AKT inhibitor

Abstract

To provide a compound useful as an AKT inhibitor.SOLUTION: For example, a compound including a nitrogen-containing condensed ring in the following formula is presented.SELECTED DRAWING: None

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application was filed on January 29, 2019 with the China Intellectual Property Office under No. 2019100848. Priority is claimed on Chinese patent application Ser. No. 01 / 30 / 2007, the entire contents of which are hereby incorporated by reference in their entirety. Further incorporated herein by reference. [Technical field]

[0002] The present invention belongs to the field of medicinal chemistry, specifically, AKT inhibitors, their preparation methods and application to medicines. Regarding use. [Background technology]

[0003] Phosphatidylinositol 3-kinase (PI3K) and its downstream protein AKT ( Protein kinase A (also called PKB) and mammalian target of rapamycin (mT The PI3K / AKT / mTOR pathway, which consists of the kinase and kinase inhibitors (ORs), is a very important signal transduction pathway within cells. Pathways include cell growth, survival, proliferation, apoptosis, angiogenesis, and autophagy. The abnormal activation of this pathway plays a vital biological role in the process of This can cause a range of diseases including cancer, neurological disorders, autoimmune diseases and hematolymphatic disorders.

[0004] AKT is a serine / threonine kinase that mediates many downstream effectors. It affects cell survival, growth, metabolism, proliferation, migration and differentiation. Over 50% of human cancers AKT is overactive in many types of cancer, primarily prostate, pancreatic, bladder, ovarian, and breast cancer. Excessive activation of AKT leads to tumor formation, metastasis, and drug resistance. Drop.

[0005] There are three subtypes of AKT: AKT1, AKT2, and AKT3. Each subtype has a PH domain (Pleckst rin homology domain, and a kinase domain that binds ATP in the middle. The three subtypes are composed of a cyclic nucleotide sequence, a cyclic nucleotide sequence, and a carboxy-terminal regulatory domain. 80% of the amino acid sequence is homologous, with only the PH and kinase domains being identical. There is a relatively large distinction in the junction region.

[0006] Currently, drugs targeting the PI3K / AKT / mTOR signal pathway are mainly PI3K inhibitors. AKT is a vasopressin inhibitor and mTOR inhibitor, but AKT is at the core of the signaling pathway. By inhibiting the activity of PI3K, we can avoid the severe side effects of inhibiting the upstream PI3K. The efficacy of drugs is affected by a negative feedback mechanism caused by the inhibition of downstream mTOR. Therefore, the search for effective and selective AKT inhibitors is currently focused on tumor-targeted drugs. This is an important direction for the development of cyclopenta[D]pyrimidinyl esters. CN101578273A contains hydroxylated and methoxylated cyclopentane derivatives. D] pyrimidine derivatives, and CN101511842A contains dihydrofuropyrimidine derivatives However, CN101970415A contains 5H-cyclopenta[D]pyrimidine derivatives. These compounds have been disclosed to have an AKT1 inhibitory IC of less than 10 μM. 50 has. Summary of the Invention

[0007] In one embodiment, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt thereof: death, [ka] where: R 1 is H, OH, halogen, CN, NH2, NO2 and optionally substituted with halogen or OH C1-C6 alkyl groups, R 2 , R 3 are each independently H, a C1-C6 alkyl group, or a C3-C6 cycloalkyl group. group, (C3-C6 cycloalkyl group)-(CH2)-, (C3-C6 cycloalkyl group)-(C H2CH2)-, benzyl group, phenethyl group, pyrrolidinyl group, tetrahydrofuranyl group and tetrahydropyranyl groups, wherein the C1-C6 alkyl groups are selected from the group consisting of , C3-C6 cycloalkyl group, (C3-C6 cycloalkyl group)-(CH2)- or (C3 -C6 cycloalkyl group)-(CH2CH2)- is optionally halogen, OH, CN, NH2 or a C1-C3 alkoxy group, and the benzyl or phenethyl group is optionally substituted with halogen, OH, CN, NO2, NH2, C1-C3 alkoxy group, halogenated C1-C3 substituted with an alkoxy group, a C1-C3 alkyl group or a halogenated C1-C3 alkyl group; The pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl group may optionally be aryl, OH, C1-C3 alkyl group, cyclopropylmethyl or C1-C4 alkanoyl is substituted with a group, Or, R 1 , R 2 and the atoms to which they are connected together form a 4- to 7-membered nitrogen-containing heterocycle. Completed, m and n are each independently selected from the group consisting of 0, 1, 2, and 3; R 4 , R 5 are all hydrogen or R 4 , R 5together form =O, [ka] is selected from the group consisting of: [ka] R 6 , R 7 , R 8 , R 9 are each independently H, CN, a C1-C6 alkyl group, or a C1 -C6 alkoxy groups, wherein the C1-C6 alkyl groups or C1 The -C6 alkoxy group is optionally substituted with halogen, OH, CN, or a C1-C3 alkoxy group. R, R 10 is selected from the group consisting of H and C1-C6 alkyl groups, the alkyl group is optionally substituted with halogen, OH, CN or a C1-C3 alkoxy group; L is an optionally substituted 5-12 membered saturated heterocycle containing 1-2 nitrogens; G is any 1-5 R 11 6-10 membered aryl group or 5-10 membered heteroaryl group substituted with is a aryl group, R 11 are independently halogen, OH, CN, NH2, NO2, benzyloxy group, -NH (C1-C6 alkyl group), -N(C1-C6 alkyl group)2, -C(=O)NH2, -C(= O)NH(C1-C6 alkyl group), -C(=O)N(C1-C6 alkyl group)2, -SO2(C 1-C6 alkyl group), C1-C6 alkyl group and C1-C6 alkoxy group wherein the C1-C6 alkyl group or the C1-C6 alkoxy group is optionally selected from the group consisting of halo. is replaced by Gen, However, R 1 , R 2 and the atoms to which they are connected together form a 4- to 7-membered nitrogen-containing heterocycle. When this is completed, R 1 , R 2 Neither of them is H.

[0008] In some embodiments, R 1 is H, OH and optionally substituted with halogen or OH C 1- C alkyl groups, and in some exemplary embodiments, R 1 is selected from the group consisting of H, OH, Me, CF3 and CH2OH, some of the more typical In certain embodiments, R 1 is selected from the group consisting of H and OH, some of the most typical In certain embodiments, R 1 is H.

[0009] In some embodiments, R 2 sum R 3 are each independently H, C1-C6 alkyl group, C3-C6 cycloalkyl group, (C3-C6 cycloalkyl group)-(CH2)-, (C3 -C6 cycloalkyl group)-(CH2CH2)-, benzyl group, phenethyl group, pyrrolidinyl group and tetrahydropyranyl, wherein the C1-C6 alkyl group is selected from the group consisting of aryl and tetrahydropyranyl. alkyl group, a C3-C6 cycloalkyl group, a (C3-C6 cycloalkyl group)-(CH2)- or (C3-C6 cycloalkyl group)-(CH2CH2)- is optionally selected from F, Cl, Br, I, OH, CN, NH2 or C1-C3 alkoxy group, and the benzyl or phenethyl group is optionally substituted with F, Cl, Br, I, OH, OMe, CF3 or Me, The tetrahydropyranyl or tetrahydropyranyl group is optionally substituted with F, Cl, Br, I, OH, C1-C3 alkoxy, substituted with alkyl, cyclopropylmethyl or C1-C4 alkanoyl group.

[0010] In some embodiments, R 2 sum R 3 are each independently H, a methyl group, or an ethyl group. , isopropyl group, isobutyl group, t-butyl group, 3-pentyl group, CH2OH, CH2 CH2OH, CH2CH2OMe, CF3, CH2CF3, CH2CHF2, CH2CH 2F, cyclopropyl group, cyclopentyl group, cyclohexyl group, cyclopropyl-(C H2)-, cyclopentyl-(CH2)-, cyclohexyl-(CH2)-, cyclopropyl -(CH2CH2)-, cyclopentyl-(CH2CH2)-, benzyl group, 4-fluorobenzyl group benzyl group, 4-chlorobenzyl group, 4-fluorophenethyl group, 4-chlorophenethyl group and tetrahydropyran-4-yl groups.

[0011] In some exemplary embodiments, R 2 and R 3 are each independently H, a methyl group , ethyl group, isopropyl group, cyclopropyl group, cyclohexyl group, cyclopropyl- (CH2)-, cyclohexyl-(CH2)- and tetrahydropyran-4-yl groups Selected from a group.

[0012] In some more exemplary embodiments, R 2 and R 3 are each independently H, iso It is selected from the group consisting of a propyl group and a cyclopropyl group.

[0013] In some embodiments, R 2 is H.

[0014] In some embodiments, R 3 is an isopropyl group or a cyclopropyl group.

[0015] In some embodiments, R 2 is H and R 3 isopropyl group or cyclopropyl group It is a propyl group.

[0016] In some embodiments, R 1 , R 2 and the atoms connected to them are as follows: Forming things, [ka] Here, R 3 has the same meaning as above.

[0017] In some exemplary embodiments, R 1 , R 2 and the atoms connected to them are to form the following: [ka] Here, R 3 has the same meaning as above.

[0018] In some embodiments, m is 0, 1, or 2. In some exemplary embodiments, In some more exemplary embodiments, m is 0 or 1, and in some more exemplary embodiments, m is 1. .

[0019] In some embodiments, n is 0, 1, or 2, and in some exemplary embodiments, In some more exemplary embodiments, n is 0 or 1, and in some more exemplary embodiments, n is 0. .

[0020] In some embodiments, R 4 , R 5 are both hydrogen.

[0021] In some embodiments, R 4 , R5 together form =O.

[0022] In some embodiments, [ka] is selected from the group consisting of: [ka] .

[0023] In some embodiments, [ka] is selected from the group consisting of: [ka] .

[0024] In some embodiments, [ka] is selected from the group consisting of: [ka] .

[0025] In some embodiments, [ka] but, [ka] and R 4 and R 5 together form =O.

[0026] In some embodiments, [ka] but [ka] and R 4 and R 5 together form =O.

[0027] In some embodiments, [ka] but [ka] and R 4 and R 5 together form =O.

[0028] In some embodiments, [ka] but [ka] and R 4 and R 5 together form =O.

[0029] In some embodiments, [ka] but [ka] and R 4 and R 5 are both H.

[0030] In some embodiments, [ka] but [ka] and R 4 and R 5 together form =O.

[0031] In some embodiments, R 6 , R 7 , R 8 , R 9 are independently H, CN, C1-C6 alkyl groups and C1-C6 alkoxy groups, The C1-C6 alkyl or C1-C6 alkoxy group is optionally substituted with F, Cl, Br, I, OH, It is replaced by CN or OMe.

[0032] In some embodiments, R 6 , R 7 , R 8 , R 9 are independently H, CN, C1-C6 alkyl groups and C1-C6 alkoxy groups, The C1-C6 alkyl group or the C1-C6 alkoxy group is optionally substituted with F, CN or OH. do.

[0033] In some embodiments, R 6 , R 7 , R 8 , R 9 are independently H, CN, Methyl, ethyl, propyl, isopropyl, CF3, CH2CF3, CH2CHF2, C H2CH2F, CH2CN, CH2CH2CN, CH2OH, CH2CH2OH, OMe , OEt, OCH2CH2CH3 and isopropoxy groups.

[0034] In some embodiments, R 6 H, CN, methyl group, ethyl group, propyl group, iso Propyl group, CF3, CH2CF3, CH2CHF2, CH2CH2F, CH2CN, C H2CH2CN, CH2OH, CH2CH2OH, OMe, OEt, OCH2CH2CH 3 or an isopropoxy group, and in some exemplary embodiments, R 6 H,CN , methyl group, ethyl group, isopropyl group, CF3, CH2CH2OH, OMe or OEt In some more exemplary embodiments, R 6 H, CN, methyl group, CF3 or OMe, and in some further exemplary embodiments, R 6 CN, methyl group, CF or OMe, and in some further exemplary embodiments, R 6 H, CN or is a methyl group, and in some further exemplary embodiments, R 6 is H, CF3 or Me In some further exemplary embodiments, R 6 is a methyl group or CF3 be.

[0035] In some embodiments, R 7 is H.

[0036] In some embodiments, R 8 H, CN, methyl group, ethyl group, propyl group, iso Propyl group, CF3, CH2CF3, CH2CHF2, CH2CH2F, CH2CN, C H2CH2CN, CH2OH, CH2CH2OH, OMe, OEt, OCH2CH2CH 3 or an isopropoxy group, and in some exemplary embodiments, R 8 H,CN , methyl group, ethyl group, isopropyl group, CF3, CH2CH2OH, OMe or OEt In some further exemplary embodiments, R 8is H, CN or a methyl group In some more exemplary embodiments, R 8 is H or CN, and some In an exemplary embodiment, R 8 is H or a methyl group, and some further exemplary embodiments In terms of form, R 8 is H.

[0037] In some embodiments, R 9 is H.

[0038] In some embodiments, R 10 is selected from the group consisting of H and C1-C6 alkyl groups. wherein the C1-C6 alkyl group is optionally substituted with halogen, OH or CN; In some embodiments, R 10 H, methyl group, ethyl group, propyl group, isopropyl group group, CF3, CH2CF3, CH2CHF2, CH2CH2F, CH2CN, CH2C HCN, CHOH, or CHCHOH, and in some exemplary embodiments R 10 are methyl, ethyl, isopropyl, CH2CF3, CH2CHF2, C HCN or CHCHOH; in some further exemplary embodiments, R 1 0 is a methyl group, an ethyl group, CH2CN, or CH2CH2OH, and some more specific In an exemplary embodiment, R 10 is methyl.

[0039] In some embodiments, L is optionally one or more R 12 The following groups substituted with be: [ka] . where: The wavy line indicates where L attaches to the carbonyl group, and the double wavy line indicates where L attaches to the pyrimidine. This is the location where R 12 is halogen, OH, CN, vinyl group, C1-C6 alkyl and C1-C6 alkoxy. wherein said C1-C6 alkyl or C1-C6 alkoxy is selected from the group consisting of aryl, aryl, aryl and aryl. The group is optionally substituted with halogen or OH; h is selected from the group consisting of 0, 1, 2, 3, and 4; j is selected from the group consisting of 0, 1, 2 and 3; k is selected from the group consisting of 1, 2, 3, and 4; q, s, v, and t are each independently selected from the group consisting of 0, 1, and 2, and q, s, v and t cannot both be 0. p is selected from the group consisting of 0, 1, 2 and 3; e is selected from the group consisting of 0, 1 and 2; u is selected from the group consisting of 1, 2 and 3; W and Z are each independently selected from the group consisting of N and C, and at least one of W and Z is One is N.

[0040] In some embodiments, R 12 are F, Cl, Br, I, OH, CN, vinyl groups, Chill group, ethyl group, propyl group, isopropyl group, CF3, CH2CF3, CH2CHF 2, CH2CH2F, OMe, OEt, CH2OH, CH2CH2OH, OCH2OH and and OCH2CH2OH; and in some exemplary embodiments, R 12 are methyl, ethyl, isopropyl, CF3, CH2CF3, OMe, OEt, In some further exemplary embodiments, Hey, R 12is selected from the group consisting of methyl, ethyl and CF3; In an exemplary embodiment, R 12 is a methyl group.

[0041] In some embodiments, h is 0, 1, 2, or 3 and j is 0, 1, or 2. In some exemplary embodiments, h is 0, 1, or 2 and j is 0 or 1. In some more exemplary embodiments, h is 0 or 1 and j is 0. and in some more typical embodiments, h is 1 and j is 0.

[0042] In some embodiments, k is 1, 2, or 3, and in some exemplary embodiments, In some more exemplary embodiments, k is 1 or 3, and in some more exemplary embodiments, k is 1. .

[0043] In some embodiments, q, s, v, and t are each independently 0 or 1; and In some exemplary embodiments, q, s, v, and t are not all 0. , q, s, v, and t are all 1, and in some more typical embodiments, q, s is 0, and v, t is 1. In some more typical implementations: In this embodiment, q and s are both 1, and v and t are both 0. In a more typical embodiment, s and v are both 0, and q and t are both 1. do.

[0044] In some embodiments, p is 0, 1, or 2, and in some exemplary embodiments, In some more exemplary embodiments, p is 0 or 2, and in some more exemplary embodiments, p is 2. .

[0045] In some embodiments, e is 0 or 1 and u is 1 or 2; In an exemplary embodiment of the present invention, e is 0 or 1 and u is 1, In an exemplary embodiment, e is 0 and u is 1.

[0046] In some embodiments, W is C and Z is N. In some embodiments, W is N and Z is C, and in some more exemplary embodiments In this case, W and Z are both N.

[0047] In some further exemplary embodiments, L is optionally one or more of R 12 Replaced by The following groups are also included: [ka] . Here, R 12 has the same meaning as above.

[0048] In some further exemplary embodiments, L is optionally one or more of R 12 Replaced by The following groups are also included: [ka] . Here, R 12 has the same meaning as above.

[0049] In some further exemplary embodiments, L is selected from the group consisting of: [ka] .

[0050] In some further exemplary embodiments, L is selected from the group consisting of: [ka] .

[0051] In some further exemplary embodiments, L is selected from the group consisting of: [ka] .

[0052] In some embodiments, G is optionally selected from 1 to 5 R 11 a phenyl group substituted with or optionally one or more R 11 and a thienyl or pyridyl group substituted with

[0053] In some embodiments, R 11 are independently F, Cl, Br, I, OH, CN, and N H2, NO2, benzyloxy, methyl, ethyl, isopropyl, CH2CF3, CF 3, selected from the group consisting of SMe, OMe, OCF3, OEt and isopropoxy groups; In some exemplary embodiments, R 11 are independently F, Cl, Br, CN, and benzene. oxy group, methyl group, ethyl group, isopropyl group, CF3, OMe, SMe and OCF 3; and in some further exemplary embodiments, R 11 is independent , F, Cl, and CF3, and in some further exemplary embodiments, , R 11 is Cl.

[0054] In some embodiments, G is a phenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, nyl group, 4-chlorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 4- Methylphenyl group, 4-ethylphenyl group, 4-isopropylphenyl group, 4-trifluorophenyl group 4-Cyanophenyl, 4-Methoxyphenyl, 4-Methylphenyl 4-trifluoromethoxyphenyl group, 4-chloro-3-fluorophenyl group, a 3,4-difluorophenyl group, a 2,4-dichlorophenyl group, or a 4-benzyloxy group; In some exemplary embodiments, G is a 4-chlorophenyl group. , 4-chloro-3-fluorophenyl group, 4-trifluoromethylphenyl group or 3,4 In some further exemplary embodiments, G is a 4-chlorophenyl group. It is a phenyl group.

[0055] In some embodiments, G is thienyl optionally substituted with one or more halogens. In some more exemplary embodiments, G is optionally one or is a thienyl or pyridyl group substituted with multiple F, Cl, Br or I; In a more typical embodiment, G is the following group: [ka] .

[0056] In another aspect, the present invention provides a compound of formula II, or a pharma- ceutically acceptable salt thereof: death, [ka] Here, R 1 , R 2 , R 4 , R 5 , G, L, m and [ka] The definitions are the same as for compounds of formula I.

[0057] In another aspect, the present invention provides a compound of formula III, or a pharma- ceutically acceptable salt thereof: Offer, [ka] Here, R 2 , R 4 , R 5 , G, L and [ka] The definitions are the same as for compounds of formula I.

[0058] In another aspect, the present invention provides a compound of formula IV, or a pharma- ceutically acceptable salt thereof: death, [ka] Here, R 2 , G, L and [ka] The definitions are the same as for compounds of formula I. In another aspect, the present invention provides a compound of formula V, or a pharma- ceutically acceptable salt thereof: , [ka] Here, R 2 , R 6 , R 8 The definitions of , G and L are the same as for the compound of formula I.

[0059] In another aspect, the present invention provides a compound of formula VI, or a pharma- ceutically acceptable salt thereof: death, [ka] Here, R 2 , R 6 , R 8 , R 11 and L is defined as in the compound of formula I, and d is 0, 1 , 2, 3, 4 and 5.

[0060] In some embodiments, d is selected from the group consisting of 0, 1, 2, and 5, In an exemplary embodiment, d is selected from the group consisting of 0, 1, and 2, and some further exemplary In typical embodiments, d is selected from the group consisting of 1 and 2, and some more typical In an embodiment, d is 1. In another aspect, the present invention provides a compound of formula VII, or a pharma- ceutically acceptable salt thereof: Offering, [ka] Here, R 2 , R 6 , R 8 , R 11 and L are defined as for compounds of formula I, and d is defined as Same as the compound of formula VI.

[0061] In another embodiment, the present invention provides a compound of formula VIII, or a pharma- ceutically acceptable salt thereof: Provide, [ka] Here, R 2 , R 8 , R 10 The definitions of , G, and L are the same as for the compound of formula I.

[0062] In another aspect, the present invention provides a compound of formula IX, or a pharma- ceutically acceptable salt thereof: death, [ka] Here, R 2 , R 8 , R 10 , R 11 and L are defined as in the compound of formula I, and d is defined as is the same as the compound of formula VI. In another embodiment, the compound of the present invention is a compound represented by formula X: Further comprising: [ka] Here, R 1 , R 2 , R 3 , G, L, m, n and [ka] The definitions are the same as for compounds of formula I. In another embodiment, the present invention further provides a compound of formula XI, or a pharma- ceutically acceptable salt thereof: Provide, [ka] Here, R 2 , R 6 The definitions of , G and L are the same as for the compound of formula I.

[0063] In another aspect, the present invention further provides a compound of formula XII or a pharma- ceutically acceptable salt thereof: Provided to [ka] Here, R 2 , R 6 , R 11 and L are defined as in the compound of formula I, and d is defined as in the compound of formula VI. It is the same as a compound. In another aspect, the present invention provides the following compound or a pharma- ceutically acceptable salt thereof: [ka] [ka] [ka] cis-(5R)-4-(5-((S)-2-(4-chlorophenyl)-3-(isopropylamino) Propionyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-methyl 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one, or trans-(5R)-4-(5-((S)-2-(4-chlorophenyl)-3-(isopropyl 3,4-diamino)propionyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5- Methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one.

[0064] In another aspect, the present invention provides the following compound: [ka] .

[0065] In another aspect, the present invention provides a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, or VII. , VIII, IX, X, XI or XII, or a pharma- ceutically acceptable form thereof. Pharmaceutical compositions comprising salts are further provided.

[0066] In some embodiments, the present invention provides a therapeutically effective amount of a compound of Formula I, II, III, IV, V, V I, VII, VIII, IX, X, XI or XII or a pharma- ceutical thereof. The pharmaceutical compositions further include an acceptable salt thereof and one or more pharma- ceutically acceptable carriers. to be provided.

[0067] The pharmaceutical compositions of the present invention can be administered in any suitable manner, for example orally or parenterally (e.g., intravenously). The compounds of Formula I, II, III, IV, V, VI, V A therapeutically effective amount of a compound of II, VIII, IX, X, XI or XII is from about 0.001 mg to about 10 mg. The recommended daily dose is 0.01 to 10 mg / kg body weight / day. is preferred.

[0068] For oral administration, the pharmaceutical compositions of the present invention are typically provided in the form of tablets, capsules or solutions. The tablets contain the compound of the present invention or a pharma- ceutically acceptable salt thereof, as well as a pharma- ceutically acceptable The carrier may include a diluent, disintegrant, adhesive, lubricant, colorant, or preservative. Capsules include, but are not limited to, hard capsules and soft capsules. Can be enjoyed.

[0069] For parenteral administration, the pharmaceutical compositions of the present invention may be administered by intravenous injection, intramuscular injection, or subcutaneous injection. They are usually prepared as sterile aqueous solutions, suspensions, or freeze-dried solutions adjusted to appropriate pH and isotonicity. It is provided as a dried powder.

[0070] In another aspect, the present invention relates to a method for treating a disease or condition mediated by the AKT protein kinase. In the preparation of a medicament for the prevention and / or treatment of The present invention further provides the use of compounds VII, VIII, IX, X, XI or XII.

[0071] In another aspect, the present invention provides a method of administering to a subject in need of treatment a compound of formula I, II, III or IV of the present invention. , V, VI, VII, VIII, IX, X, XI or XII compound or a medicament of the present invention. The present invention relates to a method for treating a disease or condition mediated by AKT protein kinase, comprising administering a pharmaceutical composition to said patient. Further provided are methods for preventing and / or treating disease conditions.

[0072] In another aspect, the present invention relates to a method for treating a disease or condition mediated by the AKT protein kinase. The compounds of formula I, II, III, IV, V, VI, VIII, VIII of the present invention for preventing and / or treating Compound II, VIII, IX, X, XI or XII, or a pharmaceutical composition of the invention. provide.

[0073] Examples of diseases or disease states mediated by the AKT protein kinase include breast cancer, Including, but not limited to, prostate cancer or ovarian cancer.

[0074] The compounds of the present invention have inhibitory effects on AKT1, AKT2, and AKT3, particularly AKT3. It has a significant inhibitory effect on the proliferation of cancer cells, and is also a drug. It has good pharmacological absorption and has a remarkably excellent oral absorption effect.

[0075] In another aspect, the present invention provides a method for preparing a compound of formula V, comprising the following synthetic route: But not limited to: Synthetic Route 1: [ka] Here, R 2 , R 6 , R 8 , G, h, and j are defined as above, and P 1 is H or amino is a protecting group, P 2 is an amino protecting group, Compounds of formula 1-1 can be prepared by the reaction of the compound with a base (e.g., sodium methoxide) and a solvent (e.g., methanol). A compound of formula 1-2 is prepared in the presence of 1-(2-methylphenyl)-2-propanediol, and a salt is obtained from the compound of formula 1-2 and formamidine acetate. in the presence of a base (e.g., sodium methoxide) and a solvent (e.g., methanol) to form a compound of formula 1-3 and reacting the compound of formula 1-3 with a base (e.g., diisopropylethylamine) and a solvent (e.g., The compound of formula 1-4 is further converted into a compound of formula 1-4 in the presence of acetonitrile, for example. The compound of formula 1-5 is produced, and the compound of formula 1-5 is reacted with the compound of formula 1-6 to produce the compound of formula 1-7. The protecting group of the compound of formula 1-7 is deprotected to prepare a compound of formula 1-8. The compound of formula 1-8 is reacted with the compound of formula 1-9 to prepare the compound of formula 1-10. 1 When is an amino protecting group, synthetic route 1 further comprises removing the amino protecting group.

[0076] Synthetic Route 2: [ka] Here, R 2 , R 6 , R 8 ,G,q,v,s,t,p are defined as above, and P 1 but H or an amino protecting group, P 2 is an amino protecting group, The compound of formula 1-5 is prepared according to synthetic route 1, and the compound of formula 1-5 and the compound of formula 2-6 are mixed. The compound of formula 2-7 is prepared by reacting the compound of formula 2-7 with the protecting group being deprotected to obtain the compound of formula 2- A compound of formula 8 is prepared, and a compound of formula 2-8 is reacted with a compound of formula 1-9 to obtain a compound of formula 2-10. Prepare a mixture. 1 When is an amino protecting group, synthetic route 2 further includes removing the amino protecting group. This includes making the person do so.

