WO2019196918A1 - Five-membered heterocyclo-pyrimidine compound, pharmaceutical composition and use thereof - Google Patents

Abstract

Disclosed are a five-membered heterocyclo-pyrimidine compound, a pharmaceutical composition comprising the compound and the use of the compound and the pharmaceutical composition for improving the activity of TLR ₇. The structure of the compound is as shown in the following formula (I), wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₉, X, Y, Z, A and B are as defined in the description herein. The compound or pharmaceutical composition of the present invention, as a TLR₇ agonist, can be used for treating diseases such as liver related diseases, tumors or AIDS.

Description

Five-membered heterocyclic pyrimidine compound, pharmaceutical composition and use thereof

The present application claims priority to Chinese Patent Application No. CN201810336351.8, filed on Apr. 13, 2018, and to the Chinese Patent Application No. CN 201811075655.X, filed on September 14, 2018. This application cites the entire text of the above-mentioned Chinese patent application.

Technical field

The present invention relates to a five-membered heterocyclic pyrimidine compound, a pharmaceutical composition containing the same, and the use of such a compound and a pharmaceutical composition for increasing the activity of TLR ₇ .

Background technique

Toll-like receptors (TLRs) are important protein molecules involved in non-specific immunity (innate immunity) and are also a bridge between non-specific immunity and specific immunity. TLR is a single transmembrane non-catalytic protein that recognizes molecules with conserved structures derived from microorganisms. When microorganisms break through the physical barriers of the body, such as skin, mucous membranes, etc., TLRs can recognize them and activate the body to produce immune cell responses. Toll-like receptors are expressed in a variety of immune cells. Toll-like receptors recognize highly conserved structural motifs: pathogen-associated microbial patterns (PAMP) expressed by microbial pathogens or damage-associated molecular patterns (DAMP) released by necrotic cells. Stimulation of Toll-like receptors by a corresponding pathogen-associated microbial pattern (PAMP) or damage-associated molecular pattern (DAMP) triggers a signal cascade leading to activation of transcription factors such as AP-1, NF-kB and interferon regulatory factors. This results in a variety of cellular responses, including the production of interferons, pro-inflammatory cytokines, and effector cytokines to produce an immune response. To date, 13 Toll-like receptors have been discovered in mammals. Toll-like receptors 1, 2, 4, 5, and 6 are mainly expressed on the cell surface, and Toll-like receptors 3, 7, 8, and 9 are expressed in endosomes. Different Toll-like receptors recognize ligands derived from different pathogens. For Toll-like receptor 7 (TLR7), it is mainly induced by plasmacytoid dendritic cell (pDC) expression and ligand recognition to induce secretion of interferon alpha (IFN-alpha). Toll-like receptor 7 (TLR ₇ ) and Toll-like receptor 8 (TLR ₈ ) are highly homologous. Thus the TLR ₇ ligand is in most cases also a TLR ₈ ligand. TLR ₈ stimulation primarily induces the production of cytokines such as tumor necrosis factor alpha (TNF-alpha) and chemokines. IFN-α is one of the main drugs for the treatment of chronic hepatitis B or hepatitis C, and TNF-α is a pro-inflammatory cytokine, and excessive secretion may cause serious side effects. Therefore, the development of highly selective TLR ₇ agonists for the treatment of diseases, including viral infectious diseases, has important clinical safety implications. TLR ₇ agonists have been reported in clinical development, such as imiquimod, resiquimod, GS-9620. According to reports, the side effects of these drugs are still relatively obvious in the clinic. Therefore, the development of novel TLR ₇ agonists with higher selectivity, better activity and safety is still of great clinical significance. We have discovered a series of novel 5-membered heterocyclic pyrimidine derivatives with high activity and high selectivity for TLR ₇ agonists.

Currently, several TLR ₇ agonists have entered clinical trials. Among them, Gilead has advanced the TLR ₇ agonist GS-9620 to clinical phase II for the treatment of chronic hepatitis B patients (D. Allen, et al, Allen, D. et al, WO 2016/044183). According to reports, clinical data show that GS-9620 has good clinical tolerance and safety, but did not significantly reduce HBeAg and HBsAg, and did not find a significant increase in the corresponding monoclonal antibody.

Through repeated studies, the applicant has discovered a novel class of TLR ₇ agonists, which have been shown to have higher TLR ₇ activity, better TLR ₈ selectivity, and higher animal liver enrichment. And better IFN-α-inducing activity of hPBMC. Therefore, these novel TLR ₇ agonists will show better anti-hepatitis B efficacy with better safety.

