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

Abstract

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

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 377,900, filed September 30, 2022, and U.S. Provisional Application No. 63 / 362,803, filed April 11, 2022, the entire contents of which are incorporated herein by reference.

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

[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 circuitry of the T cell receptor (TCR) signaling pathway. HPK1 is recruited to the TCR complex and phosphorylates the SLP76 protein, leading to its degradation and downregulation of TCR signal strength. Genetic ablation of HPK1 results in T cell activation, a lower TCR threshold, increased proliferation, and elevated levels of inflammatory cytokines such as IL-2, TNF-α, and IFN-γ. Loss of HPK1 expression enhances dendritic cell activation and antigen presentation (Hernandez S. et al., Cell Reports, 2018, vol. 25, pp. 80-94). HPK1 kinase activity is thought to be important for conferring its suppressive function on a wide range of immune cells, including CD8+, CD4+, DCs, and NKs, and regulatory T cells (Tregs). Inactivation of the HPK1 kinase domain was sufficient to induce a strong antitumor immune response (Liu et al., PLoS One, March 26, 2019). HPK1 knockout (KO) and kinase-dead (KD) mice exhibit enhanced T cell function and antitumor efficacy (You D. et al., J. Immunother. Cancer 2021). Therefore, pharmacological inhibition of HPK1 has the potential to enhance effector T cell function and antitumor activity. Summary of the Invention

[0004] In one embodiment, the compound of formula (I): [ka] [In the formula, R1, R2, R3 and R4 are each independently selected from the group consisting of 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 the group consisting of H, halogen, and C1-C6 alkyl; A is absent or (-CH2-) n , -O-(-CH2-)0, -O and [ka] is selected from the group consisting of n is selected from the group consisting of 1, 2, 3 and 4; o is selected from the group consisting of 1, 2, 3 and 4; B is absent or selected from H, CN, halogen, and optionally substituted C-C 14 Aryl, optionally substituted C-C 14 Heteroaryl, optionally substituted C-C 14 Heterocycle, optionally substituted C1-C8 alkyl, C1-C8 haloalkyl, optionally substituted C1-C8 alkyl interrupted by 1 to 4 heteroatoms, and optionally substituted C3-C 14 cycloalkyl] or a pharmaceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer or mixture of diastereomers is provided.

[0005] In another embodiment, there is provided a compound having formula Ia: [ka]

[0006] In another embodiment, there is provided a compound having formula Ib: [ka]

[0007] In another embodiment, there is provided a compound having formula Ic: [ka]

[0008] In another embodiment, there is provided a compound having formula Id: [ka]

[0009] In another embodiment, there is provided a compound having formula Ie: [ka]

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

[0011] In another embodiment, there is provided a compound having formula Ig. [ka]

[0012] In another embodiment, there is provided a compound having formula Ih. [ka]

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

[0014] In another embodiment, there is provided a compound having the formula Ij. [ka]

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

[0016] In one embodiment, a compound of formula I is provided, wherein R 1 , R 2 , R 3 and R 4 are each H.

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

[0018] In one embodiment, compounds of formula I are provided wherein R2 is F.

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

[0020] In one embodiment, compounds of formula I are provided wherein R4 is F.

[0021] In one embodiment, compounds of formula I are provided wherein R 1 and R 2 are halogen and R 3 and R 4 are H.

[0022] In one embodiment, compounds of formula I are provided wherein R 1 and R 2 are F.

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

[0024] In one embodiment, compounds of formula I are provided wherein R3 and R4 are F.

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

[0026] In one embodiment, compounds of formula I are provided wherein R5 is -CN.

[0027] In one embodiment, -AB is [ka] wherein R and R are each independently selected from the group consisting of H and C-C alkyl; R and R can be taken together with the carbon to which they are attached to form a ring having 3 to 6 carbon atoms; and R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, and -CN. Preferably, R8 and R9 are H. 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 the group consisting of H and —CH3; R 12 , R 13 , R 14 and R 15 is H. Preferably, R 12 and R 13 are both F and R 10 , R 11 , R 14 , R 15 , R 16 and R 17 is H.

[0028] Preferably, R 10 and R 11 are each independently selected from the group consisting of H and —CN; R 12 , R 13 , R 14 , R 15 , R 16 and R 17is H. Preferably, R 10 and R 11 are each independently selected from the group consisting of H and —CF3; 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 the group consisting of H and —CN; R 10 , R 11 , R 14 , R 15 , R 16 and R 17 is H. Preferably, R 12 and R 13 are each independently selected from the group consisting of H and —CF3; R 10 , R 11 , R 14 , R 15 , R 16 and R 17 is H. Preferably, R, R, 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 the group consisting of H and —CH3; R 10 , R 11 , R 14 , R 15 , R 16 and R 17 is H.

[0029] In one embodiment, compounds of formula I are provided wherein -AB is selected from the group consisting of: [ka]

[0030] In one embodiment, compounds of formula I are provided wherein -AB is selected from the group consisting of: [ka] In the formula, R 18 is selected from the group consisting of H, —OH, halogen, C1-C6 alkyl, —O—(C1-C6 alkyl), and C1-C6 haloalkyl.

[0031] In one embodiment, compounds of formula I are provided wherein -AB is selected from the group consisting of: [ka] In the formula, R 19 and R 20 are each independently selected from the group consisting of H, —OH, halogen, C1-C6 alkyl, —O—(C1-C6 alkyl), and C1-C6 haloalkyl.

[0032] In one embodiment, compounds of formula I are provided wherein -AB is selected from the group consisting of: [ka] In the formula, R 21 is selected from the group consisting of H and C1-C6 alkyl.

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

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

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

[0036] In one embodiment, a compound having formula IIb is provided. [ka]

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

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

[0039] In another embodiment, there is provided a compound having the formula IIe: [ka]

[0040] In another embodiment, a compound having the formula IIf is provided. [ka]

[0041] In another embodiment, there is provided a compound having the formula IIg. [ka]

[0042] In another embodiment, there is provided a compound having the formula IIh. [ka]

[0043] In another embodiment, there is provided a compound having formula IIi: [ka]

[0044] In another embodiment, there is provided a compound having the formula IIj. [ka]

[0045] In another embodiment, there is provided a compound having the formula IIk. [ka]

[0046] In another embodiment, R 21 , R 22, R 23 and R 24 are each H.

[0047] In another embodiment, R 21 , R 23 and R 24 is H and R 22 is a halogen.

[0048] In another embodiment, R 22 is F.

[0049] In another embodiment, R 21 , R 22 and R 23 is H and R 24 is a halogen.

[0050] In another embodiment, R 24 is F.

[0051] In another embodiment, R 21 and R 22 is a halogen and R 23 and R 24 is H.

[0052] In another embodiment, R 21 and R 22 is F.

[0053] In another embodiment, R 21 and R 22 is H and R 23 and R 24 is a halogen.

[0054] In another embodiment, R 23 and R 24 is F.

[0055] In another embodiment, W is [ka] wherein R 25 and R 26 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, halogen, -CN, -CH2-O-CH3, -CH2CH2-O-CH3, tetrahydropyranyl, morpholino, [ka] and R is independently selected from the group consisting of 27 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, [ka] and R is independently selected from the group consisting of 28 is selected from the group consisting of H, halogen, —O—C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, and —CN; R 29 is 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: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] or a pharmaceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer, or mixture of diastereomers thereof.

[0057] In one embodiment, the compound of formula (II) is one of the following compounds: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] or a pharmaceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer, or mixture of diastereomers thereof.

[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 in which 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 having an HPK-1-mediated disorder. The HPK-1-mediated disorder can be cancer. The cancer can be one or more of: breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cell, head and neck, kidney, liver, lung, larynx and hypopharynx, ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, testis, stomach, skin, ureter, vagina, and vulva cancer. The therapeutically effective amount of the compound can be in one of the following ranges: 0.1-100 mg / kg patient body weight, 0.1-50 mg / kg patient body weight, 0.5-50 mg / kg patient body weight, 1-20 mg / kg patient body weight, 5-20 mg / kg patient body weight, 10-20 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. The compound can be administered to a patient continuously, multiple times daily, once daily, once every other day, weekly, biweekly, monthly, or bimonthly. The compound can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The compounds can be administered by subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.

[0060] In one embodiment, a method is provided in which a therapeutically effective amount of a pharmaceutical composition or a physiologically acceptable salt thereof is administered to a patient having an HPK-1-mediated disorder. The HPK-1-mediated disorder can be cancer. The cancer can be one or more of the following: breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cell, head and neck, kidney, liver, lung, larynx and hypopharynx, ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, testes, stomach, skin, ureter, vagina, and vulva. The therapeutically effective amount of the pharmaceutical composition can be in the range of 0.1-100 mg / kg patient body weight, 0.1-50 mg / kg patient body weight, 0.5-50 mg / kg patient body weight, 1-20 mg / kg patient body weight, 5-20 mg / kg patient body weight, 10-20 mg / kg patient body weight, or any other dosage range disclosed herein. The pharmaceutical compositions may be administered to a patient continuously, multiple times daily, once daily, every other day, weekly, biweekly, monthly, or bimonthly. The pharmaceutical compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The pharmaceutical compositions may be administered by subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion procedures.

[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]

[0013] Additional features, advantages, and embodiments of the presently disclosed subject matter are set forth in or may be apparent from consideration of the following detailed description and claims. Furthermore, it is to be understood that both the foregoing summary and the following detailed description are exemplary and are intended to provide further explanation without limiting the scope of the claims. DETAILED DESCRIPTION OF THE INVENTION

[0063] Provided herein are chemical structures of general formulas (I) and (II), or prodrugs or pharmaceutically acceptable salts thereof (including mixtures thereof in all ratios), for use in the treatment and / or prevention of, preferably, 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 formulas (I) and (II): [ka] [In the formula, R1, R2, R3 and R4 are each independently selected from the group consisting of 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 the group consisting of H, halogen, and C1-C6 alkyl; A is absent or (-CH2-) n , -O-(-CH2-) o -, -O- and [ka] is selected from the group consisting of n is selected from the group consisting of 1, 2, 3 and 4; o is selected from the group consisting of 1, 2, 3 and 4; B is absent or selected from H, CN, halogen, and optionally substituted C-C 14 Aryl, optionally substituted C-C 14 Heteroaryl, optionally substituted C-C 14 Heterocycle, optionally substituted C1-C8 alkyl, C1-C8 haloalkyl, optionally substituted C1-C8 alkyl interrupted by 1 to 4 heteroatoms, and optionally substituted C3-C 14cycloalkyl] or a pharmaceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer or mixture of diastereomers, [ka] [In the formula, R 21 , R 22 , R 23 and R 24 are each independently selected from the group consisting of H and halogen; W is selected from the group consisting of an optionally substituted 5- to 6-membered heteroaromatic ring containing 1 to 4 heteroatoms, an optionally substituted 5- to 6-membered heterocyclic ring containing 1 to 4 heteroatoms, C1-C6 alkenyl (an optionally substituted 5- to 6-membered heterocyclic ring containing 1 to 4 heteroatoms), C1-C6 alkyl (an optionally substituted 5- to 6-membered heterocyclic ring containing 1 to 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 can be a straight-chain or branched-chain alkyl group. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. The number of carbon atoms in the alkyl group is not particularly limited.

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

[0066] Heterocyclyl is a monovalent group formed by removing a hydrogen atom from any ring atom of a heterocyclic compound. It may contain one or more heteroatoms. A heteroatom may refer to one or more of oxygen, sulfur, nitrogen, phosphorus, or any oxidized form thereof. Heterocycle, heterocyclyl, and heterocyclic ring may be 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 has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of saturated or partially unsaturated heterocyclic rings include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, oxazepinyl, thiazepinyl, and morpholinyl. Heterocyclyl can include groups in which one or more aryl rings, heteroaryl rings, or alicyclic hydrocarbon rings are fused to the heterocyclyl ring, with the bonding group or point of attachment being on the heterocyclyl ring. Heterocyclyl groups can be monocyclic or bicyclic.

[0067] Partially unsaturated can refer to a ring moiety that contains at least one double or triple bond. It can encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties. The term unsaturated can refer to a moiety that has one or more units of unsaturation.

[0068] Aryl can refer to aryl alone or to larger moieties such as aralkyl, aralkoxy, and / or aryloxyalkyl. It can refer to monocyclic and bicyclic rings. At least one ring in the system can be aromatic. Each ring in the system can contain 3 to 7 members. Exemplary aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which optionally contain one or more substituents. Aryl can also refer to groups in which an aromatic ring is fused to one or more non-aromatic rings (e.g., indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, tetrahydronaphthyl, and the like).

[0069] Heteroaryl can refer to heteroaryl alone or as part of a larger moiety such as heteroaralkyl or heteroaralkoxy. It can refer to groups having 5 to 14 ring atoms, preferably 5 or 6 ring atoms. In addition to carbon atoms, heteroaryl can contain 1 to 5 heteroatoms as provided above. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. Heteroaryl also includes groups in which a heteroaromatic ring is fused with one or more aryl, cycloaliphatic, and / or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. Heteroaralkyl can refer to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions are independently optionally substituted.

[0070] The term optionally substituted may refer to the replacement of one or more hydrogens of a specified moiety with a suitable substituent. Unless otherwise specified, an optionally substituted group has a suitable substituent at each substitutable position of the group, and when any structure has one or more positions that are substituted with multiple substituents selected from a specified group, the substituents may be the same or different at each position.

[0071] The term stable may refer to compounds that are substantially unchanged when subjected to conditions that permit their production or synthesis, detection, recovery, purification, and / or use as disclosed herein. Pharmaceutically acceptable salts may refer to salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, and fumarate. Examples of suitable salts include glucoheptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactic acid, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0072] Salts can be derived from suitable bases, including alkali metal, alkaline earth metal, and ammonium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Additionally, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, optionally formed with counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkylsulfonate, arylsulfonate, and the like.

[0073] Unless otherwise indicated, a structure depicted herein is also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of that structure. For example, the R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. In some cases, the enantiomeric excess is at least 50%, at least 60%, at least 70%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100%. Unless otherwise indicated, all tautomers of the compounds disclosed herein are within the scope of the invention. Because the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use enantiomers. In these cases, the final products or even intermediates can be separated into enantiomeric compounds by chemical or physical means known to those skilled in the art, or can be used directly in the synthesis.

[0074] Where tautomerism, e.g., keto-enol tautomerism, of the compounds disclosed herein or their prodrugs may occur, the individual forms, e.g., keto or enol forms, are claimed separately and together as mixtures in any ratio. The same applies to stereoisomers, e.g., enantiomers, cis / trans isomers, conformers, etc. If necessary, isomers can be separated by methods well known in the art, e.g., liquid chromatography. The same applies to enantiomers, e.g., by using a chiral stationary phase. Furthermore, an enantiomer can be isolated by converting it to a diastereomer, i.e., by coupling with an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound disclosed herein can be obtained from stereoselective synthesis using optically pure starting materials.

[0075] It is also contemplated that the compounds disclosed herein may include their isotopically labeled forms.Isotopically labeled forms of the compounds disclosed herein are identical to the compounds except that one or more atoms of the compound are replaced by one or more atoms with atomic masses or mass numbers different from the atomic masses or mass numbers of the atoms that normally occur in nature.Examples of isotopes that are readily commercially available and can be incorporated into compounds of formula (I) or (II) by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36Examples include, but are not limited to, Cl. Compounds of formula (I) or (II), their prodrugs, or any pharmaceutically acceptable salts containing one or more of the above 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 many beneficial ways. For example, 3 H or 14 Isotopically labeled compounds of formula (I) or (II) incorporating a radioactive isotope, such as C, are suitable for drug and / or substrate tissue distribution assays. These radioactive isotopes are particularly preferred due to their ease of preparation and superior detectability. Heavier isotopes, such as deuterium, 2 Incorporating H into compounds of formula (I) or (II) may have therapeutic advantages due to the higher metabolic stability of the isotopically labeled compounds. Higher metabolic stability directly translates into improved in vivo half-life or lower dosages. Isotopically labeled compounds of formula (I) or (II) can be adapted to the synthetic schemes disclosed herein and the procedures disclosed in the associated description, examples, and preparation sections, by replacing non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0076] The compounds of the present disclosure may be in the form of prodrug compounds. Prodrug compounds can refer to derivatives that are converted into biologically active compounds under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis, etc., each of which can be enzymatic or non-enzymatic. Examples of prodrugs are compounds in which the amino group in the compound is acylated, alkylated, or phosphorylated; the hydroxyl group is acylated, alkylated, phosphorylated, or converted to a borate; the carboxyl group is esterified or amidated; or the sulfhydryl group forms a disulfide bridge with a carrier molecule, e.g., a peptide, that selectively delivers the drug to a target and / or the cytosol of a cell. These compounds can be produced from the compounds disclosed herein according to well-known methods. Other examples of prodrugs are compounds in which the carboxylate in the compound is converted, for example, to an alkyl-, aryl-, choline-, amino-, acyloxymethyl ester, or linolenoyl ester.

[0077] According to one embodiment, the composition comprises a compound disclosed herein or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition disclosed herein can be effective to measurably inhibit HPK1 or a variant thereof in a biological sample or a patient. A therapeutically effective amount of the compound can be administered to a patient in need thereof. The patient or subject can refer to an animal, preferably a mammal, and even more preferably a human. The biological sample can refer to, but is not limited to, a cell culture or extract thereof, a biopsy or extract thereof obtained from a mammal, and blood, saliva, urine, feces, semen, tears, or other bodily 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 with which they are formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions disclosed herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. Pharmaceutically acceptable derivative means 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 directly or indirectly providing a compound disclosed herein.