[0077] Synthetic Route 3: [ka] Here, R 2 , R 6 , R 8 , G, h, j, and k are defined as above, and P1 H or A is a phenyl protecting group, 2 is an amino protecting group, Compounds of formula 1-5 were prepared according to synthetic route 1, and compounds of formula 1-5 and compounds of formula 3-6 were mixed. The compound of formula 3-7 is prepared by reacting the compound of formula 3-7 with the protecting group being deprotected to obtain the compound of formula 3- Compound 8 is prepared, and the compound of formula 3-8 is reacted with the compound of formula 1-9 to obtain the compound of formula 3-10. Prepare a mixture. 1 When is an amino protecting group, synthetic route 3 further includes removing the amino protecting group. This includes making the person do so.

[0078] Synthetic Route 4: [ka] Here, R 2 , R 6 , R 8 , e, u are defined as above, and P 1 is H or amino protected is a group, P 2 is an amino protecting group, Compounds of formula 1-5 were prepared according to synthetic route 1, and compounds of formula 1-5 and compounds of formula 4-6 were mixed. The compound of formula 4-7 is prepared by reacting the compound of formula 4-7 with the protecting group being deprotected to obtain the compound of formula 4- Compound 8 is prepared, and the compound of formula 4-8 is reacted with the compound of formula 1-9 to obtain the compound of formula 4-10. Prepare a mixture. 1 When is an amino protecting group, synthetic route 4 further includes removing the amino protecting group. This includes making the person do so.

[0079] In another aspect, the present invention provides a method for preparing a compound of formula VIII, comprising the following synthetic route: These include, but are not limited to: Synthetic Route 5: [ka] Here, R2 , R 10 , R 8 , G, h, and j are defined as above, and P 1 H or Ami is a protecting group, P 2 is an amino protecting group, Compounds of formula 5-1 can be reacted with a base (e.g., sodium hydride) and a solvent (e.g., tetrahydrofuran) to produce a compound of formula 5-1. and preparing a compound of formula 5-2 in the presence of 2 to base (e.g. triethylamine) and a solvent (e.g., isopropanol) to prepare a compound of formula 5-3. and from the compound of formula 5-3 in the presence of a base (e.g., sodium hydride) and a solvent (e.g., DMF). The compound of formula 5-4 is prepared by deprotecting the protecting group of the compound of formula 5-4 to obtain the compound of formula 5-5. A compound of formula 5-5 is reacted with a compound of formula 1-6 to prepare a compound of formula 5-7. The protecting group of the compound of formula 5-7 is deprotected to prepare a compound of formula 5-8. The compound of formula 5-10 is prepared by reacting the compound of formula 5 with the compound of formula 1-9. 1 Amino If it is a protecting group, synthetic route 5 further comprises removing the protecting group.

[0080] Synthetic Route 6: [ka] Here, R 2 , R 10 , R 8 ,G,q,s,v,t,p are defined as above, and P 1 is H or an amino protecting group, P 2 is an amino protecting group, According to synthetic route 5, the compound of formula 5-5 is prepared, and the compound of formula 5-5 and the compound of formula 2-6 are mixed. The compound of formula 6-7 is prepared by reacting the compound of formula 6-7 with the protecting group being deprotected to obtain the compound of formula 6- Compound 8 is prepared, and the compound of formula 6-8 is reacted with the compound of formula 1-9 to obtain the compound of formula 6-10. Prepare a mixture. 1 When is an amino protecting group, synthetic route 6 further comprises removing the protecting group. This includes:

[0081] Synthetic Route 7: [ka] Here, R 2 , R 10 , R 8 , G, h, j, and k are defined as above, and P 1 Is H or is an amino protecting group, P 2 is an amino protecting group, According to synthetic route 5, the compound of formula 5-5 is prepared, and the compound of formula 5-5 and the compound of formula 3-6 are mixed. The compound of formula 7-7 is prepared by reacting the compound of formula 7-7 with the protecting group of the compound of formula 7-7 being deprotected to obtain a compound of formula 7- Compound 8 is prepared, and the compound of formula 7-8 is reacted with the compound of formula 1-9 to obtain the compound of formula 7-10. Prepare a mixture of P 1 When is an amino protecting group, synthetic route 7 further comprises removing the protecting group. This includes:

[0082] Synthetic Route 8: [ka] Here, R 2 , R 10 , R 8 , G, e, and u are defined as above, and P 1 H or Ami is a protecting group, P 2 is an amino protecting group, According to synthetic route 5, the compound of formula 5-5 is prepared, and the compound of formula 5-5 and the compound of formula 4-6 are mixed. The compound of formula 8-7 is prepared by reacting the compound of formula 8-7 with the protecting group being deprotected to obtain the compound of formula 8- Compound 8 is prepared, and the compound of formula 8-8 is reacted with the compound of formula 1-9 to obtain the compound of formula 8-10. Prepare a mixture of P 1 When is an amino protecting group, synthetic route 8 further comprises removing the protecting group. This includes:

[0083] Synthetic Route 9: [ka] where X is a halogen and R 6 , h, j, and G are defined as above, and P 1 H or is an amino protecting group, P 2 is an amino protecting group. A compound of formula 9-2 is prepared from a compound of formula 9-1, and a compound of formula 9-2 and a compound of formula 1-6 are prepared. to prepare a compound of formula 9-3, which is reduced to give a compound of formula 9-4. The compound of formula 9-4 is subjected to a ring formation reaction to prepare a compound of formula 9-5. The protecting group of the compound of formula 9-6 is deprotected to give a compound of formula 1-9 or a salt thereof. to prepare a compound of formula 9-7. 1 When is an amino protecting group, Synthesis Route 9 further involves removing the protecting groups.

[0084] Synthetic Route 10: [ka] where X is a halogen and R 6 , q, v, s, t, p, and G are defined as above. , P 1 is H or an amino protecting group, P 2 is an amino protecting group.

[0085] A compound of formula 9-2 is prepared from a compound of formula 9-1, and a compound of formula 9-2 and a compound of formula 2-6 are prepared. to prepare a compound of formula 10-3, which is reduced to give a compound of formula 10-4. and then subjecting the compound of formula 10-4 to a ring-forming reaction to prepare a compound of formula 10-5. The protecting group of the compound of formula 10-5 is then deprotected to give a compound of formula 10-6 or a salt thereof. and then reacting with a compound of formula 1-9 to prepare a compound of formula 10-7. 1 Amino protection If it is a protecting group, synthetic route 10 further comprises removing the protecting group.

[0086] Synthetic Route 11: [ka] where X is a halogen and R 6 , h, k, j, and G are defined as above, and P 1 but H or an amino protecting group, P 2 is an amino protecting group. A compound of formula 9-2 is prepared from a compound of formula 9-1, and a compound of formula 9-2 is combined with a compound of formula 11-1. The compound of formula 11-2 is prepared by reacting the compound of formula 11-2, and the compound of formula 11-2 is reduced to give a compound of formula 11- Compound 3 is produced, and the compound of formula 11-3 is subjected to a ring-forming reaction to prepare compound of formula 11-4. The protecting group of the compound of formula 11-4 is then deprotected to give a compound of formula 11-5 or a salt thereof. and then reacting with a compound of formula 1-9 to prepare a compound of formula 11-6. 1 Amino insurance If it is a protecting group, synthetic route 11 further comprises removing the protecting group.

[0087] Synthetic Route 12: [ka] Here, R 6 , R 8 , h, k, j, and G are defined as above, and P 1 H or amino acid It is a protective group, P 2 is an amino protecting group.

[0088] A compound of formula 1-5 is reacted with a compound of formula 11-1 to prepare a compound of formula 12-1, The protecting group of compound 2-1 is deprotected to prepare a compound of formula 12-2; The compound of formula 12-3 is prepared by reacting the compound of formula 1-9 with the compound of formula 12-3. 1 is an amino protecting group If it is, synthetic route 12 further comprises removing the protecting group.

[0089] Those skilled in the art will recognize that L is R 12 When the compound of the present invention is substituted with I can understand that it is possible. [Brief description of the drawings]

[0090] [Figure 1] FIG. 1 is a schematic diagram of a single molecule of Isomer 2 of Example 15. [Diagram 2] FIG. 2 is a schematic diagram of the asymmetric structural unit of the single crystal of Isomer 2 of Example 15. [Diagram 3] FIG. 3 is a schematic diagram of a single molecule of Isomer 1 of Example 34. [Figure 4] FIG. 4 is a schematic diagram of the asymmetric structural unit of the single crystal of Isomer 1 of Example 34. [Diagram 5] FIG. 5 is a schematic diagram of a single molecule of Isomer 3 of Example 34. [Figure 6] FIG. 6 is a schematic diagram of the asymmetric structural unit of the single crystal of Isomer 3 of Example 34. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0091] Related Definitions Unless otherwise stated, the following terms used in the specification and claims have the following meanings: The "compounds" described in this invention include all stereoisomers and tautomers thereof.

[0092] In this application, the compounds are asymmetric, i.e., have one or more stereoisomers. Unless otherwise specified, all stereoisomers are included, e.g., enantiomers and diastereomers. The compounds of the present invention having asymmetric carbon atoms may be used in optically pure form or in a stereoisomeric form. The optically pure forms can be separated from the racemic mixtures and can be synthesized using chiral starting materials or chiral reagents. Both enantiomers are within the scope of the present invention.

[0093] The compounds of the present invention further include tautomeric forms. This is due to the exchange of the double bond with the adjacent double bond and the accompanying transfer of one proton. do.

[0094] The words "optionally" or "optionally" mean that the event or circumstance described thereafter occurs or does not occur. This expression means that it is possible that the event or circumstance will occur, and Including cases where there is no

[0095] Numeric ranges herein refer to each integer in the specified range. For example, "C1- "C6" means that the group can have 1, 2, 3, 4, 5 or 6 carbon atoms. "C3-C6" means that the group can have 3, 4, 5 or 6 carbon atoms. This refers to the following.

[0096] The term "substituted" means that any one or more hydrogens on a particular atom or group are replaced by a substituent. The valence of the particular atom or group is normal and the resulting substitution If the substituent is a ketone group (i.e., =O), the two hydrogens are Unless otherwise specified, the type and number of substituents are as far as is chemically feasible. And it may be arbitrary.

[0097] When a variable (e.g., R) appears more than once in the composition or structure of a compound, it may be Each definition in the context is independent. Thus, for example, a group may be substituted with 1-5 R. If substituted, the group may be optionally substituted with up to five R's, and in various circumstances In the formula, R has independent options. Also, the combination of the substituents and / or variations thereof can be: Combinations are permissible only if they result in stable compounds.

[0098] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched-chain saturated hydrocarbon groups. The term "C1-C6 alkyl" includes a hydrocarbon group having the indicated number of carbon atoms. The alkyl group is a C1 alkyl group, a C2 alkyl group, a C3 alkyl group, a C4 alkyl group, and a C5 alkyl group. Examples include methyl, ethyl, n-propyl, isopropyl, and C6 alkyl groups. Propyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, 2-pentyl group These include aryl, 3-pentyl, n-hexyl, 2-hexyl, and 3-hexyl groups. These may be divalent, for example, methylene, ethylene. stomach.

[0099] The term "alkoxy group" refers to a group having the structure alkyl-O-, where alkyl is linear or It includes branched, saturated monovalent hydrocarbon groups. For example, a "C1-C3 alkoxy group" is a methoxy group. , ethoxy groups, n-propoxy groups, and isopropoxy groups.

[0100] The term "alkanoyl group" refers to a group having the structure RC(=O)-, where R is H or a saturated aliphatic Aromatic hydrocarbon groups include linear or branched saturated monovalent hydrocarbon groups. For example, "C1-C "4 alkanoyl group" refers to a C1 alkanoyl group, a C2 alkanoyl group, a C3 alkanoyl group, C4 alkanoyl groups, and suitable alkanoyl groups include formyl, acetyl, n-propyl, and propyl. These include propionyl, isopropionyl, n-butyryl, isobutyryl, and t-butyryl. .

[0101] The term "halogenated" refers to substitution with one or more halogen atoms; Examples of atoms include fluorine, chlorine, bromine, and iodine. For example, the term "Halogenated C1-C3 alkoxy group" refers to a C1 alkoxy group substituted with one or more halogen atoms. -C3 alkoxy group, examples of which are OCF3, OCHF2, OCH2F, OCH2C F3, OCH2CHF2, or OCF2CF3, but are not limited to these. For example, the term "halogenated C1-C3 alkyl group" refers to a group substituted with one or more halogen atoms. It refers to a C1-C3 alkyl group, examples of which are CF3, CHF2, CH2F, CH2C Including, but not limited to, F3, CH2CHF2 or CF2CF3.

[0102] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system with no heteroatoms and no double bonds. Illustrative examples of the term "C3-C6 cycloalkyl" are cyclopropyl, cyclobutyl, cyclopropyl, cyclopropyl, cyclobutyl ... Including, but not limited to, cyclopentyl, cyclohexyl.

[0103] The term "aryl group" refers to a monocyclic or polycondensed ring system consisting of only carbon atoms having a conjugated pi-electron system. Refers to an aromatic ring group formed by removing one hydrogen atom from one carbon atom of the parent aromatic ring system. For example, aryl groups have 6-20 carbon atoms, 6-14 carbon atoms, or 6-10 carbon atoms. Saturated, partially unsaturated cyclic or aromatic carbocyclic rings. Examples of bicyclic groups include phenyl, naphthyl, aryl, and aryl rings fused to aryl. Tracenyl, indene, indane, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene Including but not limited to, dronaphthalene.

[0104] The term "heteroaryl group" refers independently to the group consisting of nitrogen, oxygen, and sulfur atoms. a monovalent 5-, 6-, or 7-membered aryl group containing at least one heteroatom selected from Also includes fused ring systems of 5-10 atoms, at least one of which is aromatic. Illustrative examples of heteroaryl groups are pyridyl, thienyl, imidazolyl, pyrimidine, nyl group, pyridyl group, furyl group, pyrazinyl group, thiazolyl group, quinolinyl group, isoquinoline group, Linyl group, indolyl group, benzimidazolyl group, imidazopyridyl group, benzofuryl group , pyridazinyl groups, and isoindolyl groups.

[0105] The term "membered" refers to the number of skeletal atoms that constitute the ring. For example, "5-10 membered" means that the ring is This refers to the number of atoms in the skeleton being 5, 6, 7, 8, 9 or 10. Thus, by way of example, pyridine, piperidine, piperazine and benzene are six-membered rings. , thiophene and pyrrole are five-membered rings.

[0106] The term "heterocycle" refers to a 5-12 membered saturated aromatic ring having carbon atoms and one to two heteroatoms in the ring. refers to a heteroaromatic system in which the heteroatoms are independently selected from nitrogen, sulfur, and oxygen atoms. In heterocyclic groups containing one or more nitrogen atoms, the valence is selected from the group consisting of The point of attachment may be a carbon atom or a nitrogen atom, as long as the heterocycle is free from any of the following: For example, it may be a bicyclic ring, where the two or more rings are fused rings, bridged rings, or the like. It exists as a bridged or spiro ring, in which at least one ring is bound to one or more heterocyclic rings. Contains an atom.

[0107] Where valence permits, the substituent R 12 may be attached to any atom on the ring. and / or combinations of variations thereof, where such combinations result in stable compounds. Those skilled in the art can use one or more R 12 For any group containing a substituent, vacancy It is understood that the invention will not introduce substitutions or substitution methods that cannot exist and / or be synthesized in the future. I can understand it.

[0108] Wavy line [ka] and double wavy line [ka] Both refer to the bonding position of a chemical bond and have the same chemical meaning, unless otherwise specified. [ka] and [ka] The difference between them merely distinguishes the position or order of attachment.

[0109] The term "amino-protecting group" refers to a suitable protecting group to prevent side reactions on the nitrogen of an amino group. Examples of amino protecting groups are Boc, DMB, benzyloxycarbonyl, 9-fluoro Examples include, but are not limited to, phenyl, methoxycarbonyl, benzyl, formyl or acetyl. I can't.

[0110] The term "pharmaceutical acceptable salt" refers to a compound that possesses the biological effectiveness of the free acids and bases of a particular compound. For example, salts with acids (including organic and inorganic acids) Salts, or base (including organic and inorganic bases) addition salts.

[0111] The pharma- ceutically acceptable salts of the present invention can be prepared by conventional chemical conversion from a parent compound which contains an acid or a base. Generally, such salts can be prepared by immersing in water, an organic solvent, or a mixture of both. These compounds in the form of a free acid or base are prepared by reacting them with a stoichiometrically appropriate base or acid. It is prepared by the method.

[0112] The term "effective amount" or "therapeutically effective amount" refers to a non-toxic but effective amount of a pharmaceutical agent capable of achieving a desired effect. A full dose of a product or drug.

[0113] The term "pharmaceutical acceptable carrier" refers to a carrier that does not cause significant irritation to the body and is suitable for administering the active compound. The carrier is a substance that does not impair the biological activity and performance of the product. Any approved diluents, disintegrants, adhesives, flow inhibitors, wetting agents, etc. for human or veterinary use This includes, but is not limited to, agents.

[0114] The following abbreviations are used in the claims and specification: M:mol / L mM:mmol / L nM:nmol / L Boc: t-butoxycarbonyl DMB: 2,4-dimethoxybenzyl NMP: N-methylpyrrolidone DMAP: p-Dimethylaminopyridine DMF: N,N-dimethylformamide DEA: Diethylamine PE: Petroleum ether EA: Ethyl acetate HATU: (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) RT: retention time SFC: Supercritical Fluid Chromatography h: time min:minutes TK: tyrosine kinase SEB: Fluorescent signal enhancer HTRF: Homogeneous time-resolved fluorescence DTT: Dithiothreitol NR: Not calculated Preparation method: The preparation method of the present invention will be described in more detail below, but the scope of the present invention does not include these specific preparation methods. The present invention is not limited to the preparation method. For example, reactants, solvents, bases, compounds used, etc. The reaction conditions such as the amount of, reaction temperature, reaction time, etc. are not limited to the following examples.

[0115] The compounds of the present invention can be prepared by any of the various synthetic methods described herein or known in the art. They may also be prepared in combination, and such combinations can be readily performed by one skilled in the art.

[0116] Scheme A: [ka] Reaction conditions: a) ethyl crotonate, sodium methoxide methanol solution (30% wt), Methanol, b) Formamidine acetate, sodium methoxide methanol solution (30% wt ), c) phosphoryl chloride, diisopropylethylamine, acetonitrile, d) ammonia Aqueous solution (25-28% wt), e) t-butyl piperazine-1-carboxylate, f) trifluoro dichloromethane, g) (S)-2-(4-chlorophenyl)-3-(isopropylamine N) Propionic acid, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyl Luronium hexafluorophosphate, diisopropylethylamine, dichloromethane hmm.

[0117] Example 1 4-(4-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propane pionyl)piperazin-1-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pi Rimidin-7(6H)-one [ka] a) Trimethyl 2-methylpropane-1,1,3-tricarboxylate Under a nitrogen gas atmosphere, sodium methoxide methanol solution (30% wt) (8.1 6g) was added to methanol (400mL), and the temperature was raised to 70°C. Dimethyl malonate (24. Mix 64g of sodium methoxide and 21.08g of ethyl crotonate uniformly, and add the sodium methoxide The mixture was added dropwise to a methanol solution and reacted at 70°C for 3 hours. After the reaction was complete, the mixture was subjected to vacuum distillation. The solvent was removed, ethyl acetate (100 mL) was added, and the pH was adjusted to 7 with 4 M hydrochloric acid. The mixture was adjusted to 45.5 ml and 100 ml of water was added. The layers were separated and the organic phase was concentrated to give a yellow liquid at 45.5 ml. 48 g was obtained and used directly in the next step without purification. 1 H NMR (400MHz, D MSO-d6)δ(ppm)0.93(d,J=6.8Hz,3H),2.26(q,J=12.0 Hz,2H),2.52-2.58(m,1H),3.56(d,J=6.8Hz,1H),3.59 (s,3H),3.65(s,3H),3.67(s,3H).

[0118] b) Methyl 3-(4,6-dihydroxypyrimidin-5-yl)butyrate Sodium methoxide methanol solution (30% wt) (97. 55g) in methanol (400mL), cooled to -15°C, and then formamidine acetate ( 22.98g) was added and reacted for 30 minutes, and then 2-methylpropane-1,1, Trimethyl carboxylate (45.72 g) was added dropwise, and the temperature was gradually raised to 20°C. The reaction was continued for 1 The reaction was continued for 2 hours. After the reaction was completed, the reaction solution was cooled to 0° C. and 4M hydrochloric acid was added to adjust the pH to 5. The mixture was adjusted to 2, the solvent was removed by distillation under reduced pressure, and 100 mL of water was added at 0°C. A solid precipitated, which was collected by suction filtration and the filter cake was washed with water (50 mL). After that, it was dried in vacuum to obtain 29.60g of a yellow solid, which was directly used in the next step without purification. Used. 1 H NMR(400MHz,DMSO-d6)δ(ppm)11.62(s,2H),7 .86(s,1H),3.53(s,3H),3.34-3.42(m,1H),2.58-2.70 (m, 2H), 1.11 (d, J = 6.8 Hz, 3H).

[0119] c) Methyl 3-(4,6-dichloropyrimidin-5-yl)butyrate Methyl 3-(4,6-dihydroxypyrimidin-5-yl)butyrate was added at 22°C under a nitrogen gas atmosphere. Disperse phosphoryl chloride (16.03 g) and phosphoryl chloride (100 mL) in acetonitrile (100 mL). and diisopropylethylamine (7.79 g) were added dropwise in this order, and the reaction system became highly exothermic. The solid gradually dissolved completely, and the temperature was raised to 60°C and the reaction was continued for 18 hours. After the reaction, the reaction mixture was cooled to 0°C, poured into 200 mL of ice water, and the pH was adjusted to 7-8 with saturated sodium bicarbonate water. The mixture was adjusted to 100 mL, extracted with ethyl acetate (50 mL x 3), and the organic phases were combined and distilled under reduced pressure. The solvent was removed by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1, volume ratio) to obtain 8.36 g of a brown liquid.

[0120] d) 4-Chloro-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidine-7(6H )-on Methyl 3-(4,6-dichloropyrimidin-5-yl)butyrate (4.12 g) and ammonia at 20°C. A 100 mL solution of NiO2 (25-28% wt, 25 mL) was placed in an autoclave and heated to 60°C. The temperature was raised to 50° C. and the reaction was allowed to proceed for 18 hours. After the reaction was complete, the reaction solution was cooled to 0° C. and filtered by suction. The filter cake was then pulverized with 30 mL of petroleum ether:ethyl acetate = 10:1 by volume. The product was polymerized to give 1.51 g of a pale yellow solid. 1 H NMR (300MHz, DMSO-d6) δ(ppm)1.09-1.12(d,J=7.2Hz,3H),2.36-2.49(m,1H) ,2.92-3.00(m,1H),3.27-3.36(m,1H),8.54(s,1H).

[0121] e) 4-(5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrid (4-(4-(aminophenyl)piperazine)-1-carboxylate t-butyl ester Under a nitrogen gas atmosphere, 4-chloro-5-methyl-5,8-dihydropyrido[2,3- d] Pyrimidin-7(6H)-one (0.42 g) and t-butyl piperazine-1-carboxylate (10.76 g) was heated to 140°C and stirred for 6 hours. After the reaction was complete, The reaction solution was cooled to 0°C, poured into 30 mL of ice water, and 4 M hydrochloric acid was added to adjust the pH to 7. The mixture was then extracted with dichloromethane (20 mL x 2), the solvent was removed by distillation under reduced pressure, and the residue was placed on silica gel. The mixture was separated by column chromatography (dichloromethane:methanol = 30:1, volume ratio). 0.67 g of a pale yellow solid was obtained. LC-MS(ESI)m / z: 348, (M+H). 1 H NMR(300MHz,CDCl3)δ(ppm)8.47(s,1H),8.42(s,1H),3 .24-3.61(m,9H),2.56-2.83(m,2H),1.48(s,9H),1.23 -1.26(d,J=6.9Hz,3H).

[0122] f) 5-Methyl-4-(piperazin-1-yl)-5,8-dihydropyrido[2,3-d]pi Rimidin-7(6H)-one At 25°C, 4-(5-methyl-7-oxo-5,6,7,8-tetrahydropyridine [2,3-d ]pyrimidin-4-yl)piperazine-1-carboxylate t-butyl (0.67 g) Dissolve in fluoromethane (10 mL), add trifluoroacetic acid (1.31 g), and react for 16 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, the mixture was cooled to 0°C, and 20% hydroxide was added. Adjust the pH to 12 with sodium solution and extract with dichloromethane (20 mL x 6). The organic phases were combined, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography. - (dichloromethane:methanol = 20:1, volume ratio) to separate, 0.39g of yellow solid was used directly in the next step.

[0123] g) 4-(4-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionyl (1-pyrazine-1-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin N-7(6H)-On 5-Methyl-4-(piperazin-1-yl)-5,8-dihydrazine was added at 20°C under a nitrogen gas atmosphere. lopirido[2,3-d]pyrimidin-7(6H)-one (0.10 g) and (S)-2-(4-chloro (3-(isopropylamino)propionic acid (0.107 g) in dichloromethane ( 5 mL) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetradecane tetramethyluronium hexafluorophosphate (0.184 g) and diisopropyl ethyl Amine (0.078 g) was added and the reaction was allowed to proceed at 25° C. for 16 hours. After that, 10 mL of water was added to the reaction mixture, the liquids were separated, and the organic phase was washed with saturated saline (2 mL) and reduced. The solvent was removed by distillation under reduced pressure, and the residue was analyzed by silica gel column chromatography (dichloromethane:methane The product was isolated in 10 mL of methanol (25:1, volume ratio) to give 0.12 g of a white solid. I) m / z: 471 (M+H). 1 H NMR(300MHz,CDCl3)δ(ppm)1.06 -1.28(m,6H),1.30-1.38(m,3H),2.57(d,J=15.0Hz,1 H),2.70-2.78(m,4H),2.80-3.25(m,2H),3.28-3.69( m,7H),3.86-4.09(m,2H),7.22-7.36(m,4H),8.38(s,1 H),8.61(s,1H).

[0124] Example 2: (S)-4-(4-((S)-2-(4-chlorophenyl)-3-(isopropylamine) (No) Propionyl) piperazin-1-yl) -5-methyl-5,8-dihydropyrido [2,3 -d]pyrimidin-7(6H)-one, and (R)-4-(4-((S)-2-(4-chlorophenoxy) Nyl)-3-(isopropylamino)propionyl)piperazin-1-yl)-5-methyl- 5,8-Dihydropyrido[2,3-d]pyrimidin-7(6H)-one [ka] 5-Methyl-4-(piperazin-1-yl)-5,8-dihydrazine was added at 20°C under a nitrogen gas atmosphere. 0.49 g of lopirido[2,3-d]pyrimidin-7(6H)-one and (S)-2-(4-chloro (3-(isopropylamino)propionic acid (0.53 g) and 2-(7-benzotriazole oxide)-N,N, N',N'-Tetramethyluronium hexafluorophosphate (1.50 g) and diisopropyl Then, the mixture was reacted at 25° C. for 4 hours. After reacting with the reaction mixture, 100 mL of water was added to separate the reaction mixture, and the organic phase was washed with saturated saline (40 mL). The solvent was removed by distillation under reduced pressure, and the mixture was subjected to silica gel column chromatography (dichloro The product was isolated using a 25:1 volume ratio of hexane and methanol to obtain 0.59 g of a white solid. By splitting, 0.21 g (de%=100%) of the (S)-configured product and 0.19 g (de% =99%) of the (R)-configured product was obtained.

