4-[(1-hydroxycyclopentyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate: To 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopentan-1-ol (500 mg; 0.68 mmol) and tert-butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (200 mg; 0.40 mmol) were added to a mixture of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopentan-1-ol (500 mg; 0.68 mmol) and (3S)-3-[(8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (200 mg; 0.40 mmol) in DMF (12 ml) at 25°C was added 1% paraformaldehyde. To the stirred mixture in 4% HCl was added Pd(AMPHOS)Cl2 (30 mg; 0.04 mmol.), K3PO4 (270 mg; 1.21 mmol.) and H2O (3 ml) portionwise. 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 eluting with PE:EA=1:1 to provide (3S)-tert-butyl 3-[(8-carbamoyl-6-{4-[(1-hydroxycyclopentyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate as a yellow solid (180 mg; 68.0%).

[0336] 6-{4-[(1-hydroxycyclopentyl)methoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of tert-butyl (3S)-3-[(8-carbamoyl-6-{4-[(1-hydroxycyclopentyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (150 mg; 0.23 mmol) in DCM (5 ml) was added TFA (1 ml) dropwise at 25°C. The resulting mixture was stirred at 25°C under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. The crude product was purified by the following method: column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B over 8 minutes, 55% B; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) to provide 6-{4-[(1-hydroxycyclopentyl)methoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (51.6 mg; 48.8%).

[0337] HPLC: 99%, 3.54min. M / S:m / z=463.25. 1H NMR(400MHz,DMSO-d6):10.07(d,J=3.7Hz,1H),8.80(s,1H),8.54(s,1H),8.32(dd ,J=8.4,5.4Hz,3H),8.22(d,J=3.8Hz,1H),7.15-7.08(m,2H),4.63(s,1H),4.28(dq ,J=9.4,5.1,4.6Hz,1H),3.97(s,2H),3.05(dd,J=11.8,3.8Hz,1H),2.82(dt,J=12. 8,4.0Hz,1H),2.73(dd,J=11.7,8.6Hz,1H),2.61-2.51(m,2H),2.01-1.24(m,12H). Example 42: 4-(((3R,4R)-4-fluoropiperidin-3-yl)amino)-6-(4-(2-hydroxy-2-methylpropyloxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0338] 1-(4-Bromophenoxy)-2-methylpropan-2-ol: To a solution of 4-bromophenol (10.00 g; 54.91 mmol) and 2,2-dimethyloxirane (6.25 g; 82.34 mmol) in DMF (100.00 ml) was added portionwise potassium carbonate (23.95 g; 164.63 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 140° C. under a nitrogen atmosphere for 3 h. Water (500 mL) was added to the resulting mixture. The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (1×500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to provide 1-(4-bromophenoxy)-2-methylpropan-2-ol as a yellow oil (13.40 g; crude product).

[0339] 2-Methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol: To a stirred mixture of 1-(4-bromophenoxy)-2-methylpropan-2-ol (13.00 g; 51.31 mmol) and BPD (27.43 g; 102.62 mmol) in dioxane-1,4-dioxane (130.00 ml) was added portionwise KOAc (15.90 g; 153.92 mmol) and Pd(dppf)Cl2 (3.95 g; 5.13 mmol) at room temperature. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 8% EA in PE to afford 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol as a yellow solid (9.32 g; 59.0%).

[0340] tert-Butyl (3R,4R)-3-({8-carbamoyl-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate: tert-Butyl (3R,4R)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate (160 mg; 0.25 mmol) was added to the mixture at room temperature. To a stirred mixture of 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol (221 mg; 0.72 mmol) in 1,4-dioxane (10 ml) and H2O (1 ml) was added portionwise K3PO4 (160 mg; 0.72 mmol) and Pd(AMPHOS)Cl2 (27 mg; 0.04 mmol). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 50% EA in PE to afford tert-butyl (3R,4R)-3-({8-carbamoyl-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate as a yellow solid (140 mg; 95.5%).

[0341] 4-{[(3R,4R)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of tert-butyl (3R,4R)-3-({8-carbamoyl-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate (120 mg; 0.20 mmol) in DCM (3 ml) at 0°C was added TFA (1 ml) dropwise. The resulting mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was concentrated under reduced pressure. 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 NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 40% B over 8 minutes, 40% B; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) to provide 4-{[(3R,4R)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-hydroxy-2-methylpropyloxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (58 mg; 60.4%).

[0342] HPLC: 96%, 3.06min. M / S:m / z=455.05. 1 H NMR (400MHz, DMSO-d6)10.03(d,J=3.8Hz,1H),8.83(s,1H),8.66-8.48(m,2H),8.38(d ,J=8.5Hz,2H),8.22(d,J=3.6Hz,1H),7.13(d,J=8.5Hz,2H),5.15-4.90(m,1H),4.69( s,1H),4.59-4.37(m,1H),3.84(s,2H),3.33(s,1H),3.21-3.09(m,1H),3.01(d,J=12. 8Hz, 1H), 2.67 (d, J = 11.1Hz, 1H), 2.55 (s, 1H), 2.15 (s, 1H), 1.63 (s, 1H), 1.25 (s, 6H). Example 43: (S)-6-(3,5-difluoro-4-((4-hydroxytetrahydro-2H-pyran-4-yl)methoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0343] 4-[(4-Bromo-2,6-difluorophenoxy)methyl]tetrahydropyran-4-ol: To a stirred mixture of 4-bromo-2,6-difluorophenol (1 g; 4.55 mmol) and 1,6-dioxaspiro[2.5]octane (1.64 g; 13.64 mmol) in DMF (15.00 ml) was added KCO (1.98 g; 13.64 mmol) at room temperature. After stirring at 80°C for 24 h, the resulting mixture was extracted with EtOAc and quenched with water. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with PE / EtOAc (7:3) to afford 4-[(4-bromo-2,6-difluorophenoxy)methyl]tetrahydropyran-4-ol as a light yellow oil (1.45 g; 33.94%).

[0344] 4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}tetrahydropyran-4-ol: To a stirred mixture of 4-[(4-bromo-2,6-difluorophenoxy)methyl]tetrahydropyran-4-ol (1.4 g; 1.51 mmol) and BPD (1.21 g; 4.53 mmol) in dioxane-1,4-dioxane (20 ml) was added KOAc (0.49 g; 4.53 mmol) and Pd(dppf)Cl2 (0.12 g; 0.15 mmol) at room temperature. The mixture was stirred at 100°C under an argon atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to provide 4-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}tetrahydropyran-4-ol as a yellow solid (750 mg; 99.47%).

[0345] tert-Butyl (3S)-3-[(8-Carbamoyl-6-{3,5-difluoro-4-[(4-hydroxytetrahydropyran-4-yl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate: tert-Butyl (3S)-3-({8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (160 mg; 0.39 mmol) and 4-{[2,6-difluoro- To a stirred mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}tetrahydropyran-4-ol (388 mg; 0.78 mmol) in dioxane-1,4-ol (10 ml) and water (2 ml) were added K 3 PO 4 (260.69 mg; 1.17 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (29 mg; 0.04 mmol). After stirring at 100° C. under argon atmosphere for 2 h, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (4:1) to provide (3S)-3-[(8-carbamoyl-6-{3,5-difluoro-4-[(4-hydroxytetrahydropyran-4-yl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester as a dark green solid (230 mg; 78.13%).

[0346] 6-{3,5-difluoro-4-[(4-hydroxytetrahydropyran-4-yl)methoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a solution of tert-butyl (3S)-3-[(8-carbamoyl-6-{3,5-difluoro-4-[(4-hydroxytetrahydropyran-4-yl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (220 mg; 0.29 mmol) in DCM (5 ml) was added TFA (1 ml) at room temperature. After stirring at room temperature for 1 h, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with CHCl / MeOH (1:1). The crude product was purified by preparative HPLC (column: Xselect CSH OBD column 30*150mm 5um; mobile phase A: water (10mmol / L NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60mL / min; gradient: 16% B to 46% B over 10 minutes, 46% B; wavelength: 254nm; RT1 (min): 8.25; number of runs: 2) to afford 6-{3,5-difluoro-4-[(4-hydroxytetrahydropyran-4-yl)methoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (67.5mg; 45.06%).

[0347] HPLC: 99%, 3.03min. M / S:m / z=515.20. 1 H NMR (300MHz, DMSO-d6): 9.91 (s, 1H), 8.81 (s, 1H), 8.55 (s, 1H), 8.47 (d, J = 8.6Hz, 1H), 8.29 -8.17(m,3H),4.72(s,1H),4.31(s,1H),4.01(s,2H),3.70-3.61(m,3H),3.05(d,J=12.1Hz,1H ), 2.85 (d, J = 12.4Hz, 2H), 2.52 (s, 2H), 1.91 (s, 1H), 1.85-1.65 (m, 4H), 1.48 (d, J = 12.8Hz, 3H). Example 44: (S)-6-(4-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0348] [(4-Bromophenyl)methyl]magnesium bromide: Under a nitrogen atmosphere, a flame-dried 250 mL three-necked round-bottom flask equipped with a dropping funnel and a reflux condenser was charged with active magnesium (0.7 g; 27.37 mmol) and 5 mL of anhydrous Et2O. The dropping funnel was charged with 1-bromo-4-(bromomethyl)benzene (6 g; 22.81 mmol) in anhydrous Et2O (65 mL). A few drops of 1,2-dibromoethane (0.9 g; 4.56 mmol) were added to the reaction flask to initiate the reaction, and the bromide was added dropwise to maintain a steady reflux. The addition was completed within 30 minutes. The solution was then cooled and concentrated under reduced pressure to provide [(4-bromophenyl)methyl]magnesium bromide as a gray solution (6.5 g; 83.1%).

[0349] 4-[(4-Bromophenyl)methyl]tetrahydropyran-4-ol: To a stirred solution of tetrahydropyran-4-one (1.3 g; 12.34 mmol) in THF (20 ml) at 0°C under N2 atmosphere was added dropwise a solution of [(4-bromophenyl)methyl]magnesium bromide (6.50 g; 18.96 mmol) in Et2O. The resulting mixture was stirred at 0°C under N2 atmosphere for 2 h. The resulting mixture was diluted with water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (150 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified on a silica gel column eluting with 15% EtOAc in PE to provide the crude product. The crude product was purified by C18 flash column eluting with 80% ACN in water to afford 4-[(4-bromophenyl)methyl]tetrahydropyran-4-ol as a white solid (800 mg; 15.56%).