Summary of the invention

The present invention provides a five-membered heterocyclic pyrimidine compound represented by the formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, a polymorph, a tautomer thereof , isotope compounds, metabolites or prodrugs,

among them:

X is selected from O, S or NR ₈ ;

Y is selected from C or N; wherein

When Y is C, R _{1 is} selected from H, CN, CF ₃ , halogen, hydrocarbyl acyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or quaternary to VIII a heteroaryl group, wherein the hydrocarbyl acyl group, C ₁ -C ₃ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, quaternary to octagonal heteroaryl group are each optionally R ₁₀ a substituent wherein the hetero atom in the four- to eight-membered heteroaryl group is selected from O, N or S; preferably, R _{1 is} selected from the group consisting of CN, CF ₃ , fluorine, chlorine, formyl, acetyl;

When Y is N, R ₁ does not exist;

Z is selected from C, N or S; wherein

When Z is C, R _{2 is} selected from a hydrogen atom, a halogen or a C ₁ -C ₃ hydrocarbon group, preferably a hydrogen atom, a fluorine atom and a methyl group, wherein each of the C ₁ -C ₃ hydrocarbon groups is optionally substituted by R ₁₀ ;

When Z is N or S, R ₂ is absent; and when Z is N, Y is only N;

R ₃ is a C ₁ -C ₈ hydrocarbon group, preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5;

A group may or may not be present, when A group is absent, R ₃ and R _{5 are} directly linked together; when A group is present, it is selected from C _3-10 cycloalkyl, C _3-10 heterocycle Hydrocarbyl, aryl, heterocyclic aryl, bicyclo[2.2.1]heptane-1,4-, bicyclo[1.1.1]pentane-1,3- or 7-oxobicyclo[2.2.1]heptane- 1,4-, wherein the C _3-10 cycloalkyl, C _3-10 heterocycloalkyl, aryl, heterocyclic aryl, bicyclo [2.2.1] heptane-1,4-, bicyclo [1.1.1 ] pentane-1,3- or 7-oxobicyclo[2.2.1]heptane-1,4- are each optionally substituted by one or more R ₁₀ ; preferably, the A group is selected from phenyl, pyridine , furan, thiophene, pyrrole, cyclohexane, cyclopentane, cyclobutane or cyclopropane, and optionally substituted by one or more R ₁₀ ;

R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5;

-N (R ₆₎ R ₇ may be present or absent, when present, R ₆ and R ₇ are each independently selected from hydrogen or C ₁ -C ₈ hydrocarbon group, each optionally substituted with ₁₀ R; R ₆ and R ₇ may be bonded to form a four- to eight-membered ring structure by a C atom or a hetero atom, wherein the hetero atom is O, S or N; optionally, a ring formed by R ₆ and R ₇ may also be bonded to A. The groups are fused together; preferably, -N(R ₆ )R _{7 is} selected from -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R- Piperazine-1-; optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the A group; optionally One of R ₆ or R ₇ may form a covalent bond with A to form a ring;

R ₄ is absent or selected from a C ₁ -C ₈ alkyl group, a C ₂ -C ₈ alkenyl group or a C ₂ -C ₈ alkynyl group, wherein the C ₁ -C ₈ alkyl group, C ₂ -C ₈ alkenyl group Or C ₂ -C ₈ alkynyl are each optionally substituted by one or more R ₁₀ ; preferably, R ₄ is C _1-4 alkyl, each optionally substituted by R ₁₀ ; more preferably, R _{4 is} selected From -CH ₂ -, -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)--CH(CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)-, -CH(CH ₂ NR ₂ )-, -CH(CH ₂ CH ₂ NR ₂ )-;

R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R may be selected from H, C ₁ -C ₈ alkyl, C _3- C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, may also be substituted by =0, —OH, —NH ₂ , —SH;

When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached;

The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R ₁₀ Preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyran, ring Oxypropane, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more independently selected R ₁₀ ; R ₉ is absent or selected from C ₁ -C ₈ hydrocarbyl groups, preferably a C ₃ -C ₅ alkyl group; wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally substituted with OR ₈ , SR ₈ or N(R ₈ ) ₂ ;

R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ ;

Wherein the five-membered heterocyclic pyrimidine compound as shown in formula (I) is not:

6-butoxy-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

1-(4-(azetidin-1-ylmethyl)benzyl)-6-butoxy-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

6-butoxy-1-(4-(piperidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

6-butoxy-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

1-(3-(azetidin-1-ylmethyl)benzyl)-6-butoxy-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

6-butoxy-1-(3-(piperidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

6-(2-methoxyethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

6-((1-methoxypropan-2-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine;

6-butoxy-1-(3-fluoro-4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

N ⁶ -Butyl-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine.