[0125] Equipment for optical separation: Waters SFC200, column: Daicel Chira lcel OD, 250×30 mm ID, 5 μm, mobile phase A: CO2, mobile phase B: iso Propanol (containing 0.1% NH3·H2O), A:B = 70:30 (volume ratio). Product with (S) configuration: LC-MS (ESI) m / z: 471(M+H). 1 H NMR (300M Hz,DMSO-d6)δ(ppm)0.93-0.96(m,6H),1.30(d,J=3.0 Hz,3H),2.23-2.36(m,1H),2.61-2.84(m,4H),3.12-3 .31(m,5H),3.35-3.49(m,2H),3.65-3.78(m,3H),4.21 -4.29(m,1H),7.33(d,J=6.6Hz,2H),7.40(d,J=6.6Hz, 2H), 8.38(s,1H), 10.66(s,1H), Product with (R) configuration: LC-MS (ESI) m / z: 471 (M+1). 1 H NMR (300M Hz,DMSO-d6)δ(ppm)0.95-1.03(m,9H),2.26-2.30(m, 1H),2.66-2.79(m,1H),2.82-2.96(m,3H),3.11-3.20 (m,4H),3.34-3.47(m,3H),3.62-3.69(m,3H),4.18-4. 22(m,1H),7.34(d,J=6.6Hz,2H),7.42(d,J=6.6Hz,2H), 8.28(s,1H),10.62(s,1H).

[0126] Scheme B: [ka] Reaction conditions: a) methyl acrylate, sodium methoxide methanol solution (30% wt), Methanol, b) formamidine acetate, sodium methoxide, methanol, c) phosphide chloride folyl, diisopropylethylamine, acetonitrile, d) aqueous ammonia solution (25-2 8% wt), e) t-butyl piperazine-1-carboxylate, f) trifluoroacetic acid, dichloro romethane, g) (S)-2-(4-chlorophenyl)-3-(isopropylamino)propion Acid, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium Hexafluorophosphate, diisopropylethylamine, dichloromethane.

[0127] Example 3: (S)-4-(4-(2-(4-chlorophenyl)-3-(isopropylamino)propane Pionyl)piperazin-1-yl)-5,8-dihydropyrido[2,3-d]pyrimidine-7 (6H)-On [ka] The same procedure as described in Example 1 was repeated except that methyl acrylate was used instead of ethyl crotonate. Prepared in the same manner as described above. LC-MS(ESI)m / z:457(M+H). 1 H NMR( 300MHz,DMSO-d6)δ(ppm)0.92-0.96(m,6H),2.42-2. 49(m,2H),2.62-2.78(m,5H),3.08-3.29(m,4H),3.38- 3.43(m,2H),3.57-3.65(m,3H),4.21-4.29(m,1H)7.3 1-7.34(m,2H),7.38-7.40(m,2H),8.27(s,1H),10.53( s,1H).

[0128] Example 4 4-((R)-4-((S)-2-(4-chlorophenyl)-3-(isopropylamine) (2-methylpiperazin-1-yl)-5,8-dihydropyrido[2,3 -d]pyrimidin-7(6H)-one [ka] (R)-3-Methylpiperazine-1-carboxylate instead of t-butyl piperazine-1-carboxylate It was prepared in the same manner as described in Example 3, except that t-butyl carboxylate was used. LC-MS(ESI)m / z:471(M+H). 1 H NMR (300MHz, DMSO-d 6)δ(ppm)0.75-0.95(m,9H),2.40-2.49(m,3H),2.51- 2.61(m,4H),2.85-3.36(m,5H),3.62-3.76(m,1H),3.9 1-3.96(m,1H),4.14-4.19(m,2H)7.29-7.42(m,4H),8 .26(d,J=7.2Hz,1H),10.54(s,1H).

[0129] Example 5 4-((S)-4-((S)-2-(4-chlorophenyl)-3-(isopropylamine (2-methylpiperazin-1-yl)-5,8-dihydropyrido[2,3 -d]pyrimidin-7(6H)-one [ka] (S)-3-Methylpiperazine-1-carboxylate instead of t-butyl piperazine-1-carboxylate It was prepared in the same manner as described in Example 3, except that t-butyl carboxylate was used. LC-MS(ESI)m / z:471(M+H) 1 H NMR (300MHz, DMSO-d6 )δ(ppm)1.10-1.33(m,9H),2.42-2.49(m,2H),2.67-2 .76((m,4H),2.84-3.05(m,4H),3.51-3.58(m,3H),3.9 1-4.19(m,2H),4.28-4.54(m,1H)7.32-7.45(m,4H),8 .27(s,1H),10.53(s,1H).

[0130] Scheme C: [ka] Reaction conditions: a) ethyl crotonate, sodium methoxide methanol solution (30% wt), Methanol, b) disodium hydrogen phosphate, deionized water, hydrochloric acid, lipase (Candida rugosa), c) formamidine acetate, sodium methoxide, methanol, d) phosphoryl chloride, diisopropylethylamine, acetonitrile, e) aqueous ammonia liquid (25-28%wt). Intermediate (R)-4-Chloro-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin N-7(6H)-On [ka] a) Trimethyl 2-methylpropane-1,1,3-tricarboxylate Under a nitrogen gas atmosphere, a sodium methoxide methanol solution (30% wt, 50. After adding 32 g of dimethyl malonate (46) to methanol (900 mL), the mixture was heated to 70°C and dimethyl malonate (46 Mix 1.12 g of sodium methoxide and 349.46 g of ethyl crotonate uniformly, and add the sodium methoxide to the mixture. The mixture was then added dropwise to the oxide methanol solution and reacted at 70°C for 3 hours. After the reaction was complete, the pressure was reduced Remove the solvent by distillation, add ethyl acetate (1 L) and adjust the pH to 7-8 with 4 M hydrochloric acid. Then, 500 mL of water was added, the layers were separated, and the organic phase was removed by distillation under reduced pressure to obtain a yellow liquid. The yield was 777.68 g. 1 H NMR(400MHz,DMSO-d6)δ(ppm)3.6 7(s,3H),3.65(s,3H),3.59(s,3H),3.56(d,J=6.8Hz,1H) ,2.45-2.58(m,2H),2.23-2.29(m,1H),0.93(d,J=6.8 Hz,3H).

[0131] b) (R)-2-Methylpropane-1,1,3-tricarboxylate trimethyl Dissolve disodium hydrogen phosphate (4.5 g) in 1.5 L of deionized water at 25°C and add 2N hydrochloric acid. Adjust the pH to 7.05 with trimethyl 2-methylpropane-1,1,3-tricarboxylate. (150.46 g) and lipase (Candida rugosa, 40 g added over 6 days). The pH was adjusted to 7.0-7.6 with 2N sodium hydroxide, and the mixture was reacted at 35°C for 6 days. Chirality measurement ee%>98%, Chirality measurement conditions (Chiralpak IC, 4 .6×250mm, 5μm, n-hexane:ethanol=9:1, volume ratio). Cool to ℃, adjust the pH to 3-4 with 3M hydrochloric acid, add 500mL of ethyl acetate, and filter by suction. The filter cake was washed with ethyl acetate (600 mL), and the layers were separated. The organic phase was concentrated to give 26.89 g of a pale yellow liquid. 1 H NMR(400MHz,CDCl3)δ(ppm)3.74(s,6H),3.68(s,3H), 3.46(d,J=7.2Hz,1H),2.71-2.79(m,1H),2.54(dd,J= 15.6, 4.8Hz, 1H), 2.32 (dd, J=16.0, 8.4Hz, 1H), 1.06 (d, J = 6.8 Hz, 3H).

[0132] c) (R)-3-(4,6-dihydroxypyrimidin-5-yl)butyric acid methyl ester Formamidine acetate (11.33 g) was dissolved in methanol (200 ml) at 20°C under a nitrogen gas atmosphere. L), cooled to 0°C, and dissolved in sodium methoxide methanol solution (30%, 55.62 g) was added dropwise and reacted at 0°C for 60 minutes to obtain (R)-2-methylpropane-1,1,3-tetrahydrofuran. A solution of trimethyl carboxylate (24.07 g) in methanol (60 mL) was added dropwise to the mixture, and the temperature was adjusted to 20°C. The temperature was naturally raised and the reaction was carried out for 10 hours. After the reaction was completed, the reaction solution was cooled to 0°C and diluted with 3N Add hydrochloric acid to adjust the pH to 5-6, remove the solvent by vacuum distillation, and then Cool to 0°C, add 3N hydrochloric acid to adjust the pH to 3, and a solid is precipitated and filtered by suction. The solid was collected by filtration, the filter cake was washed with ice water (100 mL), and then dried in vacuum to give a white solid. 18.79 g of a colored solid was obtained and used as is in the next step.

[0133] d) (R)-3-(4,6-dichloropyrimidin-5-yl)butyric acid methyl ester (R)-3-(4,6-dihydroxypyrimidin-5-yl)butyrate was added at 22°C under a nitrogen gas atmosphere. Methyl acetate (14.63 g) was dispersed in acetonitrile (70 mL) and phosphoryl chloride (26. Then, diisopropylethylamine (12.51 g) and diisopropylethylamine (42 g) were added dropwise in this order, and the reaction system became extremely The temperature rose to 60°C and the solid gradually dissolved completely. The reaction was continued for 18 hours. After the reaction was complete, the reaction mixture was cooled to 0°C, 100 mL of ethyl acetate was added, and the mixture was dissolved in saturated The pH was adjusted to 7-8 with sodium chloride solution, extracted with ethyl acetate (50 mL x 3), and the organic phase was distilled under reduced pressure. Removal of toluene gave 13.89 g of a yellow solid which was used directly in the next step.

[0134] e) (R)-4-chloro-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidine- 7(6H)-On Methyl (R)-3-(4,6-dichloropyrimidin-5-yl)butyrate (13.89 g) at 20°C and an aqueous ammonia solution (25-28% wt, 70 mL) were placed in an autoclave. The temperature was then raised to 50°C and the reaction was carried out for 18 hours. After the reaction was completed, the reaction solution was cooled to 0°C and The filter cake was filtered and diluted with petroleum ether:ethyl acetate = 10:1 by volume to 30 ml. Pulping with 100 mL gave 7.32 g of a pale yellow solid. LC-MS (ESI) m / z: 198 (M +H). 1 H NMR(300MHz,CDCl3)δ(ppm)1.30(d,J=7.2Hz, 3H),2.65-2.69(m,1H),2.86-2.92(m,1H),3.47-3.54 (m,1H),8.64(s,1H),10.10(s,1H).

[0135] Scheme D: [ka] Reaction conditions: a) 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid t-butyl b) Hydrogen chloride / 1,4-dioxol, 4-dimethylaminopyridine, N-methylpyrrolidone, San (4.0M), dioxane, c) (S)-2-(4-chlorophenyl)-3-(isopropyl Amino)propionic acid, 2-(7-benzotriazole oxide)-N,N,N',N'-tetra Methyluronium hexafluorophosphate, diisopropylethylamine, N,N- Dimethylformamide.

[0136] Example 6 (5R)-4-(5-((S)-2-(4-chlorophenyl)-3-(isopropyl Amino)propionyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5- Methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one [ka] a) 4-(5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrid (4-(4-(aminophenyl)piperazine)-1-carboxylate t-butyl ester Under a nitrogen gas atmosphere at 22°C, (R)-4-chloro-5-methyl-5,8-dihydropyridine [ 2,3-d]pyrimidin-7(6H)-one (0.30 g), 2,5-diazabicyclo[2.2 .1] t-Butyl heptane-2-carboxylate (1.21 g), and 4-dimethylaminopyridine Dissolve 0.58 g of dimethylformamide in N-methylpyrrolidone, heat to 140°C, and react for 6 hours. After the reaction was completed, the reaction mixture was cooled to 0°C and poured into 30 mL of ice water, and 4 M hydrochloric acid was added. The pH was adjusted to 4-5, and the solution was extracted with ethyl acetate (20 mL x 2). The organic phase was saturated. The organic phase was removed by distillation under reduced pressure, and the extract was subjected to silica gel column chromatography. Chromatography (petroleum ether:ethyl acetate = 1:1, volume ratio) gave a pale yellow solid, 0. Obtained 33g. LC-MS(ESI) m / z: 360(M+H).

[0137] b) (5R)-4-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-methyl 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one At 25°C, 4-(5-methyl-7-oxo-5,6,7,8-tetrahydropyridine [2,3-d ]pyrimidin-4-yl)piperazine-1-carboxylate t-butyl (0.28 g) Dissolve in 3 mL of water and add 1.91 g of hydrogen chloride / 1,4-dioxane (4.0 M) to dilute. The reaction was allowed to proceed for 6 hours. After the reaction was complete, the reaction solution was concentrated to remove the solvent and cooled to 0°C. 20% sodium hydroxide solution was added to adjust the pH to 12, and dichloromethane was added. (20 mL x 8), and the organic phase was removed by vacuum distillation to obtain 0.15 g of a brown solid. and used as is in the next step.

[0138] c) (5R)-4-(5-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionate dopionyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-methyl -5,8-Dihydropyrido[2,3-d]pyrimidin-7(6H)-one 4-(5-methyl-7-oxo-5,6,7,8-tetrahydrofuran) was added at 20°C under a nitrogen gas atmosphere. Pyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate t-butyl(0 .15g) and (S)-2-(4-chlorophenyl)-3-(isopropylamino)propionic acid ( 0.157 g) was dissolved in N,N-dimethylformamide (5 mL) and 2-(7-benzotriazole) was added. Riazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate Add 0.26 g of ethyl acetate and 0.29 g of diisopropylethylamine, and The reaction was carried out at 5°C for 16 hours. After the reaction was completed, 10 mL of water was added to the reaction solution and the mixture was separated. The organic phase was washed with saturated saline (2 mL), the organic phase was removed by distillation under reduced pressure, and the residue was then separated on a silica gel column. By chromatography (dichloromethane:methanol = 20:1, volume ratio), a brown 0.037 g of solid was obtained. LC-MS(ESI)m / z:483(M+H). 1 H NMR( 300MHz,DMSO d6)δ(ppm)0.68-1.24(m,10H),1.75-2 .38(m,3H),2.54-2.61(m,4H),3.08-3.28(m,2H),3.59 -3.61(m,2H),3.87-4.16(m,2H),4.72-4.97(m,2H)7. 31-7.38(m,4H),8.10(d,J=23.1Hz,1H),10.36(d,J=1 1.4Hz,1H).

[0139] Example 7 (R)-4-((R)-4-((S)-2-(4-chlorophenyl)-3-(isopropyl Amino)propionyl)-2-methylpiperazin-1-yl)-5-methyl-5,8-dihydr Lopirido[2,3-d]pyrimidin-7(6H)-one [ka] Instead of t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate ( The method described in Example 6 except that R)-4-Boc-2-methylpiperazine was used. LC-MS(ESI)m / z:485(M+H). 1 H NMR(30 0MHz,DMSO-d6)δ(ppm)0.94-1.04 (m,12H),2.24-2. 29(m,1H),2.67-2.93(m,5H),3.06-3.19(m,5H),3.57- 3.62(m,3H),4.21-4.24(m,1H),7.32-7.44(m,4H),8.2 6(s,1H),10.61(s,1H).

[0140] Example 8 (R)-4-((R)-4-((S)-2-(4-chlorophenyl)-3-(isopropyl Amino)propionyl)-3-methylpiperazin-1-yl)-5-methyl-5,8-dihydr Lopirido[2,3-d]pyrimidin-7(6H)-one [ka] Instead of t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate ( The same procedure as described in Example 6 was used except that R)-1-N-Boc-2-methylpiperazine was used. It was prepared in a similar manner to the method described above.

[0141] LC-MS(ESI)m / z:485(M+H). 1 H NMR (300MHz, CDCl3) δ( ppm)8.37(d,J=12.0Hz,1H),8.28(s,1H),7.36(d,J=6. 0Hz,2H),7.26(d,J=6.0Hz,2H),4.59-4.95(m,1H),4.0 8-4.31(m,2H),3.15-3.82(m,6H),2.72-3.09(m,4H),2 .52-2.58(m,1H),2.32-2.39(m,1H),1.10-1.38(m,12 H).

[0142] Example 9 (R)-4-((S)-4-((R)-2-(4-chlorophenyl)-3-(isopropyl Amino)propionyl)-3-methylpiperazin-1-yl)-5-methyl-5,8-dihydr Lopirido[2,3-d]pyrimidin-7(6H)-one [ka] Instead of t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate ( The same procedure as described in Example 6 was used except that S)-1-N-Boc-2-methylpiperazine was used. Prepared in the same manner as described above. LC-MS(ESI)m / z:485(M+H). 1 H NMR( 400MHz, CDCl3)δ(ppm)8.35(d,J=16.0Hz,1H),7.41-7 .28(m,3H),7.26-7.21(m,1H),4.89(d,J=6.8Hz,1H),4. 76-4.49(m,1H),3.75-3.65(m,1H),3.64-3.54(m,1H),3 .51-3.49(m,1H),3.44-3.34(m,1H),3.34-3.17(m,3H), 3.17-3.09(m,1H),3.06-2.96(m,1H),2.89-2.49(m,3H) ,1.44-1.29(m,7H),1.25-1.06(m,5H).

[0143] Example 10 (R)-4-(8-((S)-2-(4-chlorophenyl)-3-(isopropyl amine) (Propionyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-methyl Chil-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one [ka] Instead of t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Using t-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate Prepared in the same manner as described in Example 6, except for: LC-MS (ESI) m / z: 497(M+H). 1 H NMR(400MHz,CDCl3)δ(ppm)8.35(d,J=1 6.0Hz, 1H), 7.41-7.28(m, 3H), 7.26-7.21(m, 1H), 4.83 (s,1H),4.51-4.30(m,2H),4.25-4.22(m,1H),4.10-4.0 3(m,1H),3.92-3.84(m,1H),3.73-3.62(m,1H),3.50-3. 26(m,3H),3.24-3.21(m,1H),3.20-2.85(m,2H),2.75-2 .62(m,1H),2.49-2.41(m,1H),2.20-1.90(m,1H),1.88- 1.60(m,3H),1.44-1.29(m,6H),1.25-1.06(m,3H).

[0144] Example 11 (R)-4-(3-((S)-2-(4-chlorophenyl)-3-(isopropyl amine (Propionyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-methyl Chil-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one [ka] Instead of t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Using t-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate Prepared in the same manner as described in Example 6, except for: LC-MS (ESI) m / z: 497(M+H). 1 H NMR(400MHz,CDCl3)δ(ppm)8.66(s,1H), 8.28(d,J=5.2Hz,1H),7.15-7.38(m,4H),4.31-4.56( m,3H),3.93(s,1H),3.49-3.66(m,2H),3.15-3.31(m,2 H),2.70-3.01(m,4H),2.26-2.50(m,1H),1.74-2.03( m,3H),1.57-1.67(m,1H),1.43-1.50(m,1H),1.03-1. 26(m,9H).

[0145] Example 12 (R)-4-(4-((S)-2-(4-chlorophenyl)-3-(isopropyl amine (No)propionyl)-4,7-diazaspiro[2.5]octan-7-yl)-5-methyl- 5,8-Dihydropyrido[2,3-d]pyrimidin-7(6H)-one [ka] Instead of t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Except for using tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate , prepared in a similar manner to that described in Example 6. LC-MS (ESI) m / z=497 (M+H). 1 H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.22 (s,1H),7.33-7.38(m,4H),4.37(s,1H),3.40-4.15(m,4 H),2.97-3.09(m,3H),2.57-2.90(m,4H),2.24-2.32( m,1H),0.44-1.13(m,13H).

[0146] Example 13 (5R)-4-(5-((S)-2-(4-chlorophenyl)-3-(isopropyl 3,4-diamino)propionyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5- Methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one [ka] Instead of t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Using hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate t-butyl The final product was prepared in the same manner as in Example 6, except that the above-mentioned step was repeated. The cis and trans isomers were obtained by optical resolution. Waters SFC200, Column: Daicel Chiralcel AD, 250× 30 mm ID, 5 μm, mobile phase A: CO2, mobile phase B: ethanol (0.1% ammonia) A:B = 65:35 (volume ratio). Products with retention time of 8-10 min were collected, and the products with retention times of 11-13 min were collected, which were cis isomers. They were the trans isomers.

[0147] Cis isomer: LC-MS (ESI) m / z: 497.(M+H). 1 H NMR (300MHz, DMSO-d6)δ(ppm)10.31(d,J=6.9Hz,1H),8.08(d,J=13 .5Hz,1H),7.28-7.38(m,4H),3.76-3.93(m,3H),3.56 -3.72(m,2H),3.45-3.52(m,2H),3.38-3.40(m,2H),3. 13-3.24(m,2H),3.03-3.07(m,1H),2.84-2.90(m,2H), 2.57-2.78(m,3H),2.17-2.26(m,1H),1.04(d,J=5.1H z,2H),0.87-0.93(m,7H).

[0148] Trans isomer: LC-MS(ESI) m / z: 497.(M+H). 1 H NMR (300M Hz,DMSO-d6)δ(ppm)10.31(d,J=7.8Hz,1H),8.08(d,J =13.2Hz,1H),7.28-7.40(m,4H),3.82-3.94(m,2H),3 .68-3.79(m,1H),3.47-3.63(m,2H),3.07-3.22(m,3H) ),2.62-3.02(m,5H),2.18-2.27(m,1H),1.20-1.29(m, 3H),1.05(d,J=5.4Hz,1H),0.90-0.96(m,6H),0.81-0 .86(m,3H).

[0149] Example 14 (R)-4-(6-((S)-2-(4-chlorophenyl)-3-(isopropyl amine (No)propionyl)-2,6-diazaspiro[3.3]heptan-2-yl)-5-methyl- 5,8-Dihydropyrido[2,3-d]pyrimidin-7(6H)-one [ka] Instead of t-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Except for using t-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate , was prepared in a manner similar to that described in Example 6. LC-MS (ESI) m / z: 483 ( M+H). 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.38(s,1H), 8.09(s,1H),7.36-7.38(m,2H),7.30-7.32(m,2H),4.4 8(d,J=9.6Hz,1H),4.35(s,2H),4.26(s,2H),3.98-4.0 8(m,3H),3.63-3.67(m,1H),3.00-3.10(m,2H),2.61-2 .73(m,4H),2.23(d,J=16.0Hz,1H),1.02(d,J=7.2Hz,3 H), 0.91-0.93(m,6H).

[0150] Scheme E [ka] Reaction conditions: a) 2,5-diazabicyclo[4.1.0]heptane-2-carboxylic acid t-butyl a) Hydrogen chloride / 1,4-dioxol, N-methylpyrrolidone, 4-dimethylaminopyridine, San (4.0M), dichloromethane, c) (S)-3-(t-butoxycarbonyl)(isopropyl (phenyl)amino)-2-(4-chlorophenyl)propionic acid, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 4-di Methylaminopyridine, N,N-dimethylformamide, d) Trifluoroacetic acid, dichloro methane.

[0151] Example 15 (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(isopropyl ether) Propylamino)propionyl)-2,5-diazabicyclo[4.1.0]heptane-2- yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one or (R)-4-((1R,6S)-5-((S)-2-(4-chlorophenyl)-3-(isopropyl (amino)propionyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl) -5-Methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one [ka] a) 5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyridine [2,3-d ]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carbo t-Butyl phosphate Under a nitrogen gas atmosphere at 22°C, (R)-4-chloro-5-methyl-5,8-dihydropyridine [ 2,3-d]pyrimidin-7(6H)-one (0.21g), 2,5-diazabicyclo[4.1 .0] t-Butyl heptane-2-carboxylate (0.31 g), and 4-dimethylaminopyridine Dissolve 0.39 g of dimethylformamide in 5 mL of N-methylpyrrolidone and heat to 140°C. After the reaction was complete, the reaction mixture was cooled to 20°C and poured into 20 mL of ice water. The mixture was extracted with ethyl acetate (20 mL x 2), washed with saturated saline (10 mL x 3), and the solvent was reduced. The solvent was removed by distillation under reduced pressure, and the solvent was purified by silica gel column chromatography (petroleum ether:ethyl acetate = The mixture was separated by a 3:1 to 1:1 ratio to obtain 0.28 g of a pale yellow liquid. z:360(M+H).

[0152] b) (5R)-4-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-5-methyl Hydrochloride of 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one At 20°C, 5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyridine [2, 3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2- Dissolve t-butyl carboxylate (0.28 g) in dichloromethane (5 mL) and add hydrogen chloride / 1, 4-Dioxane (4.0 mL) was added and the reaction was allowed to proceed for 1 hour. After the reaction was complete, the reaction solution was The solvent was removed by distillation under reduced pressure to give 0.23 g of a yellow solid, which was used directly in the next step. Ta.

[0153] c) (2S)-2-(4-chlorophenyl)-3-(5-((R)-5-methyl-7-oxo-5, 6,7,8-Tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabiphenyl Cyclo[4.1.0]heptan-2-yl)-3-oxopropyl)(isopropyl)carba t-Butyl amine (5R)-4-(2,5-diazabicyclo[4.1.0]hepta) was added at 20°C under a nitrogen gas atmosphere. 6H-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidine-7(6H )-one hydrochloride (0.20 g) and (S)-3-((t-butoxycarbonyl)(isopropyl) Amino)-2-(4-chlorophenyl)-propionic acid (0.22 g) and N,N-dimethyl Dissolve in formamide (5 mL) and prepare 2-(7-benzotriazole oxide)-N,N,N',N '-Tetramethyluronium hexafluorophosphate (0.59 g) and 4-dimethyl Aminopyridine (0.48 g) was added and reacted at 25° C. for 4 hours. After the reaction was complete, Add 20 mL of water to the reaction mixture, extract with ethyl acetate (10 mL x 3), and wash the organic phase with saturated sodium chloride. The mixture was washed with water (10 mL x 2), the organic phase was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography. The mixture was separated by chromatography (dichloromethane:methanol = 50:1) to obtain 0.18 g of a yellow solid. Ta. LC-MS (ESI) m / z: 583 (M+H).

[0154] d) (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(isopropyl (amino)propionyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)- 5-Methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one, or R)-4-((1R,6S)-5-((S)-2-(4-chlorophenyl)-3-(isopropyl Amino)propionyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)-5- Methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (2S)-2-(4-chlorophenyl)-3-(5-((R)-5-methyl-7-oxo) at 20°C -5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazo Zabicyclo[4.1.0]heptan-2-yl)-3-oxopropyl)(isopropyl) Dissolve t-butyl carbamate (0.18 g) in dichloromethane (2 mL) and add trifluoroacetate. Then, acetic acid (0.86 mL) was added and the reaction was allowed to proceed for 3 hours. After the reaction was complete, the reaction mixture was Add 10 mL of dichloromethane and add 2 M sodium hydroxide solution dropwise at 0°C to pH = The mixture was adjusted to 12, the layers were separated, and the organic phase was washed with saturated saline (5 mL) and then with sodium sulfate anhydride. After drying over sodium, the organic phase was removed by distillation under reduced pressure to give 0.10 g of a yellow solid. The mixture was separated by high-performance preparative liquid chromatography to give isomer 1 (3 mg) and isomer 2 (12 mg). g). Conditions for high-speed preparative liquid chromatography: Column: Aglient 5μm prep-C 1850×21.2mm, Mobile phase A: Water (containing 0.1% aqueous ammonia solution), Mobile phase B: : Methanol. Gradient: Time 0-10 min, phase B 60-70% (volume ratio).