[0350] 4-{[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]methyl}tetrahydropyran-4-ol: To a stirred solution of 4-[(4-bromophenyl)methyl]tetrahydropyran-4-ol (780.00 mg; 2.01 mmol) and BPD (1030.06 mg; 4.02 mmol) in dioxane-1,4-ol (6.00 ml) was added portionwise at room temperature under N2. The resulting mixture was stirred at 100°C under N2 overnight. 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 dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure.The residue was purified by silica gel column eluting with 35% EtOAc in PE to provide 4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}tetrahydropyran-4-ol as a colorless oil (700 mg; 97.97%).

[0351] {4-[(4-Fluorotetrahydropyran-4-yl)methyl]phenyl}boronic acid: To a stirred solution of 4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}tetrahydropyran-4-ol (650 mg; 1.83 mmol) in DCM (5 mL) was added dropwise DAST (1.24 g; 7.31 mmol) in DCM (30 ml) at -78°C under N2. The resulting mixture was stirred at -78°C under N2 for 1.5 h. The reaction was quenched with water and the mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide {4-[(4-fluorotetrahydropyran-4-yl)methyl]phenyl}boronic acid as a yellow oil (650 mg; 71.01%).

[0352] tert-Butyl (3S)-3-[(8-carbamoyl-6-{4-[(4-fluorotetrahydropyran-4-yl)methyl]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate: To a stirred solution of (3S)-tert-butyl 3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (200 mg; 0.44 mmol), {4-[(4-fluorotetrahydropyran-4-yl)methyl]phenyl}boronic acid (554.32 mg; 1.11 mmol) and K3PO4 (30 mg; 0.13 mmol) in dioxane-1,4 (6 ml) and water (1.5 ml) was added portionwise bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (4 mg; 0.01 mmol) at room temperature. The resulting mixture was stirred at 100°C under a N2 atmosphere for 2 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 dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure.

[0353] The residue was purified by silica gel column eluting with 75% EtOAc in PE to afford tert-butyl (3S)-3-[(8-carbamoyl-6-{4-[(4-fluorotetrahydropyran-4-yl)methyl]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate as a yellow solid (160 mg; 61.81%).

[0354] 6-{4-[(4-fluorotetrahydropyran-4-yl)methyl]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred solution of (3S)-tert-butyl 3-[(8-carbamoyl-6-{4-[(4-fluorotetrahydropyran-4-yl)methyl]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (140 mg; 0.24 mmol) in DCM (3.00 ml) was added dropwise TFA (1.00 ml). The resulting mixture was stirred at 25° C. under N atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18 column, 19*250 mm, 5 um; mobile phase A: water (10 mmol / l NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20B to 60B over 8 minutes, 254 nm; RT1: 6.5; number of injection runs: 2); to provide 6-{4-[(4-fluorotetrahydropyran-4-yl)methyl]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a white solid (60.50 mg; 54.01%).

[0355] HPLC: 99% purity, 4.564 min. MS: m / z = 465.20 [M+H] +1 H NMR(300MHz, DMSO-d6)10.05(d,J=3.6Hz,1H),8.84(s,1H),8.57(s,1H),8.37(d,J= 8.6Hz,1H),8.26(dd,J=16.2,5.8Hz,3H),7.43(d,J=7.9Hz,2H),4.30(s,1H),3.72(t ,J=7.6Hz,2H),3.52(t,J=11.4Hz,2H),3.06(d,J=23.0Hz,3H),2.77(dt,J=20.7,10 .4Hz, 2H), 2.59 (d, J = 10.8Hz, 2H), 2.00-1.75 (m, 3H), 1.61 (dt, J = 32.5, 16.5Hz, 5H). Example 45: (S)-6-(6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepine -2-yl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0356] Methyl 2-(3-bromo-5-methyl-1H-pyrazol-1-yl)acetate: To a stirred solution of 3-bromo-5-methyl-1H-pyrazole (50 g; 295.03 mmol) and KCO (77.26 g; 531.07 mmol) in DMF (500 ml) was added dropwise methyl 2-chloroacetate (51 g; 446.45 mmol) at room temperature under N2. The resulting mixture was stirred overnight at 25°C under N2. The resulting mixture was poured into water (2 L) and extracted with EtOAc (600 ml x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE:EtOAc = 7:1 to provide methyl 2-(3-bromo-5-methyl-1H-pyrazol-1-yl)acetate as a white solid (65 g; 81.83%).

[0357] Methyl 2-[3-bromo-5-(bromomethyl)-1H-pyrazol-1-yl]acetate: To a stirred solution of methyl 2-(3-bromo-5-methyl-1H-pyrazol-1-yl)acetate (25 g; 107.27 mmol) and NBS (20.1 g; 107.27 mmol) in carbon tetrachloride (500 ml) was added portionwise 2-[(1Z)-2-(1-cyano-1-methylethyl)diazen-1-yl]-2-methylpropionitrile (18.54 g; 107.27 mmol) at room temperature under N2. The resulting mixture was stirred at 80°C under N2 for 3 h. The reaction mixture was diluted with water (1 L) and extracted with DCM (3 x 400 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column eluting with EtOAc:PE=8:1 to afford methyl 2-[3-bromo-5-(bromomethyl)-1H-pyrazol-1-yl]acetate as a yellow oil (22.00 g; 46.85%).

[0358] Methyl 2-[3-bromo-5-(cyanomethyl)-1H-pyrazol-1-yl]acetate: To a stirred solution of methyl 2-[3-bromo-5-(bromomethyl)-1H-pyrazol-1-yl]acetate (22 g; 50.25 mmol) in DMSO (200 ml; 2815.82 mmol) was added portionwise sodium cyanide (3.77 g; 75.38 mmol) and water (4 ml; 219.76 mmol) at room temperature under N2. The resulting mixture was stirred at 25°C under N2 for 1 h. The resulting mixture was quenched with FeSO4 (aq) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE:EA=7:1 and concentrated to afford methyl 2-[3-bromo-5-(cyanomethyl)-1H-pyrazol-1-yl]acetate as a pale yellow solid (8.5 g; 57.01%).

[0359] 2-Bromo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -7-one: To a stirred solution of methyl 2-[3-bromo-5-(cyanomethyl)-1H-pyrazol-1-yl]acetate (1.5 g; 5.06 mmol) and cobalt chloride hexahydrate (2.46 g; 10.11 mmol) in MeOH (50 ml) was added NaBH4 (1.06 g; 25.28 mmol) portionwise at 0°C under N2 atmosphere. The resulting mixture was stirred at 25°C under N2 atmosphere for 4 h. 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 dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 2-bromo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -7-ketone was obtained as a white solid (1.1 g; 64.27%).

[0360] 2-Bromo-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -7-ketone: at room temperature, under N2 atmosphere, to 2-bromo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -7-ketone (1.1 g; 3.07 mmol) and MeI (0.4 ml; 6.15 To a stirred solution of 1.0 M potassium tert-butoxide in THF (5.99 ml; 6.15 mmol) was added a solution of 1.0 M potassium tert-butoxide in THF (5.99 ml; 6.15 mmol). The resulting mixture was stirred at 25 ° C under N2 atmosphere for 3 h. The resulting mixture was diluted with water (50 mL). The solution was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by C18 flash chromatography, washing with water containing 67% ACN to provide 2-bromo-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -7-ketone was obtained as a white solid (700.00 mg; 91.38%).

[0361] (3S)-3-[(8-Carbamoyl-6-{6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -2-yl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester: Under N2 atmosphere, to 2-bromo-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine To a stirred solution of tert-butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (259 mg; 0.60 mmol), and hexamethyldistanane (245 mg; 0.74 mmol) in 1,4-dioxane (5 ml) was added portionwise cataCXium A Pd G3 (42 mg; 0.05 mmol). The resulting mixture was stirred at 100°C under an N2 atmosphere for 6 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 dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with 75% EtOAc in PE to provide (3S)-3-[(8-carbamoyl-6-{6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine [3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester was a yellow solid (180 mg; 57.76%).

[0362] 6-{6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -2-yl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: at 0 ° C, add (3S)-3-[(8-carbamoyl-6-{6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine To a stirred solution of tert-butyl 1-[(2-yl)pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (160 mg; 0.29 mmol) in DCM (4.5 ml) was added dropwise TFA (1.5 ml). The resulting mixture was stirred at 25° C. under a N atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: Xselect CSH OBD column 30*150 mm 5 μm; mobile phase A: water (10 mmol / l NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10B to 40B over 8 minutes, 254 nm; RT1: 6.8; number of injection runs: 2); to provide 6-{6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepine -2-yl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide was an off-white solid (49.6 mg; 37.72%).

[0363] HPLC: 95% purity, 3.026 min. MS: m / z = 436.10 [M+H] +1 H NMR (400MHz, DMSO-d6)10.11(d,J=3.8Hz,1H),8.89(s,1H),8.55(s,1H),8.24(dd,J=10.0,6.2Hz,2H),7.19 (s,1H),5.23(s,2H),4.27(m,J=8.4,4.3,3.8Hz,1H),3.97-3.89(m,3H),3.21(t,J=5.9Hz,2H),3.06(dd,J= 12.1,3.8Hz,1H),3.00(s,3H),2.83(m,J=13.6,4.0Hz,1H),2.70(dd,J=11.7,8.8Hz,1H),2.57(d,J=11.9Hz ,1H),1.97-1.85(m,1H),1.79(m,J=12.7,11.4,6.8Hz,1H),1.72-1.65(m,1H),1.49(m,J=13.6,5.7Hz,1H). Example 46: (S)-6-(2-cyano-4-(2-methoxyethoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0364] 2-Bromo-5-(2-methoxyethoxy)benzonitrile: To a stirred solution of 2-bromo-5-hydroxybenzonitrile (2 g; 9.60 mmol) and 1-bromo-2-methoxyethane (2.80 g; 19.14 mmol) in DMF (20 ml) was added KCO (2.80 g; 19.25 mmol). The resulting mixture was stirred at 50°C overnight. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to provide 2-bromo-5-(2-methoxyethoxy)benzonitrile as a light yellow solid (2 g; 81.4%).