[0079] The compositions disclosed herein can be administered orally, parenterally, by inhalation spray, topically, enterally, nasally, bucally, vaginally, or via an implanted reservoir. Parenteral administration can refer to subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intradural, intrahepatic, intralesional, and intracranial injection or infusion procedures. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions disclosed herein include aqueous or oily suspensions. These suspensions are formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be provided as sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[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. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When an aqueous suspension is required for oral use, the active ingredient can be combined with an emulsifying agent and / or suspending agent. If desired, certain sweeteners, flavoring agents, and / or coloring agents can be optionally added. Most preferably, the pharmaceutically acceptable compositions disclosed herein are formulated for oral administration. Such formulations can be administered with or without food.

[0081] The amount of the compounds disclosed herein that can be combined with carrier materials to produce a composition in a single dosage form can vary depending on the host being treated and the particular mode of administration. Preferably, provided compositions can be formulated so that a dosage of 0.01-100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions. In some examples, the dosage is 0.1-100 mg / kg, 0.1-50 mg / kg, 0.5-50 mg / kg, 1-50 mg / kg, 1-20 mg / kg, 5-20 mg / kg, 10-20 mg / kg, 10-50 mg / kg, or 10-100 mg / kg of patient body weight, or any other dosage range disclosed herein. In some examples, the compounds or compositions herein are administered continuously, multiple times daily, once daily, once every other day, weekly, biweekly, monthly, or bimonthly. A therapeutically effective amount of a compound or composition herein can vary according to factors known in the art, but a therapeutically effective amount can be about 0.1-100 mg / kg, 0.1-50 mg / kg, 0.5-50 mg / kg, 1-50 mg / kg, 1-20 mg / kg, 5-20 mg / kg, 10-20 mg / kg, or 10-50 mg / kg of patient body weight, or 10-100 mg / kg of patient body weight, or any other dosage range disclosed herein. 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, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound disclosed herein in a 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 a disease and act as a therapeutic agent. The aforementioned compounds and pharmaceuticals of the present invention are particularly used for therapeutic treatment. A therapeutically relevant effect is the partial alleviation of one or more symptoms of a disorder, or the partial or complete return to normal of one or more physiological or biochemical parameters associated with or causing a disease or pathological condition. Monitoring is considered a type of treatment when the compound is administered at separate intervals, for example, as long as the response is enhanced and the symptoms of the disease are completely eradicated. Either the same compound or different compounds can be applied. The methods disclosed herein can be used to reduce the likelihood of developing a disorder, or even prevent the onset of a disorder associated with HPK1 activity, or treat the symptoms that develop and continue.

[0083] The host or patient may belong to any mammalian species, such as a primate species, particularly humans, rodents (including mice, rats, and hamsters), rabbits, macaques, cows, dogs, cats, etc. Animal models are of interest in experimental investigations to provide models for the treatment of human diseases.

[0084] The compounds disclosed herein may be useful as anticancer agents for cancers that respond to HPK1 inhibition. In certain embodiments, the cancer may include, but is not limited to, cancer of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cell, head and neck, kidney, liver, lung, larynx and hypopharynx, ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, testis, stomach, skin, ureter, vagina, and vulva. In some examples, the cancer is mesothelioma, sarcoma, retinoblastoma, Wilms' tumor, leukemia, lymphoma, non-Hodgkin's lymphoma, chronic and acute myeloid leukemia, acute lymphoblastic leukemia, Hodgkin's disease, multiple myeloma, T-cell lymphoma, myelodysplastic syndrome, plasma cell neoplasm, and paraneoplastic syndrome.

[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 peripheral blood patterns, changes in blood hormone or cytokine concentrations, inhibition of a subsequent increase in tumor burden, stabilization of disease in a patient, evaluation of disease-related biomarkers or surrogate markers, an increase in overall survival in a patient, an increase in progression-free survival in a patient, an increase in disease-free survival in a patient, an improvement in quality of life in a patient, or modulation of disease comorbidities (e.g., but not limited to, pain, cachexia, mobilization, length of hospital stay, changes in peripheral blood patterns, weight loss, wound healing, fever).Significant improvements in the pharmacokinetic profile of compounds of formula (I) or (II) can thereby be obtained and can be quantitatively expressed in terms of an increase in in vivo half-life (t / 2), the concentration at maximum therapeutic effect (Cmax), and the area under the dose-response curve (AUC).

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

[0087] The compounds of formula (I) or (II) and / or physiologically acceptable salts thereof can be used as intermediates for the preparation of further medicament active ingredients. The medicaments are preferably prepared non-chemically, for example by combining the active ingredient with at least one solid, liquid and / or semi-liquid carrier or excipient, optionally together with one or more other active substances in a suitable dosage form.

[0088] Provided herein is a medicament that may contain at least one compound disclosed herein or its prodrug or pharmaceutically acceptable salt (including mixtures thereof in all ratios). A medicament may refer to any drug in the field of medicine that contains one or more compounds of formula (I) or formula (II) or preparations thereof (e.g., pharmaceutical compositions or pharmaceutical formulations) and can be used in the prevention, treatment, follow-up or aftercare of patients suffering from diseases associated with HPK1 activity in such a way that pathogenic alteration of their overall condition or the condition of a specific area of ​​the organism can be established at least temporarily.

[0089] In various embodiments, the active ingredient may be administered alone or in combination with other treatments. Synergistic effects may be achieved by using two or more compounds in a pharmaceutical composition, i.e., a compound of Formula (I) or (II) may be combined with at least another agent as the active ingredient, either another compound of Formula (I) or (II) or a compound of a different structural framework. The active ingredients may be used simultaneously or sequentially. In some embodiments, an HPK1 inhibitor compound disclosed herein is administered simultaneously with one or more additional therapeutic agents. In some embodiments, sequential administration includes administering the HPK1 inhibitor or the additional therapeutic agent about 1 minute, 5 minutes, 30 minutes, 1 hour, 5 hours, 24 hours, 48 ​​hours, or 1 week after each other. In some embodiments, the HPK1 inhibitor is administered by the same route of administration as the additional therapeutic agent. In some embodiments, the HPK1 inhibitor may be administered by a different route of administration than the additional therapeutic agent.

[0090] Therapeutic agents may include, but are not limited to, anti-inflammatory agents and / or one or more anti-tumor agents conventionally used in chemotherapy or targeted therapy. The compounds or compositions disclosed herein may be used as monotherapy or may be combined with therapeutic agents. Examples of antitumor agents include, but are not limited to, platinum compounds such as carboplatin, cisplatin, picoplatin, etc.; alkylating agents such as altretamine, carmustine, chlorambucil, mitobronitol, apaziquone, palifosfamide, etc.; DNA modifying agents such as bisantrene, decitabine, mitoxantrone, procarbazine, etc.; microtubule modifying agents such as docetaxel, eribulin, paclitaxel, vinblastine, etc.; topoisomerase inhibitors such as etoposide, razoxane, topotecan, etc.; anticancer antibodies such as bleomycin, mitomycin C, etc.; antimetabolites such as capecitabine, cladribine, etc.; hormones or antagonists such as tamoxifen, dexamethasone, etc.; cytokines such as interferons, 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, can include administering to the mammal an amount of a compound of Formula (I) or (II) disclosed herein, or a prodrug or pharmaceutically acceptable salt thereof, in combination with radiation therapy, wherein the amount of the compound, salt, or prodrug is effective to inhibit abnormal cell growth in the mammal or treat cancer or a symptom thereof in combination with radiation therapy. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapies described herein.

[0092] As used herein, the terms "treatment," "treat," and "treating" can refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to susceptible individuals (e.g., given a history of the condition or given genetic or other susceptibility factors) before symptoms develop. Treatment may also be continued after symptoms have resolved, for example, to prevent or delay recurrence.

[0093] Disclosed herein are kits comprising separate packs of a therapeutically effective amount of a compound disclosed herein or a physiologically acceptable salt or prodrug thereof, and, optionally, a therapeutically effective amount of a therapeutic agent. The kit may comprise suitable containers, such as a box, individual bottles, bags, or ampoules, and instructions for using or applying the kit. The kit may, for example, comprise separate ampoules, each containing a therapeutically effective amount of a compound disclosed herein and / or its pharmaceutically usable derivatives, solvates, and stereoisomers (including mixtures thereof in all ratios), and an effective amount of an additional therapeutic agent in dissolved or lyophilized form.

[0094] Experimental procedure As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods refer to the synthesis of specific compounds, it is understood that the following general methods, and other methods known to those of skill in the art, can be applied to all compounds and each subclass and species of these compounds, as described herein.

[0095] The symbols and conventions used in the following description of the processes, schemes, and examples are consistent with those used in the contemporary scientific literature, e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0096] Unless otherwise indicated, all temperatures are in degrees Celsius.

[0097] All solvents used were commercially available and were used without further purification. Reactions were typically carried out using anhydrous solvents under an inert atmosphere of nitrogen. Flash column chromatography was generally performed using silica gel 60 (particle size 0.035-0.070 mm).

[0098] All NMR experiments were recorded on either a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400 BBFO probe at 400 MHz for proton NMR, or a Bruker Mercury Plus 300 NMR spectrometer equipped with a Bruker 300 BBFO probe at 400 MHz for proton NMR, or a Bruker Avance III 400 NMR spectrometer equipped with a Bruker PABBO BB-1H / DZ GRD probe at 300 MHz for proton NMR. Most deuterated solvents typically contained 0.03%-0.05% v / v tetramethylsilane, which was used as a reference signal ( 1 H and 13 (d was set to 0.00 for both C and C). When 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 one of two instruments: A SHIMADZU LC-MS system consisting of a UFLC 20-AD system and an LCMS 2020 MS detector was used. The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0 × 50 mm. A linear gradient was applied, starting with 95% A (A: 0.05% trifluoroacetic acid (TFA) in water) over 2.2 min and ending with 100% B (B: 0.05% TFA in acetonitrile), for a total run time of 3.6 min. The column temperature was 40 °C, and the flow rate was 1.0 mL / min. The diode array detector scanned from 200 to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative mode. The mass spectrometer scanned from m / z 90 to 900 with a scan time of 0.6 s. 2. Agilent 1200 Series mass spectrometer from Agilent Technologies using either atmospheric pressure chemical ionization (APCI) or electrospray ionization (ESI). The diode array detector scanned from 200 to 400 nm. The mass spectrometer scanned from m / z 90 to 900 with a scan time of 0.6 seconds. Column: XBridge C8, 3.5 μm, 4.6 × 50 mm. Solvent A: water + 0.1% TFA. Solvent B: ACN [DEFINE] + 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. LC / MS Waters ZMD (ESI).

[0100] HPLC data were obtained from a SHIMAZU LC-MS instrument or an Agilent 1100 Series HPLC from Agilent Technologies using a column (XBridge C8, 3.5 μm, 4.6 × 50 mm) and two mobile phases (Mobile Phase A: water + 0.1% TFA; Mobile Phase B: ACN + 0.1% TFA). The flow rate was 2 mL / min. The gradient method was 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min: 5% B (unless otherwise indicated).

[0101] In general, compounds according to Formula (I) or (II) and related formulae described herein can be prepared from readily available starting materials. Where such starting materials are not commercially available, they can be prepared by standard synthetic techniques. Generally, the synthetic route for any individual compound of Formula (I) or (II) and related formulae will depend on the specific substituents of each molecule, and such factors are understood by those skilled in the art. The following general methods and procedures, described below in the Examples, can be used to prepare compounds of Formula (I) or (II) and related formulae. Reaction conditions (e.g., temperature, solvent, or co-reagent) depicted in the following schemes are given by way of example only and are not limiting. Where typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvent, etc.) are shown, it is understood that other experimental conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used; however, such conditions can be determined by one skilled in the art using routine optimization procedures. For all protection and deprotection methods, see Philip J. Kocienski, "Protecting Groups," Georg Thieme Verlag Stuttgart, New York, 1994 and Theodora W. Greene and Peter G.M.Wuts, "Protective Groups in Organic Synthesis," Wiley Interscience, 3 rd See Edition 1999.

[0102] Example 1: Synthesis of Compound 1 6-(2-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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 SOCl (5.00 mL, 66.02 mmol) was added three drops of DMF (dimethylformamide) at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 4 hours (at which point the mixture was a clear solution). The resulting mixture was concentrated under reduced pressure and co-evaporated with DCM four times to give 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 hour. 50 mL of water was added to the resulting mixture, which was then extracted with EA [ethyl acetate] (3 × 30 mL). The combined organic layer was washed with brine and dried over anhydrous Na2SO4. 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 NH in MeOH was stirred for 1 hour at 40° C. The resulting mixture was concentrated under reduced pressure to give 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 Na2CO3 (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 Na2SO4. 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 give 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), 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) were added at room temperature. The resulting mixture was stirred at 100 °C under an argon atmosphere for 2 hours. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 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: To a stirred mixture of 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-(2-hydroxy-2-methylpropoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (133.85 mg, 0.33 mmol) in 12.00 mL of 1,4-dioxane and 2.40 mL of HO was added AMPHOS-PdCl (16.47 mg, 0.02 mmol) and KPO (148.09 mg, 0.66 mmol) was added at room temperature. The resulting mixture was stirred at 100° C. under an argon atmosphere for 2 hours. 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 give 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 added. 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: YMC-ActusTriart C18 ExRS, 30 *Purification by 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in HO]), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18% B to 48% B, 48% B in 8 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 5) gave 6-[2-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (46.00 mg, 51.99%) as a yellow solid.

[0109] HPLC: purity 98.94%, RT=2.85 min. MS:m / z=480.2[M+H] + . 1 H NMR(300MHz,DMSO-d6,ppm):δ 9.92(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).

[0110] 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 [ka] 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) was added Pd(dppf)Cl (72.00 mg, 0.09 mmol) and 1,4-dioxane (8.00 mL) portionwise at 25 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The reaction was quenched with HO at 25 °C. The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO. 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 give (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 tert-butyl (3S,5S)-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), AMPHOS-PdCl (21.00 mg, 0.03 mmol), KPO (185.00 mg, 0.83 mmol), and HO (2.00 mL) were added portionwise at 25 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE:EA=20:80 to give tert-butyl (3S,5S)-3-{[8-carbamoyl-6-(5-cyanoquinolin-6-yl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (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 tert-butyl (3S,5S)-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 8.00 mL of DCM was added dropwise TFA (2.00 mL) at 25° C. The resulting mixture was stirred at 25° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The crude product was purified using the following conditions (column: Xselect CSH C18 OBD column 30 * Purification by preparative HPLC (150 mm 5 μm, n; mobile phase A: water (0.1% FA [formic acid]), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 30% B, 30% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 7.22; number of runs: 2) gave 6-(5-cyanoquinolin-6-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide; formic acid (51.30 mg, 62.1%) as a yellow solid.

[0113] HPLC: purity 91.6%, RT=2.6 min. MS:m / z=443.1[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.90(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).

[0114] 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 [ka] 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: To a stirred mixture of 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-dimethyl-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)dichloropalladium(II) (16.47 mg, 0.02 mmol) and KPO (148.05 mg, 0.66 mmol) at room temperature. The mixture was stirred at 100 °C under an argon atmosphere for 12 hours. 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 give 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 (90.00 mg, 67.4%) as a yellow solid.

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

[0116] HPLC: purity 98.03%, RT=2.04 min. MS:m / z=385.10[M+H] + . 1 H NMR(300MHz,DMSO-d6,ppm):δ 10.43(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).

[0117] 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 [ka] 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: To a stirred mixture of 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-(oxan-4-yl)-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)dichloropalladium(II) (16.47 mg, 0.02 mmol) and KPO (148.05 mg, 0.66 mmol) at room temperature. The resulting mixture was stirred at 100° C. for 2 hours under an argon atmosphere. 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-(oxan-4-yl)-1H-pyrazol-4-yl]pyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (110.00 mg, 80.29%) as a yellow solid.

[0118] 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-(oxan-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 added. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Xselect CSH C18 OBD column 30 *Purification by chromatography (HPLC) on a 150 mm 5 μm column (n); mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in HO]), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7% B to 37% B, 37% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 8.2; number of runs: 2) gave 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]pyrido[3,2-d]pyrimidine-8-carboxamide (43.20 mg, 55.14%) as a yellow solid.

[0119] HPLC: purity 99.74%, RT=2.13 min MS: m / z=441.15[M+H] + . 1 H NMR (300 MHz, DMSO-d, ppm): δ 9.99(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).

[0120] 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 [ka] tert-Butyl (3S,5S)-3-((6-(5-acetylthiophen-2-yl)-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluoropiperidine-1-carboxylate: To a stirred mixture of 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 equiv.) and (5-acetylthiophen-2-yl)boronic acid (57.49 mg, 0.33 mmol; 1.50 equiv.) in 1,4-dioxane (5.00 mL) and water (1.00 mL) was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (16.47 mg, 0.02 mmol) and KPO (148.05 mg, 0.66 mmol) at room temperature. 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 give 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, 64.79%) as a yellow solid.

[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 added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by prep-HPLC (column: XBridge Shield RP18 OBD column, 30 *Purification by HPLC (150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in HO]), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 19% B to 45% B, 45% B in 9 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) gave 6-(5-acetylthiophen-2-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (31.60 mg, 53.03%) as a yellow solid.

[0122] HPLC: purity 99.56%, RT=2.57 min MS: m / z=415.15[M+H] + . 1 H NMR(300MHz,DMSO-d6,ppm):δ 9.92(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).