[0155] Isomer 1: RT1=5.3min, LC-MS(ESI) m / z:483(M+H).

[0156] Isomer 2: RT2=5.9min, LC-MS(ESI) m / z:483(M+H), 1 HN MR(400MHz, CDCl3)δ(ppm)8.27(d,J=7.6Hz,1H),7.92 (s,1H),7.27-7.30(m,4H),4.23-4.29(m,1H),3.90-3. 95(m,1H),3.81-3.85(m,1H),3.69-3.72(m,1H),3.44- 3.59(m,1H), 3.20-3.38(m,3H),3.01-3.05(m,1H),2. 70-2.85(m,3H),2.47-2.57(m,1H),2.21-2.25(m,1H), 1.25-1.28(m,3H),1.03-1.11(m,6H),0.82-0.90(m,2) H).

[0157] Structure determination by single crystal diffraction: Preparation of single crystals: 30.0 mg of isomer 2 compound and 2.0 mL of isopropanol were added to a 5 mL flask. The mixture was placed in a glass bottle with a clew top and stirred for 5 minutes until the solid was completely dissolved. Weigh out 3.9 mg of the hydrate and place it in the glass bottle. A white solid gradually precipitates in the glass bottle. After stirring at room temperature for 3 hours, a large amount of white solid precipitated in the glass bottle. Upon addition of .0 mL, the white solid gradually disappeared and the solution became clear, followed by stirring for 1 h. The solution was passed through a 0.22 μm microporous filter membrane and transferred into a 3 mL screw-top glass bottle. After filtering, the mouth of the glass bottle was covered with plastic wrap. Eight holes were made in the mouth of the bottle with a needle and the mixture was stored at room temperature. After standing at rt for 7 days, a single crystal of the oxalate salt of isomer 2 was obtained. JPEG2024175091000087.jpg90166

[0158] Structure elucidation: Single crystal X-ray diffraction and structural analysis showed that the obtained single crystal is the oxalate salt of isomer 2. The asymmetric structural unit of the crystal contains four isomers. It contains two oxalic acid molecules and two isopropanol molecules, and isomers 2 and oxalic acid The acid formed the oxalate salt. A schematic diagram of a single molecule of compound isomer 2 is shown in Figure 1, and the oxalate salt The asymmetric structural unit of the single crystal is shown in Figure 2. The structural formula is: [ka]

[0159] Scheme F: [ka] Reaction conditions: a) 4,4,4-trifluorobut-2-enoic acid methyl ester, thorium methoxide ethanol solution (30% wt), b) formamidine acetate, sodium methoxide methanol Solution (30% wt), c) phosphoryl chloride, diisopropylethylamine, acetonitrile d) aqueous ammonia solution (25-28% wt), e) t-butyl piperazine-1-carboxylate , f) trifluoroacetic acid, dichloromethane, g) (S)-2-(4-chlorophenyl)-3-( Isopropylamino)propionic acid, 2-(7-benzotriazole oxide)-N,N,N' ,N'-Tetramethyluronium hexafluorophosphate, diisopropyl ethyl amine , dichloromethane.

[0160] Example 16: 4-(4-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionate (ropionyl)piperazin-1-yl)-5-trifluoromethyl-5,8-dihydropyrido [2,3-d]pyrimidin-7(6H)-one [ka] Prepared in a manner similar to that described in Example 1 according to Scheme F. LC-MS (ES I) m / z: 525 (M+H). Separation of isomers: The above-mentioned title compound was optically resolved by supercritical fluid chromatography to separate the isomers. Obtained isomer 1 and isomer 2. Equipment and conditions for optical resolution: Waters SFC200, Column: Daicel Chiralcel AS, 250×30mm ID, 5μm, Mobile phase: A is CO2 and B is ethanol (0.1% NH3H2O), A:B=8 5:15 (volume ratio), flow rate 60 mL / min, column temperature 38°C.

[0161] Isomer 1: [ka] LCMS(ESI)m / z:525(M+H). 1 HNMR(400MHz,DMSO-d6)δ (ppm):0.91-0.95,(m,6H),2.59-2.78(m,4H),3.07-3 .12(m,1H),3.20-3.31(m,4H),3.37-3.50(m,3H),3.69 -3.75(m,2H),4.08-4.19(m,2H),7.35(dd,J=25.2,8. 0Hz, 4H), 8.36 (s, 1H), 10.90 (s, 1H).

[0162] Isomer 2: [ka] LCMS(ESI)m / z:525(M+H). 1 HNMR(300MHz,DMSO-d6)δ (ppm)0.93-1.06(m,6H),2.58-2.72(m,4H),3.06-3.3 1(m,4H),3.45-3.68(m,6H),4.11-4.20(m,2H)7.31-7 .43(m,4H),8.34(d,J=6.0Hz,1H),10.92(s,1H).

[0163] Scheme G: [ka] Reaction conditions: a) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl t-Butyl 3,6-dihydropyridine-1(2H)-carboxylate, dioxane, cetearyl carbonate a) sodium, water, tetrakis(triphenylphosphine)palladium, b) methanol, formic acid, Palladium on carbon (5%), hydrogen gas, c) dichloromethane, hydrogen chloride / 1,4-dioxane solution Solution (4.0M), d) (S)-3-((t-butoxycarbonyl)(isopropyl)amino)-2-( 4-Chlorophenyl)propionic acid, N,N-dimethylformamide, 2-(7-benzothiazolidinyl) Riazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate diisopropylethylamine, e) dichloromethane, hydrogen chloride / 1,4-dioxane Solution (4.0M).

[0164] Example 17: [ka] a) (R)-4-(5-methyl-7-oxo-5,6,7,8-tetrahydropyridine [2,3-d ]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid t-butyl R Under a nitrogen gas atmosphere at 22°C, (R)-4-chloro-5-methyl-5,8-dihydropyridine [ 2,3-d]pyrimidin-7(6H)-one (0.60 g) and 4-(4,4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carbamoyl Dissolve t-butyl carboxylate (1.03 g) in dioxane (20 mL) and add cesium carbonate and water. (5 mL) and finally tetrakis(triphenylphosphine)palladium (0.35 g). The mixture was then reacted at 100°C for 7 hours. After the reaction was complete, the reaction solution was cooled to 20°C. The mixture was poured into 10 mL of ice water, extracted with ethyl acetate (20 mL), and the solvent was removed by distillation under reduced pressure. , and was simply purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1, volume ratio). Release gave 0.81 g of a pale yellow solid: MS (ESI) m / z: 345 (M+H).

[0165] b) (R)-4-(5-methyl-7-oxo-5,6,7,8-tetrahydropyridine [2,3-d ]pyrimidin-4-yl)piperidine-1-carboxylate t-butyl At 20°C, (R)-4-(5-methyl-7-oxo-5,6,7,8-tetrahydropyridine [2, 3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H))-carboxylic acid 0.75 g of butyl ether was dissolved in 50 mL of methanol and mixed with 0.11 g of formic acid and palladium. The mixture was then filled with nitrogen gas three times, and hydrogen gas was passed through the mixture. The mixture was then heated at 60°C for 16 h. After the reaction was complete, the mixture was cooled to 10°C and palladium carbon was filtered off by suction filtration. The solvent in the filtrate was removed by distillation under reduced pressure to obtain 0.66 g of a colorless oil. S(ESI) m / z: 347(M+H).

[0166] c) (R)-5-Methyl-4-(piperidin-4-yl)-5,8-dihydropyrido[2,3- d]pyrimidin-7(6H)-one At 25°C, (R)-4-(5-methyl-7-oxo-5,6,7,8-tetrahydropyridine [2, 3-d]pyrimidin-4-yl)piperidine-1-carboxylate t-butyl (0.63 g) , dissolved in dichloromethane (10 mL) and diluted with hydrogen chloride / 1,4-dioxane (4.0 M) (10 mL) L) was added and the mixture was allowed to react for 2 hours. After the reaction was complete, the reaction solution was concentrated to remove the solvent. Cool to 0℃, add 20% sodium hydroxide solution to adjust the pH to 12, and add vinegar. The mixture was extracted with ethyl acetate (10 mL x 3), washed with saturated saline (15 mL), and the organic phase was distilled under reduced pressure. Removal of the solid gave 0.346 g of a yellow solid which was used directly in the next step.

[0167] d) (S)-2-(4-chlorophenyl)-3-(4-((R)-5-methyl-7-oxo-5,6 ,7,8-Tetrahydropyrido[2,3-d]pyrimidin-4-yl)-piperidine-1-yl tert-Butyl (3-oxopropyl)(isopropyl)carbamate (R)-5-methyl-4-(piperidin-4-yl)-5,8-dichloro-2,4-diphenyl-2,5-diaminetetraacetate was added at 20° C. under a nitrogen gas atmosphere. Dihydropyrido[2,3-d]pyrimidin-7(6H)-one (0.302 g) and (S)-3 -((t-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)propionate The 2-( 7-Benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluoro Add 0.86 g of diisopropyl ethylamine and The reaction was carried out at 20°C for 3 hours. After the reaction was completed, 30 mL of water was added to the reaction solution, and acetic acid was added. Extract with ethyl acetate (50 mL), separate the liquids, wash the organic phase with saturated saline (10 mL x 2), and reduce The solvent was removed by distillation, and the mixture was analyzed by silica gel column chromatography (dichloromethane:methanol). The mixture was isolated using a 25:1 volume ratio mixture to give 0.339 g of a white solid, which was then directly subjected to the next step. Used for.

[0168] e) (R)-4-(1-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propane pionyl)piperidin-4-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pi Rimidin-7(6H)-one At 25°C, (S)-2-(4-chlorophenyl)-3-(4-((R)-5-methyl-7-oxo- 5,6,7,8-Tetrahydropyrido[2,3-d]pyrimidin-4-yl)-piperidine- 1-yl)-3-oxopropyl)(isopropyl)carbamate t-butyl (0.320g) Dissolve in dichloromethane (3 mL) and prepare a hydrogen chloride / 1,4-dioxane solution (4.0 mL ) (2.9 mL) was added and the reaction was allowed to proceed for 2 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure. The solvent was removed, and the mixture was cooled to 0° C. and 20% sodium hydroxide solution was added to adjust the pH to 12. The mixture was adjusted to 10 mL, extracted with ethyl acetate (10 mL x 3), and washed with saturated saline (15 mL). The organic phase was then removed by distillation under reduced pressure to give 0.176 g of a white solid.

[0169] LC-MS(ESI)m / z:470(M+H). 1 H NMR (400MHz, DMSO-d6 )δ(ppm)0.83-0.97(m,6H),1.03-1.10(m,3H),1.24-1 .43(m,2H),1.57-1.95(m,2H),2.29-2.35(m,1H),2.51 -2.87(m,5H),3.01-3.19(m,3H),3.35-3.41(m,1H),4. 02-4.21(m,2H),4.51-4.62(m,1H)7.32-7.43(m,4H), 8.50-8.61(m,1H),10.85(s,1H).

[0170] Scheme H: [ka] Reaction conditions: a) t-butyl piperazine-1-carboxylate, N-methylpyrrolidone, 4-di Methylaminopyridine, b) dichloromethane, hydrogen chloride / 1,4-dioxane solution (4.0 M), c) Diisopropylethylamine, N,N-dimethylformamide, 2-(7-benzothiazolidinyl) Triazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphine 1-(t-butoxycarbonyl)-4-(4-chlorophenyl)piperidine-4-carboxylate carboxylic acid, d) dichloromethane, hydrogen chloride / 1,4-dioxane solution (4.0 M).

[0171] Example 18 (R)-4-(4-(4-(4-chlorophenyl)piperidine-4-carbonyl)piperidine Perazin-1-yl)-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidine- Formate salt of 7(8H)-one [ka] a) (R)-4-(5-methyl-7-oxo-5,6,7,8-tetrahydropyridine [2,3-d ]pyrimidin-4-yl)piperazine-1-carboxylate t-butyl (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidinate at 20°C 400 mg of tert-butyl piperazine-1-carboxylate (1.8 g) and and 4-dimethylaminopyridine (494 mg) were dissolved in N-methylpyrrolidone (10 mL). The reaction solution was then replaced with nitrogen gas three times, and the temperature was raised to 150°C under a nitrogen gas atmosphere and the reaction was continued for 4 hours. After the reaction was complete, the reaction solution was poured into 20 mL of ethyl acetate and washed with water (2 mL*2). The mixture was washed with 0.5M dilute hydrochloric acid until the pH was adjusted to 5-6. The organic phase was separated and washed with anhydrous The crude product was dried over sodium sulfate and concentrated to obtain a crude product. The mixture was isolated and purified using a solvent (petroleum ether / ethyl acetate = 2:1, volume ratio) to obtain 0.6 g of a white solid. Ta. LC-MS (ESI) m / z: 348 (M+H).

[0172] b) (R)-5-Methyl-4-(piperazin-1-yl)-5,6-dihydropyrido[2,3- d]pyrimidin-7(8H)-one At 18°C, (R)-4-(5-methyl-7-oxo-5,6,7,8-tetrahydropyridine [2, 3-d]pyrimidin-4-yl)piperazine-1-carboxylate t-butyl (0.6 g) Dissolve in chloromethane (2 mL) and prepare a hydrogen chloride / 1,4-dioxane solution (4.0 M, 5 mL). After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The oily target substance is obtained by removing the amine, and the target substance is dissolved in dichloromethane and added with sodium hydroxide. Add the solids and stir until the oily liquid dissolves, then filter to remove the solids. The residue was concentrated to give a white solid (0.3 g) which was used directly in the next step.

[0173] c) (R)-4-(4-chlorophenyl)-4-(4-(5-methyl-7-oxo-5,6,7,8 -Tetrahydropyrido[2,3-d]pyrimidin-4-yl)-piperazine-1-carbonyl t-Butyl piperidine-1-carboxylate At 18°C, (R)-5-methyl-4-(piperazin-1-yl)-5,6-dihydropyrido[2, 3-d]pyrimidin-7(8H)-one (150 mg), 1-(t-butoxycarbonyl)-4 -(4-Chlorophenyl)piperidine-4-carboxylic acid (247 mg), diisopropyl ethyl Aminopropylamine (235 mg) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetrabenzotriazole Tetramethyluronium hexafluorophosphate (346 mL) was dissolved in anhydrous N,N-dimethyl The mixture was dissolved in 3 mL of diethyl ether and reacted at 18° C. for 12 hours. After the reaction was complete, The reaction mixture was poured into ethyl acetate (20 mL), washed with water (5 mL*3), and the organic phase was distilled under reduced pressure. The crude product was purified by silica column chromatography (eluent: petroleum ether) / ethyl acetate = 1:2, volume ratio) to isolate and purify the target product (280 mg) as a colorless oil. was used as is in the next step.

[0174] d) (R)-4-(4-(4-(4-chlorophenyl)piperidine-4-carbonyl)piperazine -1-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidine-7(6H) -one formate At 15°C, (R)-4-(4-chlorophenyl)-4-(4-(5-methyl-7-oxo-5,6, 7,8-Tetrahydropyrido[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylate t-Butyl carboxylate (280 mg) in dichloromethane (5 ml) L), add hydrogen chloride / 1,4-dioxane solution (4.0 mL, 5 mL), and dilute for 15 minutes. The reaction was allowed to proceed at ℃ for 1.5 hours. After the reaction was complete, the reaction solution was concentrated to obtain a white crude product. The crude product was separated by high performance liquid chromatography to obtain 60 mg of the target compound. Column: Kromasil 10 μm C18 50 × 250 mm, Mobile phase A: Water (0. 1% formic acid), mobile phase B: methanol. Gradient: Time 0-10 min, B phase 20%, 1 0-30min, B phase 20-50%, 30-40min, B phase 50% (volume ratio), RT=3 1.4min. LC-MS(ESI)m / z=469[M+H]. 1 H NMR (400MH z,DMSO-d6)δ(ppm)10.62(s,1H),8.41(s,1H),8.26(s,1 H),7.48(d,J=8.3Hz,2H),7.29(d,J=8.3Hz,2H),2.74- 3.74(m,12H),2.49-2.50(m,2H),2.22-2.26(m,3H),1. 96-2.00(m,2H),0.97-0.99(m,3H).

[0175] Scheme I: [ka] Reaction conditions: a) methyl methacrylate, sodium methoxide, methanol, b) formaldehyde Amidine, sodium methoxide, methanol, c) phosphoryl chloride, diisopropyl ether ethylamine, acetonitrile, d) aqueous ammonia solution (25-28% wt), e) piperazine -1-Carboxylic Acid t-Butyl, N,N-Dimethylpyridin-4-amine, N-Methylpyrrolidin f) Hydrogen chloride / 1,4-dioxane solution (4.0M), g) (S)-3-((t-butoxy) Diisopropylamino)-2-(4-chlorophenyl)propionic acid, diisopropyl Propylethylamine, 2-(7-benzotriazole oxide)-N,N,N',N'-tetraethylamine Tetramethyluronium hexafluorophosphate, N,N-dimethylformamide, h) salt Hydrogen chloride / 1,4-dioxane solution (4.0 M).

[0176] Example 19 4-(4-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionate 3-(4 ... Mydin-7(6H)-one hydrochloride [ka] a) 1,1,3-tricarboxylate trimethylbutane Sodium methoxide (2.45 g) was dissolved in methanol (50 mL) at 20°C under a nitrogen gas atmosphere. Dimethyl malonate (5 g) and methyl methacrylate (3.75 g) were added and the mixture was heated to 60°C. The temperature was raised to 50° C. and the reaction was allowed to proceed for 16 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove the solvent. This gave 5 g of a yellow liquid which was used directly in the next step. b) Methyl 3-(4,6-dihydroxypyrimidin-5-yl)-2-methylpropionate Sodium methoxide (11.67 g) was dissolved in methanol (30 ml) at 20°C under a nitrogen gas atmosphere. L), cooled to 0°C, and formamidine acetate (2.44 g) was added while stirring. After reacting for 0 min, 1,1,3-tricarboxylate trimethylbutane (5 g) was added dropwise and the mixture was stirred for 20 The reaction was allowed to proceed at 4°C for 16 hours. After the reaction was complete, the reaction mixture was diluted with isopropanol hydrochloride (4.0 M) was added to adjust the pH to 5, the solvent was removed by distillation under reduced pressure, and the mixture was cooled to 0°C. A solid precipitated, which was filtered off with suction. The filter cake was washed with water (50 mL). The cake was dried to give 3.7 g of a pale yellow solid which was used directly in the next step.

[0177] c) Methyl 3-(4,6-dichloropyrimidin-5-yl)-2-methylpropionate 3-(4,6-dihydroxypyrimidin-5-yl)-2-methylpyrimidine was added at 22°C under a nitrogen gas atmosphere. Disperse methyl ethylpropionate (3 g) in acetonitrile (60 mL) and add phosphoryl chloride ( 2.91 mL) and diisopropylethylamine (1.18 mL) were added dropwise in this order, and the reaction The system became extremely exothermic, the solid gradually dissolved completely, and the temperature was raised to 90°C and the reaction was continued for 16 hours. After the reaction was completed, the reaction mixture was poured into water (100 mL) and then into ethyl acetate (100 mL). The organic phase was washed with saturated saline (100mL*3) and extracted with anhydrous sodium sulfate. The product was purified by silica gel column chromatography. The mixture was purified with ethyl acetate (petroleum ether:ethyl acetate = 10:1, volume ratio) to obtain 1.50 g of a white solid. was used as is in the next step.

[0178] d) 4-Chloro-6-methyl-5,8-dihydropyrido[2,3-d]pyrimidine-7(6H )-on Methyl 3-(4,6-dichloropyrimidin-5-yl)-2-methylpropionate ( 1.5 g) was added to an aqueous ammonia solution (3 mL) and reacted at 20°C for 16 h. After that, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated saline (100 mL*3) and dried over anhydrous sodium sulfate. The product was purified by silica gel column chromatography (petroleum ether). The mixture was purified with ethyl acetate (4:1 volume ratio) to obtain 0.30 g of a white solid. ESI) m / z: 199 (M+H).

[0179] e) 4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrid (4-(4-(aminophenyl)piperazine)-1-carboxylate t-butyl ester At 20°C, 4-chloro-6-methyl-5,8-dihydropyrido[2,3-d]pyrimidine- 7(6H)-one (0.1 g) was dissolved in N-methylpyrrolidone (3 mL) and piperazine- 1-tert-Butyl carboxylate (0.28 g) and N,N-dimethylpyridin-4-amine (0.3 1g) was added and the reaction mixture was stirred at 150°C for 3 hours. After the reaction was complete, the reaction solution was The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). Wash with salt water (100 mL*3), dry with anhydrous sodium sulfate, and dissolve by distillation under reduced pressure. The solvent was removed. The product was purified by chromatography on silica gel plates (petroleum ether:ethyl acetate=1 :1, volume ratio) to give 0.31 g of a white solid. LC-MS(ESI) m / z: 348 .2(M+H).

[0180] f) 6-Methyl-4-(piperazin-1-yl)-5,8-dihydropyrido[2,3-d]pi Rimidin-7(6H)-one At 20°C, 4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyridine [2,3-d ]pyrimidin-4-yl)piperazine-1-carboxylate t-butyl (0.1 g) in aqueous solution of A solution of chlorine in 1,4-dioxane (4.0 M, 10 mL) was added, and the reaction mixture was incubated at 20° C. for 3 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain an off-white solid ( 0.1 g) was obtained. LC-MS (ESI) m / z: 248.2 (M+H).

[0181] g) (2S)-2-(4-chlorophenyl)-3-(4-(6-methyl-7-oxo-5,6,7, 8-Tetrahydropyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl) -3-Oxopropyl)(isopropyl)carbamic acid t-butyl ester At 20°C, 6-methyl-4-(piperazin-1-yl)-5,8-dihydropyrido[2,3-d ]Pyrimidin-7(6H)-one (0.1 g) dissolved in N,N-dimethylformamide (10 ml L) to (S)-3-((t-butoxycarbonyl)(isopropyl)amino)-2-(4-chloro Phenyl)propionic acid (0.17g) and diisopropylethylamine (0.16g) were added. The reaction mixture was stirred for 2 min. 2-(7-benzotriazole oxide)- Add N,N,N',N'-tetramethyluronium hexafluorophosphate (0.23 g). The reaction mixture was stirred at 20° C. for 1 h. After the reaction was completed, the reaction solution was diluted with water (100 mL). The organic phase was poured into a broth and extracted with ethyl acetate (100 mL). L*3) was added and washed, then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The product was purified by chromatography on a silica gel plate (petroleum ether:ethyl acetate = 1:2, by volume). Purification gave 0.08 g of a white solid which was used directly in the next step.

[0182] h) 4-(4-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionyl (1-pyrazine-1-yl)-6-methyl-5,8-dihydropyrido[2,3-d]pyrimidin Hydrochloride of 7(6H)-one (2R)-2-(4-chlorophenyl)-3-(4-(6-methyl-7-oxo-5, 6,7,8-Tetrahydropyrido[2,3-d]pyrimidin-4-yl)-piperazine-1- t-Butyl (3-oxopropyl) (isopropyl)carbamate (0.2 g), Hydrogen / 1,4-dioxane solution (4.0 mL, 3 mL) was added. The reaction mixture was stirred at 20° C. for 3 h. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove the solvent and separate the product. 0.06 g of an off-white solid was obtained. LC-MS (ESI) m / z: 471 (M+H ). 1 H NMR(400MHz,MeOD)δ8.42(d,J=4.5Hz,1H),7.54 -7.33(m,4H),4.64-4.52(m,1H),3.96-3.81(m,2H),3.7 9-3.73(m,2H),3.70-3.66(m,2H),3.63-3.56(m,1H),3. 51-3.40(m,2H),3.24-3.16(m,1H),3.09-2.94(m,1H),2 .84(s,1H),2.79-2.66(m,2H),1.44-1.35(m,6H),1.33- 1.25(m,3H).

[0183] Separation of isomers: The above-mentioned title compound was subjected to optical resolution by supercritical fluid chromatography. Equipment and conditions: Waters SFC200, column: Daicel Chiralcel AS, 250×30 mm ID, 5 μm, mobile phase: A is CO2, B is methanol (0.1% NH3H2O), A:B = 90:10 (volume ratio), flow rate 60 mL / min, Rum temperature 38°C.

[0184] Isomer 1: [ka] LCMS(ESI)m / z:471(M+H). 1 H NMR (400MHz, CDCl3) δ8 .36(s,1H),7.86(s,1H),7.32-7.37(m,2H),7.21-7.27 (m,2H),4.18(s,1H),3.89-4.00(m,1H),3.65-3.74(m,1 H),3.53-3.64(m,2H),3.44-3.52(m,1H),3.35-3.42( m,2H),3.27-3.34(m,2H),2.87-2.94(m,1H),2.74-2. 82(m,2H),2.57-2.64(m,1H),2.47-2.54(m,1H),1.32( d,J=6.6Hz,3H),1.07-1.19(m,6H).

[0185] Isomer 2: [ka] LCMS(ESI)m / z:471(M+H). 1 H NMR (400MHz, CDCl3) δ8 .37(s,1H),7.33-7.38(m,2H),7.21-7.27(m,2H),4.09 (s,1H),3.83-3.91(m,1H),3.62-3.72(m,1H),3.47(s,3 H),3.26-3.34(m,2H),3.12-3.21(m,1H),2.69-2.98( m,5H),2.50-2.66(m,2H),1.32(d,J=6.7Hz,3H),1.11( dd, J = 14.8, 6.2 Hz, 6H).

[0186] Scheme J: [ka] Reaction conditions: a) ethyl bromoacetate, sodium hydride, tetrabutylammonium iodide , tetrahydrofuran, b) 2,4-dimethoxybenzylamine, triethylamine, iso Propanol, c) Methyl iodide, sodium hydride, N,N-dimethylformamide, d) trifluoroacetic acid, e) t-butyl piperazine-1-carboxylate, 4-dimethylamino Pyridine, N-methylpyrrolidone, f) Hydrogen chloride / 1,4-dioxane solution (4.0M), g )(S)-3-((t-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl (7-benzotriazole oxide), diisopropylethylamine, )-N,N,N',N'-Tetramethyluronium hexafluorophosphate, N,N-Dimethyl ethylformamide, h) Hydrogen chloride / 1,4-dioxane solution (4.0 M).