[0365] 5-(2-Methoxyethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile: To a stirred solution of 2-bromo-5-(2-methoxyethoxy)benzonitrile (1 g; 3.90 mmol) and BPD (1.50 g; 5.61 mmol) in dioxane-1,4-dioxane (10 ml) was added KOAc (1.1 g; 10.65 mmol) and Pd(dppf)Cl2 (0.3 g; 0.39 mmol). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (9:1) to provide 5-(2-methoxyethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile as a pale yellow oil (800 mg; 61.2%).

[0366] tert-Butyl (3S)-3-({8-carbamoyl-6-[2-cyano-4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate: To a stirred solution of 5-(2-methoxyethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (299 mg; 0.89 mmol), Na2CO3 (156 mg; 1.40 mmol) and tert-butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (200 mg; 0.49 mmol) in DME (3 ml) and H2O (1 ml) was added Pd(PPh3)4 (57 mg; 0.05 mmol). The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate) (2: 1) to provide (3S)-3-({8-carbamoyl-6-[2-cyano-4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylic acid tert-butyl ester as a light yellow solid (120 mg; 42.5%).

[0367] 6-[2-Cyano-4-(2-methoxyethoxy)phenyl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred solution of tert-butyl (3S)-3-({8-carbamoyl-6-[2-cyano-4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (100 mg; 0.17 mmol) in DCM (1 ml) at 0°C was added TFA (0.2 ml) dropwise. The resulting mixture was stirred at room temperature for 2 h. 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 um; mobile phase A: water (10 mmol / l NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20B to 50B over 8 minutes, 254 nm) to provide 6-[2-cyano-4-(2-methoxyethoxy)phenyl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (55.50 mg; 70.4%).

[0368] HPLC: 98% purity, 4.44 min. MS: m / z = 448.15 [M+H] + . 1 H NMR (300MHz, DMSO-d6)9.95(s,1H),8.80(s,1H),8.61(s,1H),8.23(d,J=9.1Hz, 2H),7.99(d,J=8.3Hz,1H),7.64(d,J=2.7Hz,1H),7.45(dd,J=8.9,2.7Hz,1H),4. 33-4.25(m,2H),4.22(s,1H),3.75-3.66(m,2H),3.33(s,3H),3.10(d,J=11.3Hz ,1H),2.79(d,J=12.2Hz,1H),2.65-2.51(m,2H),1.95(s,1H),1.84-1.43(m,2H). Example 47: (S)-6-(4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0369] Ethyl 2-(4-bromophenoxy)-2,2-difluoroacetate: To a solution of 4-bromophenol (3.00 g; 16.47 mmol) in DMF (10.00 ml) at room temperature was added portionwise DBU (6.63 g; 41.37 mmol). The mixture was heated to 70°C and ethyl 2-bromo-2,2-difluoroacetate (8.81 g; 41.23 mmol) was added. The resulting mixture was stirred at 70°C under nitrogen overnight. The resulting mixture was diluted with 200 ml of water and extracted with EA (3 x 150 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 4% EA in PE to provide ethyl 2-(4-bromophenoxy)-2,2-difluoroacetate as a yellow liquid (2.47 g; 50.8%).

[0370] 1-(4-Bromophenoxy)-1,1-difluoro-2-methylpropan-2-ol: To a stirred mixture of ethyl 2-(4-bromophenoxy)-2,2-difluoroacetate (2.00 g; 6.78 mmol) in THF (10.00 ml) at 0°C was added (methyl)magnesium bromide (5.67 ml; 17.01 mmol) dropwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h. The reaction was quenched with water at 0°C. The mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 8% EA in PE. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 45% to 50% gradient over 10 minutes; detector, UV 220 nm to afford 1-(4-bromophenoxy)-1,1-difluoro-2-methylpropan-2-ol as a brown liquid (1.37 g; 70.4%).

[0371] (3R)-4-Methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine: To a stirred mixture of 1-(4-bromophenoxy)-1,1-difluoro-2-methylpropan-2-ol (1.33 g; 4.63 mmol) and BPD (2.46 g; 9.20 mmol) in dioxane-1,4-dioxane (10.00 ml) was added portionwise KOAc (0.96 g; 9.29 mmol) and Pd(dppf)Cl2 (0.38 g; 0.49 mmol) at room temperature. The resulting mixture was stirred at 100°C under nitrogen for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 70% DCM in PE to afford (3R)-4-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine as a white solid (1.53 g; 86.5%).

[0372] tert-Butyl (3S)-3-({8-Carbamoyl-6-[4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate: To a solution of tert-butyl (3S)-3-((8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (230 mg; 0.53 mmol) and (4-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (279.00 mg; 0.73 mmol) in 1,4-dioxane (3 ml) and H2O was added at room temperature. To the stirred mixture in 4% HCl (0.3 ml) was added K PO (361 mg; 1.62 mmol) and Pd(AMPHOS)Cl (41.00 mg; 0.06 mmol) portionwise. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 40% EA in PE to provide tert-butyl (3S)-3-({8-carbamoyl-6-[4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate as a yellow solid (200 mg; 46.6%).

[0373] 6-[4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)phenyl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of (3S)-tert-butyl 3-({8-carbamoyl-6-[4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (190 mg; 0.23 mmol) in DCM (3 ml) was added TFA (1 ml) dropwise at 0°C. The resulting mixture was stirred at room temperature under nitrogen for 1 hour. 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 um; mobile phase A: water (10 mmol / l NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 28B to 58B over 10 minutes; 254 nm; RT1: 7.3) to provide 6-[4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)phenyl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (62.50 mg; 53.2%).

[0374] HPLC: 94% purity, 3.221 min. MS: m / z = 473.10 [M+H] + . 1 H NMR (300MHz, DMSO-d6)10.04(d,J=3.8Hz,1H),8.83(s,1H),8.56(s,1H),8.39(dd,J =12.8,8.8Hz,3H),8.22(d,J=3.7Hz,1H),7.37(d,J=8.4Hz,2H),5.57(s,1H),4.27( s,1H),3.05(dd,J=12.0,3.8Hz,1H),2.87-2.65(m,2H),2.61-2.51(m,2H),1.94-1. 86(m,1H),1.80(d,J=10.1Hz,1H),1.68(d,J=11.8Hz,1H),1.50(s,1H),1.37(s,6H). Examples 48 & 49: 4-(((3R,4R)-4-fluoropiperidin-3-yl)amino)-6-(4-(2-methoxyethoxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide and 4-(((3S,4S)-4-fluoropiperidin-3-yl)amino)-6-(4-(2-methoxyethoxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0375] Tert-butyl (3R,4R)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-4-fluoropiperidine-1-carboxylate: To a stirred mixture of methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (3 g; 9.99 mmol) and tert-butyl-3-amino-4-fluoropiperidine-1-carboxylate (trans mixture) (2.75 g; 11.98 mmol) in DMSO (20 ml) at room temperature under argon was added DIEA (4.07 g; 29.96 mmol). The resulting mixture was stirred at 60°C under argon overnight. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to afford tert-butyl (3R,4R)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-4-fluoropiperidine-1-carboxylate (3.40 g; 76.2%) as a yellow solid.

[0376] tert-Butyl (3R,4R)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate: A mixture of tert-butyl (3R,4R)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-4-fluoropiperidine-1-carboxylate (3.40 g; 7.61 mmol) and NH3(g) in MeOH (20.00 ml) was stirred overnight at 60°C under an argon atmosphere. The resulting mixture was concentrated in vacuo. This gave tert-butyl (3R,4R)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate (3.10 g; 92.5%) as a yellow solid.

[0377] tert-Butyl (3R,4R)-3-({8-carbamoyl-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate: tert-Butyl (3R,4R)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate (250 mg; 0.57 mmol) and [4-(2-methoxyethoxy)phenyl]boronic acid (175.74 mg; 0.85 mmol) were added to the mixture at room temperature. To a stirred mixture of 1,4-dioxane (10 ml) and water (2 ml) were added tert-butyl (3R,4R)-3-({8-carbamoyl-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate (310 mg; 0.40 mmol; 70.58%; yellow solid; purified product) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (42.33 mg; 0.06 mmol). After stirring at 100 °C under argon atmosphere for 2 h, the residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (19:1) to provide (3R,4R)-3-({8-carbamoyl-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester as a yellow solid (310 mg; 70.58%).

[0378] 4-{[(3R,4R)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide: A stirred mixture of tert-butyl (3R,4R)-3-({8-carbamoyl-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate (300 mg; 0.34 mmol) and TFA (5 ml) in DCM (15 ml) was stirred at room temperature. After stirring at room temperature for 1 h, the crude product was purified by preparative HPLC (column: CHIRALPAK ID, 2*25 cm, 5 um; mobile phase A: MTBE (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: IPA--HPLC; flow rate: 20 mL / min; gradient: 30B to 30B over 18 min; 220 / 254 nm; RT1: 9.301; RT2: 14.362; injection volume: 2 ml; number of runs: 5;) to afford 4-{[(3R,4R)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow-green solid (120 mg 78.83%).

[0379] 4-{[(3R,4R)-4-Fluoropiperidin-3-yl]amino}-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide & 4-{[(3S,4S)-4-Fluoropiperidin-3-yl]amino}-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide: The product 4-{[(3R,4R)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (120.00 mg; 0.27 mmol) was purified by chiral preparative HPLC. The product 4-{[(3R,4R)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (120 mg; 0.27 mmol) was purified by chiral preparative HPLC (column: CHIRALPAK ID, 2*25 cm, 5 um; mobile phase A: MTBE (0.5% 2M 3-[(4-(2-methoxyethoxy)phenyl)-4-[(3S,4S)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (45.20 mg; 37.44%) and 4-{[(3S,4S)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (37.70 mg; 31.20%).