[0123] 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 [ka] 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) was added n-BuLi (1.20 mL, 2.5 M in hexane) at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 1 hour under a nitrogen atmosphere. Then, a solution of tributyl(chloro)stannane (921.00 mg, 2.80 mmol) in THF (2.00 mL) was added dropwise at −78° C. The resulting mixture was stirred at −78° C. for 2 hours under a nitrogen atmosphere. The reaction was quenched at 0° C. by adding saturated NH4Cl (50 mL). The resulting mixture was extracted with EA (3 × 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 give 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 cataCXium A Pd G3 (35.00 mg, 0.05 mmol) in portions at room temperature under a N2 atmosphere. The resulting mixture was stirred at 100 °C under a N2 atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 45% EA in PE to give 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 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 (170.00 mg, 0.32 mmol) in DCM (3.00 mL) was added TFA (1.00 mL) dropwise at 25° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified using the following conditions (column: XBridge Shield RP18 OBD column, 30 *Purification by preparative HPLC (150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in HO]), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18% B to 44% B, 44% B in 9 min; wavelength: 254 nm; RT1 (min): 7) afforded 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: purity 98.9%, RT=2.39 min. MS:m / z=388.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.94(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),8.10(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).

[0127] 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 [ka] 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)diboron (2.60 g, 9.73 mmol), KOAc (608.00 mg, 5.89 mmol), and Pd(dppf)Cl-CHCl (338.00 mg, 0.39 mmol) in 1,4-dioxane (20.00 mL) was stirred at 100 °C under a nitrogen atmosphere for 16 hours. 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 × 100 mL). The combined organic layers were washed with brine (1 × 300 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 DCM / MeOH (10:1) to give 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] 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: 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 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), AMPHOS-PdCl (180.00 mg, 0.24 mmol) and tribasic potassium phosphate (31.00 mg, 0.14 mmol) were added portionwise at room temperature under a N atmosphere. The resulting mixture was stirred at 100 °C under a N atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 55% EA in PE to give 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 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 (180.00 mg, 0.33 mmol) in 3.00 mL of DCM was added dropwise TFA (1.00 mL) at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified using the following conditions (column: XBridge Shield RP18 OBD column, 30 *Purification by preparative HPLC using a 150 mm, 5 μm column; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in HO]), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 19% B to 44% B, 44% B in 9 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) gave 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: purity 98.3%, RT=2.36 min. MS:m / z=395.0[M+H] + . 1 H NMR(400MHz,DMSO,ppm)δ 10.02(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=1.8Hz,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).

[0131] 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 [ka] 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(pinacolato)diboron] (554.25 mg, 2.07 mmol) in 1,4-dioxane (15.00 mL) was added Pd(dppf)Cl (79.85 mg, 0.10 mmol) and AcOK (308.32 mg, 3.11 mmol) at room temperature. After stirring at 100 °C for 2 h under an argon atmosphere, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (4:1) to give 1-ethyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (340.00 mg, 97.22%) as a brown solid.

[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: To a stirred mixture of 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-ethyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (111.78 mg, 0.33 mmol) in 10.00 mL of DME and 2.00 mL of HO was added Pd(PPh) (26.87 mg, 0.02 mmol) and NaCO (73.95 mg, 0.66 mmol) at room temperature. 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 CHCl / MeOH (14:1) to give 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 (110.00 mg, 85.52%) as a yellow solid.

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

[0134] HPLC: 98.92% purity, 2.21 minutes. MS:m / z=399.2[M+H] + . 1 H NMR (400MHz,DMSO,ppm):δ 1.36(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=12.3,3.8Hz,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).

[0135] 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 [ka] 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: To a stirred mixture of 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-ethyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (111.78 mg, 0.33 mmol) in 10.00 mL of DME and 2.00 mL of HO was added P4 (26.87 mg, 0.02 mmol) and NaCO (73.95 mg, 0.66 mmol) at room temperature. 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 CHCl / MeOH (14:1) to give 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 (100 mg, 71.42%) as a yellow solid.

[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 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 (100.00 mg, 0.19 mmol) in DCM (6.00 mL) and TFA (1.00 mL) was added 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 RP18 OBD column, 30 *Purification using a 150 mm, 5 μm column; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in HO]), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 17% B to 44% B, 44% B in 9 min; wavelength: 254 nm; RT1 (min): 7) afforded 6-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (24.20 mg, 30.76%) as a yellow solid.

[0137] HPLC: purity 97.51%, RT=4.97 min. MS:m / z=399.2[M+H] + . 1 H NMR(300MHz,DMSO-d6,ppm):δ 9.91(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,1 H),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).

[0138] 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 [ka] 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) was added DAST (1.19 mL; 11.08 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was quenched with saturated NaHCO3 at 0 °C and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-bromo-5-(difluoromethyl)benzonitrile (1.11 g, crude) as a light yellow solid.

[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) was added KOAc (237.54 mg, 2.18 mmol) and Pd(dppf)Cl (55.93 mg, 0.07 mmol) at room temperature. After stirring at 100 °C for 2 hours under an argon atmosphere, the resulting mixture was filtered, and the filter cake was washed with dioxane. After filtration, the filtrate was concentrated under reduced pressure to give 5-(difluoromethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (240 mg, crude) as a brown solid.

[0140] Methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate: A stirred 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 added at room temperature. The resulting mixture was stirred at 80 °C for 4 hours. The filtrate was concentrated under reduced pressure. This gave methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (2.30 g, crude) as a yellow solid, which was used in the next step without purification.

[0141] Methyl (S)-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 hours. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (1:19) to afford tert-butyl (5S)-5-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-3,3-difluoropiperidine-1-carboxylate (380 mg, 40.67%) as a yellow solid.

[0142] tert-Butyl (S)-5-((8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylate: A stirred mixture of tert-butyl (5S)-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 equiv) in NH(g) / MeOH (5.00 mL) was added at room temperature. After stirring at 40 °C for 2 hours, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (1:6) to give tert-butyl (5S)-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] tert-Butyl (S)-5-((8-carbamoyl-6-(2-cyano-4-(difluoromethyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylate: To a stirred mixture of tert-butyl (5S)-5-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-3,3-difluoropiperidine-1-carboxylate (160.00 mg, 0.32 mmol) and 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) was added Pd(dtbpf)Cl (21.94 mg, 0.03 mmol) and KPO (214.33 mg, 0.96 mmol) at room temperature. After stirring at 80°C for 2 hours under an argon atmosphere, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with EtOAc / MeOH (13:1) to give tert-butyl (5S)-5-({8-carbamoyl-6-[2-cyano-4-(difluoromethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)-3,3-difluoropiperidine-1-carboxylate (190 mg, 93.88%) as a brown solid.

[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 tert-butyl (5S)-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 hour. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC (column: YMC-Actus Triart C18 ExRS, 30 *Purification by HPLC with a 150 mm column, 5 μm column; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in HO]), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B, 55% B in 8 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) gave 6-[2-cyano-4-(difluoromethyl)phenyl]-4-{[(3S)-5,5-difluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (49.40 mg, 37.61%) as a yellow solid.

[0145] HPLC purity 99.48%, RT=3.62 min. MS:m / z=460.15[M+H] + . 1 H NMR(400MHz,DMSO-d6,ppm):δ 9.91(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).

[0146] Example 11: Synthesis of Compound 11 (S)-4-((5,5-difluoropiperidin-3-yl)amino)-6-(4-methoxyphenyl)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] tert-Butyl (S)-5-((8-carbamoyl-6-(4-methoxyphenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-3,3-difluoropiperidine-1-carboxylate: To a stirred mixture of tert-butyl (5S)-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)Cl (14.65 mg, 0.02 mmol) and KPO (143.13 mg, 0.64 mmol) at room temperature. The resulting mixture was stirred at 80 °C under an argon atmosphere for 2 hours. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12:1) to give tert-butyl (5S)-5-{[8-carbamoyl-6-(4-methoxyphenyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-3,3-difluoropiperidine-1-carboxylate (100 mg, 77.6%) as a yellow solid.

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

[0148] HPLC purity 99.16%, RT=3.26 min. MS:m / z=415.05[M+H] + . 1H NMR(300MHz,DMSO-d6,ppm):δ 10.01(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).

[0149] 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) [ka] 1-(4-Bromophenoxy)-2-methylpropan-2-ol: To a solution of 4-bromophenol (20.00 g, 109.82 mmol, 1.00 equiv.) and 2,2-dimethyloxirane (12.50 g, 164.73 mmol) in DMF (100.00 mL) was added K2CO3 (47.93 g, 329.47 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 140 °C under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure to give 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), KOAc (37.93 g, 367.18 mmol, 3.00 equiv) and Pd(dppf)Cl (4.71 g, 6.12 mmol, 0.05 equiv) were added portionwise at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 hour. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous NaSO. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc:PE=1:6 to give 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 SOCl (5.00 mL, 66.02 mmol), DMF (3 drops) was added at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 4 hours (at which point the mixture was a clear solution). The resulting mixture was concentrated under reduced pressure and coevaporated with DCM four times to give 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 a nitrogen atmosphere for 1 hour. 50 mL of water was added to the resulting mixture, which was then extracted with EA (3 × 30 mL). The combined organic layer was 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 NH3 / MeOH (10.00 mL) was stirred for 1 hour at 40° C. The resulting mixture was concentrated under reduced pressure to give 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: To a stirred mixture of tert-butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (200.00 mg, 0.39 mmol) and 2-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 HO (0.50 mL) was added KPO (200.00 mg, 0.90 mmol) and AMPHOS-PdCl (34.00 mg, 0.05 mmol) in portions 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 63% EA in PE to give 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 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 (160.00 mg, 0.22 mmol, 1.00 equiv) in DCM (3.00 mL) was added TFA (1.00 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified using the following conditions (column: XBridge Prep OBD C18 column, 30 *Purification by preparative HPLC at 150 mm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 45% B, 45% B in 9 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 4) gave 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (71.00 mg, 70.3%) as a yellow solid.

[0156] HPLC: purity 98.3%, RT=2.94 min. MS:m / z=455.05[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.06(d,J=3.7Hz,1H),8.81(s,1H),8.56(s,1H),8.43-8.30(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),3.13-2.92(m,2 H),2.74(td,J=20.4,19.4,10.9Hz,2H),2.35-2.12(m,2H),1.24(s,6H).

[0157] 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 [ka] Methyl (S)-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 ethyl bis(propan-2-yl)amine (4.03 g, 29.61 mmol). After stirring at 40° C. for 2 hours under a nitrogen atmosphere, the resulting mixture was extracted with EtOAc. The combined organic layer was 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 give 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 NH(g) / MeOH (20.00 mL) was stirred at 40° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 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), CuCN (355 mg, 3.94 mmol), tris(dibenzylideneacetone)dipalladium (180 mg, 0.197 mmol), and dppf (218 mg, 0.39 mmol) were added at room temperature. The resulting mixture was stirred at 100° C. under an argon atmosphere for 5 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:8) to give tert-butyl (S)-3-((8-carbamoyl-6-cyanopyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (397 mg, 50.76%) as a yellow solid.

[0160] tert-Butyl (S)-3-((8-carbamoyl-6-(hydrazinyl(imino)methyl)pyrido[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 hydrogen diazene hydrate (0.17 mL; 2.81 mmol) in EtOH (20.00 mL) was stirred at 80° C. for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (9:1) to give tert-butyl (3S)-3-{[6-(N-aminocarbamimidoyl)-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl]amino}piperidine-1-carboxylate (230.00 mg, 68.7%) as a yellow solid.

[0161] Methyl (S)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-6-chloropyrido[3,2-d]pyrimidine-8-carboxylate: To a stirred solution of tert-butyl (3S)-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 Na2CO3 (54.44 mg, 0.49 mmol). The mixture was allowed to cool to 0 °C. Next, 2-methoxyacetyl chloride (55.73 mg, 0.49 mmol) in DMA (3.00 mL) was added dropwise to the above mixture. 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 (3 × 100 mL), washed with 1 × 100 mL of brine, and dried over Na2SO4. The resulting mixture was concentrated under reduced pressure. To the resulting mixture was added phenoxybenzene (20.00 mL). The resulting mixture was stirred at 180° C. for an additional 2 hours. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (9:1) to afford 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 (150.00 mg, 39.3%) as a yellow solid.

[0162] tert-Butyl (S)-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 added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30 *150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in HO]), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 40% B, 40% B in 8 min; wavelength: 254 nm; RT1 (min): 6; number of runs: 1) to give 6-[3-(methoxymethyl)-1H-1,2,4-triazol-5-yl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (6.60 mg, 11.0%) as a light yellow solid.

[0163] HPLC purity 98.09%, RT=2.88 min. MS:m / z=348.10[M+H] + . 1 H NMR(400MHz,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).

[0164] 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 [ka] 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 afforded 4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}morpholine-3-carbonitrile (1.30 g, 70.03%) as a light brown solid.

[0165] tert-Butyl (3S)-3-((8-carbamoyl-6-(4-((3-cyanomorpholino)methyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate: To a stirred mixture of 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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}morpholine-3-carbonitrile (152.67 mg, 0.35 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (17.32 mg, 0.02 mmol) and KPO (155.68 mg, 0.70 mmol) at room temperature. The resulting mixture was stirred at 100 °C under an argon atmosphere for 2 hours. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (9:1) to give 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 (180 mg, 90.43%) as a yellow solid.

[0166] 6-(4-((3-cyanomorpholino)methyl)phenyl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide: A stirred mixture of 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 (180.00 mg, 0.21 mmol) and TFA (2 mL) in DCM (6 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. 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 HO]), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30 B to 60 B in 8 min; 254 nm; RT1: 6.5; RT2: 7.2; Injection volume: 1 mL; Run number: 2) to give 6-{4-[(3-cyanomorpholin-4-yl)methyl]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (24.00 mg, 23.23%) as a yellow solid.

[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)) was purified by preparative chiral HPLC (column: CHIRALPAK IC, 3 *25 cm, 5 μm; Mobile phase A: Hex:DCM=1:1 (0.5% 2M NH3-MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 40 mL / min; Gradient: 50 B to 50 in 20 min B; 220 / 254 nm; RT1:13; RT2:17.9; injection volume: 0.5 mL; run number: 1) to give 6-(4-{[(3S)-3-cyanomorpholin-4-yl]methyl}phenyl)-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (15.30 mg) as a yellow solid 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 purity 93.42%, 4.02 min. MS:m / z=473.20[M+H] + . 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.04(d,J=3.8Hz,1H),8.84(s,1H),8.58(s,1H),8.37(dd,J=11.9,8.5Hz,3H),8.24(d,J=3.8Hz,1H),7.54(d ,J=8.0Hz,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=11.7,2.6Hz,1H),3 .51(td,J=11.5,2.7Hz,1H),3.05(d,J=11.9Hz,1H),2.83(d,J=10.9Hz,1H),2.74(t,J=10.3Hz,1H),2.66-2.52 (m,2H),2.45(dd,J=11.9,3.4Hz,1H),1.90(s,1H),1.82(d,J=9.8Hz,1H),1.68(s,1H),1.50(d,J=12.9Hz,1H).

[0169] Isomer 2: HPLC purity 92.36%, 3.99 min. MS:m / z=473.15[M+H] + . 1H NMR(400MHz,DMSO-d6,ppm):δ 10.04(d,J=3.6Hz,1H),8.85(s,1H),8.58(s,1H),8.37(dd,J=14.2,8.5Hz,3H),8.24(d,J=3.8Hz,1H),7 .55(d,J=8.1Hz,2H),4.32(s,1H),4.00-3.91(m,2H),3.82(d,J=10.9Hz,1H),3.72(s,2H),3.64(dd,J=1 1.7,2.6Hz,1H),3.51(td,J=11.5,2.7Hz,1H),3.07(d,J=12.2Hz,1H),2.84(s,1H),2.76(t,J=10.2Hz,1 H),2.66-2.52(m,2H),2.51-2.41(m,1H),1.91(s,1H),1.82(d,J=10.1Hz,1H),1.69(s,1H),1.52(s,1H).

[0170] 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 [ka] 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-dioxaborolane (500.00 mg, 1.60 mmol) and 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 gave 4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-3-(trifluoromethyl)morpholine (450.00 mg, 62.38%) as a yellow solid.

[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: To a stirred mixture of 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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-3-(trifluoromethyl)morpholine (438.27 mg, 1.09 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added KPO (610.64 mg, 2.73 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (67.92 mg, 0.09 mmol) under an argon atmosphere. The resulting mixture was stirred at 100 °C for 2 hours. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:9) to give 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 (387.00 mg, 57.1%) as a yellow solid.

[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 HO]), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20 B to 50 B in 8 min; 254 nm; RT1: 6.4; RT2: 7.8) to give 4-{[(3S)-piperidin-3-yl]amino}-6-(4-{[3-(trifluoromethyl)morpholin-4-yl]methyl}phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide (120.00 mg, 45.46%) as a yellow solid.

[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 purified by preparative chiral HPLC (column: CHIRAL ART Cellulose-SC, 2 × 25 cm, 5 μm; mobile phase A: Hex:DCM = 3:1 (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: IPA-HPLC; flow rate: 20 mL / min; gradient: from 20 B to 20 C in 19 min). B; 220 / 254 nm; RT1: 15.05; RT2: 17.883; injection volume: 0.5 mL; number of runs: 6) to give 4-{[(3S)-piperidin-3-yl]amino}-6-(4-{[(3S)-3-(trifluoromethyl)morpholin-4-yl]methyl}phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide (68.40 mg) as a yellow solid and 4-{[(3S)-piperidin-3-yl]amino}-6-(4-{[(3R)-3-(trifluoromethyl)morpholin-4-yl]methyl}phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide (64.80 mg) as a yellow solid.