[0187] Example 20 (S)-4-(4-(2-(4-chlorophenyl)-3-(isopropylamino)propionate pionyl)piperazin-1-yl)-5-methyl-5,8-dihydropteridine-7(6H) -one hydrochloride [ka] a) 2-((4,6-dichloropyrimidin-5-yl)amino)ethyl acetate A solution of 4,6-dichloro-5-pyrimidine (10.0 g) in tetrahydrofuran at 0°C ( Sodium hydride (2.93 g) was added to 100 mL of water. The reaction mixture was stirred for 2 min. After the temperature was naturally raised to 20°C, ethyl bromoacetate (12.22 g) was added to obtain tetrabromo iodide. C. An additional 27.03 g of ethylammonium was added and the reaction mixture was stirred at 20.degree. C. for 16 h. After the reaction was completed, the reaction mixture was poured into water (100 mL), stirred for 30 min, and then ethyl acetate was added. The organic phase was washed with saturated saline (100mL*3) and extracted with anhydrous The mixture was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The product was purified by chromatography (petroleum ether:ethyl acetate = 20:1, volume ratio) to obtain a colorless oil. 6.5 g of a solid liquid was obtained and used as is in the next step.

[0188] b) 4-chloro-8-(2,4-dimethoxybenzyl)-5,8-dihydropteridine-7(6 H)-On At 20°C, ethyl 2-((4,6-dichloropyrimidin-5-yl)amino)acetate (5g) is dissolved. Into the isopropanol solution (150 mL), 2,4-dimethoxybenzylamine (3.67 g ) was added, followed by triethylamine (4.45 g). The reaction mixture was incubated at 80° C. for 18 h. After the reaction was completed, the reaction solution was filtered and the filter cake was washed with ethanol. The solid was dried under vacuum to give 5.0 g of an off-white solid, which was used directly in the next step. Ta.

[0189] c) 4-chloro-8-(2,4-dimethoxybenzyl)-5-methyl-5,8-dihydroptene Lysine-7(6H)-one 4-Chloro-8-(2,4-dimethoxybenzyl)-5,6-dihydropteridine-7 at 0°C The iodide was dissolved in a solution of (8H)-one (3.3 g) in N,N-dimethylformamide (30 mL). Methyl (1.68 g) was added and the reaction mixture was stirred for 20 min. The mixture was kept at 0° C. and hydrogenated. Sodium (0.47 g) was added. The reaction mixture was then stirred at 0° C. for 3 h. After that, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated saline (100 mL*3) and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The product was purified by silica gel column chromatography (petroleum The product was purified with ether:ethyl acetate = 5:1 (volume ratio) to obtain 1.5 g of a white solid. It was used as it is in the next step.

[0190] d) 4-Chloro-5-methyl-5,8-dihydropteridin-7(6H)-one 4-Chloro-8-(2,4-dimethoxybenzyl)-5-methyl-5,6-dihydro at 20°C To the pteridin-7(8H)-one (5 g) was added trifluoroacetic acid (20 mL). The reaction mixture The mixture was stirred at 60°C for 16 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the purple color A similar solid (1.0 g) was obtained. LC-MS (ESI) m / z: 199.1 (M+H). 1 H.N.M. R(300MHz,DMSO-d6)δ(ppm)11.60(s,1H),8.35(s,1H), 3.77(s,2H), 2.85(s,3H).

[0191] e) 4-(5-methyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)pyridine t-Butyl perazine-1-carboxylate 4-Chloro-5-methyl-5,8-dihydropteridin-7(6H)-one (0.3 g) dissolved in N-methylpyrrolidone solution (5 mL), piperazine-1-carboxylic acid t-bromo C. The reaction mixture was stirred for 1 hour at 40.degree. C. for 1 hour. The mixture was stirred at 50° C. for 3 h. After the reaction was completed, the reaction mixture was poured into water (100 mL) and further added with acetic acid. Ethyl acetate (100 mL) was added for extraction. The organic phase was washed with saturated saline (100 mL*3). The mixture was washed, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The mixture was purified using a silica gel plate (petroleum ether:ethyl acetate = 1:1, volume ratio) to give a white solid. 0.27 g was obtained and used directly in the next step.

[0192] f) 5-methyl-4-(piperazin-1-yl)-5,8-dihydropteridine-7(6H)- on 4-(5-methyl-7-oxo-5,6,7,8-tetrahydropteridine-4-yl) t-Butyl piperazine-1-carboxylate (0.1 g) in hydrogen chloride / 1,4-dioxane solution A 4.0M solution (3 mL) was added and the reaction mixture was stirred at 20° C. for 3 hours. The solvent was then removed by distillation under reduced pressure to give an off-white solid (0.1 g).

[0193] g) (S) (2-(4-chlorophenyl)-3-(4-(5-methyl-7-oxo-5,6,7,8 -tetrahydropteridin-4-yl)-piperazin-1-yl)-3-oxopropyl)( Isopropyl)carbamic acid t-butyl 5-Methyl-4-(piperazin-1-yl)-5,6-dihydropteridine-7(8 H)-one (0.1 g) in N,N-dimethylformamide (10 mL) was added to the (S)-3-((t -Butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)propionic acid (0.17 g) and diisopropylethylamine (0.16 g) were added and the reaction mixture was stirred for 2 min. The mixture was stirred at 20°C and then cooled to 2-(7-benzotriazole oxide)-N,N,N',N'-tetradecane. Dimethyluronium hexafluorophosphate (0.23 g) was added and the reaction mixture was stirred for 1 hour. The mixture was stirred at 20° C. for 1 h. After the reaction was completed, the reaction mixture was poured into water (100 mL) and Ethyl acetate (100 mL) was added for extraction. Saturated saline (100 mL*3) was added to the organic phase. The product was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The mixture was purified using a silica gel chromatography plate (petroleum ether:ethyl acetate = 1:1.5, volume ratio), The product was obtained as a white solid, 0.08 g. LC-MS (ESI) m / z: 572 (M+H).

[0194] h) (S)-4-(4-(2-(4-chlorophenyl)-3-(isopropylamino)propionyl 1-piperazinyl)-5-methyl-5,8-dihydropteridin-7(6H)-one The hydrochloride salt of At 20°C, (S)-(2-(4-chlorophenyl)-3-(4-(5-methyl-7-oxo-5,6 ,7,8-Tetrahydropteridin-4-yl)-piperazin-1-yl)-3-oxopropane t-Butyl (isopropyl)carbamate (0.08g) with hydrogen chloride / 1,4-dioxo The amine solution (4.0 mL, 3 mL) was added and the reaction mixture was stirred at 20° C. for 3 h. After the reaction, the reaction mixture was distilled under reduced pressure to remove the solvent, and the residue was purified by high-performance preparative liquid chromatography. Isolation gave 0.02 g of an off-white solid. LC-MS (ESI) m / z :472(M+H). 1 H NMR(300MHz,DMSO-d6)δ(ppm)10.94(s ,1H),8.12(s,1H),7.46-7.51(m,2H),7.37-7.43(m,2H) ,4.68-4.74(m,1H),3.81-3.91(m,2H),3.64-3.74(m, 2H),3.59-3.63(m,2H),3.52-3.59(m,4H),3.25-3.34 (m,2H),2.95-3.03(m,1H),2.48(s,3H),1.20-1.28(m,6 H).

[0195] Example 21 4-(8-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionate lopionyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-methyl -5,8-Dihydropteridin-7(6H)-one formate [ka] Instead of t-butyl piperazine-1-carboxylate, 3,8-diazabicyclo[3.2. 1] The same procedure as described in Example 20, except that t-butyl octane-8-carboxylate was used. Prepare in the same manner and use high-speed preparative liquid chromatography of the target substance. Conditions: Column: Aglie nt 5μm prep-C18 50×21.2mm, mobile phase A: water (containing 0.1% formic acid) ), Mobile phase B: acetonitrile. Gradient: Time 0-10 min, B phase 5-75% (volume ratio), RT=3.4min. LC-MS(ESI)m / z:498(M+H). 1 H NMR(400 MHz,DMSO-d6)δ(ppm)10.89(s,1H),8.27(s,1H),8.10( d,J=25.6Hz,1H),7.31-7.48(m,4H),4.48-4.68(m,3H), 4.09-4.30(m,2H),3.50-3.60(m,3H),3.11-3.24(m,2H) ,2.62-2.84(m,3H),2.37-2.47(m,3H),1.49-1.88(m,4H ),0.89-1.02(m,6H).

[0196] Example 22 4-((S)-4-((S)-2-(4-chlorophenyl)-3-(isopropyl ether) 3-Methylpiperazin-1-yl)-5-methyl-5,8-dihydro- Pteridin-7(6H)-one [ka] (S)-1-N-Boc-2-methyl piperazine-1-carboxylate instead of t-butyl piperazine-1-carboxylate The final product was prepared in a manner similar to that described in Example 20, except that piperazine was used. Add 10% sodium hydroxide solution at 0℃ to adjust the pH to 9, and dichloromethane is added. Extract with hexane (10 mL x 3), wash with saturated saline (15 mL), and add anhydrous sodium sulfate. The organic phase was removed by distillation under reduced pressure to give 70 mg of a white solid. SI) m / z: 486 (M+H). 1 H NMR(400MHz,DMSO-d6)δ(ppm)1 0.88(s,1H),8.09(d,J=5.6Hz,1H),7.35-7.42(m,3H), 7.27(d,J=8.4Hz,1H),4.55-4.74(m,3H),4.44-4.53( m,1H),4.31-4.39(m,1H),4.16-4.26(m,1H),4.00-4. 10(m,1H),3.87-3.96(m,1H),3.04-3.16(m,2H),2.87- 2.96(m,1H),2.77-2.85(m,1H),2.56-2.63(m,2H),2.4 2-2.47(m,3H),1.18-1.29(m,3H),0.90-0.96(m,6H).

[0197] Scheme K: [ka] Reagents: a) Ammonia solution (25%-28%wt), tetrahydrofuran, b) Acetate nitrile, piperazine-1-carboxylate t-butyl, N,N-diisopropylethyl c) sodium borohydride, methanol, saturated aqueous ammonium chloride solution, d) trimethylamine Chloromethyl carbonate, N,N-diisopropylethylamine, tetrahydrofuran , e) dichloromethane, hydrogen chloride / 1,4-dioxane solution (4.0M), f) (S)-3-(( t-Butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)propion Acid, N,N-diisopropylethylamine, N,N-dimethylformamide, 2-(7-phenylenediamine Triazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate Sulfate, g) dichloromethane, hydrogen chloride / 1,4-dioxane solution (4.0M).

[0198] Example 23 5-(4-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionate 4-methyl-1,4-dihydro-2H-pyrimido[ Formate salt of 4,5-d][1,3]oxazin-2-one [ka] a) 1-(4-amino-6-chloropyrimidin-5-yl)ethanone 1-(4,6-dichloropyrimidin-5-yl)ethanone (2.5 g) was added to tetrahydrofuran at 20°C. The reaction mixture was dissolved in 15 mL of fluorouracil, and then aqueous ammonia (9 g) was added. The reaction mixture was then incubated at 20° C. for 5 hours. The mixture was stirred for 10 minutes, concentrated, diluted with a small amount of water, and filtered under suction to obtain a white solid. After drying in vacuum, 2 g of a white solid was obtained, which was used directly in the next step.

[0199] b) 4-(5-acetyl-6-aminopyrimidin-4-yl)piperazine-1-carboxylic acid t-Butyl 1-(4-amino-6-chloropyrimidin-5-yl)ethanone (2 g), N,N- Diisopropylethylamine (3 g) was dissolved in acetonitrile (20 mL) and 1-( 4-Amino-6-chloropyrimidin-5-yl)ethanone was added and the reaction mixture was heated at 40°C for 5 minutes. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude product. The product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1, volume The solid was separated and purified by HPLC (HPLC-MS / MS) to give 3.2 g of a pale yellow solid, which was used directly in the next step.

[0200] c) 4-(6-amino-5-(1-hydroxyethyl)pyrimidin-4-yl)piperazine- 1-T-Butyl carboxylate 4-(5-acetyl-6-aminopyrimidin-4-yl)piperazine-1-carboxamide at 20°C Dissolve t-butyl phosphate (1.5 g) in methanol (15 mL), cool to -10°C, and add water. Add sodium borohydride (1g) in portions, and after the addition is complete, gradually warm the reaction mixture to 20°C. After the reaction was completed, the reaction solution was diluted with a saturated aqueous solution of ammonium chloride. The reaction mixture was then concentrated and quenched with ethyl acetate (20 mL*2). The mother liquor was concentrated to give an oily crude product. Separated and refined with roughy (dichloromethane:methanol = 1:30, volume ratio), it becomes a white oil 400 mg of the product was obtained in the form of a solid. LC-MS (ESI): m / z=324 [M+H].

[0201] d) 4-(4-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d][1 ,3]Oxazin-5-yl)piperazine-1-carboxylate t-butyl 4-(6-amino-5-(1-hydroxyethyl)pyrimidin-4-yl)piperazine at 20°C t-Butyl tert-butyl ether (300 mg), N,N-diisopropylethylamine (28 Dissolve 2 mg of tetrahydrofuran in 3 mL of tetrahydrofuran and lower the temperature to -5°C. Then, dimethyl carbonate was slowly added and the mixture was stirred at -5°C for 0.5 hours. The temperature was raised to 18°C ​​and the mixture was stirred for 1.5 hours. After the reaction was complete, the reaction was quenched with sodium bicarbonate water. Extract with ethyl acetate (10 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, The crude product was purified by silica gel column chromatography. Separated and purified with ethyl acetate (petroleum ether: ethyl acetate = 1:1, volume ratio), and a white solid of 108 ml was obtained. g was obtained. LC-MS (ESI) m / z = 350 [M+H].

[0202] e) 4-Methyl-5-(piperazin-1-yl)-1,4-dihydro-2H-pyrimidin[4 ,5-d][1,3]Oxazin-2-one hydrochloride At 20°C, 4-(4-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d ][1,3]Oxazin-5-yl)piperazine-1-carboxylate t-butyl (100 mg) Dissolve in dichloromethane (3 mL) and add hydrogen chloride / 1,4-dioxane solution (4.0 mL) under stirring. M, 3 mL) was added, and the reaction solution was stirred at 20°C for 1 hour, and a white solid was precipitated. The solvent was removed by distillation under reduced pressure to obtain 80 mg of the target product as a white solid, which was then directly carried on to the next step. It was used for tepp.

[0203] f) (2S)-2-(4-chlorophenyl)-3-(4-(4-methyl-2-oxo-1,4-diphenyl)- Hydro-2H-pyrimido[4,5-d][1,3]oxazin-5-yl)piperazine-1 -yl)-3-oxopropyl)(isopropyl)carbamic acid t-butyl ester At 20°C, 4-methyl-5-(piperazin-1-yl)-1H-pyrimidinide [4,5-d][ 1,3]Oxazin-2(4H)-one (80 mg), (S)-3-((t-butoxycarbonyl) (Isopropyl)amino)-2-(4-chlorophenyl)propionic acid (100 mg), N,N- Diisopropylethylamine (113 mg) and 2-(7-benzotriazole oxide)- N,N,N',N'-tetramethyluronium hexafluorophosphate (167 mg), Dissolve in anhydrous N,N-dimethylformamide (2.5 mL) and stir the reaction mixture at 20°C for 12 hours. After the reaction was complete, the reaction mixture was poured into ethyl acetate (20 mL), washed twice with water, and then the chloride was removed. The organic phase was concentrated to give the crude product. The mixture was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1, volume ratio). 130 mg of a white solid was obtained. LC-MS (ESI) m / z=573 [M+H].

[0204] g) 5-(4-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionyl 4-methyl-1,4-dihydro-2H-pyrimido[4,5-d ][1,3]Oxazin-2-one formate At 20°C, (2S)-2-(4-chlorophenyl)-3-(4-(4-methyl-2-oxo-1, 4-Dihydro-1H-pyrimido[4,5-d][1,3]oxazin-5-yl)piperazine (1-phenyl-3-oxopropyl) (isopropyl)carbamate t-butyl (130m g) in dichloromethane (2 mL) and add hydrogen chloride / 1,4-dioxane solution ( 4.0 mL, 2 mL) was added and the reaction mixture was stirred at 20° C. for 2 hours. After the reaction was complete, The reaction mixture was cooled to 0°C and adjusted to pH 9 by adding 10% sodium hydroxide. The mixture was extracted with dichloromethane (10 mL x 3), washed with saturated saline (15 mL), and then diluted with sodium sulfate. The mixture was dried over sodium hydroxide, the organic phase was removed by vacuum distillation, and the remaining product was purified by high-speed preparative liquid chromatography. The solid was isolated and purified by chromatography to obtain 32 mg of a white solid. Preparation conditions: Column: Agilent 10000000000000000 ent 5μm prep-C18 50×21.2mm, mobile phase A: water (containing 0.1% formic acid) (including acetonitrile), mobile phase B: acetonitrile, gradient: time 0-10 min, B phase 5-45% (volume ratio) , RT=3.7min. LC-MS (ESI): m / z=473[M+H]. 1 H NMR( 400MHz,DMSO-d6)δ(ppm)8.22-8.31(m,2H),7.37-7. 45(m,2H),7.28-7.36(m,2H),5.68-5.81(m,1H),4.18- 4.28(m,1H),3.41-3.78(m,8H),3.03-3.26(m,3H),2.8 9-3.01(m,1H),2.74-2.83(m,1H).2.64-2.72(m,1H).1 .33-2.49(m,3H).0.89-1.04(m,6H).

[0205] Isomer separation: The above-mentioned title compound was subjected to optical resolution by supercritical fluid chromatography. Equipment and conditions: Waters SFC200, column: Daicel Chiralcel AD, 250×30 mm ID, 5 μm, mobile phase: A is CO2, B is ethanol (0.1% NH3H2O), A:B = 65:35 (volume ratio), flow rate 60 mL / min, Rum temperature 38°C.

[0206] Isomer 1: [ka] LCMS(ESI): m / z=473(M+H). 1 H NMR (400MHz, DMSO-d6 )δ8.28(s,1H),7.47-7.23(m,4H),5.76(d,J=6.3Hz,1H) ,4.15(s,1H),3.75-3.44(m,6H),3.28-3.20(m,2H),3.1 5-3.04(m,2H),2.74-2.58(m,2H),1.41(d,J=6.2Hz,3H) , 0.93(t,J=6.9Hz,6H). Isomer 2: [ka] LCMS(ESI):M / Z=473(M+H). 1 H NMR (400MHz, DMSO-d6 )δ10.85(s,1H),8.29(s,1H),7.43(dd,J=42.1,8.2Hz, 4H),5.75(q,J=6.2Hz,1H),4.76-4.54(m,1H),3.79-3. 39(m,8H),3.32-3.20(m,2H),3.10-2.85(m,2H),1.43(d, J=6.4Hz,3H),1.25(t,J=5.6Hz,6H). Example 24 [ka] Instead of t-butyl piperazine-1-carboxylate, 3,8-diazabicyclo[3.2.1 The same procedure as described in Scheme F was used, except that t-butyl octane-8-carboxylate was used. The final product was separated by supercritical fluid chromatography to identify isomer 1 and Isomer 2 was obtained. Equipment and conditions for optical resolution: Waters SFC200, column :Daicel Chiralcel OD, 250×30mm ID, 5μm, mobile phase : A is CO2 and B is ethanol (0.1% NH3H2O), A:B = 70:30 (volume ratio), flow rate 60 mL / min, column temperature 38°C.

[0207] Isomer 1: LCMS (ESI) m / z: 551 (M+H). 1 HNMR (300MHz, DMS O-d6)δ(ppm):1.28-1.11(m,6H),2.10-1.47(m,6H),3. 18-2.75(m,7H),4.28-3.65(m,5H),4.85-4.83(m,1H), 7.41-7.25(m,4H),8.42-8.33(m,1H). Isomer 2: LCMS (ESI) m / z: 551 (M+H). 1 HNMR (300MHz, DMS O-d6)δ(ppm):2.28-1.20(m,13H),3.43-2.89(m,6H), 4.37-3.71(m,5H),4.86-4.81(m,1H),7.39-7.27(m,4 H),8.36(s,1H).

[0208] Example 25 [ka] Instead of t-butyl piperazine-1-carboxylate, 3,8-diazabicyclo[3.2.1 The same procedure as described in Scheme F was used, except that t-butyl octane-3-carboxylate was used. The final product was separated by supercritical fluid chromatography to identify isomer 1 and Isomer 2 was obtained. Equipment and conditions for optical resolution: Waters SFC200, column: Daicel Chiralcel OZ, 250×30mm ID, 5μm, mobile phase: A is CO2 and B is ethanol (0.1% NH3H2O), A:B = 60:40 ( volume ratio), flow rate 60 mL / min, column temperature 38°C.

[0209] Isomer 1: LCMS(ESI)m / z:551(M+H). 1 HNMR(400MHz,DMSO-d6)δ (ppm):0.98-0.92(m,6H),1.96-1.57(m,3H),2.87-2. 59(m,5H),3.29-3.12(m,2H),3.63-3.42(m,2H),3.99( s,1H),4.67-4.24(m,5H),7.46-7.27(m,4H),8.30(d,J =3.6Hz,1H),10.84(s,1H).

[0210] Isomer 2: LCMS(ESI)m / z:551(M+H). 1 HNMR(400MHz,DMSO-d6)δ (ppm):0.98-0.89(m,6H),2.03-1.54(m,4H),2.76-2. 57(m,4H),3.27-2.95(m,4H),3.70-3.67(m,1H),3.99- 3.95(m,1H),4.67-4.20(m,4H),7.45-7.27(m,4H),8.2 8(s,1H),10.83(s,1H).

[0211] Example 26 [ka] Instead of t-butyl piperazine-1-carboxylate, 3,8-diazabicyclo[3.2.1 The same procedure as described in Scheme J was used, except that t-butyl octane-3-carboxylate was used. Prepared as above. LCMS(ESI): m / z=498(M+H). 1 H NMR (400 M Hz,DMSO-d6)δ10.86(s,1H),8.06-8.15(m,1H),7.23- 7.47(m,4H),4.85-5.09(m,2H),4.11-4.31(m,2H),3.9 2-4.04(m,1H),3.54-3.62(m,2H),3.05-3.17(m,1H),2. 84-2.95(m,1H),2.72-2.82(m,1H),2.55-2.63(m,1H),2 .41(s,3H),1.91(s,1H),1.61-1.77(m,1H),1.40-1.55 (m,1H),1.22-1.33(m,1H),0.84-1.01(m,6H),0.40-0.5 3(m,1H). Example 27 [ka] Instead of t-butyl piperazine-1-carboxylate, 2,5-diazabicyclo[4.1.0 ] The same procedure as described in Scheme J was used, except that t-butyl heptane-2-carboxylate was used. The final product was separated by supercritical fluid chromatography to identify isomer 1 and Isomer 2 was obtained. Equipment and conditions for optical resolution: Waters SFC200, column :Daicel Chiralcel OZ, 250×30mm ID, 5μm, mobile phase : A is CO2 and B is ethanol (0.1% NH3H2O), A:B = 60:40 (volume ratio), flow rate 60 mL / min, column temperature 38°C.

[0212] Conditions for ultra-high performance convergence chromatography: Column: Daicel Chir alcel AD, 2.1×150mm ID, 3μm, Mobile phase A: CO2, Mobile phase B: Ethanol (0.1% DEA), gradient: time 0-8 min, B phase 5-40% (volume ratio), flow rate : 1 mL / min, column temperature 40 °C. Isomer 1: RT = 4.0 min, Isomer 2: RT =4.8min.

[0213] Isomer 1: LCMS (ESI): m / z=484(M+H). 1 H NMR (400MHz, DM SO-d6)δ10.97(s,1H),8.17-8.25(m,1H),7.38-7.52( m,4H),4.44-4.51(m,1H),4.20-4.38(m,1H),3.65-3.7 8(m 1H),3.50-3.63(m,4H),3.13-3.33(m,3H),2.69-2. 86(m,2H),2.49-2.58(m,3H),1.44-1.51(m,1H),0.93-1 .06(m,7H),0.51(d,J=5.6Hz,1H).

[0214] Isomer 2: LCMS (ESI): m / z=484(M+H). 1 H NMR (400MHz, DM SO-d6)δ10.89(s,1H),7.99-8.19(m,1H),7.16-7.47( m,4H),4.07-4.36(m,2H),3.56-3.69(m,2H),3.39-3. 54(m,3H),3.03-3.25(m,3H),2.71-2.79(m,1H),2.57-2 .69(m,2H),2.27-2.32(m,3H),1.23-1.35(m,1H),0.80- 1.02(m,6H),0.66(q,J=4.9Hz,1H).

[0215] Example 28 [ka] Using ethyl iodide instead of methyl iodide, the reaction of t-butyl piperazine-1-carboxylate was Instead, 3,8-diazabicyclo[3.2.1]octane-8-carboxylate t-butyl Prepared in a similar manner to that described in Scheme J, except that 1,2-dichlorophenyl ether was used. LCMS (ESI): / z=512(M+H). 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1 H),8.15(d,J=26.0Hz,1H),7.54-7.39(m,4H),4.71-4. 52(m,4H),4.26-4.19(m,1H),4.15-4.06(m,1H),3.75- 3.57(m,2H),3.29-3.11(m,2H),3.01-2.93(m,1H),2.8 5-2.78(m,1H),2.72-2.64(m,4H),2.09-1.98(m,1H),1 .96-1.86(m,1H),1.88-1.59(m,3H),1.04-0.87(m,7H) .

[0216] Example 29 [ka] The procedure was the same as in Scheme J, except that bromoacetonitrile was used instead of methyl iodide. It was prepared in the same manner as described above.

[0217] LCMS(ESI):m / z:523(M+H). 1 H NMR (400MHz, DMSO-d6 )δ11.02(s,1H),8.16(d,J=22.9Hz,1H),7.38(dd,J=11 .8、2.4Hz,4H),4.61-4.44(m,2H),4.34-4.08(m,3H),4 .05-3.94(m,2H),3.85-3.80(m,2H),3.23-3.01(m,2H), 2.77-2.66(m,2H),1.90-1.53(m,4H),0.94(t,J=5.6Hz ,6H).

[0218] Example 30 [ka] The reaction was carried out as described in Scheme J, except that 1-fluoro-2-iodoethane was used instead of methyl iodide. It was prepared similarly to the method described previously.

[0219] LCMS(ESI)m / z:530(M+H) 1 H NMR (400MHz, DMSO-d6) δ 8.28(d,J=5.3Hz,1H),8.05-8.15(m,1H),7.33-7.49( m,4H),4.22-4.70(m,8H),3.48-3.74(m,1H),3.21-3. 43(m,2H),2.88-3.16(m,3H),2.74-2.86(m,1H),1.44- 2.02(m,4H), 0.97-1.11(m,6H).

[0220] Scheme J-1: [ka] Reaction conditions: a) Dimethyl t-butyl(2-iodoethoxy)silane, sodium hydride, N, N-dimethylformamide, b) 3,8-diazabicyclo[3.2.1]octane-8-carboxylate t-Butyl carboxylate, 4-dimethylaminopyridine, N-methylpyrrolidone, c) water chloride dioxane solution, d) (S)-3-((t-butoxycarbonyl)(isopropyl)amino)- 2-(4-chlorophenyl)propionic acid, diisopropylethylamine, 2-(7-benzoyl 2,3-Triazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophos phosphate, N,N-dimethylformamide, e) trifluoroacetic acid, dichloromethane.