[0380] Enantiomer 1: HPLC: 98% purity, 3.068 min. MS: m / z = 441.10 [M+H] + . 1 H NMR(300MHz,DMSO-d6):10.01(d,J=3.5Hz,1H),8.81(s,1H),8.63-8.53(m,2H ),8.43-8.33(m,2H),8.22(d,J=3.6Hz,1H),7.12(d,J=8.8Hz,2H),5.10(s,1H ),4.51(s,1H),4.25-4.16(m,2H),3.75-3.66(m,2H),3.33(s,3H),3.01(s,1H ),2.74-2.61(m,2H),2.56(d,J=12.4Hz,1H),2.15(s,1H),1.71-1.58(m,1H).

[0381] Enantiomer 2: HPLC: 98% purity, 3.070 min. MS: m / z = 441.10 [M+H] + . 1 H NMR(300MHz,DMSO-d6):10.02(d,J=3.4Hz,1H),8.81(s,1H),8.62-8.52(m,2 H),8.42-8.33(m,2H),8.22(d,J=3.5Hz,1H),7.17-7.08(m,2H),5.16-5.06(m ,1H),4.49(dd,J=12.4,7.6Hz,1H),4.25-4.16(m,2H),3.75-3.66(m,2H),3.3 3(s,3H),3.01(s,2H),2.71-2.57(m,2H),2.14(s,1H),1.64(d,J=7.2Hz,1H). Example 50: 4-(((S)-piperidin-3-yl)amino)-6-(4-(((R)-quinuclidin-3-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0382] ((3R)-3-(4-iodophenoxy)-1-azabicyclo[2.2.2]octane: To a stirred solution of (3R)-1-azabicyclo[2.2.2]octan-3-ol (10 g; 74.69 mmol) and 1,4-diiodobenzene (31.13 g; 89.63 mmol) in dry DMF (200 ml) (dried over 4A molecular sieves) was added portionwise sodium tert-butoxide (9.07 g; 89.63 mmol) and cuprous iodide (1.50 g; 7.47 mmol) at room temperature under N2 atmosphere. The resulting mixture was stirred at 80°C under N2 atmosphere for 2 days. The resulting mixture was diluted with water (1000 mL) and extracted with EtOAc (3 x 400 mL), and the combined organic layers were washed with brine (600 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column, purified by elution with 10% Purification by elution with MeOH in DCM afforded (3R)-3-(4-iodophenoxy)-1-azabicyclo[2.2.2]octane as a grey solid (3.00 g; 10.99%).

[0383] (3R)-3-[4-(Trimethylstannyl)phenoxy]-1-azabicyclo[2.2.2]octane: To a stirred solution of (3-(4-iodophenoxy)-1-azabicyclo[2.2.2]octane (1 g; 2.74 mmol) and hexamethyldistannane (1.81 g; 5.47 mmol) in toluene (15 ml) was added portionwise Pd(PPh3)4 (333 mg; 0.27 mmol) at room temperature under N2 atmosphere. The resulting mixture was stirred at 110°C under N2 atmosphere overnight. 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 dried over anhydrous Na2SO4. The residue was purified by silica gel column and washed with 10% MeOH in DCM elution afforded (3R)-3-[4-(trimethylstannyl)phenoxy]-1-azabicyclo[2.2.2]octane as a yellow oil (1.20 g; 93.32%).

[0384] (3S)-3-[(6-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester: tert-Butyl (3S)-3-[(6-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate was added to a mixture of tert-butyl 3-[(6-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate at room temperature under a nitrogen atmosphere. To a stirred solution of tert-butyl 8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (200 mg; 0.49 mmol) in DMF (5.00 ml) was added Pd(PPh3)4 (58 mg; 0.05 mmol) in portions. The resulting mixture was stirred at 100°C under N2 atmosphere for 4 h. The resulting mixture was diluted with water (15 mL) and washed with EtOAc (3 x 10 The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4. The residue was purified by silica gel column eluting with 15% MeOH in DCM to provide a crude product. The crude product was purified by preparative TLC (MeOH:DCM=1:8) to provide (3S)-3-[(6-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester as a yellow solid (80 mg; 26.16%).

[0385] 6-{4-[(3R)-1-Azabicyclo[2.2.2]oct-3-yloxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred solution of (3S)-tert-butyl 3-[(6-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (70 mg; 0.11 mmol) in DCM (3 mL) was added dropwise TFA (1 mL) at room temperature under N2. The resulting mixture was stirred at 25°C under N2 for 1 h. The reaction was concentrated under reduced pressure. 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 NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B over 8 minutes, 50% B; wavelength: 254 nm; RT1 (min): 7.0; number of runs: 2 to provide 6-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (7.50 mg; 13.84%).

[0386] HPLC: 97% purity, 3.062 min. MS: m / z = 474.15 [M+H] + . 1 H NMR(300MHz,DMSO-d6)10.05(d,J=3.8Hz,1H),8.77(s,1H),8.53(s,1H),8.4 0-8.00(m,4H),7.35-6.72(m,2H),4.75-4.46(m,1H),4.40-4.11(m,1H),3.3 5-3.18(m,2H),3.08(dd,J=23.1,9.9Hz,1H),2.91-2.54(m,8H),2.09q,J=3. 4Hz, 1H), 1.83 (m, J = 12.5, 7.5Hz, 3H), 1.74-1.41 (m, 4H), 1.41-1.27 (m, 1H). Example 51: 6-(4-((R)-2-hydroxypropyloxy)phenyl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0387] (2R)-1-(4-bromophenoxy)propan-2-ol: To a stirred solution of 4-bromophenol (2 g; 10.98 mmol) and KCO (3.20 g; 21.96 mmol) in N,N-dimethylformamide (20 ml) was added (2R)-2-methyloxirane (2.69 g; 43.93 mmol) dropwise. The mixture was stirred at 80°C for 16 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, then filtered and concentrated under reduced pressure. The crude product was purified by passing through a C18 flash column eluting with 56% ACN in water to provide (2R)-1-(4-bromophenoxy)propan-2-ol as a yellow solid (380 mg; 14.97%).

[0388] (2R)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol: To a stirred solution of (2R)-1-(4-bromophenoxy)propan-2-ol (380 mg; 1.56 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (418 mg; 1.56 mmol) in dioxane-1,4-dioxane (5 ml; 58.45 mmol) was added portionwise KOAc (307 mg; 3.13 mmol) and Pd(dppf)Cl (121 mg; 0.16 mmol) at room temperature under N2 atmosphere. The resulting mixture was stirred at 100 degrees for 2 hours. The resulting mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by C18 flash column to provide (2R)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol as a yellow solid (300 mg; 69.0%).

[0389] tert-Butyl (3S)-3-[(8-carbamoyl-6-{4-[(2R)-2-hydroxypropoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate: To a solution of tert-butyl (S)-3-((8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (200 mg; 0.46 mmol) and (2R)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol (129 mg; 0.46 mmol) in DME (10 ml) and water (3 ml) were added Na2CO3 (162 mg; 1.45 mmol) and Pd(PPh3)4 (59 mg; 0.05 mmol). After stirring at 80°C under a nitrogen atmosphere for 1 hour, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 70% EA in PE to provide tert-butyl (3S)-3-[(8-carbamoyl-6-{4-[(2R)-2-hydroxypropyloxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate as a yellow solid (200 mg; 76.8%).

[0390] 6-{4-[(2R)-2-hydroxypropoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred mixture of tert-butyl (3S)-3-[(8-carbamoyl-6-{4-[(2R)-2-hydroxypropoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (180 mg; 0.34 mmol) in DCM (3 ml) was added TFA (1 ml) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The residue was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18 column, 30×150 mm 5 um; mobile phase A: water (10 mmol / l NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26B to 56B over 9 minutes; 254 nm; RT 1: 7) to provide 6-{4-[(2R)-2-hydroxypropoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (67 mg; 45.6%).

[0391] HPLC 98% purity, 2.89 min, MS: m / s=423.15 [M+H] + . 1H NMR (300MHz, DMSO-d6): 10.05 (d, J=3.6Hz, 1H), 8.79 (s, 1H), 8.53 (s, 1H), 8.31 (d, J=8.3Hz,3H),8.20(d,J=3.6Hz,1H),7.10(d,J=8.5Hz,2H),4.92(s,1H),4.32-4.2 4(m,1H),4.02-3.85(m,3H),3.04(d,J=10.8Hz,1H),2.74(dd,J=19.5,10.1Hz,2H) ,2.57(d,J=11.4Hz,2H),1.88(s,2H),1.66(s,1H),1.50(s,1H),1.30-1.14(m,3H). Example 52: (S)-6-(4-(3-morpholinopropoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0392] 6-{4-[3-(morpholin-4-yl)propoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: (3S)-tert-butyl 3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (200 mg; 0.47 mmol) and 4-{3-[4-(4,4,5,5-tetramethyl-1-piperidin-1-yl)propoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide To a solution of 1,4-dioxaborolan-2-yl)phenoxy]propyl}morpholine (258.74 mg; 0.71 mmol) in dioxane-1,4-dioxazoline (10 ml) and H₂O (2 ml) was added K₃PO₄ (316.31 mg; 1.42 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (35.18 mg; 0.05 mmol). After stirring at 80° C. under a nitrogen atmosphere for 2 h, the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12:1) to provide 6-{4-[3-(morpholin-4-yl)propoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (196 mg; 66.2%).

[0393] 6-{4-[3-(Morpholin-4-yl)propoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: In a 50 mL round-bottom flask, 6-{4-[3-(Morpholin-4-yl)propoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (160 mg; 0.25 mmol) in 6 mL of DCM and 3 mL of TFA were added at room temperature. The mixture was stirred at room temperature for 2 h. 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 NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B over 9 minutes, 50% B; wavelength: 254 nm; RT1 (min): 7.2; number of runs: 2) to provide 6-{4-[3-(morpholin-4-yl)propoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (73.7 mg; 55.9%).

[0394] HPLC 95% purity, 2.26 min, MS: m / s=492.30 [M+H] + . 1 H NMR(300MHz,DMSO-d6):10.04(d,1H),8.77(s,1H),8.52(s,1H),8.30(dd,3H),8.20(d,1H),7.14-7.02(m,2H),4.27(dt,1H),4.10(t,2H) ),3.57(t,4H),3.02(dd,1H),2.78(s,2H),2.71(dd,1H),2.56(d,2H),2.48-2.32(m,5H),1.98-1.75(m,4H),1.67(d,1H),1.47(dd,1H). Example 53: 6-(4-((S)-1-morpholinoethyl)phenyl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0395] 4-[1-(4-bromophenyl)ethyl]morpholine: To a stirred solution of 1-(4-bromophenyl)ethanamine (3 g, 14.244 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (4.17 g, 17.093 mmol) in DMF (30 mL, 389.854 mmol) was added DIEA (5.81 g, 42.706 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere 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 (2 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:7) to afford 4-[1-(4-bromophenyl)ethyl]morpholine as a yellow oil (3.3 g, 80.18%).