[0174] Isomer 1: HPLC purity 98.92%, 3.78 min. MS:m / z=516.20[M+H] + . 1 H NMR(300MHz,DMSO-d6,ppm):δ 10.03(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=3.7H z,1H),7.53(d,J=8.1Hz,2H),4.05(d,J=14.1Hz,1H),4.00-3.85(m,3H),3.81-3.66(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 purity 99.08%, 3.77 min. m / z=516.20[M+H] + .

[0176] 1 H NMR(300MHz,DMSO-d6,ppm):δ 10.03(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),3.76-3.6 5(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).

[0177] 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) [ka] 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 K2CO3 (11.38 g, 78.25 mmol, 1.50 equiv) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 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 equiv) in THF (80.00 mL) was added titanium tetraisopropanolate (9.67 g, 32.32 mmol, 0.98 equiv) and bromo(ethyl)magnesium (30.60 mL) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 5% EA in PE to give 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), KOAc (3.65 g, 35.33 mmol, 3.42 equiv.) and Pd(dppf)Cl (0.91 g, 1.18 mmol, 0.11 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 h. The residue was purified by silica gel column chromatography eluting with 10% EA in PE. The residue was purified by reverse-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: ACN in water, gradient from 45% to 55% in 10 min; detector: UV 254 nm) to give 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] tert-Butyl (R)-3-((8-carbamoyl-6-(4-((1-hydroxycyclopropyl)methoxy)phenyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-4,4-difluoropiperidine-1-carboxylate: To a stirred mixture of tert-butyl (3R)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-4,4-difluoropiperidine-1-carboxylate (280.00 mg, 0.61 mmol) and 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 3.00 mL of DME and 1.00 mL of HO, NaCO (269.00 mg, 2.41 mmol) and Pd(PPh) (74.00 mg, 0.06 mmol) were added in portions at room temperature. 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 give 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 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 (190.00 mg, 0.30 mmol; 1.00 equiv) in DCM (3.00 mL) was added TFA (1.00 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 hour. 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: ACN in water, gradient from 20% to 25% in 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 HO]), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 18 B to 48 B in 8 min) to give 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: purity 93.7%, RT=3.20 min. MS:m / z=471.10[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 9.90(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),5.63(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).

[0183] 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 [ka] tert-Butyl (3S)-3-((8-carbamoyl-6-(4-morpholinocyclohex-1-en-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate: To a stirred mixture of 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-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 HO (3 mL) was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (52.24 mg, 0.07 mmol) and KPO (469.74 mg, 2.10 mmol) under an argon atmosphere. After stirring at 100° C. for 2 hours, the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (7:3) to give 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 (390.00 mg, 92.0%) as a yellow solid.

[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 hour. 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 HO]), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10 B to 40 B in 8 min) to give 6-[4-(morpholin-4-yl)cyclohex-1-en-1-yl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (107.20 mg, 38.8%) as a yellow solid.

[0185] HPLC purity 99.4%, RT=2.42 min. MS:m / z=438.25[M+H] + . 1 H NMR(400MHz,DMSO,ppm):δ 10.04(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,4H),3.05-2.9 0(m,2H),2.83-2.67(m,2H),2.60-2.52(m,4H),2.47(d,J=6.0Hz,4H),2.35-2.20(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).

[0186] 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) [ka] Ethyl 4-nitro-4-phenylbutanoate: To a stirred solution of (nitromethyl)benzene (7.00 g, 48.491 mmol) and ethyl acrylate (5.11 g, 48.491 mmol) in 1,4-dioxane (70.00 mL, 826.286 mmol) was added Amberlyst A-21 (21 g) at 0 °C under a nitrogen atmosphere. 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 by silica gel flash column chromatography (eluent: heptane / ethyl acetate 0–10%) to afford ethyl 4-nitro-4-phenylbutanoate (8 g, 65.99%) as a colorless oil.

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

[0188] 5-amino-5-phenylpiperidin-2-one: To a stirred solution of 5-nitro-5-phenylpiperidin-2-one (5.00 g, 21.57 mmol) in tetrahydrofuran (30.00 mL) under a N atmosphere, Raney Ni (2.00 g) was added portionwise. The resulting mixture was stirred overnight under a H atmosphere. The mixture was filtered and concentrated under reduced pressure to give 5-amino-5-phenylpiperidin-2-one (4.10 g, 18.32 mmol) as a white solid.

[0189] 3-Phenylpiperidin-3-amine: A solution of 5-amino-5-phenylpiperidin-2-one (4.10 g, 21.55 mmol) in tetrahydrofuran (50.00 mL) was added dropwise to a solution of lithium aluminum hydride (5.45 g, 43.10 mmol) in THF 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 5N NaOH, and finally 15.51 mL of water. Ethyl acetate was added. The mixture was filtered, and the filtrate was concentrated in vacuo to give 3-phenylpiperidin-3-amine (2.80 g, 13.11 mmol, 60.82%, yellow oil; crude product).

[0190] tert-Butyl 3-amino-3-phenylpiperidine-1-carboxylate: To a stirred solution of 3-phenylpiperidin-3-amine (2.80 g, 13.11 mmol) and triethylamine (2.09 g, 19.66 mmol) in DCM (30.00 mL) was added a solution of di-tert-butyl dicarbonate (3.61 g, 15.73 mmol) in DCM at 0 °C under a N atmosphere. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was quenched with NaCO (aq). The solution was extracted with DCM and concentrated under reduced pressure. The residue was purified by C18 flash column (30% ACN in water) to give tert-butyl 3-amino-3-phenylpiperidine-1-carboxylate (2.50 g, 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 overnight at 65 °C under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE:EA = 7:3 to give 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 stirred mixture of tert-butyl 3-{[6-chloro-8-(methoxycarbonyl)bis(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 NH(g) / MeOH (15.00 mL, 13%) was added at room temperature. The resulting mixture was stirred at 40° C. under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo to afford 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: To a stirred mixture of 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-{[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(PPh 34 (76.00 mg, 0.062 mmol), Na2CO3 (208.00 mg, 1.96 mmol), and water (4.00 mL) were added at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The residue was purified by silica gel column chromatography eluting with PE:EA = 4:6 to give 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 a nitrogen atmosphere for 2 hours. The reaction was quenched with NaHCO3 (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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo. This gave 6-{4-[(morpholin-4-yl)methyl]phenyl}-4-[(3-phenylpiperidin-3-yl)amino]pyrido[3,2-d]pyrimidine-8-carboxamide (200.00 mg, crude) 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 and 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 using a column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 50 B to 50 B in 15 min. Purification by HPLC with HPLC-MS / ...

[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: Purity 98.08%, RT = 4.38 min. MS: m / z = 524.25 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.92(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),7.27-7.18(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: Purity 97.3%, RT = 4.37 min. MS: m / z = 524.25 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.92(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).

[0198] 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 [ka] tert-Butyl (S)-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 HO (3 mL) was added KPO (339 mg, 1.521 mmol) and AMPHOS-PdCl (37 mg, 0.051 mmol) at 25° C. The resulting mixture was stirred at 100° C. under an argon atmosphere for 2 hours. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (6:1) to give tert-butyl (3S)-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 was added TFA (4 mL, 51.160 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 1 hour. The solvent was removed under vacuum, and the crude product was purified by preparative HPLC under the following conditions (2# SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 150 mm 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in HO]) and ACN (20% Phase B, up to 50% in 8 min); 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 purity 99.2%, 1.987 minutes. MS:m / z=397.4[M+H] + . 1 H NMR (300MHz, DMSO-d6, ppm): δ 10.04(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=5.2H z,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).

[0201] Example 20: Synthesis of Compound 20 4-((3-azabicyclo[3.1.0]hexan-1-yl)amino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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 methyl 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 a nitrogen atmosphere for 16 h. The solvent was removed, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:17) to give methyl 4-[[3-(tert-butoxycarbonyl)bicyclo[3.1.0]hexane-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 NH3 (g) in MeOH (3 mL) was stirred at 40 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo to afford 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 light 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 a solution of 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 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 HO (1 mL) was added KPO (167.29 mg, 0.749 mmol) and AMPHOS-PdCl (18.60 mg, 0.025 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours, and the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC / silica gel column chromatography eluting with CHCl / MeOH (9:1) to give 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 prepared under air. The resulting mixture was concentrated under vacuum. The crude product (85 mg) was purified by preparative HPLC under 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 HO]) and ACN (26% Phase B, up to 56% in 8 min); detector: UV 254 nm). The product was obtained. This gave 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 purity 97.8%, 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. Purification was performed on a Waters SFC Prep 200 (Phenomenex Cellulose-3, 250 × 21 mm, 5 μm particle size, 1000 Å pore size) using a column temperature of 40 °C and mobile phase A: methanol + 20 mm NH4OH B: CO2. The desired enantiomer was isolated at an isocratic flow rate of 100 g / min with 45% solvent A and 55% solvent B. The product-containing fractions were combined and concentrated under vacuum. Enantiomeric excess was measured on an Agilent 1100 equipped with an Aurora Fusion A5 SFC (Phenomenex Cellulose-3, 4.6 x 150 mm, 5 μm particle size, 1000A pore size) at a column temperature of 40 °C using mobile phases A: CO2 and B: methanol + 20 mM NH4OH. Enantiomers were chromatographed using a gradient from 95% solvent A + 5% solvent B to 40% solvent A + 60% solvent B over 3.5 min, an isocratic gradient at 40% solvent A + 60% solvent B from 3.5 to 5 min, and an isocratic gradient at 95% solvent A + 5% solvent B from 5 to 6 min (flow rate 3 mL / min). Chirality was arbitrarily assigned to peak 1 as 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% enantiomeric purity) with a RT of 3.251 min, and peak 2 as 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% enantiomeric purity) with a RT of 3.579 min.

[0207] 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 [ka] 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-aminoazepane-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 a nitrogen atmosphere for 4 hours. 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}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 NH3 (g) in MeOH (8 mL) was stirred at 40 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo to give 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 HO (1.00 mL) was added KPO (142.58 mg, 0.638 mmol) and AMPHOS-PdCl (15.85 mg, 0.021 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (9:1) to give 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 HCl (g) in MeOH (8 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The crude product (140 mg) was purified using the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Shield RP18 OBD column, 30 * Purification by preparative HPLC using a 150 mm column, 5 μm column; mobile phase: water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in HO]) and ACN (20% Phase B, up to 40% in 8 min); detector: UV 254 nm) afforded 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-(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: The product (40 mg) was purified under the following conditions (preparative HPLC-032): column, CHIRALPAK ID, 2 * Separation by chiral preparative HPLC using a 25 cm (5 μm) column; mobile phase: MTBE (10 mM NH3-MEOH) and EtOH (50% EtOH held for 14 min); detector: UV 254 nm) 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] Isomerate 1: HPLC purity 96.8%, RT = 2.351 min. MS: m / z = 462.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6,ppm):δ 10.04(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,2H),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] Isomerate 2: HPLC purity 95.2%, RT = 2.359 min. MS: m / z = 462.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6,ppm):δ 10.04(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,2H),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).

[0214] 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 [ka] 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 a nitrogen atmosphere for 4 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to give 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 NH3(g) in MeOH (10 mL) was stirred at 40 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo to afford 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 HO (2 mL) was added AMPHOS-PdCl (78 mg, 0.1 mmol) and KPO (690 mg, 3.2 mmol). After stirring 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 CHCl / MeOH (9:1) to give 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 HCl (g) in MeOH (8 mL) was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated in vacuo. The crude product (250 mg) was purified by preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30iA 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in HO]) and ACN (15% Phase B, up to 40% in 8 min). 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 separated by chiral preparative HPLC under the following conditions (Prep HPLC-083): column, CHIRALPAK IG, 3 × 25 cm, 5 μm; mobile phase, MTBE (10 mmHg 3-MEOH)- and MeOH (50% MeOHin held for 18 min); 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, 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%) was obtained 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%) was obtained as a light yellow solid.

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

[0220] 1H NMR(300MHz,DMSO-d6,ppm):δ 10.02(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,1 H),2.39(t,J=4.7Hz,4H),2.18(q,J=9.6,8.3Hz,1H),2.18-1.87(m,3H).

[0221] Isoform 2: HPLC purity 99.5%, RT = 2.13 min. MS: m / z = 462.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6,ppm):δ 10.02(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,1 H),2.39(t,J=4.7Hz,4H),2.18(q,J=9.6,8.3Hz,1H),2.18-1.87(m,3H).

[0222] Isomerate 3: HPLC purity 98.5%, RT = 2.07 min. MS: m / z = 462.2 [M+H] + . 1H NMR(300MHz,DMSO-d6,ppm):δ 10.02(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,1 H),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 purity 99.0%, RT=2.07 min. MS:m / z=462.2[M+H] + . 1 H NMR(300MHz,DMSO-d6,ppm):δ 10.02(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,1 H),2.39(t,J=4.7Hz,4H),2.18(q,J=9.6,8.3Hz,1H),2.18-1.87(m,3H).

[0224] Example 23: Synthesis of Compound 23 4-((2-aminoethyl)amino)-6-(4-(morpholinomethyl)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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 a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:7) to give 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 NH3(g) in MeOH (5 mL) was stirred at 40 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo to give 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 HO (1 mL) was added KPO (132.90 mg, 0.595 mmol) and AMPHOS-PdCl (14.78 mg, 0.020 mmol). The resulting mixture was stirred under a nitrogen atmosphere at 100 °C for 2 hours, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (9:1) to give 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 HCl (g) in MeOH (5 mL) was stirred at room temperature for 1 hour under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The crude product (60 mg) was purified by preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (10% Phase B, up to 30% in 8 min); detector: UV 254 nm). This gave 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 purity 98.0%, RT=1.923 min. MS:m / z=408.3[M+H] + .

[0229] 1 H NMR(300MHz,DMSO-d6,ppm):δ 10.08(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).

[0230] Example 24: Synthesis of Compound 24 (S)-6-(4-(2-methoxyethoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] Tert-butyl (S)-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 HO (3.00 mL) was added KPO (654 mg, 3.084 mmol) and AMPHOS-PdCl (89 mg, 0.119 mmol). 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 PE / EtOAc (1:1) to give 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 tert-butyl (3S)-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 a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (18% Phase B, up to 48% in 8 min); detector: UV 254 nm). (S)-6-(4-(2-methoxyethoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide (112.7 mg, 76.20%) product was obtained as a light yellow solid.

[0232] HPLC: purity 99.5%, RT=8.98 min. MS:m / z=423.1[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 10.04(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).

[0233] 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 [ka] 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 a nitrogen atmosphere for 16 hours. The resulting mixture was concentrated in vacuo to afford 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 NH3(g) in MeOH (3 mL) was stirred at 40 °C for 4 h under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo to afford 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: A solution of tert-butyl N-[1-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)propan-2-yl]carbamate (120 mg, 0.199 mmol), 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (115.23 mg, 0.361 mmol), AMPHOS-PdCl (22.30 mg, 0.030 mmol), KPO (200.10 mg, 0.896 mmol) in 1,4-dioxane (10 mL) and HO (3 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 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] 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 HCl (gas) in 1,4-dioxane (6 mL) was stirred under a nitrogen atmosphere at 25° C. for 2 hours. The solvent was removed and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (8:1) to give 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 under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in HO]) and ACN (28% Phase B, up to 58% in 8 min); detector: UV 254 nm). The product was purified by preparative HPLC under the following conditions (Agela High-pressure Flash): (column, CHIRALPAK IC, 3 *Chiral separation was performed by chiral preparative HPLC using a 25 cm column, 5 μm column; mobile phase: MTBE (10 mM NH3-MEOH) and EtOH (10% EtOH held for 20 min); 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 purity 94.8%, RT=2.472 min. MS:m / z=422.2[M+H] + .

[0239] 1 H NMR(300MHz,DMSO-d6,ppm):δ 10.08(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 purity 95.8%, RT=2.472 min. MS:m / z=422.2[M+H] + .

[0241] 1 H NMR(300MHz,DMSO-d6,ppm):δ 10.08(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).

[0242] 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 [ka] 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 CHCN (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 hours. 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 yellow 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 NH3(g) in MeOH (10.00 mL, 45.800 mmol) was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo to give 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: To a solution of 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-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (300.00 mg, 0.940 mmol) in 1,4-dioxane (9.00 mL, 106.237 mmol) and HO (1.71 mL, 94.919 mmol) was added KPO (420.00 mg, 1.880 mmol) and AMPHOS-PdCl (48.00 mg, 0.064 mmol). After stirring 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 DCM / MeOH (10:1) to give 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 using the following conditions (Agela High-pressure Flash): column, CHIRALPAK IG, 3 * Purification by chiral preparative HPLC (25 cm, 5 μm; mobile phase, MTBE (10 mM NH3-MEOH) and EtOH (50% EtOH held for 30 min); detector: UV 254 nm) gave 4-[[(3S,5R)-5-fluoropiperidin-3-yl]amino]-6-[4-(morpholin-4-ylmethyl)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (24.1 mg, 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 (24.1 mg, 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 (16.4 mg, 11.41%, 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) were obtained.

[0246] Isomer 1: HPLC: 96.6% purity, RT=2.37 min. MS:m / z=466.2[M+H] + . 1H 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] Isoform 2: HPLC: purity 93.9%, 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] Isoform 3: HPLC: purity 91.3%, RT = 2.67 min. MS: m / z = 466.3 [M+H] + . 1H 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] + . 1 H 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).