[0221] Example 31 [ka] a) 5-(2-((t-butyldimethylsilyl)oxyethyl)-4-chloro-8-(2,4-di Methoxybenzyl)-5,8-dihydropteridin-7(6H)-one 4-Chloro-8-(2,4-dimethoxybenzyl)-5,8-dihydropteridine-7 at 0°C The (6H)-one (2.2 g) was dissolved in N,N-dimethylformamide (30 mL) and sodium hydride was added. The reaction mixture was stirred for 20 minutes. (2-Iodoethoxy)silane (2.82 g) was added and the reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). Wash with saturated saline (100 mL*3), dry with anhydrous sodium sulfate, and evaporate. The product was purified by silica gel column chromatography (petroleum ether:acetic acid Ethyl acetate=5:1) to give 0.8 g of a white solid as the product.

[0222] b) 5-(2-((t-butyldimethylsilyl)oxyethyl)-4-(8-t-butyloxy Carbonyl-3,8-diazabicyclo[3,2,1]octan-3-yl)-8-(2,4-di Methoxybenzyl)-5,8-dihydropteridin-7(6H)-one The product of step a) (0.2 g) was dissolved in N-methylpyrrolidone (5 mL) at 20°C, and 3, t-Butyl 8-diazabicyclo[3.2.1]octane-8-carboxylate (0.85 g), 4-Dimethylaminopyridine (0.17 g) was added. The reaction mixture was stirred at 150° C. for 3 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated saline (100 mL*3), dried over anhydrous sodium sulfate, and evaporated. The product was purified by chromatography on silica gel plates (petroleum ether:acetic acid Ethyl acetate=1:1) to give 0.08 g of a white solid as the product.

[0223] c) 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(2,4-dimethyl (2-Hydroxybenzyl)-5-(2-hydroxyethyl)-5,8-dihydropteridine-7(6H) -on To the product of step b) (0.08 g) was added a solution of hydrogen chloride in dioxane (3 mL) at 20° C. The reaction mixture was stirred at 20°C for 3 h. The reaction mixture was dried in an evaporator and the off-white The solid (0.06 g) was obtained.

[0224] d) t-Butyl((S)-2-(4-chlorophenyl)-3-3-(8-(2,4-dimethoxyphenyl) Benzyl)-5-(2-hydroxyethyl)-7-oxo-5,6,7,8-tetrahydropt 3,8-diazabicyclo[3.2.1]octane-8-carbamoyl) -3-Oxopropyl(isopropyl) ester The product of step c) (0.06 g) was dissolved in N,N-dimethylformamide (10 mL) with (S)-3-((t-butoxycarbonyl)(isopropyl)amino)-2-(4-chloro (phenyl)propionic acid (0.04g) and diisopropylethylamine (0.03g) were added. The reaction mixture was stirred for 2 min. 2-(7-benzotriazole oxide)-N was added at 20° C. ,N,N',N'-tetramethyluronium hexafluorophosphate (0.04 g) was added. The reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was poured into water (100 mL) and further added with ethyl acetate. (100mL) was added to the organic phase, which was then washed with saturated saline (100mL*3), The mixture was dried over anhydrous sodium sulfate and evaporated to dryness. The product was purified by chromatography. -Purify on silica gel plate (petroleum ether: ethyl acetate = 1:2) and obtain a white solid 0. 04g was obtained.

[0225] e) 4-(-8-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionate 3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(2-hydroxyphenyl) Diethyl)-5,6-dihydropteridin-7(8H)-one Trifluoroacetic acid (3 mL) was added to the product of step d) (40 mg) at 20 °C. The mixture was stirred at 60°C for 3 h. The reaction mixture was dried in an evaporator, and NaHCO3 was added. The mixture was stirred for 20 min and filtered to give an off-white solid (10 mg). I) m / z: 528 (M+H). 1 H NMR:(400MHz,DMSO-d6)δ10.78( d,J=19.6Hz,1H),8.07(d,J=29.4Hz,1H),7.30-7.51( m,4H),4.61-4.70(m,1H),4.384-4.54(m,1H),4.26-4.3 6(m,1H),4.04-4.25(m,1H),3.49-3.78(m,6H),2.97-3. 23(m,4H),2.82-2.91(m,1H),2.63-2.80(m,1H),1.62-2 .02(m,4H),1.27-1.17(m,8H).

[0226] Example 32 [ka] Instead of t-butyl piperazine-1-carboxylate, 3,8-diazabicyclo[3.2.1 The same procedure as described in Scheme K was used, except that t-butyl octane-8-carboxylate was used. The final product was separated by supercritical fluid chromatography to identify isomer 1 and Isomer 2 was obtained. Equipment and conditions for optical resolution: Waters SFC200, column :Daicel Chiralcel OZ, 250×30mm ID, 5μm, mobile phase : A is CO2 and B is isopropanol (0.1% NH3H2O), A:B=6 0:40 (volume ratio), flow rate 60 mL / min, column temperature 38°C.

[0227] Conditions for ultra-high performance convergence chromatography: Column: Daicel Chir alcel AD, 2.1×150mm ID, 3μm, Mobile phase A: CO2, Mobile phase B: Isopropanol (0.1% DEA), gradient: time 0-8 min, B phase 5-40% (volume ratio) , Flow rate: 1 mL / min, Column temperature 40 °C. Isomer 1: RT = 4.3 min, Isomer 2 :RT=4.5min.

[0228] Isomer 1: LCMS(ESI)m / z:499(M+H). 1 H NMR (400MHz, DMSO-d6) δ8.23(d,J=11.7Hz,1H),7.50-7.21(m,4H),5.79-5.5 9(m,1H),4.64-4.47(m,2H),4.08-3.94(m,2H),3.70-3. 40(m,2H),3.31-3.20(m,2H),3.16-3.06(m,1H),2.82(d ,J=9.2Hz,0.5H),2.75-2.62(m,2H),2.17(d,J=8.7Hz, 0.5H)1.96-1.49(m,4H),1.46-1.28(m,3H),0.98-0.8 7(m,6H).

[0229] Isomer 2: LCMS(ESI)m / z:499(M+H). 1 H NMR (400MHz, DMSO-d6) δ8.24(d,J=16.4Hz,1H),7.53-7.21(m,4H),5.81-5.6 5(m,1H),4.73-4.60(m,2H),4.46(d,J=4.9Hz,0.5H),4. 19(d,J=5.1Hz,0.5H),4.03(d,J=9.3Hz,0.5H),3.76( d,J=9.3Hz,0.5H),3.70-3.49(m,3H),3.21-3.16(m,1 H),3.06-2.92(m,2H),2.11-1.86(m,1.5H),1.84-1.52 (m,4H),1.48-1.33(m,3.5H),1.30-1.22(m,6H).

[0230] Example 33 [ka] Instead of t-butyl piperazine-1-carboxylate, 3,8-diazabicyclo[3.2.1 The same procedure as described in Scheme K was used, except that t-butyl octane-3-carboxylate was used. The final product was separated by supercritical fluid chromatography to identify isomer 1 and Isomer 2 was obtained. Equipment and conditions for optical resolution: Waters SFC200, column: Daicel Chiralcel OZ, 250×30mm ID, 5μm, mobile phase: A is CO2 and B is ethanol (0.1% NH3H2O), A:B = 60:40 ( volume ratio), flow rate 60 mL / min, column temperature 38°C.

[0231] Conditions for ultra-high performance convergence chromatography: Column: Daicel Chir alcel AD, 2.1×150mm ID, 3μm, Mobile phase A: CO2, Mobile phase B: Ethanol (0.1% DEA), gradient: time 0-8 min, B phase 5-40% (volume ratio), flow rate :1mL / min, Kura temperature 40℃. Opposite sex 1:RT=4.6min, Opposite sex 2:RT =5.0min.

[0232] Opposite sex body 1: LCMS (ESI) m / z: 499 (M+H). 1 H NMR (400 MHz, DMSO-d6) δ10.87(s,1H),8.23(d,J=11.7Hz,1H),7.50-7.21(m,4 H),5.80-5.76(m,1H),4.68-4.64(m,1H),4.44-4.39(m, 1H),4.33-4.14(m,2H),4.07-3.88(m,2H),3.66-3.62(m ,1H),3.16-2.88(m,2H),2.79-2.55(m,4H),2.01-1.77( m,1H),1.72-1.49(m,2H),1.48-1.36(m,2H),1.31-1.18 (m,1H),1.04-0.85(m,4H),0.54-0.44(m,1H). Opposite sex body 2: LCMS (ESI) m / z: 499 (M+H). 1 H NMR (400 MHz, DMSO-d6) δ10.69(s,1H),8.24(d,J=3.8Hz,1H),7.53-7.21(m,4H ),5.80-5.76(m,1H),4.64-4.48(m,1H),4.43-4.42(m,1 H),4.27-4.18(m,1H),4.02-3.92(m,1H),3.68-3.60(m, 1H),3.21-3.02(m,1H),2.95-2.64(m,4H),2.02-1.70(m ,2H),1.60-1.22(m,5H),1.04-0.83(m,6H),0.43-0.40( m, 1H).

[0233] Example 34 [ka] a) 1-(4-amino-6-chloropyrimidin-5-yl)ethanone (compound 34-1) 1-(4,6-dichloropyrimidin-5-yl)ethanone (2.5 g) was added to tetrahydrofuran at 20°C. The reaction mixture was dissolved in 15 mL of fluorouracil, and then aqueous ammonia (9 g) was added. The reaction mixture was then incubated at 20° C. for 5 hours. The mixture was stirred for 10 minutes, concentrated, diluted with a small amount of water, and filtered under suction to obtain a white solid. After drying in vacuum, 2 g of a white solid was obtained, which was used directly in the next step.

[0234] b) 1-(4-amino-6-chloropyrimidin-5-yl)ethan-1-ol (compound 34 -2) 1-(4-amino-6-chloropyrimidin-5-yl)ethanone (1.5 g) was dissolved in methacrylate at 20°C. Dissolve in alcohol (15 mL), cool to -10°C, and add sodium borohydride (1 g) After the addition was completed, the reaction mixture was slowly warmed to 20° C. and stirring was continued for 3 hours. After the reaction was completed, the reaction solution was quenched with a saturated aqueous solution of ammonium chloride. The reaction solution was concentrated and pulped with ethyl acetate (20 mL*2). The mother liquor was concentrated to give an oily mixture. The crude product was isolated by column chromatography to give a white oily product. 400 mg of the product was obtained. LC-MS (ESI) m / z: 174 (M+H).

[0235] c) 5-chloro-4-methyl-1,4-dihydro-2H-pyrimidinide [4,5-d][1,3 ]Oxazin-2-one (compound 34-3) 1-(4-amino-6-chloropyrimidin-5-yl)ethan-1-ol (30 0 mg), N,N-diisopropylethylamine (282 mg) in tetrahydrofuran (3 m The mixture was then cooled to -5°C and di(trichloromethyl)carbonate (300 L) was added. The mixture was slowly added with 1.5 mg of ethyl acetate and stirred at -5°C for 0.5 hours. The temperature was then slowly raised to 18°C. After the reaction was completed, the reaction was quenched with sodium bicarbonate water and ethyl acetate ( Extract with 10mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product was isolated and purified by column chromatography. Obtained 108 mg of a white solid. LC / MS(ESI) m / z: 200(M+H).

[0236] d) (S)-5-chloro-4-methyl-1,4-dihydro-2H-pyrimidide [4,5-d] [1,3]Oxazin-2-one (compound 34-4a), and (R)-5-chloro-4-methyl 1,4-dihydro-2H-pyrimidin[4,5-d][1,3]oxazin-2-one ( Compound 34-4b) Compound 34-3 was optically resolved using an SFC chiral column to obtain the desired compound 34-4. a and compound 34-4b were obtained.

[0237] The conditions for SFC optical resolution were as follows: Equipment: Waters SFC200, Column: Dai cel Chiralcel AD, 250×50mm ID, 10μm, Mobile phase: A:C O2, B: methanol (0.1% NH3H2O), A:B = 65:35 (volume ratio), flow rate: 1 50mL / min, pressure: 100bar, column temperature: 38℃, measurement wavelength: 220nm, circulation Solvent time: 14 min. Sample preparation: 10 g of sample was dissolved in 300 ml of MeOH. , Injection volume: 16ml.

[0238] Post-treatment: The sample was concentrated at 40°C and then freeze-dried to obtain the title compound 34-4a and compound 34-4b. Compound 34-4b was obtained, respectively.

[0239] Route 1: Preparation of Isomer 1 and Isomer 4 e) 5-((S)4-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d] [1,3]oxazin-5-yl)-2,5-diazabicyclo[4.1.0]heptane-2 -t-Butyl carboxylate (compound 34-5a) Compound 34-4a (2g), 2,5-diazabicyclo[4.1.0]heptane-2-carbo t-Butyl phosphate (3.58 g) was dissolved in anhydrous MeCN (20 mL) and DIEA (3.89 g) was added. The reaction mixture was then flushed with nitrogen gas, sealed, and stirred at 95°C for 6 hours. After completion, it was concentrated to give the desired crude product, which was dissolved in DCM and washed with water. After that, the mixture was concentrated to obtain a crude product, which was then isolated by column chromatography (EA:PE=1:1). Purification gave 3.2 g of a pale brown solid.

[0240] f) (4S)-5-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-4-methyl 1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one Hydrochloride (Compound 34-6a) The product of step e) (3.2 g) was dissolved in HCl / i-PrOH (10 mL) at room temperature. After stirring for 2 h, the reaction was completed and concentrated to give the crude product, which was directly used in the next step without purification. It was used for the top.

[0241] g) Compound 34-7a The product of step f) (3.3 g), (S)-3-((t-butoxycarbonyl)(isopropyl) Amino)-2-(4-chlorophenyl)propionic acid (4.9 g), HATU (6.32 g), DIPEA (4.3 g) was dissolved in anhydrous DMF (50 mL) and the reaction mixture was stirred at room temperature for 12 hours. After the reaction is complete, the reaction mixture is poured into 100 mL of ethyl acetate and diluted with water (20 mL*3) and saturated sodium chloride solution. The organic phase was washed with 10 mL of brine, dried and concentrated to give the crude product. The product was isolated and purified by chromatography (PE:EA=1:1) to give 7.2 g of a brown solid. S(ESI) m / z: 585(M+H).

[0242] h) Compound 34-8a The product of step g) (7.2 g) is dissolved in MeOH (25 mL) and After adding 70 mL of dimethylformamide, the reaction mixture was stirred at room temperature for 2 h, and then concentrated to give a red oil. The crude product was dissolved in MeOH (20 mL) and released with Na2CO3. Concentration gave 6 g of crude product.

[0243] i) Isomer 1 Harmonic isomer 4 Compound 34-8a was optically resolved using an SFC chiral column to give isomer 1 and isomer 4. SFC optical separation conditions: Equipment: Waters SFC200, Column: Daicel Chi ralcel AD, 250×50mm ID, 10μm, Mobile phase: A: CO2, B: M eOH (0.1% NH3H2O), A:B = 75:25, flow rate: 70mL / min, pressure: 1 00 bar, column temperature: 38°C, measurement wavelength: 254 nm, circulation time: 5 min, sample Pretreatment: 10 g of sample was dissolved in 200 ml of MeOH, amount: 16 ml.

[0244] Post-treatment: The sample was concentrated at 40°C and then freeze-dried to obtain the title compound isomer 1 and isomer They each got 4.

[0245] Route 2: Preparation of Isomer 2 and Isomer 3 Using compound 34-4b as a starting material, isomer 2 and isomer 3 were obtained in the same manner as described in Route 1. Three isomers were prepared respectively.

[0246] Isomer 1: LCMS m / z:485(M+H). 1 H NMR (400MHz, DMSO-d 6)δ10.70(s,1H),8.23(s,1H),7.46(d,J=8.5Hz,2H),7. 39(d,J=8.6Hz,2H),6.13(q,J=6.6Hz,1H),4.51(s,1H), 4.42-4.30(m,1H),3.53-3.45(m,1H),3.28-3.06(m,5 H),3.01-2.59(m,3H),1.52-1.34(m,4H),1.08-0.97(m, 6H), 0.93-0.84(m,1H).

[0247] Isomer 4: LCMS m / z:485(M+H). 1 H NMR (400MHz, DMSO-d 6)δ10.73(s,1H),8.23(s,1H),7.41-7.32(m,4H),6.14( q,J=8.0Hz,1H),4.40-4.36(m,1H),4.19-4.11(m,1H),3 .62-3.51(m,2H),3.49-3.35(m,1H),3.24-3.05(m,4H), 2.73-2.63(m,2H),1.45(d,J=8.0Hz,1H),1.33(d,J=8. 0Hz,2H),1.12(q,J=4.0Hz,1H),0.95-0.88(m,6H),0.2 6(q, J = 4.0 Hz, 1H).

[0248] Isomer 2: LCMS m / z:485(M+H). 1 H NMR (400MHz, DMSO-d 6)δ10.86(s,1H),8.27(s,1H),7.54-7.27(m,4H),6.32- 6.18(m,1H),4.69-4.52(m,1H),4.27-3.97(m,2H),3.66 -3.43(m,2H),3.29-2.92(m,6H),2.61-2.55(m,1H),1.6 3-1.58(m,1H),1.53-1.28(m,3H),1.28-1.12(m,6H).

[0249] Isomer 3: LCMS m / z:485(M+H). 1 H NMR (400MHz, DMSO-d 6) δ10.71(s,1H),8.18(s,1H),7.46-7.39(m,1H),7.36- 7.28(m,3H),6.00(q,J=6.4Hz,1H),4.53(s,1H),4.46-4 .33(m,1H),3.56-3.44(m,2H),3.26-3.09(m,5H),3.00- 2.71(m,2H),1.43-1.38(m,3H),1.10-0.93(m,7H),-0. 07--0.11(m,1H).

[0250] Determining configuration by single crystal diffraction: (1) Determination of the configuration of isomer 1 Preparation of single crystals: Compound isomer 1 (50.0 mg) and 3.0 ml of isopropanol were weighed out. The mixture was added to a 5 ml screw-top glass bottle and stirred for 5 min until the solid was completely dissolved. Weigh out 13.0 mg of oxalic acid dihydrate and place it in the above glass bottle. The glass bottle gradually becomes white. A solid precipitated, and the mixture was stirred at room temperature for 3 hours. A large amount of white solid precipitated in the glass bottle. After adding 1.5 ml of ethanol and 0.2 ml of purified water, the white solid gradually disappeared and the solution became The solution became clear and was then stirred for 1 h. The solution was passed through a 0.22 μm microporous filter membrane and The mixture was filtered into a 0 ml screw-top glass bottle and the mouth of the glass bottle was covered with plastic wrap. The bottle was then pierced with eight holes using a needle and left at room temperature for 10 days to determine the amount of oxalate of isomer 1. A single crystal was obtained. JPEG2024175091000121.jpg81166

[0251] Structure elucidation: Single crystal X-ray diffraction and structural analysis showed that the obtained single crystal is the oxalate salt of isomer 1. The asymmetric unit of the crystal contains two molecules of the isomer and one molecule of oxalic acid. A schematic diagram of the single molecule of compound isomer 1 is shown in Figure 3, and a single crystal of the oxalate salt is shown in Figure 4. The structural formula is shown below: [ka] (2) Determination of the configuration of isomer 3 Preparation of single crystals: The oxalate of isomer 3 was prepared according to the method described for the preparation of single crystals of isomer 1 above. A single crystal of the salt was prepared. Single crystal diffraction study: JPEG2024175091000123.jpg79166

[0252] Structure elucidation: Single crystal X-ray diffraction and structural analysis confirmed that the obtained single crystal is the oxalate hydrochloride of isomer 3. The asymmetric structural unit of the crystal is a dimer of isomers3 and a dimer of sh The compound contains oxalic acid and one molecule of water, and isomer 3 and oxalic acid form an oxalate salt. A schematic diagram of a single molecule of isomer 3 is shown in Figure 5, and the asymmetric structural unit of the oxalate single crystal is shown in Figure 6. The structural formula is shown below: [ka] Scheme L: [ka] Reaction conditions: a) (2,4-dimethoxyphenyl)methylamine, triethylamine, tetrahydrofuran 4,6-Dichloropyrimidin-5-amine, triethylamine, isopropylamine alkanol, c) methyl iodide, sodium hydride, N,N-dimethylformamide, d) picolinol t-Butyl perazine-1-carboxylate, 4-dimethylaminopyridine, N-methylpyrrolidone e) Hydrogen chloride in dioxane, f) (S)-3-((t-butoxycarbonyl)(isopropyl) (p-amino)-2-(4-chlorophenyl)propionic acid, diisopropylethylamine, 2-(7-Benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexahydrate trifluorophosphate, N,N dimethylformamide, g) trifluoroacetic acid.

[0253] Example 35 [ka] a) Ethyl 2-(2,4-dimethoxybenzyl)aminoacetate Triethylamine was added to a solution (10 mL) of ethyl bromoacetate (1.0 g) in THF at 0°C. (0.6 g) and (2,4-dimethoxyphenyl)methylamine (1.0 g) were added to the reaction mixture. The mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water (100 mL) and further added with ethyl acetate (100 mL). The organic phase was washed with saturated saline (100mL*3) and extracted with anhydrous sodium sulfate. The product was purified by silica gel column chromatography. The product was purified by elution with petroleum ether:ethyl acetate = 3:1 to give 1.3 g of a white solid. Got it.

[0254] b) 4-chloro-8-(2,4-dimethoxybenzyl)-7,8-dihydropteridine-6(5 H)-On Isopropyl alcohol dissolved in ethyl 2-(2,4-dimethoxybenzyl)aminoacetate (1.3 g) at 0°C. In methanol (10 mL), triethylamine (1.56 g) and 4,6-dichloropyrimidine -5-amine (0.84 g) was added. The reaction mixture was stirred at 90° C. for 3 h. The reaction mixture was filtered. As a result, 0.7 g of a white solid was obtained as the product.

[0255] c) 4-chloro-8-(2,4-dimethoxybenzyl)-5-methyl-7,8-dihydroptene Lysine-6(5H)-one 4-Chloro-8-(2,4-dimethoxybenzyl)-7,8-dihydropteridine-6 ​​at 0°C The (5H)-one (0.5 g) was dissolved in N,N-dimethylformamide (5 mL) and the hydrogenated Sodium (76.7 mg) was added. The reaction mixture was stirred for 20 minutes. Methyl iodide was added at 0° C. (255 mg) was added. The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was poured into water (100 mL). The organic phase was extracted with saturated saline (100mL*3 ) was added to wash the mixture, dried over anhydrous sodium sulfate, and then dried in an evaporator. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) The product was obtained as a white solid (0.5 g).

[0256] d) 4-(8-(2,4-dimethoxybenzyl)-5-methyl-6-oxo-5,6,7,8-tetramethyl- tetrahydropteridin-4-yl)piperazine-1-carboxylic acid ester 4-Chloro-8-(2,4-dimethoxybenzyl)-5-methyl-7,8-dihydro at 20°C Pteridin-6(5H)-one (0.5 g) dissolved in N-methylpyrrolidone (10 mL) , piperazine-1-carboxylate t-butyl (0.53 g), 4-dimethylaminopyridine ( The reaction mixture was stirred at 150° C. for 3 h. The reaction mixture was diluted with water (100 mL). The organic phase was poured into a broth and extracted with ethyl acetate (100 mL). The mixture was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and then dried in an evaporator. The product was purified by chromatography on a silica gel plate (petroleum ether: ethyl acetate = 1:1) and The product was obtained as a white solid (0.5 g).

[0257] e) 8-(2,4-dimethoxybenzyl)-5-methyl-4-(piperazin-1-yl)-7, 8-Dihydropteridin-6(5H)-one 4-(8-(2,4-dimethoxybenzyl)-5-methyl-6-oxo-5,6,7, 8-Tetrahydropteridin-4-yl)piperazine-1-carboxylic acid ester (0.1g Hydrogen chloride in dioxane (5 mL) was added to the reaction mixture, and the reaction mixture was stirred at 20° C. for 3 h. The reaction mixture was dried in an evaporator to give an off-white solid (0.1 g).

[0258] f) (S)-t-butyl(2-(4-chlorophenyl)-3-(4-(8-(2,4-dimethoxyphenyl) (5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-4-yl) -piperazin-1-yl)-3-oxopropyl)(isopropyl)carbamate 8-(2,4-dimethoxybenzyl)-5-methyl-4-(piperazin-1-yl) at 20°C -7,8-Dihydropteridin-6(5H)-one (0.1 g) dissolved in N,N-dimethylformamide In a 10 mL solution of (S)-3-((t-butoxycarbonyl)(isopropyl)amino)- 2-(4-chlorophenyl)propionic acid (0.12 g), diisopropylethylamine (0 0.10 g) was added. The reaction mixture was stirred for 2 min. 2-(7-benzotriazole) was added at 20° C. Oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0. 12 g) was added, and the reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was poured into water (100 mL), Further extraction was performed by adding ethyl acetate (100 mL). Saturated saline (100 mL*3) was added to the organic phase. The product was washed with water, dried over anhydrous sodium sulfate, and then dried in an evaporator. The product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1:2). This gave 0.1 g of a white solid.

[0259] g) (S)-4-(4-(2-(4-chlorophenyl)-3-(isopropylamino)propionyl 1-piperazinyl)-5-methyl-7,8-dihydropteridin-6(5H)-one At 20°C, (S)-t-butyl(2-(4-chlorophenyl)-3-(4-(8-(2,4-dimeth- (Xybenzyl)-5-methyl-6-oxo-5,6,7,8-tetrahydropteridine-4- (1-yl)-piperazin-1-yl)-3-oxopropyl)(isopropyl) carbamate (1 00 mg) was added with trifluoroacetic acid (5 mL). The reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was dried on an evaporator to give an off-white solid (20 mg). LCMS (ESI) m / z: 472 (M+H) 1 H NMR (400MHz, CDCl3) δ 7.89 (s, 1H),7.22-7.29(m,2H),7.10-7.18(m,2H),4.08-4.17(m ,1H),3.86(s,2H),3.32-3.45(m,2H),3.15-3.30(m,3H), 3.08(s,3H),2.82-2.93(m,2H),2.51-2.78(m,4H),1.21 -1.31(m,2H),1.03-1.12(m,6H).

[0260] Scheme M: [ka] Reaction conditions: a) 2,4-dimethoxybenzylamine, N,N-diisopropylethylamine , acetonitrile, b) tetrahydrofuran, potassium carbonate, 2-chloro-2-oxoacetic acid methyl ester, c) N,N-diisopropylethylamine, ethanol, d) 3,8-diazabis(2,4-diphenyl ether) t-Butyl chloro[3.2.1]octane-8-carboxylate, N,N-diisopropyl ethyl e) N,N-dimethylformamide, potassium carbonate, iodide Methyl, f) trifluoroacetic acid, g) (S)-3-((t-butoxycarbonyl)(isopropyl )amino)-2-(4-chlorophenyl)propionic acid, N,N-diisopropylethylamino h) Dichloromethane, Hydrogen chloride / Isopropanol Alkanol solution.