[0396] 4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]morpholine: To a solution of 4-[1-(4-bromophenyl)ethyl]morpholine (2000 mg, 6.922 mmol) and BPD (2220.20 mg, 8.306 mmol) in dioxane (20 mL, 227.014 mmol) was added KOAc (2145.15 mg, 20.765 mmol) and Pd(dppf)Cl in CHCl (594.99 mg, 0.692 mmol). The mixture was stirred at 100°C under nitrogen for 2 h, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to afford 4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]morpholine as a yellow oil (2.1 g, 95.54%).

[0397] (3S)-3-[(8-Carbamoyl-6-[4-[1-(morpholin-4-yl)ethyl]phenyl]pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate: To the reaction mixture was added tert-butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (200 mg, 0.346 mmol) and 4-[1-[4-(4,4,5, To a solution of 5-tetramethyl-1,3,2-dioxaborolan-2-yl]phenyl]ethyl]morpholine (140 mg, 0.441 mmol) in 1,4-dioxane (5 mL, 59.020 mmol) and H2O (1 mL, 55.508 mmol) were added K3PO4 (232 mg, 1.038 mmol) and Pd(Amphos)Cl2 (21 mg, 0.028 mmol). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (95:5) to afford tert-butyl (3S)-3-[(8-carbamoyl-6-[4-[1-(morpholin-4-yl)ethyl]phenyl]pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate as a yellow solid (210 mg, 88.28%).

[0398] 6-{4-[1-(morpholin-4-yl)ethyl]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: A solution of tert-butyl (3S)-3-[(8-carbamoyl-6-[4-[1-(morpholin-4-yl)ethyl]phenyl]pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (200 mg, 0.291 mmol) in HCl(g) in 1,4-dioxane (2 mL, 4.204 mmol, 14.47 equiv, 12%) was stirred at room temperature under nitrogen for 1 h. The resulting mixture was concentrated in vacuo. The crude product (210 mg) was purified by preparative HPLC using the following conditions: (#2 SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 x 150 mm 5 μm; mobile phase, water (10 mmol / l NH4HCO3 + 0.05% NH4OH) and ACN (20% phase B up to 50% over 8 minutes); detector, UV 254. The product was obtained. This afforded 6-[4-[1-(morpholin-4-yl)ethyl]phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide (130 mg, 96.64%) as a light yellow solid. It was separated by chiral preparative HPLC to obtain two single isomers: 6-{4-[(1S)-1-(morpholin-4-yl)ethyl]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (45.30 mg; 31.4%) as a light yellow solid and 6-{4-[(1R)-1-(morpholin-4-yl)ethyl]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide as a light yellow solid (49.90 mg; 34.7%).

[0399] HPLC isomer 1: 96% purity, 2.18 min, MS: m / s=462.20 [M+H] + . 1H NMR(300MHz,DMSO,ppm)10.05(d,J=3.6Hz,1H),8.82(s,1H),8.56(s,1H),8.35(d,J=8.6Hz,1H),8.25(dd, J=15.8,5.9Hz,3H),7.49(d,J=8.1Hz,2H),4.30(dd,J=8.8,4.4Hz,1H),3.57(t,J=4.7Hz,4H),3.44(q,J=6. 6Hz,1H),3.05(dd,J=11.7,3.7Hz,1H),2.86-2.68(m,2H),2.65-2.51(m,1H),2.42(q,J=5.5,4.4Hz,2H),2 .30(dt,J=10.9,4.6Hz,2H),1.89(s,2H),1.68(d,J=12.1Hz,1H),1.57-1.44(m,1H),1.32(d,J=6.6Hz,3H).

[0400] HPLC isomer 2: 97% purity, 2.17 min, MS: m / s=462.20 [M+H] + . 1 H NMR(300MHz,DMSO,ppm)10.05(d,J=3.6Hz,1H),8.82(s,1H),8.56(s,1H),8.35(d,J=8.6Hz,1H),8.25(dd, J=15.8,5.9Hz,3H),7.49(d,J=8.1Hz,2H),4.30(dd,J=8.8,4.4Hz,1H),3.57(t,J=4.7Hz,4H),3.44(q,J=6. 6Hz,1H),3.05(dd,J=11.7,3.7Hz,1H),2.86-2.68(m,2H),2.65-2.51(m,1H),2.42(q,J=5.5,4.4Hz,2H),2 .30(dt,J=10.9,4.6Hz,2H),1.89(s,2H),1.68(d,J=12.1Hz,1H),1.57-1.44(m,1H),1.32(d,J=6.6Hz,3H). Example 54: (S)-6-(4-((methylsulfonyl)methyl)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0401] 2-[4-(Methylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of 1-bromo-4-(methylsulfonylmethyl)benzene (300 mg, 1.144 mmol) and BPD (612 mg, 2.290 mmol) in dioxane (30 mL, 340.502 mmol) was added Pd(dppf)Cl2 (88 mg, 0.114 mmol) and KOAc (355 mg, 3.436 mmol). After stirring at 100°C under nitrogen for 3 h, the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (9:1) to provide 2-[4-(methylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a yellow oil (310 mg, 77.76%).

[0402] tert-Butyl (3S)-3-([8-carbamoyl-6-[4-(methylsulfonylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate: To the reaction mixture was added tert-butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (150 mg, 0.332 mmol) and 2-[4-(methylsulfonylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylate. To a solution of (8-carbamoyl-6-[4-(methylsulfonylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylic acid tert-butyl ester (231 mg, 0.664 mmol) in dioxane (10 mL, 118.041 mmol) and H₂O (2 mL, 111.017 mmol) was added Pd(Amphos)Cl₂ (25 mg, 0.033 mmol) and K₃PO₄ (222 mg, 0.995 mmol). After stirring at 100° C. under a nitrogen atmosphere for 3 h, the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (8:1) to afford tert-butyl (3S)-3-([8-carbamoyl-6-[4-(methylsulfonylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate as a yellow solid (155 mg, 86.41%).

[0403] 6-[4-(Methylsulfonylmethyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide: To a 10 mL vial was added tert-butyl (3S)-3-([8-carbamoyl-6-[4-(methylsulfonylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (150 mg, 0.277 mmol) in TFA (5 mL, 67.315 mmol) and DCM (10 mL, 157.300 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. 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 NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 24% B to 54% B over 8 minutes, 54% B; wavelength: 254 nm; RT1 (min): 6.48; number of runs: 2) to provide 6-[4-(methylsulfonylmethyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (54.1 mg, 43.38%).

[0404] HPLC: 98% purity, 2.170 min, MS: m / s=441.0 [M+H] + . 1 H NMR(300MHz,DMSO-d6):10.04(d,1H),8.87(s,1H),8.58(s,1H),8.40(dd,3H),8.24(d,1H),7.62(d,2H),4.61(s,2H) ,4.34-4.25(m,1H),3.04(d,1H),2.95(s,3H),2.87-2.66(m,2H),2.57(d,1H),1.89(s,2H),1.67(s,1H),1.51(s,1H). Example 55: (S)-6-(6-(2-methoxyethoxy)pyridin-3-yl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide tert-Butyl (3S)-3-([8-carbamoyl-6-[6-(2-methoxyethoxy)pyridin-3-yl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate: To a solution of tert-butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (200 mg, 0.444 mmol) and 6-(2-methoxyethoxy)pyridin-3-ylboronic acid (139 mg, 0.670 mmol) in dioxane (10 mL, 118.041 mmol) and H2O (2 mL, 111.017 mmol) were added Pd(Amphos)Cl2 (34 mg, 0.046 mmol) and K3PO4 (298 mg, 1.334 mmol). After stirring at 100 °C under nitrogen atmosphere for 2 h, the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:99) to afford tert-butyl (3S)-3-([8-carbamoyl-6-[6-(2-methoxyethoxy)pyridin-3-yl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate as a yellow solid (156 mg, 65.24%).

[0405] 6-[6-(2-methoxyethoxy)pyridin-3-yl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide: Prepare a solution of tert-butyl (3S)-3-([8-carbamoyl-6-[6-(2-methoxyethoxy)pyridin-3-yl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (145 mg, 0.269 mmol) and TFA (5 mL, 63.949 mmol) in DCM (15.00 mL, 235.951 mmol). After stirring at room temperature for 1 h, the residue was purified by preparative HPLC (column: Atlantis HILIC OBD column, 19*150 mm*5 μm; mobile phase A: water (10 mmol / l NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 17% B to 47% B over 8 minutes, 47% B; wavelength: 254 nm; RT1 (min): 6.2; number of runs: 2) to provide 6-[6-(2-methoxyethoxy)pyridin-3-yl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid (78.1 mg, 67.83%).

[0406] HPLC: 99% purity, 2.446 min, MS: m / s=424.2 [M+H] + . 1H NMR(300MHz,DMSO-d6,ppm):10.00(d,J=3.6Hz,1H),9.20(d,J=2.5Hz,1H),8.79(s,1H),8.67(dd,J=8.8 ,2.6Hz,1H),8.54(s,1H),8.41(d,J=8.7Hz,1H),8.21(d,J=3.7Hz,1H),6.98(d,J=8.7Hz,1H),4.52-4.43 (m,3H),3.75-3.66(m,2H),3.32(s,3H),3.04(dd,J=11.6,3.8Hz,1H),2.83(d,J=12.0Hz,1H),2.71(dd,J =11.7,9.0Hz,1H),1.90(s,2H),1.76(dd,J=21.6,8.7Hz,1H),1.72-1.63(m,1H),1.48(d,J=11.6Hz,1H). Example 56: (S)-6-(4-((3-fluoro-3-methylazetidin-1-yl)methyl)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide

[0407] 3-Fluoro-3-methyl-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]azetidine: A solution of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (1 g, 3.199 mmol), 3-fluoro-3-methylazetidine hydrochloride (0.50 g, 3.783 mmol), and KCO (2.78 g, 19.109 mmol) in ACN (5.00 mL, 95.123 mmol) was stirred at 50°C for 3 h. The resulting mixture was filtered, and the filter cake was washed with ACN. The filtrate was concentrated under reduced pressure. This afforded 3-fluoro-3-methyl-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]azetidine as an off-white oil (1.2 g, 86.05%).