[0250] 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 [ka] 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 HO (1.60 mL) was added KPO (781.00 mg, 3.495 mmol, 3.97 equiv, 95.0%) and AMPHOS-PdCl (87.00 mg, 0.117 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 CHCl / MeOH (10:1) to give tert-butyl (3S)-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 a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo to afford 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 under a nitrogen atmosphere at 40° C. for 3 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (1:1) to give 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 (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 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 (45.00 mg, 0.080 mmol) in HCl (gas) in 1,4-dioxane (1.00 mL, 12%) was stirred at 25°C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The crude product was purified under the following conditions (2# SHIMADZU (HPLC-01)): Column, XBridge Shield RP18 OBD column, 30 *Purification by preparative HPLC using a 150 mm column, 5 μm column; mobile phase: water (0.05% HCl) and ACN (35% B phase to 55% in 8 min); detector: UV 254 nm) afforded 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: purity 95.0%, RT=4.52 min. MS:m / z=462.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.95(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).

[0255] 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 [ka] 4-[1-(4-bromophenyl)cyclopropyl]morpholine: A 30 mL sealed tube was charged with 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 mixture 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 using ethyl acetate / petroleum ether (1:10 to 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: A 30 mL sealed tube, purged with nitrogen and maintaining an inert atmosphere, was charged with 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 using ethyl acetate / petroleum ether (1:10 to 1:4). This gave 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] 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: To a solution of tert-butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (80.00 mg, 0.138 mmol) and 4-[1-[4-(4,4,5,5-tetramethyl-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 HO (1.43 mL, 79.377 mmol) was added KPO (120.00 mg, 0.537 mmol) and AMPHOS-PdCl (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 under vacuum, and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (12:1) to give 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 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 (40.00 mg, 0.044 mmol) in HCl (gas) in 1,4-dioxane (5.00 mL, 16.456 mmol) was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. The crude product was purified under the following conditions (2# SHIMADZU (HPLC-01)): Column, XBridge Shield RP18 OBD column, 5 μm, 19 *Purification by preparative HPLC at 150 mm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% [28% NH3 in HO]) and ACN (25% Phase B, up to 55% in 8 min; detector: UV 254 nm) afforded 6-[4-[1-(morpholin-4-yl)cyclopropyl]phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide (10 mg, 44.95%) as a yellow solid.

[0259] HPLC: purity 93.5%, 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).

[0260] 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 [ka] 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 a nitrogen atmosphere. The resulting mixture was stirred at 40° C. for 3 hours under a nitrogen atmosphere. The reaction was quenched at room temperature by adding water (60 mL). The resulting mixture was extracted with EtOAc (3×60 mL). The combined organic layers were washed with brine (2×30 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 PE / EtOAc (7:3) to give tert-butyl (3R)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-4,4-difluoropiperidine-1-carboxylate (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 NH(g) in MeOH (30.00 mL) was stirred for 1 hour at 40° C. The resulting mixture was concentrated in vacuo to give 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), 4-(hydroxymethyl)phenylboronic acid (435.00 mg, 2.719 mmol), AMPHOS-PdCl (134.00 mg, 0.180 mmol), KPO (1.20 g, 5.369 mmol) in 1,4-dioxane (10.00 mL) and HO (2.00 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 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] 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) was added dropwise MsCl (81.08 mg, 0.672 mmol) under an argon atmosphere at 0° C. The resulting mixture was stirred at room temperature under an argon atmosphere overnight. The resulting mixture was concentrated in vacuo. This gave 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), (3R,5S)-3,5-dimethylmorpholine (46.71 mg, 0.385 mmol), KCO (77.92 mg, 0.536 mmol) in ACN (2.00 mL) was stirred at 70 °C under a nitrogen atmosphere for 32 h. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:10) to give 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 (gas) in 1,4-dioxane (2.00 mL) was stirred at 25 °C under a nitrogen atmosphere for 2 hours. 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 to pH = 9 with saturated NaHCO (aq). The resulting mixture was extracted with CHCl (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous NaSO. 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: purity 99.0%, RT=4.429 min. MS:m / z=512.25[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 9.89(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).

[0267] Example 30: Synthesis of Compound 31 6-[4-(morpholin-4-ylmethyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 3-Amino-6-chloropyridine-2-carboxamide: To a mixture of 6-chloro-3-nitropyridine-2-carbonitrile (182.00 g, 793.244 mmol) in THF (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 (2 × 2000 mL). The combined organic layers were washed with NaHCO3 (aq) and brine (2 × 3000 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This afforded 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), NBS (62.24 g, 332.207 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 50° C. under a nitrogen atmosphere for 3 hours. The resulting mixture was filtered, and the filter cake was washed with PE (3×500 mL). The organic layer was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3×1500 mL). The combined organic layers were washed with brine (4×1000 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 PE / EtOAc (3:2) to give 3-amino-4-bromo-6-chloropyridine-2-carboxamide (47 g, 61.20%) as a brown solid.

[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. for 16 hours under a nitrogen atmosphere. The precipitated solid was collected by filtration and washed with PE (3×1000 mL). The resulting solid was dried in an oven under reduced pressure. 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 a solution of 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 mixture was heated to 100 °C and stirred overnight. The mixture was cooled to room temperature. The pH of the mixture was adjusted to 10–11 by adding NaOH (aqueous solution, 4 N) at 0 °C. The solid was removed by filtration. The filter was extracted with EtOAc (500 mL × 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 (12.40 g, crude product) as a dark brown oil.

[0271] Methyl 6-chloro-4-oxo-3H-pyrido[3,2-d]pyrimidine-8-carboxylate: 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), H2SO4 (0.50 mL, 9.193 mmol) was added dropwise at room temperature. The mixture was stirred at 60 °C for 4-8 h. When the reaction was complete, it was quenched by the addition of ice-cold water (200 mL). The precipitated solid was collected by filtration and dried to give methyl 6-chloro-4-oxo-3H-pyrido[3,2-d]pyrimidine-8-carboxylate (6.5 g, 55.60%) as a yellow solid.

[0272] Methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate: To a stirred solution of methyl 6-chloro-4-oxo-3H-pyrido[3,2-d]pyrimidine-8-carboxylate (7.30 g, 15.842 mmol) in SOCl (50.00 mL, 420.289 mmol) was added DMF (3 drops) at room temperature. The resulting mixture was stirred at 80 °C for 3 hours. The resulting mixture was concentrated in vacuo to give methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (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 give 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 NH3(g) in MeOH (20.00 mL, 152.622 mmol, 7 mol / L) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to give 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] tert-Butyl (3S)-3-([8-carbamoyl-6-[4-(morpholin-4-ylmethyl)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 (7.50 g, 17.198 mmol) and 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (5.98 g, 18.736 mmol) in 1,4-dioxane (50.00 mL) and HO (10.00 mL, 555.084 mmol, 32.28 equiv., 100%) was added KPO (11.26 g, 50.391 mmol) and AMPHOS-PdCl (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 × 300 mL). The combined organic layers were washed with brine (3 × 400 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, ACN in water, gradient from 60% to 70% in 10 min, 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 tert-butyl (3S)-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 (gas) in 1,4-dioxane (50.00 mL, 12%) was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration and washed with 1,4-dioxane (3 × 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 × 100 mL). The combined organic layers were washed with brine (1 × 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: purity 99.6%, RT=3.580 min. MS:m / z=448.1[M+H] + . 1 H NMR(400MHz,DMSO-d6,ppm)δ 10.06(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),7.5 0(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).

[0278] Example 31: Synthesis of Compound 32 6-[4-(morpholin-4-ylmethyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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 HO (10.00 mL) was added KPO (8023.28 mg, 35.908 mmol) and AMPHOS-PdCl (892.13 mg, 1.197 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours, 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 give tert-butyl (3S)-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 tert-butyl (3S)-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 HCl (g) in MeOH (35.00 mL, 12%) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The crude product was recrystallized from EtOAc (30 mL) to give 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: purity 98.8%, RT=5.54 min. MS:m / z=433.2[M+H] + . 1 H NMR (300MHz,DMSO-d6,ppm)δ 10.00(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).

[0281] Example 32: 4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)-6-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)pyridin[3,2-d]pyrimidine-8-carboxamide [ka] 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 K2CO3 (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 layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (3:1) to afford 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyrrolidin-3-ol (700 mg, 44.68%) as a brown oil.

[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 DMF (0.5 mL) dropwise. 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 coevaporated with DCM four times. This afforded methyl 4,6-dichloropyrido[3,2-d]pyrimidine-8-carboxylate (8 g, 79.6%) as a light brown solid.

[0283] tert-Butyl (3S,5S)-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 iPrNEt (12.17 mL; 68.01 mmol) in portions at room temperature under a N atmosphere. The resulting mixture was stirred at 40 °C for 2 h under a N atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 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 give tert-butyl (3S,5S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-5-fluoropiperidine-1-carboxylate (12.1 g, crude product) as a brown solid.

[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 NHMeOH (50 mL; 350.00 mmol) was added and stirred for 4 hours at 40° C. The resulting mixture was concentrated under reduced pressure to give tert-butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (8.5 g, crude product) as a brown solid.

[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: To a stirred mixture of 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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyrrolidin-3-ol (136.4 mg, 0.41 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (20.58 mg, 0.03 mmol) and KPO (185.06 mg, 0.83 mmol) at room temperature. After stirring at 100°C for 2 hours under an argon atmosphere, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with CHCl / MeOH (9:1) to give 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 (130 mg, 64.11%) as a yellow solid.

[0286] 4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)-6-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)pyridin[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 hours, 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, 37% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 5.6; number of runs: 2) to give 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-[6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl]pyrido[3,2-d]pyrimidine-8-carboxamide (28 mg, 35.2%) as a yellow-orange solid.

[0287] HPLC purity 92%, 9.02 minutes. 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).

[0289] 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 [ka] (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) was added TEA (4.09 mL; 27.98 mmol) and DMAP (0.12 g, 0.93 mmol) portionwise at 0 °C. Then, 4-methylbenzene-1-sulfonyl chloride (2.06 g, 10.26 mmol) in DCM (5.00 mL) was added dropwise 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 × 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 silica gel column chromatography eluting with 15% EA in PE to give (1-hydroxycyclobutyl)methyl 4-methylbenzene-1-sulfonate (1.8 g, 69.1%) as a white solid.

[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 potassium carbonate (1.07 g, 7.35 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80° C. under a nitrogen atmosphere. Water was added to the reaction mixture. The resulting mixture was extracted with EA (3×30 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 under the following conditions (column: C18 silica gel; mobile phase: ACN in water, gradient from 55% to 65% in 10 min; detector: UV 220 nm) to give 1-[(4-bromo-2,6-difluorophenoxy)methyl]cyclobutan-1-ol (550 mg, 55.6%) as a yellow oil.

[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 1,4-dioxane (5 mL), KOAc (165 mg, 1.60 mmol) and Pd(dppf)Cl (50 mg, 0.06 mmol) were added portionwise at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated to give 1-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclobutan-1-ol (200 mg, crude product) as a brown solid.

[0292] 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: tert-Butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (140 mg, 0. To a stirred solution of 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) and 1,4-dioxane (4.5 mL) and water (1.5 mL), Pd(AMPHOS)Cl (195 mg, 0.26 mmol) and potassium phosphate tribasic (22 mg, 0.10 mmol) were added portionwise at room temperature under a N atmosphere. The resulting mixture was stirred at 100 °C under a N atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 40% EA in PE to give 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 (200 mg, 87.3%) as a yellow-orange solid.

[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 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 (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 a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified using the following conditions (column: XBridge Prep OBD C18 column, 30 * Purification by preparative HPLC (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, 50% B in 8 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 4) afforded 6-{3,5-difluoro-4-[(1-hydroxycyclobutyl)methoxy]phenyl}-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (93.90 mg, 85.8%) as a yellow solid.

[0294] HPLC purity 93%, 3.35 minutes. MS:m / z=503.00[M+H] + 1 H NMR(DMSO,400MHz):δ 9.93(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),4.89(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

[0295] Example 34: 4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)-6-(4-((1-hydroxycyclopropyl)methoxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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 potassium carbonate (11.38 g, 78.25 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. 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 give methyl 2-(4-bromophenoxy)acetate (11.32 g, crude product) as a brown liquid.

[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) was added Ti(Oi-Pr) (13.18 g, 44.05 mmol) and bromo(ethyl)magnesium (41.76 mL; 125.28 mmol) dropwise 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 resulting mixture was filtered, and the filter cake was washed with EA (3 × 20 mL). The filtrate was extracted with EA (3 × 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 give 1-[(4-bromophenoxy)methyl]cyclopropan-1-ol (4.67 g, 40.3%) as a white solid.

[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 1,4-dioxane (30 mL), KOAc (5.68 g, 54.98 mmol) and Pd(dppf)Cl (1.42 g, 1.84 mmol) were added portionwise 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 under the following conditions (column: C18 silica gel; mobile phase: ACN in water, gradient from 45% to 50% in 10 min; detector: UV 254 nm) to give 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopropan-1-ol (1.70 g, 26.4%) as a white solid.

[0298] 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: 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 (300 mg, 0.55 mmol) and 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopropan-1-ol (513 mg, 1.47 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL), KPO (600 mg, 2.69 mmol) and Pd(dppf)Cl (47 mg, 0.07 mmol) were added portionwise at room temperature under a N atmosphere. The resulting mixture was stirred at 80 °C under a N atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 80% EA in PE to give 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 (200 mg, 36.4%) as a yellow solid.

[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 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 (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 a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified using the following conditions: Column: XBridge Prep OBD C18 column, 30 *Purification by preparative HPLC using a 150 mm column; 5 μm column; 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, 44% B in 9 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 3) gave 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-{4-[(1-hydroxycyclopropyl)methoxy]phenyl}pyrido[3,2-d]pyrimidine-8-carboxamide (42.7 mg, 50.1%) as a yellow solid.

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

[0301] 1H NMR (400MHz, DMSO, 24℃)δ 0.56-0.81(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,1H),8.28-8.49(m,3H),8.55(s,1H),8.80(s,1H),10.05(d,J=3.7Hz,1H).

[0302] Example 35: 4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)-6-(4-((1-hydroxycyclopentyl)methoxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] (1-Hydroxycyclopentyl)methyl 4-methylbenzene-1-sulfonate: 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) was added DMAP (55.00 mg, 0.41 mmol) dropwise at 25 °C. The resulting mixture was stirred at 25 °C under a nitrogen atmosphere for 12 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE:EA = 8:2 to give (1-hydroxycyclopentyl)methyl 4-methylbenzene-1-sulfonate (800 mg, 72.4%) as a yellow oil.

[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) in portions at 25 °C. The resulting mixture was stirred at 25 °C under a nitrogen atmosphere for 12 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopentan-1-ol (300 mg, crude product) as a yellow oil.

[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: To a stirred mixture of 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclopentan-1-ol (250 mg, 0.50 mmol) and tert-butyl (3S,5S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-5-fluoropiperidine-1-carboxylate (270 mg, 0.50 mmol) in 10 mL of DMF, Pd(AmPhos)Cl (37 mg, 0.05 mmol), KPO (333 mg, 1.49 mmol), and HO (2 mL) were added in portions at 25 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE:EA=1:1 to give 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 (200 mg, 55.6%) as a yellow solid.

[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 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 (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. for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The crude product was purified by HPLC under the following conditions: Column: YMC-ActusTriart C18 ExRS, 20 *Purification by preparative HPLC using a 250 mm, 5 μm column, 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, 55% B in 8 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) gave 4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-6-{4-[(1-hydroxycyclopentyl)methoxy]phenyl}pyrido[3,2-d]pyrimidine-8-carboxamide (64.40 mg, 53.2%) as a yellow solid.

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

[0307] 1 H NMR(400MHz,DMSO,23℃)δ 1.56-1.84(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=47.9H) z,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)

[0308] Example 36: 6-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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: To a stirred mixture of 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) and 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (63.33 mg, 0.27 mmol) in 1,4-dioxane (10 mL) and HO (2 mL) was added Pd(AmPhos)Cl (16.47 mg, 0.02 mmol) and KPO (148.09 mg, 0.66 mmol) at room temperature. After stirring 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 CHCl / MeOH (12:1) to give 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 (110 mg, 90.38%) as a yellow solid.

[0309] 6-(1-cyclopropyl-1H-pyrazol-4-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-{[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 added at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 ExRS, 20 *Purification by 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, 45% B in 8 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) gave 6-(1-cyclopropyl-1H-pyrazol-4-yl)-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (38.5 mg, 38.06%) as a yellow solid.

[0310] HPLC purity 99%, 2.16 minutes. 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).

[0312] 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 [ka] 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 K2CO3 (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 Na2SO4. 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 give 4-[(4-bromo-2,6-difluorophenoxy)methyl]oxan-4-ol (1.45 g, 33.94%) as a light yellow oil.

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

[0314] tert-Butyl (3S,5S)-3-[(8-carbamoyl-6-{3,5-difluoro-4-[(4-hydroxyoxan-4-yl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylate: To a stirred mixture of 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-{[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}oxan-4-ol (155.20 mg, 0.31 mmol) in 1,4-dioxane (5.00 mL) and water (1.00 mL) was added KPO (160.39 mg, 0.72 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (17.84 mg, 0.02 mmol) at room temperature. After stirring at 100°C for 2 hours under an argon atmosphere, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with CHCl / MeOH (7:3) to give tert-butyl (3S,5S)-3-[(8-carbamoyl-6-{3,5-difluoro-4-[(4-hydroxyoxan-4-yl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]-5-fluoropiperidine-1-carboxylate (125.00 mg, 68.07%) as a yellow solid.