[0261] Example 36 [ka] a) 6-chloro-N-(2,4-dimethoxybenzyl)pyrimidine-4,5-diamine 4,6-Dichloropyrimidin-5-amine (2g) and N,N-diisopropylethylamine (4.7 g) and 2,4-dimethoxybenzylamine (2.45 g) in acetonitrile (20 1 mL) and the reaction was stirred at 90 °C for 5 h and concentrated to give the crude product, which was The solution was dissolved in dichloromethane, washed with a small amount of water, and the organic phase was dried in an evaporator. After that, the crude product was obtained and isolated by column chromatography (PE:EA=1:1). The mixture was purified by filtration and concentrated to give the target product (3.5 g) as a pale yellow solid.

[0262] b) 2-((4-chloro-6-(((2,4-dimethoxybenzyl)amino)pyrimidin-5-yl (III)amino)-2-oxoacetate methyl 6-Chloro-N-(2,4-dimethoxybenzyl)pyrimidine-4,5-diamine (1.5g) , potassium carbonate (1.1 g), and methyl 2-chloro-2-oxoacetate (623 mg) were added. The reaction mixture was dissolved in aqueous ethanol (20 mL) and stirred at 20° C. for 3 hours. Pour into 30 mL of ethyl acetate, wash with water (10 mL*2), and concentrate the organic phase until the weight remains the same. The crude product is obtained, and the crude product is pulped and purified with a mixed solvent (PE:EA=3:1). The product was obtained as a white solid (1.6 g).

[0263] c) 4-chloro-8-(2,4-dimethoxybenzyl)-5,8-dihydropteridine-6,7 -Zion 2-((4-chloro-6-(((2,4-dimethoxybenzyl)amino)pyrimidin-5-yl) Methyl 2-oxoacetate (1 g) was dissolved in absolute ethanol (10 mL) and N,N-diamine was added. Isopropylethylamine (1.02 g) was added and the reaction mixture was heated to 90°C under a nitrogen gas atmosphere. The mixture was stirred at 10° C. for 2 hours. The reaction mixture was concentrated to give the crude product, which was then dissolved again in dichloromethane. The mixture was adjusted to a weak acidity with dilute hydrochloric acid, and the salt was removed by washing with water. The organic phase was concentrated to obtain a crude product. The product is obtained, and the crude product is pulped and purified with a mixed solvent (PE:EA=3:1); The product was obtained as a white oil (800 mg). 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),8.47(s,1H),6.88(d,J=8.4Hz,1H),6.5 9(d,J=2.3Hz,1H),6.32(dd,J=8.4,2.3Hz,1H),5.21(s ,2H),3.84(s,3H),3.72(s,3H).

[0264] d) t-Butyl-3-(8-(2,4-dimethoxybenzyl)-6,7-dioxo-5,6,7, 8-Tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octa 8-Carboxylic Acid Ester 4-Chloro-8-(2,4-dimethoxybenzyl)-5,8-dihydropteridine-6,7- dione (250 mg) and (1R,5S)-3,8-diazabicyclo[3.2.1]octane- 8-tert-butyl carboxylate (456 mg) and N,N-diisopropylethylamine (278 mg) was dissolved in anhydrous acetonitrile (5 mL), and the reaction solution was sealed under a nitrogen gas atmosphere. The mixture was stirred at 90° C. for 3 hours. The mixture was concentrated to give an oily crude product. Dissolve in chilled water (30 mL), adjust with dilute hydrochloric acid to pH 3-4, and add water to pH 5-6. The crude product was purified by column chromatography (P E:EA=1:1) to give 200 mg of a white solid, m / z=525 (M+H). .

[0265] e) (t-Butyl-3-(8-(2,4-dimethoxybenzyl)-5-methyl-6,7-dioxa So-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3. 2.1] Octane-8-carboxylate t-Butyl-3-(8-(2,4-dimethoxybenzyl)-6,7-dioxo-5,6,7,8- Tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylic acid ester (180 mg), methyl iodide (146 mg), potassium carbonate (14 2 mg) was dissolved in anhydrous DMF (3 mL), the reaction mixture was stirred at 20° C. for 1 h, and the reaction mixture was Pour into 30 mL EA, wash with water (10 mL*2) and saturated saline (10 mL), and concentrate the organic phase. The crude product was isolated by column chromatography (PE:EA=3:1). , and purified to obtain 180 mg of a pale yellow solid.

[0266] f) 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5 -Methyl-5,8-dihydropteridine-6,7-dione t-Butyl-3-(8-(2,4-dimethoxybenzyl)-5-methyl-6,7-dioxo- 5,6,7,8-Tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2. 1] Octane-8-carboxylate (120 mg) was dissolved in anhydrous DCM (1 mL) TFA (2 mL) was added dropwise, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution turned red, and the reaction solution was The crude product is then concentrated as is, adjusted to pH 8-9 with sodium bicarbonate water, and further concentrated. The mixture was dissolved in THF, the salts were removed by filtration, and the remaining material was subjected to column chromatography (DC M:MeOH=10:1) to give 60 mg of an oily product.

[0267] g) t-Butyl((s)-2-(4-chlorophenyl)-3-3-(5-methyl-6,7-dioxa So-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3. 2.1]Octan-8-yl)-3-oxopropyl carbamate (isopropyl) The compound 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-methyl- 5,8-Dihydropteridine-6,7-dione (60 mg), (S)-3-((t-butoxycarbonyl) (isopropyl)amino)-2-(4-chlorophenyl)propionic acid (90 mg), 2 -(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluoro Orophosphate (130 mg), N,N-diisopropylethylamine (102 mg), Dissolve in anhydrous DMF (2 mL), stir the reaction at room temperature for 3 hours, and then add ethyl acetate. Pour into 20mL, wash with water (50mL*2), dry the organic phase over anhydrous sodium sulfate, and The crude product was purified by silica gel column chromatography (DCM:Me The product was isolated and purified using a solvent (OH=10:1) to give 120 mg of an oily product.

[0268] h) 4-(8-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionyl (3,8-diazabicyclo[3.2.1]octan-3-yl)-5-methyl-5,8- Dihydropteridin-6,7-one t-Butyl((s)-2-(4-chlorophenyl)-3-3-(5-methyl-6,7-dioxo -5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2 1] Octan-8-yl)-3-oxopropyl carbamate (isopropyl) in DCM ( HCl / i-PrOH (2 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then concentrated to give a crude product, which was then isolated and freeze-dried to give the crude product. 14 mg of a white solid was obtained. m / z: 499 (M+H). 1 H NMR (400MHz, CD3 OD)δ8.32(d,J=25.7Hz,1H),7.68-7.32(m,4H),5.14(m ,1H),4.71-4.28(m,3H),4.12-3.92(m,3H),3.80-3.40( m,3H),3.23-3.15(m,2H),2.24-2.16(m,1H),1.92-1. 82 (m, 2H), 1.80-1.70 (m, 1H), 1.48-1.16 (m, 8H).

[0269] Example 37 Scheme N: [ka] Reaction conditions: a) triethylamine, di-t-butyl dicarbonate, dichloromethane, b) sodium Mubis(trimethylsilyl)amide (2.0 mol / L tetrahydrofuran solution), ethyl methyl ether, 2-methyltetrahydrofuran, c) (R)-4-benzyloxazo Lysine-2-one, diisopropylethylamine, trimethylacetyl chloride, toluene d) Titanium tetrachloride (1 mol / L toluene solution), diisopropylethylamine, dichloromethane e) Hydrogen peroxide solution (30%), Lithium hydroxide monohydrate, Tetrahydrofuran f) t-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate , 4-Dimethylaminopyridine, N-Methylpyrrolidone, g) Hydrogen chloride, dioxane (4.0 M), h) 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronid Umium hexafluorophosphate, diisopropylethylamine, N,N-dimethylformamide amide, i) Hydrogen chloride in dioxane (4.0M).

[0270] a) t-Butyl cyclopropylcarbamate Cyclopropylamine (9.3 g) and triethylamine (19 0.7g) in dichloromethane (100mL) and heated at 0°C to prepare di-t-butyl dicarbonate (35.4 8g) was added dropwise and reacted at 20°C for 16h. After the reaction was completed, the solvent was removed and the reaction mixture was cooled to 24°C. 3 g of a colorless liquid was obtained. 1 H NMR(400MHz,CDCl3)δ(ppm)0.47- 0.50(m,2H),0.66-0.72(m,2H),1.44(s,9H),2.53(m,1H ),4.79(s,1H).

[0271] b) t-Butyl cyclopropyl(methoxymethyl)carbamate Under a nitrogen gas atmosphere, t-butyl cyclopropylcarbamate (24.3 g) was dissolved in 2-methyltetrahydrofuran. Dissolve in tetrahydrofuran (100 mL) and heat at 0°C to sodium bis(trimethylsilyl)amide. Add dropwise 120 mL of bromomethyl ether and stir the reaction mixture at 0° C. for 1 hour. Then, 35.7 g of tert-butyl ether was added dropwise, and the reaction mixture was stirred at 0° C. for 6 hours. The reaction mixture was then poured into 50 g of ice water. The mixture was separated, extracted with ethyl acetate (100 mL*2), and the reaction mixture was concentrated to give the product. The resulting mixture was used in the next step without purification.

[0272] c) (R)-4-benzyl-3-(2-(4-(chlorophenyl)acetyl)oxazolidine-2 -on Under a nitrogen gas atmosphere, 2-(4-chlorophenyl)acetic acid (50 g) and (R)-4-benzyloxy Sazolidin-2-one (45.5 g) and diisopropylethylamine (127.3 g) Dissolve in toluene (600 mL) and add trimethylacetyl chloride (38.4 g) dropwise at 15°C. The reaction mixture was stirred at reflux for 16 hours, and then poured into 200 mL of water and separated. The organic phase was washed with 120 mL of saturated aqueous sodium chloride, dried and concentrated to give the crude product. The compound was isolated and purified by column chromatography (PE:EA=5:1) to obtain 32 g of a white solid. . 1 H NMR(400MHz,DMSO-d6)δ(ppm)2.88-3.02(m,2H), 4.12-4.37(m,4H),4.64-4.70(m,1H),7.13-7.16(m,2 H),7.23-7.32(m,5H),7.39-7.42(m,2H).

[0273] d) ((S)-3-((R)-4-benzyl-2-oxazolidin-3-yl)-2-(4-chloro (cyclopropyl)-3-oxopropyl)carbamate t-butyl ester Under nitrogen gas atmosphere, (R)-4-benzyl-3-(2-(4-chlorophenyl)acetyl)- Dissolve xazolidin-2-one (3.48 g) in dichloromethane (60 mL) and prepare the tetrasalt at 0°C. A solution of titanium dioxide in toluene (13 mL) was added dropwise, and the reaction mixture was stirred at 0° C. for 2 hours. (1.49 g) was added dropwise, and the reaction mixture was stirred at 0° C. for 1.5 hours. t-Butyl (ethyl)carbamate (2.77 g) was added dropwise, and the reaction solution was stirred at 0°C for 6 hours. The reaction was completed. The reaction mixture was poured into 30 mL of saturated ammonium chloride solution, and the layers were separated. The organic phase was washed with 120 mL of saturated aqueous sodium chloride, dried and concentrated to give the crude product. The product was isolated and purified by silica gel column chromatography (PE:EA=10:1) to give a colorless o The resulting product was 2.50 g in the form of a silyl compound.

[0274] e) (S)-3-((t-butoxycarbonyl)(cyclopropyl)amino)-2-(4-chlorophenyl) (phenyl)propionic acid Dissolve lithium hydroxide monohydrate (0.63 g) in water (18 mL) and add tetrahydrofuran (2 0 mL) was added, and hydrogen peroxide solution (1.6 mL) was added dropwise at 0°C. Then, ((S)-3-((R) -4-benzyl-2-oxazolidin-3-yl)-2-(4-chlorophenyl)-3-o 2.50 g of t-butyl 2-hydroxypropyl (cyclopropyl)carbamate was added, and the reaction mixture was The mixture was stirred at 0°C for 3 hours, and then saturated sodium sulfite solution (15 mL) was added to the reaction mixture and the mixture was reacted for 1.5 hours. The mixture was reacted with saturated potassium hydrogen sulfate solution to adjust the pH to 3-4, and ethyl acetate (3 The mixture was extracted with 100 mL of ethyl acetate, the liquids were separated, and the organic phase was dried and concentrated to obtain the crude product. The product was isolated and purified by column chromatography (PE:EA=1:1) to obtain 1.26 g of a colorless solid. Got it. 1 H NMR(400MHz,DMSO-d6)δ(ppm):0.45-0.48(m, 2H),0.60-0.64(m,2H),1.30(s,9H),2.19(s,1H),3.61( d,J=7.6Hz,1H),3.95(t,J=8.0Hz,1H),7.37(dd,J=26 .8, 8.8Hz,4H),12.7(s,1H).

[0275] f) 5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyridine [2,3-d ]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carbo Phosphate ester Under a nitrogen gas atmosphere, (R)-4-chloro-5-methyl-5,8-dihydropyridine [2,3- d]pyrimidin-7(6H)-one (300 mg), 2,5-diazabicyclo[4.1.0] t-Butyl heptane-2-carboxylate (455 mg), 4-dimethylaminopyridine (60 0 mg) was dissolved in N-methylpyrrolidone (5 mL), stirred at 120°C for 12 h, and The reaction mixture was poured into 50 mL of water, extracted with ethyl acetate (20 mL*2), and then washed with 15 mL of saturated saline. The organic phase was washed and dried to remove the solvent to obtain a crude product. The solid was isolated and purified by column chromatography (PE:EA = 1:1 to 1:2) to give a yellow solid (400 ml). I got g.

[0276] g) (5R)-4-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-5-methyl 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one 5-((R)-5-Methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d] Pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxone Dissolve the acid ester (400 mg) in dioxane (5 mL) and add hydrogen chloride dioxane solution (5 mL). L) was added dropwise, and the mixture was stirred at 25°C for 2 hours. The reaction was completed, and the reaction solution was concentrated as it was to obtain a crude product. The product was a yellow solid which was used directly in the next step.

[0277] h) t-Butyl((S)-2-(4-chlorophenyl)-3-((1R,6S)-5((R)-5- Methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4- (yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)-3-oxopropionate Cyclopropyl carbamate Under a nitrogen gas atmosphere, (5R)-4-(2,5-diazabicyclo[4.1.0]heptane-2- yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ( 270 mg), compound 5 (389 mg), and 2-(7-benzotriazole oxide)-N, N,N',N'-Tetramethyluronium hexafluorophosphate (474 ​​mg) and diisopropyl urea Diisopropylethylamine (671 mg) in N,N-dimethylformamide (10 mL) The reaction mixture was stirred at 25°C for 3 hours to complete the reaction. The reaction mixture was then diluted with 50% water. Pour into 10 mL of water, extract with ethyl acetate (20 mL*2), wash with saturated saline (10 mL*3), and The organic phase was dried and concentrated to give the crude product. The crude product was purified by column chromatography (PE: EA=1:2) to obtain 320 mg of a yellow solid.

[0278] i) (R)-4-((1R,6S)-5-((S)-2-(4-chlorophenyl)-3-(cyclopropyl) (amino)propionyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl) -5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one, and (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(cyclopropyl Amino)propionyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)-5 -Methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one t-Butyl((S)-2-(4-chlorophenyl)-3-((1R,6S)-5((R)-5-methylphenyl) Thiol-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl (2,5-diazabicyclo[4.1.0]heptan-2-yl)-3-oxopropyl (Cyclopropyl)carbamate (320 mg) was dissolved in dioxane (2.5 mL) and chloride was added. Hydrogen dioxane (2.7 mL) was added dropwise and the reaction was stirred at 25° C. for 14 hours until the reaction was complete. The reaction mixture was then concentrated to obtain a crude product, which was then diluted with saturated potassium carbonate solution to pH 13-14. Adjust the solution to 14, extract with DCM (10 mL*2), wash with water (10 mL), and The product was optically resolved by supercritical fluid chromatography to give isomer 1 (61.2 mg) and isomer 2 (31.2 mg).

[0279] Equipment and conditions for optical resolution: Waters SFC200, column: Daicel C hiralcel AS, 250×30mm ID, 5μm, mobile phase: A is CO2 , B is isopropanol (0.1% NH3H2O), A:B = 70:30 (volume ratio), flow Flow rate: 60 mL / min, column temperature: 38°C. Conditions for ultra-high performance convergence chromatography: Column: Daicel Chir alcel AD, 2.1×150mm ID, 3μm, Mobile phase A: CO2, Mobile phase B: Isopropanol (0.1% DEA), gradient: time 0-8 min, B phase 5-40% (volume ratio) , Flow rate: 1 mL / min, Column temperature 40 °C. Isomer 1: RT = 3.7 min, Isomer 2 :RT=4.6min.

[0280] Isomer 1: LCMS (ESI) m / z: 481 (M+H). 1 H NMR (400MHz, DMS O-d6)δ(ppm):0.03-0.12(m,2H),0.25-0.30(m,2H),0. 66-0.70(m,1H),0.96-1.05(m,3H),1.35-1.40(m, 1H) ,1.93-2.11(m,2H),2.29-2.35(m,1H),2.67-2.77(m, 2H), 2.80-2.86(m, 1H), 3.03-3.25(m, 4H), 3.39-3.48 (m,1H),3.69-3.79(m,1H),4.24-4.34(m,2H),7.34-7. 41(m,4H),8.17(s,1H),10.52(s,1H).

[0281] Isomer 2: LCMS (ESI) m / z: 481 (M+H). 1 H NMR (400MHz, DMS O-d6)δ(ppm):0.14-0.21(m,2H),0.30-0.37(m,2H),0. 93-1.07(m,4H),2.03-2.34(m,3H),2.66-2.86(m,2H), 3.10-3.25(m,4H),3.36-3.94(m,4H),4.07-4.15(m,1 H),4.41-4.45(m,1H),7.32-7.42(m,4H),8.19(s,1H),1 0.48(s,1H).

[0282] Example 38 [ka] Instead of t-butyl 2,5-diazabicyclo[4.1.1]heptane-2-carboxylate Using t-butyl 3,8-diazabicyclo[3.2.0]octane-8-carboxylate The target compound was prepared according to the method described in Scheme N, except for the following: I) m / z: 495 (M+H). 1 HNMR(400MHz,DMSO-d6)δ(ppm):0 .11-0.22(m,2H),0.29-0.37(m,2H),1.01(dd,J=30.8 ,6.8Hz,3H),1.52-1.69(m,1H),1.72-1.93(m,3H),2. 04-2.14(m,1H),2.25(d,J=16Hz,1H),2.32(d,J=13.2 Hz,1H),2.66-2.83(m,3H),3.11-3.26(m,3H),3.52(d, J=16Hz,1H),3.75-3.83(m,1H),4.09-4.15(m,1H),4. 45-4.63(m,2H),7.33-7.41(m,4H),8.14(d,J=32Hz,1 H), 10.57 (d, J = 9.6 Hz, 1H).

[0283] Example 39 Scheme P: [ka] Reaction conditions: a) t-butylamine, N,N-dimethylformamide, b) 2-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate ethyl, palladium acetate, tricyclohexylphosphine, potassium carbonate, toluene, water, c) sulfuric acid, dichloromethane, d) triethylamine, ethanol, e) 3,8-diazabicin B[3.2.1]octane-8-carboxylate t-butyl, N,N-diisopropylethyl Amine, N,N-dimethylformamide, f) Hydrogen chloride dioxane solution, g) (S)-3-(( t-Butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)propion Acid, diisopropylethylamine, 2-(7-benzotriazole oxide)-N,N,N', N'-Tetramethyluronium hexafluorophosphate, N,N-dimethylformamide h) SFC; i) Hydrogen chloride in dioxane.

[0284] a) N-(t-butyl)-6-chloro-5-iodopyrimidin-4-amine 4,6-Dichloro-5-iodopyrimidine (4.00 g) was dissolved in N,N-dimethylformamide ( 60 ml) and stirred at room temperature under a nitrogen gas atmosphere. The mixture was stirred at room temperature overnight, and then poured into water (300 mL) and ethyl acetate was added. The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave a pale yellow solid (4.1 g).

[0285] b) 2-(4-(t-butyl)-6-chloropyrimidin-5-yl)cyclopropyl formate R N-(t-butyl)-6-chloro-5-iodopyrimidin-4-amine (4.10 g) and 2- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane Ethyl 1-carboxylate (6.32 g) was dissolved in toluene (64.00 mL) and water (16.00 mL). Dissolve in 1.4 mL of tricyclohexylphosphine and 1.475 g of palladium acetate. The mixture was then heated at 90°C under a nitrogen gas atmosphere. The mixture was then cooled to room temperature, diluted with water (100 mL) and diluted with ethyl acetate (2× The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the product was purified by chromatography on silica gel plates (petroleum ether:acetic acid Ethyl acetate=10:1) to give 2.50 g of a dark yellow solid as the product.

[0286] c) 2-(4-amino-6-chloropyrimidin-5-yl)cyclopropylformate ethyl 2-(4-(t-butyl)-6-chloropyrimidine-5-acetate in dichloromethane (40.00 mL) 2.50 g of ethyl cyclopropyl formate was added to the reaction mixture at 0-5° C. under a nitrogen gas atmosphere. Sulfuric acid (4.94 g) was added dropwise. The reaction was stirred at room temperature for 1 hour and then cooled to 0° C. The mixture was neutralized to pH = 8 with saturated sodium bicarbonate solution. The organic phases were combined and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 2.4 g of a yellow liquid.

[0287] d) 1-chloro-7,7a-dihydro-5H-cyclopropane[4,5]pyridine [2,3- d]pyrimidin-6(6aH)-one At room temperature, under a nitrogen gas atmosphere, 2-(4-amino-6-chloropyrimidin-5-yl)cyclopentadiene Ethyl propylformate (2.40 g) and triethylamine (6.03 g) were dissolved in ethanol solution 2. 00.00 mL of 100 ml of water was added to the reaction mixture. The reaction mixture was stirred at 80° C. overnight. Then the mixture was allowed to warm to room temperature. It was cooled and concentrated in vacuo. The product was purified by chromatography on silica gel plates (petroleum ether:acetic acid Ethyl acetate=1:1) to give 1.05 g of a pale yellow solid as the product.

[0288] e) t-Butyl-3-(6-oxo-6,6a,7,7a-tetrahydro-5H-cyclopropane Pampyrido[4,5]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]o Citrate-8-carboxylate At 20°C, 1-chloro-7,7a-dihydro-5H-cyclopropane[4,5]pyridine[2 ,3-d]pyrimidin-6(6aH)-one (0.20 g) dissolved in N,N-dimethylformamide 3,8-Diazabicyclo[3.2.1]octane-8-carboxylic acid t- Butyl (0.43 g) and N,N-diisopropylethylamine (0.39 g) were added. The mixture was stirred at 110° C. for 24 h. The reaction mixture was then poured into water (100 mL) and further added with acetic acid. Ethyl acetate (100 mL) was added for extraction. The organic phase was washed with saturated saline (100 mL*3). The product was washed, dried over anhydrous sodium sulfate, and evaporated to dryness. The product was purified using a silica gel plate (petroleum ether:ethyl acetate=1:1) and obtained as a white solid. 0.30 g of the compound was obtained.

[0289] f) 1-3,8-diazabicyclo[3.2.1]octan-3-yl)-7,7-dihydro- 5H-Cyclopropane[4,5]pyrido[2,3-d]pyrimidin-6(6aH)-one t-Butyl-3-(6-oxo-6,6a,7,7a-tetrahydro-5H-cyclopentadiene) at 20°C Propane pyrido[4,5]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1 ] Octane-8-carboxylate (0.15 g) was added to 4 M hydrogen chloride dioxane solution ( 2 mL) was added. The reaction mixture was stirred at 20°C for 3 h. The reaction mixture was dried in an evaporator. This gave an off-white solid (0.12 g).

[0290] g) t-Butyl ((2R)-2-(4-chlorophenyl)-3-oxo-3-(6-oxo -6,6-a,7,7a-tetrahydro-5H-cyclopropyl-[4,5]pyridine poly[ 2,3-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Isopropyl propyl carbamate 1-3,8-diazabicyclo[3.2.1]octan-3-yl)-7,7-dihydrochloride at 20°C Doro-5H-cyclopropane[4,5]pyrido[2,3-d]pyrimidine-6(6aH)-o (S)-3-((t-butyl)benzenediamine (1.0 mL) was added to 0.12 g of benzenediamine (1.0 mL). (isopropyl)amino)-2-(4-chlorophenyl)propionic acid (0 0.18 g) and diisopropylethylamine (0.17 g) were added. The reaction mixture was stirred for 2 min. At 20°C, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyl Uronium hexafluorophosphate (0.20 g) was added and the reaction mixture was incubated at 20 °C for 1 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated saline (100 mL*3) and dried over anhydrous sodium sulfate. The product was purified by chromatography on silica gel plates (petroleum ether The mixture was purified with 1:1.5 dichloromethane and 1:2 ethyl acetate to give 0.20 g of a white solid as the product.

[0291] h) Optical splitting Equipment and conditions for optical resolution: Waters SFC200, column: Daicel C hiralcel AS, 250×50mm ID, 10μm, mobile phase: A is CO2 A is ethanol (0.1% NH3H2O), A:B = 60:40 (volume ratio), flow rate 6 0 mL / min, column temperature 38°C.

[0292] i) Preparation of Isomer 1 and Isomer 2 At 20°C, 4M hydrogen chloride in dioxane (1 mL) was added to isomer 1a (20 mg). The mixture was stirred at 20°C for 3 h. The reaction mixture was dried in an evaporator and isolated to obtain This gave an off-white solid (10 mg).

[0293] The method is the same as that of the opposite sex, the raw material of the opposite sex 2a is the same, and the preparation of the opposite sex 2a is the same. Isomerate 1: LCMS (ESI) m / z: 495 (M+H) 1 H NMR (400 MHz, DMSO -d6)δ8.69-8.59(m,1H),7.34-7.52(m,4H),5.39-5.5 3(m,1H),4.69-4.81(m,3H),4.52-4.67(m,1H),4.09-4 .38(m,2H),3.75-3.81(m,1H),3.64-3.73(m,2H),3.45 -3.53(m,2H),3.26-3.36(m,1H),2.95-3.06(m,1H),1. 96-2.07(m,1H),1.50-1.66(m,2H),1.21-1.30(m,8H), 1.01-1.11(m,1H),0.83-0.90(m,1H).

[0294] Isomerate 2: LCMS (ESI) m / z: 495 (M+H) 1 H NMR (400 MHz, DMSO -d6)δ10.43(d,J=15.9Hz,1H),8.20(d,J=26.6Hz,1H) ,7.37-7.51(m,4H),4.64-4.74(m,1H),4.46-4.61(m, 2H),4.19-4.23(m,2H),4.09-4.14(m,2H),3.67-3.73 (m,2H),3.56-3.62(m,2H),2.97-3.13(m,2H),2.17-2. 28(m,1H),1.96-2.10(m,2H),1.75-1.84(m,1H),1.62- 1.68(m,1H),1.20-1.30(m,6H),0.67-0.77(m,1H).