[0408] (3S)-3-[(8-Carbamoyl-6-[4-[(3-fluoro-3-methylazetidin-1-yl)methyl]phenyl]pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester: To (3S)-3-([8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.332 mmol) and 3-fluoro-3-methyl-1-[[4 To a solution of [4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]phenyl]methyl]azetidine (289 mg, 0.663 mmol) in dioxane (10 mL, 118.041 mmol) and H2O (2 mL, 111.017 mmol) was added Pd(Amphos)Cl2 (25 mg, 0.034 mmol) and K3PO4 (222 mg, 0.994 mmol). After stirring at 100° C. under nitrogen atmosphere for 3 h, the residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (8:1) to provide (3S)-tert-butyl 3-[(8-carbamoyl-6-[4-[(3-fluoro-3-methylazetidin-1-yl)methyl]phenyl]pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate as a yellow oil (185 mg, 77.40%).

[0409] 6-[4-[(3-Fluoro-3-methylazetidin-1-yl)methyl]phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide: In a 50 mL round-bottom flask, tert-butyl (3S)-3-[(8-carbamoyl-6-[4-[(3-fluoro-3-methylazetidin-1-yl)methyl]phenyl]pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (180 mg, 0.250 mmol) in TFA (1 mL, 63.949 mmol) and DCM (5 mL, 78.650 mmol) were added at room temperature. The mixture was stirred at room temperature under argon atmosphere for 2 h. 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 NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23% B to 53% B over 8 minutes, 53% B; wavelength: 254 nm; RT1 (min): 6.4; number of runs: 2) to provide 6-[4-[(3-fluoro-3-methylazetidin-1-yl)methyl]phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide as an off-white solid (36.7 mg, 31.99%).

[0410] HPLC: 98% purity, 1.975 min, MS: m / s=450.3 [M+H] + . 1 H NMR(300MHz,DMSO-d6):10.04(d,1H),8.82(s,1H),8.56(s,1H),8.35(d, 1H),8.29(d,2H),8.22(d,1H),7.47(d,2H),4.33-4.24(m,1H),3.34(d,4H ),3.34-3.23(m,2H),3.20(d,1H),3.09-2.98(m,1H),2.79(s,1H),2.73( dd,1H),1.88(s,2H),1.66(s,1H),1.58(s,1H),1.51(s,2H),1.47(s,1H). Example 57: 4-[(3S)-piperidin-3-ylamino]-6-(4-[[(2S)-2(trifluoromethyl)morpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide

[0411] (2S)-4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-(trifluoromethyl)morpholine: A solution of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (500 mg, 1.650 mmol), (2S)-2-(trifluoromethyl)morpholine hydrochloride (400 mg, 1.984 mmol), and KCO (480 mg, 3.299 mmol) in ACN (10.00 mL) was stirred at 50°C for 3 h. The resulting mixture was filtered, and the filter cake was washed with ACN. The filtrate was concentrated under reduced pressure. This afforded (2S)-4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-(trifluoromethyl)morpholine (660 mg, 68.76%) as a white oil.

[0412] (3S)-3-[[8-Carbamoyl-6-(4-[[(2S)-2-(trifluoromethyl)morpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester: To (3S)-3-([8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.333 mmol) and (2 To a solution of S)-4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-(trifluoromethyl)morpholine (264 mg, 0.498 mmol) in dioxane (10 mL) and H2O (2 mL) was added Pd(AMPHOS)Cl2 (26 mg, 0.035 mmol) and K3PO4 (223 mg, 0.998 mmol). After stirring at 100 °C under nitrogen atmosphere for 2 h, the residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (12:1) to provide (3S)-tert-butyl 3-[[8-carbamoyl-6-(4-[[(2S)-2-(trifluoromethyl)morpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylate (168 mg, 73.28%) as a yellow solid.

[0413]

[0266] 4-[(3S)-Piperidin-3-ylamino]-6-(4-[[(2S)-2-(trifluoromethyl)morpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide: A solution of tert-butyl (3S)-3-[[8-carbamoyl-6-(4-[[(2S)-2-(trifluoromethyl)morpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylate (155 mg, 0.225 mmol) and TFA (5.00 mL, 67.315 mmol) in DCM (15.00 mL) was prepared. After stirring at room temperature for 1 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 / l NH4HCO3+0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 70% B over 8 minutes, 70% B; wavelength: 254 nm; RT1 (min): 6.8) to provide 4-[(3S)-piperidin-3-ylamino]-6-(4-[[(2S)-2-(trifluoromethyl)morpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide (65.9 mg, 55.26%) as a white solid.

[0414] HPLC: 97% purity, RT = 2.449 min. MS: m / z = 516.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6): 10.01-9.94(m,1H),8.87(s,1H),8.62(s,1H),8.56(d,J=8.6Hz,1H),8.38(d,J=8.1H z,2H),8.26(d,J=3.7Hz,1H),7.53(d,J=8.1Hz,2H),4.63(d,J=10.1Hz,1H),4.19(t,J=7.4Hz,1H),3.95(d,J =11.2Hz,1H),3.68(s,2H),3.64(d,J=10.8Hz,1H),3.20(d,J=12.1Hz,1H),3.08(t,J=11.2Hz,1H),2.91(d,J =11.0Hz,1H),2.75(dd,J=23.0,11.6Hz,2H),2.29-2.08(m,2H),2.00(s,2H),1.83(dt,J=40.9,12.3Hz,3H). Example 58: 6-[4-(1-hydroxycyclopropyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide

[0415] 1-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropan-1-ol: To a stirred solution of methyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5.00 g, 18.122 mmol) in THF (50.00 mL) was added dropwise Ti(i-PrO) (5.42 g, 18.117 mmol) and EtMgBr (17.20 mL, 26.070 mmol) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with water (50 nmol). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 14% EtOAc in PE to afford 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropan-1-ol (3.86 g, 72.38%) as a white solid.

[0416] tert-Butyl (3S)-3-([8-Carbamoyl-6-[4-(1-hydroxycyclopropyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate: tert-Butyl (3S)-3-([8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (250 mg, 0.573 mmol) and 1 To a stirred solution of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropan-1-ol (321 mg, 1.091 mmol) in DME (2.40 mL) and H₂O (0.80 mL) was added portionwise Na₂CO₃ (262 mg, 2.348 mmol) and Pd(PPh₃)₄ (72 mg, 0.059 mmol). The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography, eluting with 45% EtOAc in PE. The residue was purified by silica gel column chromatography eluting with 25% EtOAc in DCM to afford tert-butyl (3S)-3-([8-carbamoyl-6-[4-(1-hydroxycyclopropyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (200 mg, 47.12%) as a yellow solid.

[0417] 6-[4-(1-hydroxycyclopropyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred solution of tert-butyl (3S)-3-([8-carbamoyl-6-[4-(1-hydroxycyclopropyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (200 mg, 0.270 mmol) in DCM (3.00 mL) was added dropwise TFA (1.00 mL) at 0° C. under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 1 h. The crude product was purified by preparative HPLC using the following conditions: (2# SHIMADZU (HPLC-01)): column, Xselect CSH OBD column 30*150mm 5um, n; mobile phase, water (0.1% FA) and ACN (5% phase B to up to 30% over 8 minutes); detector, uv254, to provide 6-[4-(1-hydroxycyclopropyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide (12.7 mg, 10.61%) as a yellow solid and 4-[(3S)-piperidin-3-ylamino]-6-(4-propionylphenyl)pyrido[3,2-d]pyrimidine-8-carboxamide as a yellow solid; formate (19.5 mg, 15.51%).

[0418] 6-[4-(1-Hydroxycyclopropyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide: HPLC: 91% purity, RT = 2.360 min. MS: m / z = 405.2 [M+H] +1 H NMR (300MHz, DMSO-d6): 10.03(d,J=3.7Hz,1H),8.85(s,1H),8.59(s,1H),8.49(d,J=8.6Hz,1H),8.42(s,1H),8.32(d,J=8.1Hz,1H),8.25(d,J=3. 7Hz,1H),7.42(d,J=8.2Hz,2H),4.47(s,1H),3.20(d,J=12.1Hz,1H),2.9 8(s,2H),2.72(d,J=11.0Hz,1H),2.51(d,J=7.8Hz,1H),1.96(s,1H),1.89 -1.79(m,2H),1.63(s,1H),1.20(q,J=4.8,4.3Hz,2H),1.17-1.02(m,2H). Example 59: 6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide

[0419] (3S)-3-([8-Carbamoyl-6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylic acid tert-butyl ester: To (3S)-3-([8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.275 mmol) and 1-methyl-4-piperazin-1-yl)pyridin-3-yl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylic acid tert-butyl ester was added. To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine (120 mg, 0.376 mmol) in 1,4-dioxane (5.00 mL) and H2O (1.00 mL) was added K3PO4 (168 mg, 0.752 mmol) and Pd(Amphos)Cl2 (24 mg, 0.033 mmol). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to afford tert-butyl (3S)-3-([8-carbamoyl-6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (130 mg, 78.93%) as a yellow solid.

[0420] 6-[6-(4-Methylpiperazin-1-yl)pyridin-3-yl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide: A solution of tert-butyl (3S)-3-([8-carbamoyl-6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (130 mg, 0.217 mmol) and HCl (g) in MeOH (5.00 mL, 10.510 mmol, 52.54 equiv, 12%) was stirred at 25°C under nitrogen for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC using the following conditions: (#2 SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 x 150 mm 5 μm; mobile phase, water (10 mmol / l NH4HCO3 + 0.05% NH4OH) and ACN (20% phase B up to 50% over 8 minutes); detector, UV, 254 nm. The product was obtained. This afforded 6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide (50 mg, 51.14%) as a yellow solid.