According to one embodiment of the present invention, the five-membered heterocyclic pyrimidine compound represented by the formula (I) has a structure represented by the formula (I-1).

among them:

X is selected from O, S or NR ₈ ;

Y is selected from C or N;

When Y is C, R _{1 is} selected from H, CN, CF ₃ , halogen, hydrocarbyl acyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or quaternary to VIII a heteroaryl group, wherein the hydrocarbyl acyl group, C ₁ -C ₃ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group or a tetra- to 8-membered heteroaryl group is optionally substituted by R ₁₀ , preferably, R _{1 is} selected from the group consisting of CN, CF ₃ , fluorine, chlorine, bromine, formyl, acetyl; wherein the hetero atom in the four- to eight-membered heteroaryl is selected from O, N or S;

When Y is N, R ₁ does not exist;

R ₃ is a C ₁ -C ₈ hydrocarbon group, preferably -(CH ₂ ) n-; n is 1, 2, 3, 4 or 5;

A group may or may not be present, when A group is absent, R ₃ and R _{5 are} directly linked together; when A group is present, it is selected from C _3-10 cycloalkyl, C _3-10 heterocycle Hydrocarbyl, aryl, heterocyclic aryl, bicyclo[2.2.1]heptane-1,4-, bicyclo[1.1.1]pentane-1,3- or 7-oxobicyclo[2.2.1]heptane- 1,4-, wherein the C _3-10 cycloalkyl, C _3-10 heterocycloalkyl, aryl, heterocyclic aryl, bicyclo [2.2.1] heptane-1,4-, bicyclo [1.1.1 ] pentane-1,3-, 7-oxobicyclo[2.2.1]heptane-1,4- are each optionally substituted by one or more R ₁₀ ; preferably, the A group is selected from phenyl, pyridine , furan, thiophene, pyrrole, cyclohexane, cyclopentane, cyclobutane and cyclopropane, and optionally substituted by one or more R ₁₀ ;

R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5;

-N (R ₆₎ R ₇ may be present or absent; when it is present, R ₆ and R ₇ are each independently selected from hydrogen or C ₁ -C ₈ hydrocarbon group, each optionally substituted with ₁₀ R; R ₆ and R ₇ may be bonded to form a four- to eight-membered ring structure by a C atom or a hetero atom, wherein the hetero atom is O, S, N; optionally, a ring formed of R ₆ and R ₇ may also be bonded to A. The groups are fused together; preferably, -N(R ₆ )R _{7 is} selected from -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R- Piperazine-1-; optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the A group; optionally One of R ₆ or R ₇ may form a covalent bond with A to form a ring;

R ₄ is absent or selected from C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, wherein said C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl And a C ₂ -C ₈ alkynyl group is each optionally substituted by one or more R ₁₀ ; preferably, R ₄ is C _1-4 alkyl, optionally substituted by R ₁₀ ; more preferably, R _{4 is} selected from -CH ₂ -, -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH(CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)-, -CH(CH ₂ NR ₂ )-, -CH(CH ₂ CH ₂ NR ₂ )-;

R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ , wherein R may be selected from H, C ₁ -C ₈ alkyl, C _{3 a} C ₈ cycloalkyl group, a 3-8 membered heterocycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, which may also be substituted by =O, -OH, -NH ₂ or -SH;

When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached;

The B group is present or absent. When the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from C ₃ -C ₁₀ cyclic hydrocarbon group, C ₃ -C ₁₀ hetero a cycloalkyl, aryl, heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl, heteroaryl is optionally substituted by one or more R ₁₀ ; Preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyran, epoxy Propane, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more independently selected R ₁₀ ;

R ₉ is absent or selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally OR ₈ , SR ₈ , N(R ₈ ) ₂ substituted;

R _{8 is} selected from hydrogen, C ₁ -C ₃ hydrocarbyl, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ .

According to one embodiment of the present invention, the five-membered heterocyclic pyrimidine compound represented by the formula (I) has a structure represented by the formula (I-2),

among them:

X is selected from O, S or NR ₈ ;

R _{1 is} selected from the group consisting of H, CN, CF ₃ , halogen, hydrocarbyl acyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, quaternary to octagonal heteroaryl, wherein The hydrocarbyl acyl group, C ₁ -C ₃ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, tetra- to octa-heteroaryl group are optionally substituted by R ₁₀ , preferably, R ₁ Selected from CN, CF ₃ , fluorine, chlorine, bromine, formyl, acetyl;

R _{3 is} selected from a C ₁ -C ₈ hydrocarbon group, preferably -(CH ₂ )n-;

Wherein n is 1, 2, 3, 4 or 5;