[0315] 6-{3,5-difluoro-4-[(4-hydroxyoxan-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-hydroxyoxan-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 hour, the resulting mixture was concentrated under reduced pressure and purified by preparative HPLC (column: YMC-Actus Triart C18 ExRS, 30 *Purification by 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, 50% B in 8 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 3) gave 6-{3,5-difluoro-4-[(4-hydroxyoxan-4-yl)methoxy]phenyl}-4-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (63.3 mg, 74.58%) as a yellow solid.

[0316] HPLC purity 98%, 2.72 minutes. 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).

[0318] Example 38: 4-(((3R,4S)-4-fluoropiperidin-3-yl)amino)-6-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 1-(4-bromophenoxy)-2-methylpropan-2-ol: To a solution of 4-bromophenol (10.00 g) and 2,2-dimethyloxirane (6.25 g, 54.91 mmol, 82.34 mmol) in DMF (100.00 mL) was added potassium carbonate (23.95 g, 164.63 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 140 °C for 3 hours under a nitrogen atmosphere. 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 give 1-(4-bromophenoxy)-2-methylpropan-2-ol (13.40 g, crude product) as a yellow oil.

[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) and BPD (27.43 g, 51.31 mmol, 102.62 mmol) in 1,4-dioxane (130.00 mL), KOAc (15.90 g, 153.92 mmol) and PCl2 (3.95 g, 5.13 mmol) were added portionwise 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 give 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol (9.32 g, 59.0%) as a yellow solid.

[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 then the mixture was extracted with EA (3 × 15 mL). The combined organic layer was 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 give tert-butyl (3R,4S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}-4-fluoropiperidine-1-carboxylate (600 mg, 54.4%) as a yellow solid.

[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 NH in MeOH (10 mL) was stirred for 1 hour at 40° C. The resulting mixture was concentrated under reduced pressure to give tert-butyl (3R,4S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate (440 mg, crude product) as an orange-yellow solid.

[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: To a stirred solution of tert-butyl (3R,4S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)-4-fluoropiperidine-1-carboxylate (150 mg, 0.28 mmol) 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 1,4-dioxane (4 mL) and water (0.40 mL) was added PCl (26 mg, 0.03 mmol) and tribasic potassium phosphate (225 mg, 1.01 mmol) in portions at room temperature under a N atmosphere. The resulting mixture was stirred at 100 °C for 2 h under a N atmosphere. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine (15 mL) and dried over anhydrous NaSO. The resulting mixture was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with 75% EtOAc in PE to give 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 (140.00 mg, 84.06%) as a yellow solid.

[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 TFA (1 mL) dropwise at 0°C under a N atmosphere. The resulting mixture was stirred at room temperature under a N atmosphere for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30 *Purification by preparative HPLC using a 150 mm, 5 μm column; 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, 50% B in 9 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) gave 4-{[(3R,4S)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (56.70 mg, 60.22%) as a yellow solid.

[0324] HPLC 98%, 2.90 minutes. 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).

[0325] Example 39: (S)-6-(3,5-difluoro-4-((1-hydroxycyclobutyl)methoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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: To a stirred mixture of tert-butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (150 mg, 0.30 mmol) and 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 HO (3 mL) and 1,4-dioxane (10 mL), KPO (235 mg, 1.05 mmol) and PCl (26 mg, 0.03 mmol) were added portionwise 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 40% EA in PE to give 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 (190 mg, 99.0%) as a yellow solid.

[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 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 (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 a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified using the following conditions (column: Xselect CSH OBD column 30 *Purification by preparative HPLC using a 150 mm 5 μm column; 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, 53% B in 10 min; wavelength: 254 nm; RT1 (min): 7.58; number of runs: 2) gave 6-{3,5-difluoro-4-[(1-hydroxycyclobutyl)methoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (79.70 mg, 59.0%) as a yellow solid.

[0327] HPLC 95%, 3.43 minutes. 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).

[0328] Example 40: 6-(4-(2-cyano-2-hydroxypropoxy)phenyl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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) was added K2CO3 (9.42 g, 64.75 mmol) portionwise at 25 °C. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 12 h. The reaction was quenched with HO at 25 °C. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 column chromatography eluting with ACN:H2O=80:20 to give 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-one (2 g, 31.8%) as a yellow solid.

[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 ethyl bis(propan-2-yl)amine (4.03 g, 29.61 mmol). After stirring at 40 °C under a nitrogen atmosphere for 2 hours, the resulting mixture was extracted with EtOAc. The combined organic layer was 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 give tert-butyl (3S)-3-{[6-chloro-8-(methoxycarbonyl)pyrido[3,2-d]pyrimidin-4-yl]amino}piperidine-1-carboxylate (2.8 g, 64.6%) as a yellow solid.

[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 NH3 (g) in MeOH (20 mL) was stirred at 40 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure to give tert-butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (2.30 g, 85.9%) as a light yellow solid.

[0331] tert-Butyl (3S)-3-({8-carbamoyl-6-[4-(2-oxopropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate: To a stirred mixture of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-one (220 mg, 0.76 mmol) and tert-butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (250 mg, 0.50 mmol) in 1,4-dioxane (8 mL), PCl (37.41 mg, 0.05 mmol), KPO (336.45 mg, 1.51 mmol), and HO (2 mL) were added in portions at 25 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE:EA=4:6 to give tert-butyl (3S)-3-({8-carbamoyl-6-[4-(2-oxopropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (250 mg, 92.5%) as a yellow solid.

[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) and TMSCN (97 mg, 0.46 mmol, 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 under a nitrogen atmosphere at 25 °C for 12 h. The reaction was quenched with HO at room temperature. The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure to give 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, crude) as a yellow solid.

[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 HCl (5 mL; 10.00 mmol) dropwise at 25° C. The resulting mixture was stirred at 25° C. under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by column: Xselect CSH OBD column 30 *Purification by 150 mm 5 um; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 20% B, 20% B in 10 min; wavelength: 254 nm; RT1 (min): 9.37; number of runs: 2) gave 6-[4-(2-cyano-2-hydroxy-2-methylethoxy)phenyl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide hydrochloride (52.50 mg, 36.0%) as a yellow solid.

[0334] HPLC: 99%, 2.89 minutes. 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).

[0335] Example 41: (S)-6-(4-((1-hydroxycyclopentyl)methoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka]

[0336] tert-Butyl (3S)-3-[(8-carbamoyl-6-{4-[(1-hydroxycyclopentyl)methoxy]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]methyl}cyclopentan-1-ol (500 mg, 0.68 mmol. To a stirred mixture of 1,2-dimethyl-3,4-dichloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (200 mg, 0.40 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) in 12 mL of DMF, Pd(AMPHOS)Cl (30 mg, 0.04 mmol), KPO (270 mg, 1.21 mmol), and HO (3 mL) were added portionwise at 25 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE:EA=1:1 to give tert-butyl (3S)-3-[(8-carbamoyl-6-{4-[(1-hydroxycyclopentyl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (180 mg, 68.0%) as a yellow solid. 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. for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The crude product was purified by column: YMC-Actus Triart C18 ExRS, 30 *Purification by 150 mm, 5 μm column, 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, 55% B in 8 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) gave 6-{4-[(1-hydroxycyclopentyl)methoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (51.6 mg, 48.8%) as a yellow solid.

[0337] HPLC 99%, 3.54 minutes. M / S:m / z=463.25. 1 H 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).

[0338] Example 42: 4-(((3R,4R)-4-fluoropiperidin-3-yl)amino)-6-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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 potassium carbonate (23.95 g, 164.63 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 140 °C for 3 hours under a nitrogen atmosphere. 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 give 1-(4-bromophenoxy)-2-methylpropan-2-ol (13.40 g, crude product) as a yellow oil.

[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 1,4-dioxane (130.00 mL), KOAc (15.90 g, 153.92 mmol) and Pd(dppf)Cl (3.95 g, 5.13 mmol) were added portionwise 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 give 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol (9.32 g, 59.0%) as a yellow solid.

[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: To a stirred mixture of 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) and 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 HO (1 mL) was added KPO (160 mg, 0.72 mmol) and Pd(AMPHOS)Cl (27 mg, 0.04 mmol) in portions 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 50% EA in PE to give 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 (140 mg, 95.5%) as a yellow solid.

[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) was added TFA (1 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified using the following conditions (column: YMC-ActusTriart C18 ExRS, 30 *Purification by preparative HPLC using a 150 mm, 5 μm column, 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, 40% B in 8 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 2) gave 4-{[(3R,4R)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (58 mg, 60.4%) as a yellow solid.

[0342] HPLC 96%, 3.06 min. 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).

[0343] 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 [ka] 4-[(4-bromo-2,6-difluorophenoxy)methyl]oxan-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 K2CO3 (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 Na2SO4. 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 give 4-[(4-bromo-2,6-difluorophenoxy)methyl]oxan-4-ol (1.45 g, 33.94%) as a light yellow oil.

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

[0345] tert-Butyl (3S)-3-[(8-carbamoyl-6-{3,5-difluoro-4-[(-4-hydroxyoxan-4-yl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate: To a stirred mixture of 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-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}oxan-4-ol (388 mg, 0.78 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added KPO (260.69 mg, 1.17 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (29 mg, 0.04 mmol) at room temperature. After stirring at 100°C for 2 hours under an argon atmosphere, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with CHCl / MeOH (4:1) to give tert-butyl (3S)-3-[(8-carbamoyl-6-{3,5-difluoro-4-[(4-hydroxyoxan-4-yl)methoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (230 mg, 78.13%) as a dark green solid.

[0346] 6-{3,5-difluoro-4-[(4-hydroxyoxan-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-hydroxyoxan-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 hour, 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). *Purification by HPLC on a 150 mm 5 μm column; mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 16% B to 46% B, 46% B in 10 min; wavelength: 254 nm; RT1 (min): 8.25; number of runs: 2) gave 6-{3,5-difluoro-4-[(4-hydroxyoxan-4-yl)methoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (67.5 mg, 45.06%) as a yellow solid.

[0347] HPLC 99%, 3.03 min. 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).

[0348] Example 44: (S)-6-(4-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] Bromo[(4-bromophenyl)methyl]magnesium: A flame-dried 250 mL three-necked round-bottom flask equipped with a dropping funnel and reflux condenser was charged with activated magnesium (0.7 g, 27.37 mmol) and 5 mL of anhydrous EtO under a nitrogen atmosphere. The dropping funnel was charged with 1-bromo-4-(bromomethyl)benzene (6 g, 22.81 mmol) in anhydrous EtO (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 of the solution. The addition was completed over 30 min. The solution was then cooled and concentrated under reduced pressure to give bromo[(4-bromophenyl)methyl]magnesium (6.5 g, 83.1%) as a gray solution.

[0349] 4-[(4-Bromophenyl)methyl]oxan-4-ol: To a stirred solution of oxan-4-one (1.3 g, 12.34 mmol) in THF (20 mL) was added a solution of bromo[(4-bromophenyl)methyl]magnesium (6.50 g, 18.96 mmol) in EtO dropwise at 0 °C under N atmosphere. The resulting mixture was stirred at 0 °C under N atmosphere for 2 h. The resulting mixture was diluted with water (150 mL) and EtOAc (3 × 100 mL) was added. The resulting mixture was extracted with hexane (1L). 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 eluted with 15% EtOAc in PE to give the crude product. The crude product was purified on a C18 flash column eluted with 80% ACN in water to give 4-[(4-bromophenyl)methyl]oxan-4-ol (800 mg, 15.56%) as a white solid.

[0350] 4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}oxan-4-ol: To a stirred solution of 4-[(4-bromophenyl)methyl]oxan-4-ol (780.00 mg, 2.01 mmol) and BPD (1030.06 mg, 4.02 mmol) in 1,4-dioxane (6.00 mL) was added Pd(dppf)Cl (154.65 mg, 0.20 mmol) and KOAc (622.28 mg, 6.02 mmol) in portions at room temperature under a N atmosphere. The resulting mixture was stirred overnight at 100 °C under a N atmosphere. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous NaSO. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluted with 35% EtOAc in PE to give 4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}oxan-4-ol (700 mg, 97.97%) as a colorless oil.

[0351] {4-[(4-fluorooxan-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}oxan-4-ol (650 mg, 1.83 mmol) in DCM (5 mL) was added dropwise a solution of DAST (1.24 g, 7.31 mmol) in DCM (30 mL) at −78° C. under a N atmosphere. The resulting mixture was stirred at −78° C. under a N atmosphere for 1.5 hours. The reaction was quenched with water, and the mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give {4-[(4-fluorooxan-4-yl)methyl]phenyl}boronic acid (650 mg, 71.01%) as a yellow oil.

[0352] tert-Butyl (3S)-3-[(8-carbamoyl-6-{4-[(4-fluorooxan-4-yl)methyl]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate: To a stirred solution of tert-butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (200 mg, 0.44 mmol), {4-[(4-fluorooxan-4-yl)methyl]phenyl}boronic acid (554.32 mg, 1.11 mmol), and KPO (30 mg, 0.13 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL) was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4 mg, 0.01 mmol) in portions at room temperature. The resulting mixture was stirred at 100 °C under a N atmosphere for 2 hours. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4, and the resulting mixture was concentrated under reduced pressure.

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

[0354] 6-{4-[(4-fluorooxan-4-yl)methyl]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-{4-[(4-fluorooxan-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 TFA (1.00 mL) dropwise. The resulting mixture was stirred at 25° C. under a N atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by HPLC using the following conditions: column: XBridge Prep OBD C18 column, 19 *Purification by preparative HPLC (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: 20 B to 60 B in 8 min, 254 nm; RT1:6.5; number of injections: 2) gave 6-{4-[(4-fluorooxan-4-yl)methyl]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (60.50 mg, 54.01%) as a white solid.

[0355] HPLC: 99% purity, 4.564 minutes. 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).

[0356] Example 45: (S)-6-(6-methyl-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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 K2CO3 (77.26 g, 531.07 mmol) in DMF (500 mL) was added methyl 2-chloroacetate (51 g, 446.45 mmol) dropwise at room temperature under a N2 atmosphere. The resulting mixture was stirred overnight at 25 °C under a N2 atmosphere. The resulting mixture was poured into water (2 L), and the mixture was extracted with EtOAc (600 mL × 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 chromatography eluting with PE:EtOAc = 7:1 to give methyl 2-(3-bromo-5-methyl-1H-pyrazol-1-yl)acetate (65 g, 81.83%) as a white solid.

[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 2-[(1Z)-2-(1-cyano-1-methylethyl)diazen-1-yl]-2-methylpropanenitrile (18.54 g, 107.27 mmol) in portions at room temperature under a N atmosphere. The resulting mixture was stirred at 80 °C under a N atmosphere for 3 h. The reaction mixture was diluted with water (1 L) and extracted with DCM (3 × 400 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc:PE=8:1 to give methyl 2-[3-bromo-5-(bromomethyl)-1H-pyrazol-1-yl]acetate (22.00 g, 46.85%) as a yellow oil.

[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), sodium cyanide (3.77 g, 75.38 mmol) and water (4 mL; 219.76 mmol) were added portionwise at room temperature under a N atmosphere. The resulting mixture was stirred at 25 °C under a N atmosphere for 1 h. The resulting mixture was quenched with FeSO (aq) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous NaSO. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluted with PE:EA=7:1 and concentrated to give methyl 2-[3-bromo-5-(cyanomethyl)-1H-pyrazol-1-yl]acetate (8.5 g, 57.01%) as a light yellow solid.

[0359] 2-Bromo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one: To a stirred solution of methyl 2-[3-bromo-5-(cyanomethyl)-1H-pyrazol-1-yl]acetate (1.5 g, 5.06 mmol) and cobalt chloride hexahydrate (2.46 g, 10.11 mmol) in MeOH (50 mL) was added NaBH (1.06 g, 25.28 mmol) in portions at 0 °C under a N atmosphere. The resulting mixture was stirred at 25 °C under a N 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 × 50 mL), and the combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give 2-bromo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (1.1 g, 64.27%) as a white solid.

[0360] 2-Bromo-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one: To a stirred solution of 2-bromo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (1.1 g, 3.07 mmol) and MeI (0.4 mL; 6.15 mmol) in THF (15 mL) was added a solution of potassium tert-butoxide (1.0 M) in THF (5.99 mL; 6.15 mmol) at room temperature under a N atmosphere. The resulting mixture was stirred at 25 °C under a N atmosphere for 3 hours. The resulting mixture was diluted with water (50 mL). The solution was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by C18 flash eluting with 67% ACN in water to give 2-bromo-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (700.00 mg, 91.38%) as a white solid.

[0361] tert-Butyl (3S)-3-[(8-carbamoyl-6-{6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate: To a stirred solution of 2-bromo-6-methyl-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-7-one (140 mg, 0.56 mmol), tert-butyl (3S)-3-({8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (259 mg, 0.60 mmol), and hexamethyldistannane (245 mg, 0.74 mmol) in 1,4-dioxane (5 mL) was added cataCXium A Pd G3 (42 mg, 0.05 mmol) in portions at room temperature under a N atmosphere. The resulting mixture was stirred at 100 °C under a N atmosphere for 6 h. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine (15 mL) and dried over anhydrous NaSO. The resulting mixture was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with 75% EtOAc in PE to give tert-butyl (3S)-3-[(8-carbamoyl-6-{6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (180 mg, 57.76%) as a yellow solid.

[0362] 6-{6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl}-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-{6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-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 TFA (1.5 mL) dropwise at 0° C. The resulting mixture was stirred at 25° C. under a N atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified using the following conditions (column: Xselect CSH OBD column 30 *Purification by preparative HPLC on a 150 mm column (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 in 8 min at 254 nm; RT: 6.8; number of injections: 2) afforded 6-{6-methyl-7-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-d][1,4]diazepin-2-yl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (49.6 mg, 37.72%) as an off-white solid.