[0421] HPLC: 96%, RT=2.914min MS: m / z=448.1[M+H] +1 H NMR (400MHz, DMSO-d6): 10.03(d,J=3.6Hz,1H),9.19(d,J=2.4Hz,1H),8.74(s,1H),8.55-8.43(m ,2H),8.37(d,J=8.7Hz,1H),8.20(d,J=3.7Hz,1H),6.97(d,J=9.1Hz,1H),4.30(d,J=10.6Hz,1H) ,3.65(t,J=5.1Hz,4H),3.05(d,J=9.7Hz,1H),2.84(d,J=12.3Hz,1H),2.58(d,J=10.4Hz,1H),2. 54(s,4H),2.42(t,J=5.1Hz,4H),2.23(s,3H),1.90(s,1H),1.81(d,J=10.4Hz,1H),1.68(s,1H). Example 60: 6-(4-[[(3S)-3-fluoropyrrolidin-1-yl]methyl]phenyl)-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide

[0422] (3S)-3-Fluoro-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine: A solution of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (1.00 g, 3.199 mmol), (3S)-3-fluoropyrrolidine hydrochloride (507 mg, 3.838 mmol), and KCO (931 mg, 6.397 mmol) in ACN (20.00 mL) was stirred at 50° C. for 3 h. The resulting mixture was concentrated under reduced pressure. This afforded (3S)-3-fluoro-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine (950 mg, 68.12%) as a white solid.

[0423] (3S)-3-[[8-Carbamoyl-6-(4-[[(3S)-3-fluoropyrrolidin-1-yl]methyl]phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylic acid tert-butyl ester: (3S)-3-([8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.343 mmol) and (3S)- To a solution of 3-fluoro-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine (290 mg, 0.665 mmol) in dioxane (10.00 mL) and H2O (2.00 mL) was added Pd(AMPHOS)Cl2 (25 mg, 0.034 mmol) and K3PO4 (222 mg, 0.994 mmol). After stirring at 100 °C under nitrogen atmosphere for 3 h, the residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (8:1) to provide (3S)-tert-butyl 3-[[8-carbamoyl-6-(4-[[(3S)-3-fluoropyrrolidin-1-yl]methyl]phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylate (190 mg, 73.55%) as a yellow oil.

[0424] 6-(4-[[(3S)-3-fluoropyrrolidin-1-yl]methyl]phenyl)-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide: In a 50 mL round-bottom flask at room temperature was added tert-butyl (3S)-3-[[8-carbamoyl-6-(4-[[(3S)-3-fluoropyrrolidin-1-yl]methyl]phenyl)pyrido[3,2-d]pyrimidin-4-yl]amino]piperidine-1-carboxylate (180 mg, 0.231 mmol), DCM (5.00 mL) and TFA (5.00 mL). The mixture was stirred at room temperature under argon atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The desired product was detected by LCMS. The residue was purified by preparative HPLC to afford 6-(4-[[(3S)-3-fluoropyrrolidin-1-yl]methyl]phenyl)-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide (44.8 mg, 41.51%) as a white solid. HPLC: 96% RT=1.879min MS: m / z=450.3[M+H] + 1 H NMR(400MHz,DMSO-d6):10.04(s,1H),8.84(s,1H),8.57(s,1H),8.34(dd,3H),8.23( s,1H),7.51(d,2H),5.12(s,1H),4.35-4.26(m,1H),3.71(s,2H),3.06(d,1H),2.85( d,1H),2.84(s,1H),2.77(d,1H),2.73-2.64(m,1H),2.69-2.52(m,2H),2.36(q,2H), 2.25-2.08(m,1H),1.96(d,1H),1.89(s,1H),1.81(s,1H),1.68(s,1H),1.52(s,1H). Example 61: 6-[4-(2-methoxy-2-methylpropyloxy)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide

[0425] 1-(4-Bromophenoxy)-2-methylpropan-2-ol: To a stirred solution of 4-bromophenol (2.00 g, 10.982 mmol) and KCO (4.79 g, 32.946 mmol) in DMF (20.00 mL) was added portionwise 2,2-dimethyloxirane (1.25 g, 16.469 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 140°C under a nitrogen atmosphere for 4 h. Water (30 mL) was added to the resulting mixture. The resulting mixture was extracted with EtOAc (3*30 mL). The combined organic layers were washed with brine (1*50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to provide 1-(4-bromophenoxy)-2-methylpropan-2-ol (2.71 g, 99.97%) as a brown solid.

[0426] 1-Bromo-4-(2-methoxy-2-methylpropoxy)benzene: To a stirred mixture of 1-(4-bromophenoxy)-2-methylpropan-2-ol (1.17 g, 4.692 mmol) in THF (20.00 mL, 234.517 mmol) at 0°C under a nitrogen atmosphere was added NaH (0.35 g, 8.751 mmol). The resulting mixture was stirred at 0°C under a nitrogen atmosphere for 10 min. To this mixture was added CH3I (2.04 g, 13.654 mmol) at 0°C. 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 50 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. 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, ACN in water, 70% to 80% gradient over 10 minutes; detector, UV 254 nm. This gave 1-bromo-4-(2-methoxy-2-methylpropoxy)benzene (1.25 g, 99.92%) as a yellow oil.

[0427] 2-[4-(2-methoxy-2-methylpropoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a stirred solution of 1-bromo-4-(2-methoxy-2-methylpropoxy)benzene (1.23 g, 4.614 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.70 g, 13.841 mmol) in dioxane (10.00 mL) was added Pd(dppf)Cl2 (0.36 g, 0.461 mmol) and KOAc (1.42 g, 13.702 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous NaSO. 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 ACN, 65% to 75% gradient over 10 minutes; detector, UV 254 nm. This yielded 2-[4-(2-methoxy-2-methylpropyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.46 g, 99.11%) as a white solid.

[0428] tert-Butyl (3S)-3-([8-Carbamoyl-6-[4-(2-methoxy-2-methylpropyloxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate: tert-Butyl (3S)-3-([8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (180 mg, 0.311 mmol) and 2 To a stirred solution of 4-[4-(2-methoxy-2-methylpropoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (272 mg, 0.852 mmol) in DME (2.40 mL) and H₂O (0.80 mL) was added portionwise Na₂CO₃ (188 mg, 1.685 mmol) and Pd(PPh₃)₄ (52 mg, 0.043 mmol). The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography eluting with 38% EtOAc in PE to provide tert-butyl (3S)-3-([8-carbamoyl-6-[4-(2-methoxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (196 mg, 99.80%) as a yellow solid.

[0429] 6-[4-(2-methoxy-2-methylpropoxy)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide formate: To a stirred solution of tert-butyl (3S)-3-([8-carbamoyl-6-[4-(2-methoxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (186 mg, 0.295 mmol) in DCM (2.40 mL) was added dropwise TFA (0.80 mL) at 0° C. under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 2 h. The crude product was purified by preparative HPLC using the following conditions: (2#SHIMADZU (HPLC-01)): column, Xselect CSH OBD column 30*150mm 5um, n; mobile phase, water (0.1% FA) and ACN (30% phase B to up to 50% over 8 minutes); detector, uv254 to provide 6-[4-(2-methoxy-2-methylpropyloxy)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide formate (60.0 mg, 40.24%) as a yellow solid. HPLC: 98%, RT=3.053min MS: m / z=451.2[M+H] + 1 H NMR (400MHz, DMSO-d6): 9.99 (d, J = 3.7 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.57 (d, J = 1. 2Hz,1H),8.47(d,J=7.8Hz,1H),8.39-8.29(m,3H),8.24-8.17(m,1H),7.12(dd,J=8 .9,3.0Hz,2H),4.54(s,1H),3.94(d,J=1.7Hz,2H),3.26(s,1H),3.18(s,3H),3.07( s, 2H), 2.75 (s, 1H), 1.98 (s, 1H), 1.86 (d, J = 11.6Hz, 3H), 1.69 (s, 1H), 1.24 (s, 6H). Example 62: 6-[4-(2-hydroxy-2-methylpropyloxy)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide

[0430] tert-Butyl (3S)-3-([8-Carbamoyl-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate: tert-Butyl (3S)-3-([8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (150 mg, 0.272 mmol) and 2-methyl-1-[4-(4 To a stirred solution of [(4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol (216 mg, 0.731 mmol) in DME (1.80 mL, 17.667 mmol) and H2O (0.60 mL, 31.640 mmol) was added portionwise Na2CO3 (157 mg, 1.407 mmol) and Pd(PPh3)4 (43 mg, 0.035 mmol). The resulting mixture was stirred at 80°C under nitrogen for 2 h. The residue was purified by silica gel column chromatography eluting with 38% EtOAc in PE to afford tert-butyl (3S)-3-([8-carbamoyl-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (150 mg, 99.99%) as a yellow solid.

[0431] 6-[4-(2-hydroxy-2-methylpropoxy)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred solution of tert-butyl (3S)-3-([8-carbamoyl-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (140 mg, 0.254 mmol) in DCM (1.80 mL, 26.898 mmol) was added dropwise TFA (0.60 mL, 7.674 mmol) at 0°C under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: (2#SHIMADZU (HPLC-01)): column, Xselect CSH OBD column 30*150mm 5um, n; mobile phase, water (0.1% FA) and ACN (35% phase B to up to 55% over 8 minutes); detector, uv254, to provide 6-[4-(2-hydroxy-2-methylpropyloxy)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide (62.3 mg, 55.61%) as a yellow solid.