A group may or may not be present, when A group is absent, R ₃ and R _{5 are} directly linked together; when A group is present, it is selected from C _3-10 cycloalkyl, C _3-10 heterocycle Hydrocarbyl, aryl, heterocyclic aryl, bicyclo[2.2.1]heptane-1,4-, bicyclo[1.1.1]pentane-1,3- or 7-oxobicyclo[2.2.1]heptane- 1,4-, wherein the C _3-10 cycloalkyl, C _3-10 heterocycloalkyl, aryl, heterocyclic aryl, bicyclo [2.2.1] heptane-1,4-, bicyclo [1.1.1 ] pentane-1,3- or 7-oxobicyclo[2.2.1]heptane-1,4- are each optionally substituted by one or more R ₁₀ ; preferably, the A group is selected from phenyl, pyridine , furan, thiophene, pyrrole, cyclohexane, cyclopentane, cyclobutane and cyclopropane, and optionally substituted by one or more R ₁₀ ;

R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5;

-N (R ₆₎ R ₇ may be present or absent, when present, R ₆ and R ₇ are each independently selected from hydrogen or C ₁ -C ₈ hydrocarbon group, each optionally substituted with ₁₀ R; R ₆ and R ₇ may be bonded to form a four- to eight-membered ring structure by a C atom or a hetero atom, wherein the hetero atom is O, S, N; optionally, a ring formed of R ₆ and R ₇ may also be bonded to A. The groups are fused together; preferably, -N(R ₆ )R _{7 is} selected from -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R- Piperazine-1-; optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the A group; optionally One of R ₆ or R ₇ may form a covalent bond with A to form a ring;

R _{4 is} selected from C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, wherein said C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ - The C ₈ alkynyl group is optionally substituted by one or more R ₁₀ ; preferably, R ₄ is C _1-4 alkyl, each optionally substituted by R ₁₀ ; more preferably, R _{4 is} selected from -CH ₂ - , -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH(CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)- , -CH(CH ₂ NR ₂ )- or -CH(CH ₂ CH ₂ NR ₂ )-;

R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R may be selected from H, C ₁ -C ₈ alkyl, C _3- C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, may also be substituted by =0, —OH, —NH ₂ , —SH;

When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached;

The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl or heteroaryl is optionally independently selected by one or more R _{10 is} substituted; preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydrogen Pyran, propylene oxide, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted with one or more independently selected R ₁₀ ;

R ₉ is absent or selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally OR ₈ , SR ₈ , N(R ₈ ) ₂ substituted;

R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ .

According to one embodiment of the present invention, the five-membered heterocyclic pyrimidine compound represented by the formula (I) has a structure represented by the formula (I-3).

among them:

X is selected from O, S or NR ₈ ;

R _{3 is} selected from a C ₁ -C ₈ hydrocarbon group, preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5;

A group may or may not be present, when A group is absent, R ₃ and R _{5 are} directly linked together; when A group is present, it is selected from C _3-10 cycloalkyl, C _3-10 heterocycle Hydrocarbyl, aryl, heterocyclic aryl, bicyclo[2.2.1]heptane-1,4-, bicyclo[1.1.1]pentane-1,3- or 7-oxobicyclo[2.2.1]heptane- 1,4-, wherein the C _3-10 cycloalkyl, C _3-10 heterocycloalkyl, aryl, heterocyclic aryl, bicyclo [2.2.1] heptane-1,4-, bicyclo [1.1.1 ] pentane-1,3-, 7-oxobicyclo[2.2.1]heptane-1,4- is optionally substituted by one or more R ₁₀ ; preferably, the A group is selected from phenyl, pyridine, Furan, thiophene, pyrrole, cyclohexane, cyclopentane, cyclobutane and cyclopropane, and optionally substituted by one or more R ₁₀ ;

R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5;

-N (R ₆₎ R ₇ may be present or absent, when present, R ₆ and R ₇ are each independently selected from hydrogen or C ₁ -C ₈ hydrocarbon group, each optionally substituted with ₁₀ R; R ₆ and R ₇ may be bonded to form a four- to eight-membered ring structure through a C atom or a hetero atom, wherein the hetero atom is O, S, N; a ring formed by R ₆ and R ₇ may also be fused to the A group. Together; preferably, -N(R ₆ )R _{7 is} selected from -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R-piperazine-1 One of R ₆ or R ₇ may form a ring with R _{5 , and the} ring formed by R ₆ or R ₇ and R ₅ may be fused to the A group; optionally, in R ₆ or R ₇ One can form a covalent bond with A to form a ring;

R ₄ is absent or selected from a C ₁ -C ₈ linear hydrocarbon group, each of which is optionally substituted by one or more R ₁₀ ; preferably, R ₄ is a C _1-4 linear alkyl group, optionally R _{10 is} substituted; more preferably, R _{4 is} selected from -CH ₂ -, -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH ( CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)-, -CH(CH ₂ NR ₂ )- or -CH(CH ₂ CH ₂ NR ₂ )-;