[0363] HPLC: 95% purity, 3.026 minutes. 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).

[0364] Example 46: (S)-6-(2-cyano-4-(2-methoxyethoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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 K2CO3 (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 × 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 (5:1) to give 2-bromo-5-(2-methoxyethoxy)benzonitrile (2 g, 81.4%) as a light yellow solid.

[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 1,4-dioxane (10 mL) was added KOAc (1.1 g, 10.65 mmol) and Pd(dppf)Cl (0.3 g, 0.39 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 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 (9:1) to give 5-(2-methoxyethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (800 mg, 61.2%) as a light yellow oil.

[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 HO (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 (3 × 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, and the residue was purified by preparative TLC (petroleum ether / ethyl acetate) (2:1) to give tert-butyl (3S)-3-({8-carbamoyl-6-[2-cyano-4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl}amino)piperidine-1-carboxylate (120 mg, 42.5%) as a light yellow solid.

[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) was added TFA (0.2 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The crude product was purified using the following conditions: Column: XBridge Prep OBD C18 column, 30 *Purification by preparative HPLC (150 mm; 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20 B to 50 B in 8 min, 254 nm) gave 6-[2-cyano-4-(2-methoxyethoxy)phenyl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (55.50 mg, 70.4%) as a yellow solid.

[0368] HPLC: 98% purity, 4.44 minutes. 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).

[0369] Example 47: (S)-6-(4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] Ethyl 2-(4-bromophenoxy)-2,2-difluoroacetate: To a solution of 4-bromophenol (3.00 g, 16.47 mmol) in DMF (10.00 mL) was added DBU (6.63 g, 41.37 mmol) portionwise at room temperature. 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 overnight under nitrogen. The resulting mixture was diluted with 200 mL of water and extracted with EA (3 × 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 give ethyl 2-(4-bromophenoxy)-2,2-difluoroacetate (2.47 g, 50.8%) as a yellow liquid.

[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) was added bromo(methyl)magnesium (5.67 mL; 17.01 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was quenched with water at 0° C. The mixture was extracted with EA (3×50 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 8% EA in PE. The residue was purified by reverse-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: ACN in water, gradient from 45% to 50% in 10 min; detector: UV 220 nm) to give 1-(4-bromophenoxy)-1,1-difluoro-2-methylpropan-2-ol (1.37 g, 70.4%) as a brown liquid.

[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 1,4-dioxane (10.00 mL), KOAc (0.96 g, 9.29 mmol) and Pd(dppf)Cl (0.38 g, 0.49 mmol) were added portionwise 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 70% DCM in PE to give (3R)-4-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (1.53 g, 86.5%) as a white solid.

[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 stirred mixture of tert-butyl (S)-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 HO (0.3 mL) was added KPO (361 mg, 1.62 mmol) and Pd(AMPHOS)Cl (41. To the resulting mixture was added 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 (200 mg, 46.6%) as a yellow solid. 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 give 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 (200 mg, 46.6%) as a yellow solid.

[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 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 (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 a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified using the following conditions: Column: XBridge Prep OBD C18 column, 30 * Purification by preparative HPLC (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: 28 B to 58 B in 10 min; 254 nm; RT 1:7.3) gave 6-[4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)phenyl]-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (62.50 mg, 53.2%) as a yellow solid.

[0374] HPLC: 94% purity, 3.221 minutes. 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).

[0375] Examples 48 and 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 [ka] 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) was added DIEA (4.07 g, 29.96 mmol) at room temperature under an argon atmosphere. The resulting mixture was stirred at 60 °C overnight under an argon atmosphere. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:2) to give 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 NH (g) in MeOH (20.00 mL) was stirred overnight at 60 °C under an argon atmosphere. The resulting mixture was concentrated in vacuo to give 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: To a stirred mixture of 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)) in 1,4-dioxane (10 mL) and water (2 mL) was 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, 7 To the resulting mixture was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (42.33 mg, 0.06 mmol) at room temperature. After stirring at 100 °C for 2 hours under an argon atmosphere, the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (19:1) to give 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, 70.58%) as a yellow solid.

[0378] 4-{[(3R,4R)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide: To 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) at room temperature. After stirring at room temperature for 1 hour, the crude product was purified by preparative HPLC (column: CHIRALPAK ID, 2 × 25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: IPA-HPLC; flow rate: 20 mL / min; gradient: 30 B to 30 B in 18 min; 220 / 254 nm; RT1: 9.301; RT2: 14.362; injection volume: 2 mL; number of runs: 5) to give 4-{[(3R,4R)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (120 mg, 78.83%) as a yellow-green solid.

[0379] 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: 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 preparative chiral 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 preparative chiral HPLC (column: CHIRALPAK ID, 2 x 25 cm, 5 um; mobile phase A: MTBE (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: IPA-HPLC; flow rate: 18 mL / min; gradient: 30 min in 21 min). Purification by HPLC (from B to 30 B; 220 / 254 nm; RT1: 10.597; RT2: 19.055; injection volume: 2.4 mL; run number: 3) afforded 4-{[(3R,4R)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (45.20 mg, 37.44%) as a yellow solid and 4-{[(3S,4S)-4-fluoropiperidin-3-yl]amino}-6-[4-(2-methoxyethoxy)phenyl]pyrido[3,2-d]pyrimidine-8-carboxamide (37.70 mg, 31.20%) as a yellow solid.

[0380] Ena1:HPLC: 98% purity, 3.068 minutes. 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] Ena2:HPLC: 98% purity, 3.070 minutes. 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).

[0382] Example 50: 4-(((S)-piperidin-3-yl)amino)-6-(4-(((R)-quinuclidin-3-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] ((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) (containing 4 Å molecular sieves) was added sodium tert-butoxide (9.07 g, 89.63 mmol) and cuprous iodide (1.50 g, 7.47 mmol) in portions at room temperature under a N atmosphere. The resulting mixture was stirred at 80 °C under a N atmosphere for 2 days. The resulting mixture was diluted with water (1000 mL) and extracted with EtOAc (3 × 400 mL). The combined organic layers were washed with brine (600 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column eluting with 10% MeOH in DCM to give (3R)-3-(4-iodophenoxy)-1-azabicyclo[2.2.2]octane (3.00 g, 10.99%) as a grey solid.

[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 Pd(PPh3)4 (333 mg, 0.27 mmol) in portions at room temperature under a N2 atmosphere. The resulting mixture was stirred at 110 °C overnight under a N2 atmosphere. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4. The residue was purified by silica gel column eluting with 10% MeOH in DCM to give (3R)-3-[4-(trimethylstannyl)phenoxy]-1-azabicyclo[2.2.2]octane (1.20 g, 93.32%) as a yellow oil.

[0384] tert-Butyl (3S)-3-[(6-{4-[(3R)-1-azabicyclo[2.2.2]octan-3-yloxy]phenyl}-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate: To a stirred solution of (-3-[4-(trimethylstannyl)phenoxy]-1-azabicyclo[2.2.2]octane (689 mg, 1.47 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 DMF (5.00 mL) was added Pd(PPh3)4 (58 mg, 0.05 mmol) in portions at room temperature under a N2 atmosphere. The resulting mixture was stirred at 100 °C under a N2 atmosphere for 4 h. The resulting mixture was diluted with water (15 mL) and ethanol. The mixture was extracted with HCl (3×10 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous NaSO. The residue was purified on a silica gel column eluted with 15% MeOH in DCM to give the crude product. The crude product was purified by preparative TLC (MeOH:DCM=1:8) to give tert-butyl (3S)-3-[(6-{4-[(3R)-1-azabicyclo[2.2.2]octan-3-yloxy]phenyl}-8-carbamoylpyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (80 mg, 26.16%) as a yellow solid.

[0385] 6-{4-[(3R)-1-azabicyclo[2.2.2]octan-3-yloxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a stirred solution of tert-butyl (3S)-3-[(6-{4-[(3R)-1-azabicyclo[2.2.2]octan-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 TFA (1 mL) dropwise at room temperature under N2 atmosphere. The resulting mixture was stirred at 25 °C under N2 atmosphere for 1 hour. The reaction was concentrated under reduced pressure. The residue was purified by HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30 * Purification by preparative HPLC (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, 50% B in 8 min; wavelength: 254 nm; RT1 (min): 7.0; number of runs: 2) gave 6-{4-[(3R)-1-azabicyclo[2.2.2]octan-3-yloxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (7.50 mg, 13.84%) as a yellow solid.

[0386] HPLC: 97% purity, 3.062 minutes. 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).

[0387] Example 51: 6-(4-((R)-2-hydroxypropoxy)phenyl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] (2R)-1-(4-bromophenoxy)propan-2-ol: To a stirred solution of 4-bromophenol (2 g, 10.98 mmol) and K2CO3 (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 Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by C18 flash column eluting with 56% ACN in water to give (2R)-1-(4-bromophenoxy)propan-2-ol (380 mg, 14.97%) as a yellow solid.

[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 1,4-dioxane (5 mL; 58.45 mmol) was added KOAc (307 mg, 3.13 mmol) and Pd(dppf)Cl (121 mg, 0.16 mmol) in portions at room temperature under a N atmosphere. The resulting mixture was stirred at 100 °C for 2 h. The resulting mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by C18 flash column to give (2R)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-2-ol (300 mg, 69.0%) as a yellow solid.

[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) was added NaCO (162 mg, 1.45 mmol) and Pd(PPh) (59 mg, 0.05 mmol). After stirring at 80 °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 70% EA in PE to give tert-butyl (3S)-3-[(8-carbamoyl-6-{4-[(2R)-2-hydroxypropoxy]phenyl}pyrido[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (200 mg, 76.8%) as a yellow solid.

[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 hour. The residue was purified by HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30 *Purification by preparative HPLC at 150 mm, 5 μm; mobile phase A: water (10 mmol / l NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26 B to 56 B in 9 min; 254 nm; (RT 1:7) gave 6-{4-[(2R)-2-hydroxypropoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (67 mg, 45.6%) as a yellow solid.

[0391] HPLC purity 98%, 2.89 min, MS: m / s=423.15[M+H] + . 1 H 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).

[0392] Example 52: (S)-6-(4-(3-morpholinopropoxy)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 6-{4-[3-(morpholin-4-yl)propoxy]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-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-1,3,2-dioxaborolan-2-yl)phenoxy]propyl}morpholine (258.74 mg, 0.71 mmol) in 1,4-dioxane (10 mL) and HO (2 mL) was added KPO (316.31 mg, 1.42 mmol) and bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (35.18 mg, 0.05 mmol). After stirring at 80 °C under nitrogen atmosphere for 2 h, the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12:1) to give 6-{4-[3-(morpholin-4-yl)propoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (196 mg, 66.2%) as a yellow solid.

[0393] 6-{4-[3-(morpholin-4-yl)propoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide: To a 50 mL round-bottom flask was added 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 at room temperature. The mixture was stirred at room temperature for 2 hours. 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, 50% B in 9 min; wavelength: 254 nm; RT1 (min): 7.2; number of runs: 2) to give 6-{4-[3-(morpholin-4-yl)propoxy]phenyl}-4-{[(3S)-piperidin-3-yl]amino}pyrido[3,2-d]pyrimidine-8-carboxamide (73.7 mg, 55.9%) as a yellow solid.

[0394] HPLC purity 95%, 2.26 minutes, 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).

[0395] Example 53: 6-(4-((S)-1-morpholinoethyl)phenyl)-4-(((S)-piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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 overnight at 100 °C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 300 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 PE / EtOAc (3:7) to give 4-[1-(4-bromophenyl)ethyl]morpholine (3.3 g, 80.18%) as a yellow oil.

[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 (594.99 mg, 0.692 mmol) in CHCl. ​​After stirring at 100 °C for 2 h under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give 4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]morpholine (2.1 g, 95.54%) as a yellow oil.

[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 a solution of 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-(4,4,5,5-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 HO (1 mL, 55.508 mmol) was added KPO (232 mg, 1.038 mmol) and Pd(Amphos)Cl (21 mg, 0.028 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (95:5) to give 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 (210 mg, 88.28%) as a yellow solid.

[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 (gas) in 1,4-dioxane (2 mL, 4.204 mmol, 14.47 equiv., 12%) was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated in vacuo. The crude product (210 mg) was purified using the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 *The product was purified by preparative HPLC (150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.05% NH4OH) and ACN (20% Phase B, up to 50% in 8 min; detector, UV 254) to give 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. This was separated by chiral preparative HPLC to give two single isomers, i.e., 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 (49.90 mg, 34.7%) as a light yellow solid.

[0399] HPLC isomer 1: 96% purity, 2.18 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).

[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).

[0401] Example 54: (S)-6-(4-((methylsulfonyl)methyl)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 2-[4-(methanesulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of 1-bromo-4-(methanesulfonylmethyl)benzene (300 mg, 1.144 mmol) and BPD (612 mg, 2.290 mmol) in dioxane (30 mL, 340.502 mmol) was added Pd(dppf)Cl (88 mg, 0.114 mmol) and KOAc (355 mg, 3.436 mmol). After stirring at 100 °C for 3 h under a nitrogen atmosphere, the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (9:1) to give 2-[4-(methanesulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (310 mg, 77.76%) as a yellow oil.

[0402] tert-Butyl (3S)-3-([8-carbamoyl-6-[4-(methanesulfonylmethyl)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 (150 mg, 0.332 mmol) and 2-[4-(methanesulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (231 mg, 0.664 mmol) in dioxane (10 mL, 118.041 mmol) and HO (2 mL, 111.017 mmol) was added Pd(Ampos)Cl (25 mg, 0.033 mmol) and KPO (222 mg, 0.995 mmol). After stirring at 100°C for 3 hours under nitrogen atmosphere, the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (8:1) to give tert-butyl (3S)-3-([8-carbamoyl-6-[4-(methanesulfonylmethyl)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (155 mg, 86.41%) as a yellow solid.

[0403] 6-[4-(methanesulfonylmethyl)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-(methanesulfonylmethyl)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 hours. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30 *Purification by chromatography (HPLC) on a 150 mm column, 5 μm column; 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, 54% B in 8 min; wavelength: 254 nm; RT1 (min): 6.48; number of runs: 2) gave 6-[4-(methanesulfonylmethyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide (54.1 mg, 43.38%) as a yellow solid.

[0404] HPLC purity 98%, 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 [ka] 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 HO (2 mL, 111.017 mmol) was added Pd(Amphos)Cl (34 mg, 0.046 mmol) and KPO (298 mg, 1.334 mmol). After stirring at 100° C. for 2 h under nitrogen atmosphere, the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:99) to give tert-butyl (3S)-3-([8-carbamoyl-6-[6-(2-methoxyethoxy)pyridin-3-yl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (156 mg, 65.24%) as a yellow solid.

[0405] 6-[6-(2-methoxyethoxy)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-(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) was prepared. After stirring at room temperature for 1 hour, the residue was purified by preparative HPLC (column: Atlantis HILIC OBD column, 19 * 150mm *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, 47% B in 8 min; wavelength: 254 nm; RT1 (min): 6.2; number of runs: 2) to give 6-[6-(2-methoxyethoxy)pyridin-3-yl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide (78.1 mg, 67.83%) as a yellow solid.

[0406] HPLC purity 99%, 2.446 min, MS: m / s=424.2[M+H] + . 1 H 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).

[0407] Example 56: (S)-6-(4-((3-fluoro-3-methylazetidin-1-yl)methyl)phenyl)-4-(piperidin-3-ylamino)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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-dioxaborolane (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 CAN (5.00 mL, 95.123 mmol) was stirred at 50 °C for 3 h. The resulting mixture was filtered, and the cake was washed with ACN. The filtrate was concentrated under reduced pressure. This gave 3-fluoro-3-methyl-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]azetidine (1.2 g, 86.05%) as an off-white oil.

[0408] 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: To a solution of tert-butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (150 mg, 0.332 mmol) and 3-fluoro-3-methyl-1-[[4-(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 HO (2 mL, 111.017 mmol) was added Pd(Amphos)Cl (25 mg, 0.034 mmol) and KPO (222 mg, 0.994 mmol). After stirring at 100°C for 3 hours under nitrogen atmosphere, the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (8:1) to give 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 (185 mg, 77.40%) as a yellow oil.

[0409] 6-[4-[(3-fluoro-3-methylazetidin-1-yl)methyl]phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide: To a 50 mL round-bottom flask was added 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) at room temperature. The mixture was stirred at room temperature under an argon atmosphere for 2 hours. 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, 53% B in 8 min; wavelength: 254 nm; RT1 (min): 6.4; number of runs: 2) to afford 6-[4-[(3-fluoro-3-methylazetidin-1-yl)methyl]phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide (36.7 mg, 31.99%) as an off-white solid.

[0410] HPLC purity 98%, 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).

[0411] Example 57: 4-[(3S)-piperidin-3-ylamino]-6-(4-[[(2S)-2(trifluoromethyl)morpholin-4-yl]methyl]phenyl)pyrido[3,2-d]pyrimidine-8-carboxamide [ka] (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-dioxaborolane (500 mg, 1.650 mmol), (2S)-2-(trifluoromethyl)morpholine hydrochloride (400 mg, 1.984 mmol), and K2CO3 (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 to give (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] 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: To a solution of tert-butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (150 mg, 0.333 mmol) and (2S)-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 HO (2 mL) was added Pd(AMPHOS)Cl (26 mg, 0.035 mmol) and KPO (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 CHCl / MeOH (12:1). 、 Obtained 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 (168 mg, 73.28%) as a yellow solid.