[0432] HPLC: 99% purity, RT = 2.57 min. MS: m / z = 437.10 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ10.02(d,J=3.6Hz,1H),8.82(s,1H),8.58(s,1H),8.47(d,J= 8.6Hz,1H),8.35(dd,J=9.8,2.8Hz,2H),8.23(d,J=3.7Hz,1H),7.17-7.07(m,2H),4.5 1(s,1H),3.83(s,2H),3.25(d,J=11.7Hz,1H),3.12-2.92(m,2H),2.79-2.66(m,1H), 2.51(p,J=1.8Hz,2H),1.98(s,1H),1.85(t,J=10.1Hz,2H),1.67(s,1H),1.25(s,6H). Example 63: 6-(4-[6-oxa-3-azabicyclo[3.1.1]hept-3-ylmethyl]phenyl)-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide

[0433] Tert-Butyl (3S)-3-([8-Carbamoyl-6-[4-(hydroxymethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate: A solution of tert-butyl (3S)-3-([8-Carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (900.00 mg, 1.916 mmol), 4-(hydroxymethyl)phenylboronic acid (502.52 mg, 3.142 mmol), Pd(Amphos)Cl2 (157.00 mg, 0.211 mmol), and K3PO4 (1.42 g, 6.360 mmol) in dioxane (5.00 mL) and H2O (1.00 mL) was stirred at 100°C under nitrogen for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (1:1) to afford tert-butyl (3S)-3-([8-carbamoyl-6-[4-(hydroxymethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-...

Claims

1. Compounds of Formula I in: R1, R2, R3 and R4 are each independently selected from H and halogen; R5 is selected from the group consisting of H, halogen, -O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, and -CN; X is selected from the group consisting of N and CR6 Y is selected from the group consisting of N and CR7 R6 and R7 are each independently selected from H, halogen and C1-C6 alkyl; A is absent or selected from (-CH2-) n ,-O-(-CH2-) o -,-O- and n is selected from the group consisting of 1, 2, 3 and 4; o Selected from the group consisting of 1, 2, 3 and 4; B is absent or selected from H, CN, halogen, optionally substituted C6-C 14 Aryl, optionally substituted C2-C 14 Heteroaryl, optionally substituted C1-C 14 heterocyclic ring, optionally substituted C1-C8 alkyl, C1-C8 haloalkyl, optionally substituted C1-C8 alkyl interrupted by 1-4 heteroatoms, and optionally substituted C3-C 14 Cycloalkyl; or a pharmaceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer or mixture of diastereomers.

2. The compound according to claim 1, which has formula Ia 3. The compound according to claim 2, which has formula Ib 4. The compound according to claim 1, which has formula Ic 5. The compound according to claim 1, which has formula Id 6. The compound according to claim 1, which has formula Ie 7. The compound according to claim 4, which has the formula If 8. The compound according to claim 1, which has the formula Ig 9. The compound according to claim 6, which has the formula Ih 10. The compound according to claim 1, which has formula Ii 11. The compound according to claim 1, which has the formula 12. The compound according to claim 1, which has the formula Ik 13. The compound according to claim 1, wherein R1, R2, R3 and R4 are each H.

14. The compound according to claim 1, wherein R1, R3 and R4 are H and R2 is halogen.

15. The compound according to claim 14, wherein R2 is F.

16. The compound according to claim 1, wherein R1, R2 and R3 are H and R4 is halogen.

17. The compound according to claim 16, wherein R4 is F.

18. The compound according to claim 1, wherein R1 and R2 are halogen and R3 and R4 are H.

19. The compound according to claim 18, wherein R1 and R2 are F.

20. The compound according to claim 1, wherein R1 and R2 are H and R3 and R4 are halogen.

21. The compound according to claim 20, wherein R3 and R4 are F.

22. The compound according to claim 1, wherein R5 is selected from the group consisting of H, -CN and -CF3.

23. The compound according to claim 1, wherein R5 is -CN.

24. The compound according to claim 1, wherein -AB is selected from the group consisting of: wherein R8 and R9 are each independently selected from H and C1-C6 alkyl; R8 and R9 together with the carbon to which they are attached may form a ring having 3-6 carbon atoms; R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 Each is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, halogen and -CN.

25. The compound according to claim 24, wherein R8 and R9 are H.

26. The compound according to claim 24, wherein R8 and R9 together with the carbon to which they are attached form a cyclopropyl ring.

27. The compound according to claim 24, wherein R 10 , R 11 , R 16 and R 17 are each independently selected from H and -CH3; and R 12 , R 13 , R 14 and R 15 It's H.

28. The compound according to claim 24, wherein R 12 and R 13 Both F and R 10 , R 11 , R 14 , R 15 , R 16 and R 17 It's H.

29. The compound according to claim 24, wherein R 10 and R 11 are each independently selected from H and -CN; and R 12 , R 13 , R 14 , R 15 , R 16 and R 17 It's H.

30. The compound according to claim 24, wherein R 10 and R 11 are each independently selected from H and -CF3; and R 12 , R 13 , R 14 , R 15 , R 16 and R 17 It's H.

31. The compound according to claim 24, wherein R 12 and R 13 are each independently selected from H and -CN; and R 10 , R 11 , R 14 , R 15 , R 16 and R 17 It's H.

32. The compound according to claim 24, wherein R 12 and R 13 are each independently selected from H and -CF3; and R 10 , R 11 , R 14 , R 15 , R 16 and R 17 It's H.

33. The compound according to claim 24, wherein R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 It's H.

34. The compound according to claim 24, wherein R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 It's H.

35. The compound according to claim 24, wherein R 12 and R 13 are each independently selected from H and -CH3; and R 10 , R 11 , R 14 , R 15 , R 16 and R 17 It's H.

36. The compound according to claim 1, wherein -AB is selected from the group consisting of:

37. The compound according to claim 1, wherein -AB is selected from the group consisting of: Where R 18 Selected from the group consisting of H, -OH, halogen, C1-C6 alkyl, -O-(C1-C6 alkyl) and C1-C6 haloalkyl.

38. The compound according to claim 1, wherein -AB is selected from the group consisting of: Where R 19 and R 20 Each is independently selected from H, -OH, halogen, C1-C6 alkyl, -O-(C1-C6 alkyl) and C1-C6 haloalkyl.

39. The compound according to claim 1, wherein -AB is selected from the group consisting of: Where R 21 Selected from the group consisting of H and C1-C6 alkyl.

40. The compound according to claim 1, wherein -AB is selected from the group consisting of -OCH3, -CN, -CH2SO2CH3, -OCF3, -CF3, -CHF2, 41. Compound I of formula I in: R 21 , R 22 , R 23 and R 24 are each independently selected from H and halogen; W is selected from the group consisting of an optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms, an optionally substituted 5-6 membered heterocycle containing 1-4 heteroatoms, a C1-C6 alkenyl (an optionally substituted 5-6 membered heterocycle containing 1-4 heteroatoms), a C1-C6 alkyl (an optionally substituted 5-6 membered heterocycle containing 1-4 heteroatoms) and an optionally substituted cyclohexene. or a pharmaceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer or mixture of diastereomers.

42. The compound according to claim 41, which has the formula IIa 43. The compound according to claim 42, which has the formula IIb 44. The compound according to claim 41, which has the formula IIc 45. The compound according to claim 44, which has the formula IId 46. ​​The compound according to claim 41, which has the formula IIe 47. The compound according to claim 44, which has the formula IIf 48. The compound according to claim 41, which has the formula IIg 49. The compound according to claim 48, which has the formula IIh 50. The compound according to claim 41, which has the formula III 51. The compound according to claim 41, which has the formula IIj 52. The compound according to claim 41, which has the formula IIk 53. The compound according to claim 41, wherein R 21 , R 22 , R 23 and R 24 Each is H.

54. The compound according to claim 41, wherein R 21 , R 23 and R 24 is H and R 22 It's a halogen.

55. The compound according to claim 54, wherein R 22 It's F.

56. The compound according to claim 41, wherein R 21 , R 22 and R 23 is H and R 24 It's a halogen.

57. The compound according to claim 56, wherein R 24 It's F.

58. The compound according to claim 41, wherein R 21 and R 22 is a halogen and R 23 and R 24 It's H.

59. The compound according to claim 58, wherein R 21 and R 22 It's F.

60. The compound according to claim 41, wherein R 21 and R 22 is H and R 23 and R 24 It's a halogen.

61. The compound according to claim 60, wherein R 23 and R 24 It's F.

62. The compound according to claim 41, wherein W is selected from the following group: Where R 25 and R 26 independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, halogen, -CN, -CH2-O-CH3, -CH2CH2-O-CH3, tetrahydropyranyl, morpholino, R 27 Selected from the following group: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, R 28 is selected from the group consisting of H, halogen, -O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, and -CN; R 29 Selected from the group consisting of H and C1-C6 alkyl.

63. The compound according to claim 1, selected from the group consisting of: or a prodrug or a pharmaceutically acceptable salt thereof.

64. The compound according to claim 41, selected from the group consisting of and or a prodrug or a pharmaceutically acceptable salt thereof.

65. A pharmaceutical composition comprising a compound of claim 1, 41, 63 or 64 and a pharmaceutically acceptable adjuvant, carrier or vehicle.

66. A method comprising administering to a patient suffering from an HPK1 -mediated disorder a therapeutically effective amount of a compound of claim 1, 41, 63 or 64, or a pharmaceutically acceptable salt thereof.

67. The method of claim 66, wherein: An HPK-1 mediated disorder is cancer.

68. The method of claim 67, 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.

69. The method of claim 66, 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.

70. The method of claim 66, wherein: The compound is administered to the patient continuously, multiple times daily, once daily, once every other day, weekly, biweekly, monthly, or bimonthly.

71. The method of claim 66, wherein: The compounds are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.

72. The method of claim 66, wherein: The compounds are administered subcutaneously, intravenously, intramuscularly, intra-articularly, intra-synovially, intrasternally, intrathecally, intrahepatically, intralesionally and by intracranial injection or infusion techniques.

73. A method comprising administering to a patient suffering from an HPK1 -mediated disorder a therapeutically effective amount of the pharmaceutical composition of claim 65 or a pharmaceutically acceptable salt thereof.

74. The method of claim 73, wherein: An HPK1-mediated disorder is cancer.

75. The method of claim 74, 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.

76. The method of claim 73, 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.

77. The method of claim 76, wherein: The pharmaceutical composition is administered to the patient continuously, multiple times daily, once daily, once every other day, weekly, biweekly, monthly, or bimonthly.

78. The method of claim 76, wherein: The compounds are administered subcutaneously, intravenously, intramuscularly, intra-articularly, intra-synovially, intrasternally, intrathecally, intrahepatically, intralesionally and by intracranial injection or infusion techniques.

79. A kit comprising a therapeutically effective amount of a compound of claim 1, 41, 63, or 64, or a pharmaceutically acceptable salt or prodrug thereof; and instructions for using the compound.

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