R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R may be selected from H, C ₁ -C ₈ alkyl, C _3- C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, may also be substituted by =0, —OH, —NH ₂ , —SH;

When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached;

The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R ₁₀ Preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyran, ring Oxypropane, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more R ₁₀ ; when the B group is selected from a C ₃ -C ₁₀ cycloalkyl or aryl group, wherein C ₃ -C ₁₀ cycloalkyl, aryl optionally substituted by one or more R ₁₀ wherein R ₁₀ selected or contains a hydrogen atom, or the group necessarily contains one or more heteroatoms; preferably, B The group is selected from the group consisting of phenyl, cyclohexane, cyclopentane, cyclobutane and cyclopropane, the selected group of which may be substituted by one or more independently selected R ₁₀ , wherein R _{10 is} selected or included Hydrogen atom, or Group must contain one or more hetero atoms.

When a B group is present, R ₉ is absent; when the B group is absent, R _{9 is} selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group Or C ₃ -C ₅ alkyl is optionally substituted by SR ₈ or N(R ₈ ) ₂ ; when R ₉ is methyl, R ₄ is not -CH(CH ₂ OCH ₃ )-;

R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more R ₁₀ ;

Wherein, when the -R ₄ -BR ₉ moiety is a butyl group, the A group is not a benzene ring, or -N(R ₆ )R _{7 is} present and one of R ₆ or R ₇ forms a ring with R ₅ and is R ₆ Or the ring formed by R ₇ and R ₅ is fused to the A group.

According to one embodiment of the present invention, the five-membered heterocyclic pyrimidine compound represented by the formula (I) has a structure represented by the formula (I-4).

among them:

R _{1 is} selected from H, CN, CF ₃ , halogen, hydrocarbyl acyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or quaternary to octagonal heteroaryl, wherein The hydrocarbyl acyl group, C ₁ -C ₃ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group or tetra- to 8-membered heteroaryl group is optionally substituted by R ₁₀ , preferably, R ₁ Selected from CN, CF ₃ , fluorine, chlorine, bromine, formyl, acetyl;

X is selected from O, S or NR ₈ ;

R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5;

-N (R ₆₎ R ₇ may be present or absent, when present, R ₆ and R ₇ are each independently selected from hydrogen or C ₁ -C ₈ hydrocarbon group, each optionally substituted with ₁₀ R; R ₆ and R ₇ may be bonded to form a four- to eight-membered ring structure through a C atom or a hetero atom, wherein the hetero atom is O, S, N; a ring formed by R ₆ and R ₇ may also be fused with a benzene ring. Together; preferably, -N(R ₆ )R _{7 is} selected from -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R-piperazin-1- Optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the phenyl ring; optionally, R ₆ or R ₇ One of them may form a ring by forming a covalent bond with the benzene ring;

R _{4 is} selected from C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, wherein said C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ - The C ₈ alkynyl groups are each optionally substituted by one or more R ₁₀ ; preferably, R ₄ is C _1-4 alkyl, optionally substituted by R ₁₀ ; more preferably, R _{4 is} selected from -CH ₂ - , -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH(CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)- , -CH(CH ₂ NR ₂ )-, -CH(CH ₂ CH ₂ NR ₂ )-;

R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R may be selected from H, C ₁ -C ₈ alkyl, C _3- C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, which may also be substituted by =0, —OH, —NH ₂ , —SH;

When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached;

The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl, heterocyclic aryl are optionally independently selected by one or more R _{10 is} substituted; preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydrogen Pyran, propylene oxide, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more R ₁₀ ;

R ₉ is absent or selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally OR ₈ , SR ₈ Or N(R ₈ ) ₂ substituted;

R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ .

According to one embodiment of the present invention, the five-membered heterocyclic pyrimidine compound represented by the formula (I) has a structure represented by the formula (I-5).

among them:

X is selected from O, S or NR ₈ ;

R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) _n -; wherein n is 1, 2, 3, 4 or 5;

-N (R ₆₎ R ₇ may be present or absent, when present, R ₆ and R ₇ are each independently selected from hydrogen or C ₁ -C ₈ hydrocarbon group, each optionally substituted with ₁₀ R; R ₆ and R ₇ may be bonded to form a four- to eight-membered ring structure through a C atom or a hetero atom, wherein the hetero atom is O, S, N; a ring formed by R ₆ and R ₇ may also be fused with a benzene ring. Together; preferably, -N(R ₆ )R _{7 is} selected from -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R-piperazin-1- Optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the phenyl ring; optionally, R ₆ or R ₇ One of them may form a ring by forming a covalent bond with the benzene ring;