[0413] 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 hour, the crude product was purified using the following conditions: Column: XBridge Prep OBD C18 column, 30 * Purification by preparative HPLC (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, 70% B in 8 min; wavelength: 254 nm; RT1 (min): 6.8) gave 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: purity 97%, RT=2.449 min MS: m / z=516.2[M+H] + . 1H 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).

[0415] Example 58: 6-[4-(1-hydroxycyclopropyl)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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) under a nitrogen atmosphere at 0 °C, Ti(i-PrO) (5.42 g, 18.117 mmol) and EtMgBr (17.20 mL, 26.070 mmol) were added dropwise. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 100 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 14% EtOAc in PE to give 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: To a stirred solution of 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-[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 HO (0.80 mL) was added NaCO (262 mg, 2.348 mmol) and Pd(PPh) (72 mg, 0.059 mmol) portionwise under a nitrogen atmosphere at room temperature. 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 give 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 TFA (1.00 mL) dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The crude product was purified using the following conditions (2#SHIMADZU (HPLC-01)): Column, Xselect CSH OBD column 30 *Purification by preparative HPLC using a 150 mm column, 5 μm column; mobile phase, water (0.1% FA) and ACN (5% phase B, up to 30% in 8 min); detector, UV 254, gave 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-propanoylphenyl)pyrido[3,2-d]pyrimidine-8-carboxamide formate (19.5 mg, 15.51%) as a yellow solid.

[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 HNMR(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),2.98(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).

[0419] Example 59: 6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 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: To a solution of tert-butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (120 mg, 0.275 mmol) and 1-methyl-4-[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 HO (1.00 mL) was added KPO (168 mg, 0.752 mmol) and Pd(Amphos)Cl (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 CHCl / MeOH (9:1) to give 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 stirred 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 for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified under the following conditions (2#SHIMADZU (HPLC-01)): Column: XBridge Prep OBD C18 column, 30 *The product was purified by preparative HPLC using a 150 mm column, 5 μm column; mobile phase: water (10 mmol / L NH4HCO3 + 0.05% NH4OH) and ACN (20% Phase B, up to 50% in 8 min; detector: UV 254 nm) to give 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=2.914 min, 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).

[0422] Example 60: 6-(4-[[(3S)-3-fluoropyrrolidin-1-yl]methyl]phenyl)-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide [ka] (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-dioxaborolane (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 to give (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] 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: To a solution of tert-butyl (3S)-3-([8-carbamoyl-6-chloropyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate (150 mg, 0.343 mmol) and (3S)-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 HO (2.00 mL) was added Pd(AMPHOS)Cl (25 mg, 0.034 mmol) and KPO (222 mg, 0.994 mmol). After stirring at 100°C under nitrogen atmosphere for 3 hours, the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (8:1) to give 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 (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, 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) were added at room temperature. The mixture was stirred at room temperature under an argon atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The desired product could be detected by LCMS. The residue was purified by preparative HPLC to give 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 HNMR(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).

[0425] Example 61: 6-[4-(2-methoxy-2-methylpropoxy)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide [ka] 1-(4-bromophenoxy)-2-methylpropan-2-ol: To a stirred solution of 4-bromophenol (2.00 g, 10.982 mmol) and K2CO3 (4.79 g, 32.946 mmol) in DMF (20.00 mL) was added 2,2-dimethyloxirane (1.25 g, 16.469 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 140 °C for 4 hours under a nitrogen atmosphere. 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 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) was added NaH (0.35 g, 8.751 mmol) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 10 minutes under a nitrogen atmosphere. To the above mixture was added CHCl (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 (3×50 mL). The combined organic layers were washed with brine (1×100 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: ACN in water, gradient from 70% to 80% in 10 min; detector: UV 254 nm, to give 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)Cl (0.36 g, 0.461 mmol) and KOAc (1.42 g, 13.702 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 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: ACN in water, gradient from 65% to 75% in 10 min; detector: UV 254 nm, to give 2-[4-(2-methoxy-2-methylpropoxy)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-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate: To a stirred solution of 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-[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 HO (0.80 mL) was added NaCO (188 mg, 1.685 mmol) and Pd(PPh) (52 mg, 0.043 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The residue was purified by silica gel column chromatography eluting with 38% EtOAc in PE to give 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; Formic acid: 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 TFA (0.80 mL) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The crude product was purified using the following conditions (2#SHIMADZU (HPLC-01)): Column, Xselect CSH OBD column 30 *Purification by preparative HPLC using a 150 mm column, 5 μm column; mobile phase, water (0.1% FA) and ACN (30% phase B, up to 50% in 8 min); detector, UV 254) gave 6-[4-(2-methoxy-2-methylpropoxy)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide; formic acid (60.0 mg, 40.24%) as a yellow solid. HPLC:98%,RT=3.053 min MS:m / z=451.2[M+H] + 1 H NMR(400MHz,DMSO-d6):9.99(d,J=3.7Hz,1H),8.80(d,J=2.0Hz,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).

[0430] Example 62: 6-[4-(2-hydroxy-2-methylpropoxy)phenyl]-4-[(3S)-piperidin-3-ylamino]pyrido[3,2-d]pyrimidine-8-carboxamide [ka] tert-Butyl (3S)-3-([8-carbamoyl-6-[4-(2-hydroxy-2-methylpropoxy)phenyl]pyrido[3,2-d]pyrimidin-4-yl]amino)piperidine-1-carboxylate: To a stirred solution of 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-(4,4,5,5-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 HO (0.60 mL, 31.640 mmol) was added NaCO (157 mg, 1.407 mmol) and Pd(PPh) at room temperature under a nitrogen atmosphere. 34 (43 mg, 0.035 mmol) was added portionwise. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The residue was purified by silica gel column chromatography eluting with 38% EtOAc in PE to give 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 TFA (0.60 mL, 7.674 mmol) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature...

Claims

1. Compounds of Formula I: 【Chemistry 1】 [In the formula, R １ , R ２ , R ３ and R ４ are each independently selected from the group consisting of H and halogen; R ５ is H, halogen, —O—C １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ selected from the group consisting of haloalkyl, and -CN; X is N and CR ６ is selected from the group consisting of Y is N and CR ７ is selected from the group consisting of R ６ and R7 are each independently H, halogen, or C １ -C ６ is selected from the group consisting of alkyl, A is absent or (-CH ２ -) ｎ , —O—(—CH ２ -) ｏ -, -O- and 【Chemistry 2】 is selected from the group consisting of n is selected from the group consisting of 1, 2, 3 and 4; o is selected from the group consisting of 1, 2, 3 and 4; B is absent or is H, CN, halogen, optionally substituted C ６ -C １４ Aryl, optionally substituted C ２ -C １４ Heteroaryl, optionally substituted C １ -C １４ Heterocycle, optionally substituted C １ -C ８ Alkyl, C １ -C ８ haloalkyl, optionally substituted C interrupted by 1 to 4 heteroatoms １ -C ８ Alkyl, and optionally substituted C ３ -C １４ cycloalkyl; or a pharma- ceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer, or mixture of diastereomers.

2. Formula Ia 【Chemistry 3】 2. The compound of claim 1 having the formula:

3. Formula Ib 【Chemistry 4】 3. The compound of claim 2 having the formula:

4. Formula Ic 【Chemistry 5】 2. The compound of claim 1 having the formula:

5. Formula Id 【Chemistry 6】 2. The compound of claim 1 having the formula:

6. Formula Ie 【Chemistry 7】 2. The compound of claim 1 having the formula:

7. Formula If 【Chemistry 8】 5. The compound of claim 4 having the formula:

8. Formula Ig 【Chemistry 9】 2. The compound of claim 1 having the formula:

9. Formula Ih 【Chemistry 10】 7. The compound of claim 6 having the formula:

10. Formula II 【Chemistry 11】 2. The compound of claim 1 having the formula:

11. Formula Ij 【Chemistry 12】 2. The compound of claim 1 having the formula:

12. Formula Ik 【Chemistry 13】 2. The compound of claim 1 having the formula:

13. R １ , R ２ , R ３ and R ４ The compound of claim 1 , wherein each is H.

14. R １ , R ３ and R ４ is H, and R ２ The compound of claim 1 , wherein is a halogen.

15. R ２ The compound of claim 14 , wherein is F.

16. R １ , R ２ and R ３ is H, and R ４ The compound of claim 1 , wherein is a halogen.

17. R ４ The compound of claim 16 , wherein is F.

18. R １ and R ２ is halogen, R ３ and R ４ The compound of claim 1 , wherein

19. R １ and R ２ The compound of claim 18, wherein is F.

20. R １ and R ２ is H, and R ３ and R ４ The compound of claim 1 , wherein is a halogen.

21. R ３ and R ４ The compound of claim 20, wherein is F.

22. R ５ is H, -CN and -CF ３ 2. The compound of claim 1 selected from the group consisting of:

23. R ５ The compound of claim 1, wherein is -CN.

24. -A-B is 【Chemistry 14】 R ８ and R ９ But H and C １ -C ６ alkyl; R ８ and R ９ can be taken together with the carbon to which they are attached to form a ring having 3 to 6 carbon atoms, R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ and R １７ Each independently represents H, C １ -C ６ Alkyl, C １ -C ６ The compound of claim 1, selected from the group consisting of haloalkyl, halogen and -CN.

25. R ８ and R ９ The compound of claim 24, wherein is H.

26. R ８ and R ９ 25. The compound of claim 24, wherein together with the carbons to which they are attached form a cyclopropyl ring.

27. R １０ , R １１ , R １６ and R １７ each independently represents H or -CH ３ R １２ , R １３ , R １４ and R １５ The compound of claim 24, wherein is H.

28. R １２ and R １３ But both are F and R １０ , R １１ , R １４ , R １５ , R １６ and R １７ The compound of claim 24, wherein is H.

29. R １０ and R １１ are each independently selected from the group consisting of H and —CN; R １２ , R １３ , R １４ , R １５ , R １６ and R １７ The compound of claim 24, wherein is H.

30. R １０ and R １１ each independently represents H and -CF ３ R １２ , R １３ , R １４ , R １５ , R １６ and R １７ The compound of claim 24, wherein is H.

31. R １２ and R １３ are each independently selected from the group consisting of H and —CN; R １０ , R １１ , R １４ , R １５ , R １６ and R １７ The compound of claim 24, wherein is H.

32. R １２ and R １３ each independently represents H and -CF ３ R １０ , R １１ , R １４ , R １５ , R １６ and R １７ The compound of claim 24, wherein is H.

33. R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ and R １７ The compound of claim 24, wherein is H.

34. R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ and R １７ The compound of claim 24, wherein is H.

35. R １２ and R １３ each independently represents H or -CH ３ R １０ , R １１ , R １４ , R １５ , R １６ and R １７ The compound of claim 24, wherein is H.

36. The compound of claim 1, wherein -A-B is selected from the group consisting of: 【Chemistry 15】

37. -A-B is 【Chemistry 16】 R １８ H, -OH, halogen, C １ -C ６ Alkyl, —O—(C １ -C ６ Alkyl) and C １ -C ６ The compound of claim 1 , selected from the group consisting of haloalkyl.

38. -A-B is 【Chemistry 17】 R １９ and R ２０ each independently represents H, —OH, halogen, C １ -C ６ Alkyl, —O—(C １ -C ６ Alkyl) and C １ -C ６ The compound of claim 1 , selected from the group consisting of haloalkyl.

39. -A-B is 【Chemistry 18】 R ２１ But H and C １ -C ６ 2. The compound of claim 1, wherein the compound is selected from the group consisting of alkyl.

40. -A-Bが、-OCH ３ ,-CN,-CH ２ SO ２ CH ３ ,-OCF ３ ,-CF ３ ,-CHF ２ 、 【Chemistry 19】 2. The compound of claim 1 selected from the group consisting of:

41. Compound of Formula II: 【Chemistry 20】 [In the formula, R ２１ , R ２２ , R ２３ and R ２４ are each independently selected from the group consisting of H and halogen; W is an optionally substituted 5- to 6-membered heteroaromatic ring containing 1 to 4 heteroatoms, an optionally substituted 5- to 6-membered heterocyclic ring containing 1 to 4 heteroatoms, C １ -C ６ alkenyl (optionally substituted 5-6 membered heterocycle containing 1-4 heteroatoms), C １ -C ６ alkyl (optionally substituted 5-6 membered heterocycle containing 1-4 heteroatoms) and optionally substituted cyclohexene. or a pharma- ceutically acceptable salt, prodrug, enantiomer, mixture of enantiomers, diastereomer, or mixture of diastereomers.

42. Formula IIa 【Chemistry 21】 42. The compound of claim 41 having the formula:

43. Formula IIb 【Chemical 22】 43. The compound of claim 42, having the formula:

44. Formula IIc 【Chemistry 23】 42. The compound of claim 41 having the formula:

45. Formula IId 【Chemistry 24】 45. The compound of claim 44, having the formula:

46. Formula IIe 【Chemistry 25】 42. The compound of claim 41 having the formula:

47. Formula IIf 【Chemistry 26】 45. The compound of claim 44, having the formula:

48. Formula IIg 【Chemical 27】 42. The compound of claim 41 having the formula:

49. Formula IIh 【Chemistry 28】 49. The compound of claim 48, having the formula:

50. Formula IIi 【Chemical 29】 42. The compound of claim 41 having the formula:

51. Formula IIj 【Chemistry 30】 42. The compound of claim 41 having the formula:

52. 42. The compound of claim 41 having the formula IIk: 【Chemistry 31】

53. R ２１ , R ２２ , R ２３ and R ２４ The compound of claim 41 , wherein each is H.

54. R ２１ , R ２３ and R ２４ is H, and R ２２ 42. The compound of claim 41 , wherein is a halogen.

55. R ２２ The compound of claim 54, wherein is F.

56. R ２１ , R ２２ and R ２３ is H, and R ２４ 42. The compound of claim 41 , wherein is a halogen.

57. R ２４ The compound of claim 56, wherein is F.

58. R ２１ and R ２２ is halogen, R ２３ and R ２４ The compound of claim 41 , wherein

59. R ２１ and R ２２ The compound of claim 58, wherein is F.

60. R ２１ and R ２２ is H, and R ２３ and R ２４ 42. The compound of claim 41 , wherein is a halogen.

61. R ２３ and R ２４ The compound of claim 60, wherein is F.

62. W, 【Chemistry 32】 R ２５ and R ２６ But, H, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Haloalkyl, halogen, -CN, -CH ２ -O-CH ３ -CH ２ CH ２ -O-CH ３ , tetrahydropyranyl, morpholino, 【Chemical 33】 R is independently selected from the group consisting of ２７ But, H, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Haloalkyl 【Chemical 34】 R ２８ is H, halogen, -O-C １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ haloalkyl and -CN; R ２９ But H and C １ -C ６ 42. The compound of claim 41, wherein said compound is selected from the group consisting of alkyl.

63. The compound of claim 1 selected from the group consisting of: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 or a prodrug or a pharma- ceutically acceptable salt thereof.

64. 42. The compound of claim 41, selected from the group consisting of: 【Table 2-1】 【Table 2-2】 【Table 2-3】 【Table 2-4】 【Table 2-5】 or a prodrug or a pharma- ceutically acceptable salt thereof.

65. 65. A pharmaceutical composition comprising a compound according to claim 1, 41, 63 or 64, and a pharma- ceutically acceptable adjuvant, carrier, or vehicle.

66. 65. A method comprising administering to a patient having an HPK-1 mediated disorder a therapeutically effective amount of a compound of claim 1, 41, 63 or 64, or a pharma- ceutically acceptable salt thereof.

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

68. 68. The method of claim 67, wherein the cancer is selected from the group consisting of breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cell, head and neck, kidney, liver, lung, larynx and hypopharynx, ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, testis, stomach, skin, ureter, vagina, and vulva cancer.

69. 67. The method of claim 66, wherein the therapeutically effective amount of the compound is selected from the ranges consisting of 0.1-100 mg / kg of the patient's body weight, 0.1-50 mg / kg of the patient's body weight, 0.5-50 mg / kg of the patient's body weight, 1-20 mg / kg of the patient's body weight, 5-20 mg / kg of the patient's body weight, 10-20 mg / kg of the patient's body weight, 10-50 mg / kg of the patient's body weight, and 10-100 mg / kg of the patient's body weight.

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

71. 67. The method of claim 66, wherein the compound is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir.

72. 67. The method of claim 66, wherein the compound is administered by subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or injection technique.

73. 66. A method comprising administering to a patient having an HPK-1 mediated disorder a therapeutically effective amount of the pharmaceutical composition of claim 65, or a pharma- ceutically acceptable salt thereof.

74. 74. The method of claim 73, wherein the HPK-1 mediated disorder is cancer.

75. 75. The method of claim 74, wherein the cancer is selected from the group consisting of breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cell, head and neck, kidney, liver, lung, larynx and hypopharynx, ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, testis, stomach, skin, ureter, vagina, and vulva cancer.

76. 74. The method of claim 73, wherein the therapeutically effective amount of the pharmaceutical composition is selected from the ranges consisting of 0.1-100 mg / kg of the patient's body weight, 0.1-50 mg / kg of the patient's body weight, 0.5-50 mg / kg of the patient's body weight, 1-20 mg / kg of the patient's body weight, 5-20 mg / kg of the patient's body weight, 10-20 mg / kg of the patient's body weight, 10-50 mg / kg of the patient's body weight, and 10-100 mg / kg of the patient's body weight.

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

78. 77. The method of claim 76, wherein the compound is administered by subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or injection technique.

79. 70. A kit comprising a therapeutically effective amount of a compound of claim 1, 41, 63 or 64, or a pharma- ceutically acceptable salt or prodrug thereof, and instructions for use of the compound.

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