[0295] Example 40

change

[0296] Isomer 1: LCMS(ESI)m / z:469(M+H) 1 H NMR (400MHz, DMSO-d6) δ 10.49(s,1H),8.24(s,1H),7.34-7.52(m,4H),4.66-4. 74(m,1H),3.77-3.85(m,1H),3.60-3.73(m,4H),3.49- 3.51(m,1H),3.43-3.48(m,2H),3.24-3.35(m,2H),2.9 5-3.04(m,1H),2.80-2.92(m,1H),2.62-2.73(m,1H),2 .21-2.29(m,1H),2.01-2.11(m,1H),1.66-1.76(m,1H) ),1.21-1.27(m,6H),0.72(q,J=4.9Hz,1H).

[0297] Isomer 2: LCMS(ESI)m / z:469(M+H) 1 H NMR (400MHz, DMSO-d6) δ 10.48(s,1H),8.22(s,1H),7.33-7.57(m,4H),4.59-4. 68(m,1H),3.64-3.72(m,4H),3.45-3.53(m,3H),3.27- 3.36(m,2H),3.16-3.24(m,1H),3.04-3.12(m,1H),2.9 3-3.03(m,1H),2.17-2.28(m,1H),1.99-2.09(m,1H),1 .67-1.76(m,1H),1.19-1.31(m,6H),0.72(q,J=4.4Hz ,1H).

[0298] Experimental Example 1 In vitro enzyme activity test 1. Materials and Reagents Envision plate reader (Molecular Devices) White 384-well plate (product number #264706, Thermo) Main Reagents Included in HTRF kinEASE TK Reagent Kit (Product No. 62 TK OPEC, Cisbio) TK-Biotin Substrate Streptavidin-XL665 Europium-labeled tyrosine kinase substrate antibody 5x Enzyme Reaction Buffer SEB HTRF Testing Buffer AKT1 (Product number #01-101, Carna) AKT2 (Product number #01-102, Carna) AKT3 (Product No. PV3185, Invitrogen) ATP 10mM (Product No. PV3227, Invitrogen) DTT 1M (Product number #D5545, Sigma) MgCl21M (product number #M8266, Sigma) Compounds of the Invention Positive control: GDC-0068

[0299] 2. Experimental Procedure 2.1 Preparation of reagents Table 1. Components and concentrations in the kinase reaction system [Table 1] 1x Kinase Reaction Buffer 1 mL of 1x kinase reaction buffer for kinases AKT1, 2, 3, 5x kinase reaction buffer Contains 200μL, 25μL of 1M MgCl, 1μL of 1M DTT, and 794μL of ultrapure water. will be done.

[0300] 5x TK-Biotin Substrate and ATP Working Solution Specific concentrations of TK-biotin substrate and ATP are shown in Table 1.

[0301] Substrate and ATP were diluted to 5-fold the reaction concentration in 1x kinase reaction buffer.

[0302] 5x Kinase Working Solution The concentrations used for enzyme screening are shown in Table 1. x Enzyme working solution was prepared.

[0303] 4x Streptavidin-XL665 working solution The concentration of streptavidin-XL665 in the reaction is shown in Table 1. A 4x streptavidin-XL665 working solution was prepared using 100% ethanol.

[0304] 4x Europium-labeled tyrosine kinase substrate antibody working solution As the working solution, dilute europium-labeled tyrosine kinase substrate antibody at 10 0-fold diluted solution was used.

[0305] 2.2 Experimental scheme After preparing all the reagents using the above method, bring all the reagents except the enzyme to room temperature and start adding the sample. I did.

[0306] a) First, dilute the compound stock solution (10 mM DMSO solution) in DMSO to a concentration of 100 μM. Dilute compound solution and make 2.5 μM compound working solution in 1x kinase reaction buffer. The reaction mixture was diluted in 1x kinase reaction buffer (containing 2.5% DMSO). Prepare a DMSO solution and dilute the compound at 2.5 μM in 2.5% DMSO solution. The solution was diluted seven times in a 4-fold gradient to give a total of eight concentrations (2500 nM, 625 nM, 156nM, 39nM, 9.8nM, 2.4nM, 0.6nM, 0.15nM) A compound working solution was obtained. The diluted compound working solution was added to all reaction wells except the control wells. Add 4 μL of King's solution to the control wells, and add 4 μL of the prepared 2.5% DMSO / kinase buffer. μL was added.

[0307] b) 2 μL of the prepared TK-biotin substrate solution was added to all reaction wells (enzyme screening). The concentrations of the cleavage substrates are shown in Table 1).

[0308] c) Add 2 μL of the prepared enzyme solution to all reaction wells except the negative wells (enzyme concentration is Add 2 μL of the corresponding enzyme solution (shown in Table 1) to the negative wells in 1x kinase reaction buffer. The plate was sealed with a sealing film, mixed uniformly, and then stored at room temperature. The mixture was incubated for 10 minutes to allow the compound and the enzyme to bind sufficiently.

[0309] d) 2 μL of ATP solution was added to all reaction wells to start the kinase reaction (enzyme screening). The ATP concentrations and reaction times for the assay are shown in Table 1.

[0310] e) 5 minutes before the kinase reaction was completed, start preparing the test solution. Streptavidin-XL665 and europium-labeled tyrosine kinase substrate anti- The concentration of the enzyme screening test reagent is shown in Table 1. be).

[0311] f) After the kinase reaction is complete, add diluted streptavidin-X to all reaction wells. Add 5 μL of L665 and mix evenly. Immediately after, add diluted europium-labeled tyrosine kinase. A test solution containing enzyme substrate antibody was added.

[0312] g) The plate was sealed, mixed evenly, and incubated at room temperature for 1 h. The fluorescence signal was detected using a 320 nm excitation, 665 nm, 615 nm, and 100 nm excitation light sources. nm emission). Per well, total activity and background signal wells were Percent inhibition was calculated, averaged if multiple wells were tested, and plotted in a specialized plot. The median inhibitory activity of each compound was measured using the analytical software PRISM 6.0. The activity (IC50) was fitted. Table 2: Flow chart of sample addition for the experiment. [Table 2]

[0313] 2.3 Data analysis ER = 665 nm fluorescence value / 615 nm fluorescence value Inhibition rate=(ER 陽性対照 -ER サンプル ) / (ER 陽性対照 -ER 陰性対照 )*100% 3. Experimental Results The experimental results are shown in Table 3: Table 3: AKT inhibitory activity [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] Experimental Example 2: Pharmacokinetic evaluation Formulation preparation of isomer 4 compounds of Example 10, Example 21, GDC-0068, and Example 34: Mixture solvent: Tween 80: PEG 400: water = 1: 9: 90 (v / v / v) Compounds were prepared as 10 mg / mL stock solutions in DMSO.

[0314] Accurately draw up 400 μl of the 10 mg / mL stock solution into a glass bottle and mix. The ratio of the solvent in the final formulation was DMSO:mixed solvent (v / v) = 10: 90, and then uniformly dispersed by vortex (or ultrasonication) until the concentration of each compound reached 1 mg mL -1 Thus, 4 mL of a dosing solution was obtained.

[0315] Formulation preparation of isomer 2 compound of Example 15: Solvent: DMSO:PEG400:ultrapure water = 5:20:75 (v / v / v) In a glass bottle, 5.37 mg of the isomer 2 compound of Example 15 was weighed as a sample. Add 0.269 mL of MSO, vortex and completely dissolve the solids. Add 1.074 mL of 0, vortex, mix evenly, and add 4.028 mL of ultrapure water. Add the solution, vortex, and mix uniformly to a concentration of 1 mg mL -1 A colourless solution of

[0316] Experimental animals: Mouse, ICR strain, Vital River Laboratory Animals The animals were provided by al Technology Co., Ltd., and were male, aged 6 to 10 weeks. Experimental Design: Table 4: Animal experiment protocol [Table 4] The experimental animals were kept in the animal room of Shengsu New Drug Development Co., Ltd., Suzhou, China. The animal room was well ventilated. There was air conditioning to keep the temperature at 20-25°C and the humidity at 40%-70%. The light and dark conditions were 12 hours each, and the animals had free access to food and water. After keeping the mice for at least 5 days, mice in good physical condition as determined by a veterinarian were selected for the study. Each mouse was labeled by its tail number. Details of the animal experimental design are shown in Table 4.

[0317] After measuring the body weight, the theoretical administration volume for each mouse was calculated using the following formula:

number

[0318] On the day before the experiment, the mice were fasted overnight, allowed free access to water, and were fed 4 hours after administration. Ta.

[0319] On the day of the experiment, mice in groups A to E were given 10 mg kg -1 Example 10, Example 21, GDC- The administration solutions of Isomer 2 of Example 15 and Isomer 4 of Example 34 were administered orally by gavage. After administration, approximately 100 μL of blood was collected from the mouse via the orbit at each time point, and then EDTA- The whole blood samples were centrifuged at 5,500 rpm for 10 min and then separated into K2 anticoagulant tubes. The isolated plasma was stored in a refrigerator at -40 to -20°C and used for the analysis of biological samples. The LC-MS / MS analytical method for measuring the concentration of compounds in the plasma of mice was established. It was used to measure the concentration of compounds in the biological samples obtained. Pharmacokinetic parameters were calculated using a noncompartmental model in oenix 7.0.

[0320] Experimental Results: The experimental results are shown in Table 5: Table 5: Pharmacokinetic parameters of compounds of the invention [Table 5] NR: Not calculated

Claims

1. A compound of formula I or a pharma- ceutically acceptable salt thereof, [C130] Where: R １ H, OH, halogens, CN, NH ２ , NO ２ and optionally substituted with halogen or OH C1-C6 alkyl groups are selected from the group consisting of R ２ , R ３ are each independently H, a C1-C6 alkyl group, or a C3-C6 cycloalkyl group. Group, (C3-C6 cycloalkyl group)-(CH ２ )-, (C3-C6 cycloalkyl group)-(C H ２ CH ２ )-, benzyl group, phenethyl group, pyrrolidinyl group, tetrahydrofuranyl group and tetrahydropyranyl, wherein said C1-C6 alkyl group, C3-C6 cycloalkyl group, (C3-C6 cycloalkyl group)-(CH ２ )- or (C3- C6 cycloalkyl group)-(CH ２ CH ２ )- is optionally halogen, OH, CN, NH ２ also is substituted with a C1-C3 alkoxy group, and the benzyl or phenethyl group is optionally substituted with a halo Gen, OH, CN, NO ２ , N.H. ２ , C1-C3 alkoxy group, halogenated C1-C3 a substituted with an alkoxy group, a C1-C3 alkyl group or a halogenated C1-C3 alkyl group; The pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl group may optionally be halo. aryl, OH, a C1-C3 alkyl group, a cyclopropylmethyl group or a C1-C4 alkanoyl group substituted with a aryl group, Or R １ , R ２ and the atoms to which they are connected together form a 4-7 membered nitrogen-containing heterocycle death, m and n are each independently selected from the group consisting of 0, 1, 2 and 3, and preferably m is m is 0, 1 or 2, more preferably m is 0 or 1, more preferably m is 1. Preferably, n is 0, 1 or 2, more preferably, n is 0 or 1, and even more preferably More preferably, n is 0, R ４ , R ５ are all hydrogen, or R ４ , R ５ together form =O, preferably R ４ , R ５ together form =O, [C131] teeth: [C132] Selected from the group consisting of: R ６ , R ７ , R ８ , R ９ are each independently H, CN, a C1-C6 alkyl group, or a C1 -C6 alkoxy groups, wherein the C1-C6 alkyl group or the C1- The C6 alkoxy group is optionally substituted with halogen, OH, CN, or a C1-C3 alkoxy group. R, R １０ is selected from the group consisting of H and C1-C6 alkyl groups, the alkyl group is optionally substituted with halogen, OH, CN or a C1-C3 alkoxy group; L is an optionally substituted 5-12 membered saturated heterocycle containing 1-2 nitrogens; G is any 1-5 R １１ a 6-10 membered aryl group or a 5-10 membered heteroaryl group substituted with aryl group, R １１ are independently halogen, OH, CN, NH ２ , NO ２ , benzyloxy group, -N H(C1-C6 alkyl group), -N(C1-C6 alkyl group) ２ , -C(=O)NH ２ , -C( =O)NH(C1-C6 alkyl group), -C(=O)N(C1-C6 alkyl group) ２ , -SO ２ ( C1-C6 alkyl group), C1-C6 alkyl group and C1-C6 alkoxy group wherein the C1-C6 alkyl or C1-C6 alkoxy group is optionally selected from the group consisting of halo, is replaced by Gen, However, R １ , R ２ and the atoms to which they are connected together form a 4-7 membered nitrogen-containing heterocycle. In this case, R １ , R ２ None of them are H, Preferably, the compound has the structure shown in Formula II: [C133] Preferably, it has the structure shown in Formula III: [C134] More preferably, it has the structure shown in formula IV: [C135] More preferably, it has the structure shown in Formula V: [C136] More preferably, it has the structure shown in formula VI: [C137] wherein d is selected from the group consisting of 0, 1, 2 and 5, and preferably d is selected from the group consisting of 0, 1 and 2. More preferably, d is selected from the group consisting of 1 and 2. In most cases, d is 1, More preferably, it has the structure shown in Formula VII: [C138] wherein d is selected from the group consisting of 0, 1, 2 and 5, and preferably d is selected from the group consisting of 0, 1 and 2. More preferably, d is selected from the group consisting of 1 and 2. In most cases, d is 1, Preferably, the compound has the structure shown in Formula VIII: [C139] More preferably, it has the structure shown in formula IX: [C140] wherein d is selected from the group consisting of 0, 1, 2 and 5, and preferably d is selected from the group consisting of 0, 1 and 2. More preferably, d is selected from the group consisting of 1 and 2. In most cases, d is 1, Preferably, the compound has the structure shown in formula XI: [C141] More preferably, it has the structure shown in formula XII: [C142] wherein d is selected from the group consisting of 0, 1, 2 and 5, and preferably d is selected from the group consisting of 0, 1 and 2. More preferably, d is selected from the group consisting of 1 and 2. or a pharma- ceutically acceptable salt thereof, wherein d is 1.

2. R １ consists of H, OH and C1-C6 alkyl groups optionally substituted with halogen or OH Preferably, R １ H, OH, Me, CF ３ and C.H. ２ The group consisting of OH More preferably, R １is selected from the group consisting of H and OH, most preferably , R １ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein

3. R ２ and R ３ are each independently H, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, alkyl group, (C3-C6 cycloalkyl group)-(CH ２ )-, (C3-C6 cycloalkyl group)- (CH ２ CH ２ )-, benzyl group, phenethyl group, pyrrolidinyl group and tetrahydropyranyl group wherein the C1-C6 alkyl group, the C3-C6 cycloalkyl group, cycloalkyl group, (C3-C6 cycloalkyl group)-(CH ２ )- or (C3-C6 cycloalkyl group)- (CH ２ CH ２ )- is optionally F, Cl, Br, I, OH, CN, NH ２ Or C1-C3A The benzyl or phenethyl group is optionally substituted with F, Cl, Br, I ,OH,OMe,CF ３ or Me, and the pyrrolidinyl group or tetrahydropyridine group The yl group is optionally substituted with F, Cl, Br, I, OH, a C1-C3 alkyl group, a cyclopropyl group, substituted with a methyl group or a C1-C4 alkanoyl group; Preferably, R ２ and R ３ are each independently H, a methyl group, an ethyl group, or an isopropyl group. butyl group, isobutyl group, t-butyl group, 3-pentyl group, CH ２ O.H., C.H. ２ CH ２ O.H. CH ２ CH ２ OMe, CF ３ , C.H. ２ CF ３ , C.H. ２ CHF ２ , C.H. ２ CH ２ F, Cyclo Propyl group, cyclopentyl group, cyclohexyl group, cyclopropyl-(CH ２ )-, Shik pentyl-(CH ２ )-, cyclohexyl-(CH ２ )-, cyclopropyl-(CH ２ CH ２ )-, cyclopentyl-(CH ２ CH ２ )-, benzyl group, 4-fluorobenzyl group, 4 -chlorobenzyl group, 4-fluorophenethyl group, 4-chlorophenethyl group and tetrahydrofuran dropyran-4-yl group; More preferably, R ２ and R ３ are each independently H, a methyl group, an ethyl group, an isopropyl group, cyclopropyl group, cyclopropyl group, cyclohexyl group, cyclopropyl-(CH ２ )-, Cyclo Hexyl-(CH ２ )- and tetrahydropyran-4-yl groups; More preferably, R ２ and R ３ are each independently H, an isopropyl group, or a cyclopropyl group. is selected from the group consisting of aryl groups; More preferably, R ２ is H, More preferably, R ３ is an isopropyl group or a cyclopropyl group, Most preferably, R ２ is H and R ３ is an isopropyl group or a cyclopropyl group 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof.

4. R １ , R ２ and the atoms connected to them together form: [C143] , Preferably, R １ , R ２ and the atoms to which they are connected together form: [C144] 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

5.

145. teeth: [C146] Selected from the group consisting of: Preferably [C147] and More preferably, [C148] and Preferably, [C149] teeth, [C150] and R ４ and R ５ together form =O, Preferably, [C151] teeth, [C152] and R ４ and R ５ together form =O, Preferably, [C153] teeth, [C154] and R ４ and R ５together form =O, Preferably, [C155] teeth, [C156] and R ４ and R ５ together form =O, Preferably, [C157] teeth, [C158] and R ４ and R ５ are both H, Preferably, [C159] teeth, [C160] and R ４ and R ５ and together form =O, A physiologically acceptable salt.

6. R ６ , R ７ , R ８ , R ９ are each independently H, CN, a C1-C6 alkyl group, or C 1-C6 alkoxy groups, wherein the C1-C6 alkyl group or C1 the -C6 alkoxy group is optionally substituted with F, Cl, Br, I, OH, CN or OMe; Preferably, R ６ , R ７ , R ８ , R ９ are each independently H, CN, C1-C6 ar alkyl groups and C1-C6 alkoxy groups, wherein the C1-C6 alkyl groups are selected from the group consisting of a C1-C6 alkoxy group is optionally substituted with F, CN or OH; More preferably, R ６ , R ７ , R ８ , R ９ are each independently H, CN, a methyl group, Ethyl group, propyl group, isopropyl group, CF ３ , C.H. ２ CF ３ , C.H. ２ CHF ２ , C.H. ２ CH ２ F, C.H. ２ C.N., C.H. ２ CH ２ C.N., C.H. ２ O.H., C.H. ２ CH ２ OH, OMe, OEt, OCH ２ CH ２ CH ３ and isopropoxyl groups; More preferably, R ６ is H, CN, methyl group, ethyl group, propyl group, isopropyl group, CF ３ , C.H. ２ CF ３ , C.H. ２ CHF ２ , C.H. ２ CH ２ F, C.H. ２ C.N., C.H. ２ CH ２ C N, C.H. ２ O.H., C.H. ２ CH ２ OH, OMe, OEt, OCH ２ CH ２ CH ３ Or Isopro More preferably, R ６ H, CN, methyl group, ethyl group, isopropyl Pyridine group, CF ３ , C.H. ２ CH ２ OH, OMe or OEt, more preferably R ６ but H, CN, methyl group, CF ３or OMe, more preferably R ６ CN, methyl group , C.F. ３ or OMe, more preferably R ６ is H, CN or a methyl group, Preferably, R ６ H, CF ３ or a methyl group, and most preferably R ６ is a methyl group or is CF ３ and More preferably, R ７ is H, More preferably, R ８ is H, CN, methyl group, ethyl group, propyl group, isopropyl group, CF ３ , C.H. ２ CF ３ , C.H. ２ CHF ２ , C.H. ２ CH ２ F, C.H. ２ C.N., C.H. ２ CH ２ C N, C.H. ２ OH, CH ２ CH ２ OH, OMe, OEt, OCH ２ CH ２ CH ３ Or Isopro is a propyloxyl group, Preferably, R ８ H, CN, methyl group, ethyl group, isopropyl group, CF ３ , C.H. ２ C H ２ OH, OMe or OEt, more preferably R ８ is H, CN or a methyl group More preferably, R ８ is H or CN, more preferably R ８ is H or a methyl group and most preferably R ８ is H, More preferably, R ９is H, or a pharma- ceutically acceptable salt thereof. salt.

7. R １０ is selected from the group consisting of H and C1-C6 alkyl groups, The alkyl group is optionally substituted with halogen, OH or CN, preferably R １０ H, Meth ethyl group, propyl group, isopropyl group, CF ３ , C.H. ２ CF ３ , C.H. ２ CHF ２ , C.H. ２ CH ２ F, C.H. ２ C.N., C.H. ２ CH ２ C.N., C.H. ２ OH or CH ２ CH ２ In OH More preferably, R １０ is a methyl group, an ethyl group, an isopropyl group, or a CH ２ CF ３ , CH ２ CHF ２ , C.H. ２ CN or CH ２ CH ２ OH, more preferably R １０ GaMe Chil group, ethyl group, CH ２ CN or CH ２ CH ２ OH, more preferably R １０ but 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R is a methyl group.

8. L is optionally one or more R １２ is a group substituted with: [C161] where: the wavy line indicates where L is attached to the carbonyl group, and the double wavy line indicates where L is attached to the pyrimidine is the location where it connects to R １２ is halogen, OH, CN, vinyl group, C1-C6 alkyl group and C1-C6 alkoxy group. wherein said C1-C6 alkyl group or C1-C6 alkoxy group is selected from the group consisting of the oxy group is optionally substituted with halogen or OH; h is selected from the group consisting of 0, 1, 2, 3 and 4; j is selected from the group consisting of 0, 1, 2 and 3; k is selected from the group consisting of 1, 2, 3, and 4; q, s, v, and t are each independently selected from the group consisting of 0, 1, and 2; v and t cannot both be 0. p is selected from the group consisting of 0, 1, 2 and 3; e is selected from the group consisting of 0, 1 and 2; u is selected from the group consisting of 1, 2 and 3; W and Z are each independently selected from the group consisting of N and C, and at least One is N, Preferably, R １２ is F, Cl, Br, I, OH, CN, vinyl group, methyl group, ethyl group , propyl group, isopropyl group, CF ３ , C.H. ２ CF ３ , C.H. ２ CHF ２ , C.H. ２ CH ２ F, OMe, OEt, CH ２ O.H., C.H. ２ CH ２ O.H., O.C.H. ２ OH and OCH ２ CH ２ OH, more preferably R １２ Methyl, ethyl, and isopropyl groups CF ３ , C.H. ２ CF ３, OMe, OEt, CH ２ OH and OCH ２ The group consisting of OH More preferably, R １２ is a methyl group, an ethyl group, or a CF ３ Selected from the group consisting of Most preferably, R １２ is a methyl group, Preferably, h is 0, 1, 2 or 3 and j is 0, 1 or 2, preferably h is 0, 1 or 2 and j is 0 or 1, more preferably h is 0 or 1. and j is 0, most preferably h is 1 and j is 0; Preferably, k is 1, 2 or 3, more preferably, k is 1 or 3, and even more preferably where k is 1, Preferably, q, s, v, and t are each independently 0 or 1, and q, s, v, None of t is 0, and preferably, q, s, v, and t are all 1, and more preferably More preferably, q and s are both 0, and v and t are both 1. Preferably, q and s are both 1, and v and t are both 0. Most preferably, s , v are all 0, and q and t are all 1; Preferably, p is 0, 1 or 2, more preferably p is 0 or 2, more preferably p is 2, Preferably, e is 0 or 1 and u is 1 or 2, preferably, e is 0 or 1. and u is 1, more preferably e is 0 and u is 1; Preferably, W is C and Z is N, preferably W is N and Z is C. and more preferably, W and Z are both N. Pharmaceutically acceptable salts.

9. L is optionally one or more R １２ is a group substituted with: [C162] Preferably, L is optionally one or more of R １２ is a group substituted with: [C163] More preferably, L is the following group: [C164] Selected from the group consisting of: More preferably, L is the following group: [C165] Selected from the group consisting of: More preferably, L is the following group: [C166] 9. The compound of claim 8, selected from the group consisting of:

10. G is optionally 1-5 R １１ or optionally one or more R １１ a thienyl or pyridyl group substituted with Preferably, R １１ are independently F, Cl, Br, I, OH, CN, NH ２ , NO ２ , Be benzyloxy group, methyl group, ethyl group, isopropyl group, CH ２ CF ３ , C.F. ３ , S.M.E. , OMe, OCF ３ , OEt and isopropoxy groups, preferably R １１ are independently F, Cl, Br, CN, a benzyloxy group, a methyl group, an ethyl group, an i isopropyl group, CF ３ , OMe, SMe and OCF ３ More preferably, Kuha, R １１ are independently F, Cl and CF ３ and most preferably selected from the group consisting of: R １１ is Cl, Preferably, G is a phenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, 4-fluorophenyl, 4-bromophenyl, 4-methylphenyl group, 4-ethyl group, phenyl group, 4-isopropyl group, phenyl group, 4-trifluoromethyl Phenyl group, 4-cyanophenyl group, 4-methoxyphenyl group, 4-methylthiophenyl group 4-chloro-3-fluorophenyl group, 4-trifluoromethoxyphenyl group, 4-chloro-3-fluorophenyl group, , 4-difluorophenyl group, 2,4-dichlorophenyl group or 4-benzyloxyphenyl group G is preferably a 4-chlorophenyl group, a 4-chloro-3-fluorophenyl group, a phenyl group, a 4-trifluoromethyl group, a phenyl group, or a 3,4-difluorophenyl group. More preferably, G is a 4-chlorophenyl group; Preferably, G is a thienyl or pyridyl group optionally substituted with one or more halogens. and preferably G is a thienoic acid optionally substituted with one or more of F, Cl, Br or I. More preferably, G is: [C167] 2. The compound of claim 1, wherein:

11. The compound or a pharma- ceutically acceptable salt thereof, [C168] [C169] [C170] [C171] cis-(5R)-4-(5-((S)-2-(4-chlorophenyl)-3-(isopropylamino) hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-methyl 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one, or trans-(5R)-4-(5-((S)-2-(4-chlorophenyl)-3-(isopropyl Amino)propionyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5 -methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one, or a pharma- ceutically acceptable salt thereof.

12. The compound: [C172] A compound which is

13. A pharmaceutical comprising a compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof. A composition, preferably comprising a compound according to any one of claims 1 to 12. or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers. , pharmaceutical compositions.

14. Preventing and / or Treating Diseases or Conditions Mediated by AKT Protein Kinase A compound according to any one of claims 1 to 12 or a pharma- ceutical thereof in the preparation of a medicament.

14. The use of an acceptable salt or a pharmaceutical composition according to claim 13, preferably comprising The disease or condition is cancer, and more preferably, the disease or condition is breast cancer, prostate cancer, Adenocarcinoma or ovarian cancer, use.

15. A compound according to any one of claims 1 to 12 or a pharmaceutical composition thereof is administered to a subject in need of treatment. or the pharmaceutical composition of claim 13. Methods for preventing and / or treating diseases or disease states mediated by protein kinases. Preferably, the disease or disease state is cancer, and more preferably, the disease or disease state is The method, wherein the disease state is breast cancer, prostate cancer, or ovarian cancer.

16. Preventing and / or Treating Diseases or Conditions Mediated by AKT Protein Kinase A compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof for use in or a pharmaceutical composition according to claim 13, preferably wherein the disease or condition is and more preferably, the disease or condition is breast cancer, prostate cancer, or ovarian cancer. That's it.

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