R ₄ is absent or selected from a C ₁ -C ₈ linear hydrocarbon group, each of which is optionally substituted by one or more R ₁₀ ; preferably, R ₄ is a C _1-4 linear alkyl group, optionally R _{10 is} substituted; more preferably, R _{4 is} selected from -CH ₂ -, -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH ( CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)-, -CH(CH ₂ NR ₂ )- or -CH(CH ₂ CH ₂ NR ₂ )-;

R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R is selected from H, C ₁ -C ₈ alkyl, C _{3 a} C ₈ cycloalkyl group, a 3-8 membered heterocycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, which may also be substituted by =O, -OH, -NH ₂ or -SH;

When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached;

The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R ₁₀ Preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyran, ring Oxypropane, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more R ₁₀ ; when the B group is selected from a C ₃ -C ₁₀ cycloalkyl or aryl group, wherein C ₃ -C ₁₀ cycloalkyl, aryl optionally substituted by one or more R ₁₀ wherein R ₁₀ selected or contains a hydrogen atom, or the group necessarily contains one or more heteroatoms; preferably, B The group is selected from the group consisting of phenyl, cyclohexane, cyclopentane, cyclobutane and cyclopropane, the selected group of which may be substituted by one or more independently selected R ₁₀ , wherein R _{10 is} selected or included Hydrogen atom, or Group must contain one or more hetero atoms.

When a B group is present, R ₉ is absent; when the B group is absent, R _{9 is} selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group Or C ₃ -C ₅ alkyl optionally substituted by SR ₈ or N(R ₈ ) ₂ ; when R ₉ is methyl, R ₄ is not -CH(CH ₂ OCH ₃ )-;

R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ ;

Wherein, when the -R ₄ -BR ₉ moiety is a butyl group, the A group is not a benzene ring, or -N(R ₆ )R _{7 is} present and one of R ₆ or R ₇ forms a ring with R ₅ and is R ₆ Or the ring formed by R ₇ and R ₅ is fused to the A group.

According to one embodiment of the present invention, the five-membered heterocyclic pyrimidine compound represented by the formula (I) has a structure represented by the formula (I-6).

among them:

R _{1 is} selected from the group consisting of H, CN, CF ₃ , halogen, hydrocarbyl acyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, quaternary to octagonal heteroaryl, wherein The hydrocarbyl acyl group, C ₁ -C ₃ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, quaternary to octagonal heteroaryl group are each optionally substituted by R ₁₀ , preferably, R _{1 is} selected from the group consisting of CN, CF ₃ , fluorine, chlorine, bromine, formyl or acetyl;

X is selected from O, S or NR ₈ ;

R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5;

-N(R ₆ )R ₇ may or may not be present, and when present, R ₆ and R ₇ are each independently selected from hydrogen or a C ₁ -C ₈ hydrocarbyl group, optionally substituted by R ₁₀ ; R ₆ and R ₇ may be bonded through a C atom or a hetero atom to form a four- to eight-membered ring structure, wherein the hetero atom is O, S, N; a ring formed by R ₆ and R ₇ may also be fused with a benzene ring. Preferably, -N(R ₆ )R _{7 is} selected from -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1- or 4-R-piperazine-1-; Optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the phenyl ring; optionally, R ₆ or R ₇ One of which can form a ring by forming a covalent bond with the benzene ring;

R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; R may be selected from H, C ₁ -C ₈ alkyl, C _{3 a} C ₈ cycloalkyl group, a 3-8 membered heterocycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, which may also be substituted by =O, -OH, -NH ₂ or -SH;

When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached;

The B group may or may not be present. When the B group is absent, R ₉ and the adjacent group are directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cyclic hydrocarbon group, C ₃ a C ₁₀ Heterocyclic hydrocarbon group, an aryl group or a heterocyclic aryl group, wherein the C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ heterocycloalkylene group, aryl group or heterocyclic aryl group is optionally one or more R _{10 is} substituted; preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyridinium Methane, propylene oxide, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more independently selected R ₁₀ ;

R ₉ is absent or selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally OR ₈ , SR ₈ Or N(R ₈ ) ₂ substituted;

R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ .

According to one embodiment of the present invention, the five-membered heterocyclic pyrimidine compound represented by the formula (I) has a structure represented by the formula (I-7).

among them:

X is selected from O, S or NR ₈ ;

R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5;

-N(R ₆ )R ₇ may or may not be present, and when present, R ₆ and R ₇ are each independently selected from hydrogen or a C ₁ -C ₈ hydrocarbyl group, optionally substituted by R ₁₀ ; R ₆ and R ₇ may be formed by a C atom or a hetero atom to form a four- to eight-membered ring, wherein the hetero atom is O, S or N; a ring formed by R ₆ and R ₇ may also be fused with a benzene ring. Preferably, -N(R ₆ )R _{7 is} selected from the group consisting of -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R-piperazine-1-; Optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the phenyl ring; optionally, R ₆ or R ₇ One of which can form a ring by forming a covalent bond with the benzene ring;

R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R is selected from H, C ₁ -C ₈ alkyl, C _{3 a} C ₈ cycloalkyl group, a 3-8 membered heterocycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, which may also be substituted by =O, -OH, -NH ₂ or -SH;

When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached;

The B group may or may not be present. When the B group is absent, R ₉ and the adjacent group are directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cyclic hydrocarbon group, C ₃ a C ₁₀ Heterocyclic hydrocarbon group, an aryl group or a heterocyclic aryl group, wherein the C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ heterocycloalkylene group, aryl group or heterocyclic aryl group is optionally one or more R _{10 is} substituted; preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyridinium , propylene oxide, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more independently selected R ₁₀ ; when the B group is selected from a C ₃ -C ₁₀ cycloalkyl group Or an aryl group, wherein the C ₃ -C ₁₀ cycloalkyl group, aryl group is optionally substituted by one or more R ₁₀ groups, wherein the R ₁₀ selected group or contains a hydrogen atom, or the group necessarily contains one or more a hetero atom; preferably, the B group is selected from the group consisting of phenyl, cyclohexane, cyclopentane, cyclobutane and cyclopropane, the selected group of which may be substituted by one or more independently selected R ₁₀ , wherein R ₁₀ Group or a hydrogen atom, or a group containing one or more heteroatoms certain atoms.

When a B group is present, R ₉ is absent; when the B group is absent, R _{9 is} selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group Or a C ₃ -C ₅ alkyl group is optionally substituted by OR ₈ , SR ₈ , N(R ₈ ) ₂ ;

R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more R ₁₀ .

According to one embodiment of the present invention, the five-membered heterocyclic pyrimidine compound represented by the formula (I) has a structure represented by the formula (I-8).

among them:

R _{1 is} selected from H, CN, CF ₃ , halogen, hydrocarbyl acyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or quaternary to octagonal heteroaryl, wherein The hydrocarbyl acyl group, C ₁ -C ₃ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group or tetra- to 8-membered heteroaryl group is optionally substituted by R ₁₀ , preferably, R ₁ Selected from CN, CF ₃ , fluorine, chlorine, bromine, formyl, acetyl;

X is selected from O, S or NR ₈ ;

R _{6 is} selected from hydrogen or a C ₁ -C ₈ hydrocarbyl group, wherein the C ₁ -C ₈ hydrocarbyl group is optionally substituted with R ₁₀ ;

R _{4 is} selected from C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, wherein said C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ - The C ₈ alkynyl groups are each optionally substituted by one or more R ₁₀ ; preferably, R ₄ is C _1-4 alkyl, optionally substituted by R ₁₀ ; more preferably, R _{4 is} selected from -CH ₂ - , -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH(CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)- , -CH(CH ₂ NR ₂ )-, -CH(CH ₂ CH ₂ NR ₂ )-;

R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R may be selected from H, C ₁ -C ₈ alkyl, C _3- C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, which may also be substituted by =0, —OH, —NH ₂ , —SH;

When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached;

The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl, heterocyclic aryl are optionally independently selected by one or more R _{10 is} substituted; preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydrogen Pyran, propylene oxide, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more R ₁₀ ;

R ₉ is absent or selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally OR ₈ , SR ₈ Or N(R ₈ ) ₂ substituted;

R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ .

According to one embodiment of the present invention, the five-membered heterocyclic pyrimidine compound represented by the formula (I) has a structure represented by the formula (I-9).

among them:

X is selected from O, S or NR ₈ ;

R _{6 is} selected from hydrogen or a C ₁ -C ₈ hydrocarbyl group, wherein the C ₁ -C ₈ hydrocarbyl group is optionally substituted with R ₁₀ ;

R _{4 is} selected from C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, wherein said C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ - The C ₈ alkynyl groups are each optionally substituted by one or more R ₁₀ ; preferably, R ₄ is C _1-4 alkyl, optionally substituted by R ₁₀ ; more preferably, R _{4 is} selected from -CH ₂ - , -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH(CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)- , -CH(CH ₂ NR ₂ )- or -CH(CH ₂ CH ₂ NR ₂ )-;

R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R is selected from H, C ₁ -C ₈ alkyl, C _{3 a} C ₈ cycloalkyl group, a 3-8 membered heterocycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, which may also be substituted by =O, -OH, -NH ₂ or -SH;

When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached;

The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R ₁₀ Preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyran, ring Oxypropane, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more R ₁₀ ;

R ₉ is absent or selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally OR ₈ , SR ₈ or N(R ₈ ) ₂ substituted;

R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ .

Herein, in the compounds of the above formula I and formula I-1 to formula I-7, when the A group or the B group is a cyclic structure, unless otherwise specified or structurally undefined. The linking sites of R3 and R5 with the A group and the R4 and R9 and B groups may be any suitable sites.

According to an embodiment of the present invention, the five-membered heterocyclic pyrimidine compound represented by the formula (I) is selected from the group consisting of:

2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

(S)-1-(4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yloxy) -2-ol,

(S)-2-(4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yloxy) -1-ol,

7-(4-(Pyrrolidin-1-ylmethyl)benzyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)-7H-pyrrolo[2,3-d Pyrimidine-4-amine,

2-butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

4-amino-2-butoxy-N-methyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-A Amide,

2-(cyclopentylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

2-(pyridin-3-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

(S)-2-(2-pentyloxy)-7-(4-(pyrrolidin-1-methyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

(R)-2-(2-pentyloxy)-7-(4-(pyrrolidin-1-methyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)-7H-pyrrolo[2 ,3-d]pyrimidine-6-carbonitrile,

2-butoxy-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

2-butoxy-6-methyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

Methyl 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate,

4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-carboxaldehyde,

2-butoxy-6-(ethoxymethyl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4- amine,

1-(4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)B 1-ketone,

2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine ,

2-butoxy-6-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

4-amino-2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6 -carbonitrile,

1-((4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)oxy)butane-2 -alcohol,

2-((4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)oxy)butane-1 -alcohol,

2-(oxetan-3-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -amine,

6-((4,4-Difluorocyclohexyl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine 4-amine,

6-butoxy-1-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine,

(4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol,

4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6 -carbonitrile,

1-((4-Methylenecyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-((2-Methylpyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine,

1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-((2-(trifluoromethyl)pyridin-4-yl)methoxy)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine,

6-(2-methoxypyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine,

1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(thiazol-5-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

(S)-6-(pent-2-yloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine,

(R)-6-(pent-2-yloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine,

1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazolo[3,4- d]pyrimidine-4-amine,

6-(pyridin-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexyl- 1-alcohol,

1-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexyl- 3-alcohol,

6-(pyridin-4-ylmethoxy)-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-(1-(pyridin-4-yl)butoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine,

(R)-3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hexa-1-ol,

(S)-3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hexa-1-ol,

2-butoxy-6-(5-methylthiazol-2-yl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-amine,

6-((1-methoxypent-2-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine,

6-((2-Methoxypentyl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine,

4-amino-7-(4-(piperidin-1-ylmethyl)benzyl)-2-(pyridin-4-ylmethoxy)-7H-pyrrolo[2,3-d]pyrimidine-6 -carbonitrile,

1-benzyl-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-(pyridin-4-ylmethoxy)-1-(5-(pyrrolidin-1-yl)pentyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

4-amino-2-((2-methoxypyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2, 3-d]pyrimidine-6-carbonitrile,

(S)-4-amino-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile,

(R)-4-amino-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile,

6-(pyridin-2-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-(isoxazol-3-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4- amine,

6-(pent-2-yloxy)-1-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine,

3-(4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yloxy)pent-1- alcohol,

6-(pyridin-4-ylmethoxy)-1-((cis-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3,4-d Pyrimidine-4-amine,

(S)-4-amino-2-((1-hydroxyhex-3-yl)oxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2 ,3-d]pyrimidine-6-carbonitrile,

(R)-4-amino-2-(1-hydroxyhex-3-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3 -d]pyrimidine-6-carbonitrile,

6-(pyridin-4-ylmethoxy)-1-(7-(pyrrolidin-1-yl)heptyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-((2-Methylpyridin-4-yl)methoxy)-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-(Pyridin-4-ylmethoxy)-1-(trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine,

6-(4-Fluoro-3-methoxybenzyloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine,

(S)-4-Amino-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile,

(R)-4-amino-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile,

6-((5-Methylisoxazol-3-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d]pyrimidine-4-amine,

6-butoxy-1-(isoindoline-5-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-((2-Methylpyridin-4-yl)methoxy)-1-(pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-butoxy-1-((2-isopropylisoindoline-5-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

(S)-2-(1-(Pyridin-4-yl)butoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H -pyrrolo[2,3-d]pyrimidin-4-amine,

(R)-2-(1-(pyridin-4-yl)butoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H -pyrrolo[2,3-d]pyrimidin-4-amine,

7-(4-(Pyrrolidin-1-ylmethyl)benzyl)-2-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)-7H-pyrrolo[2,3 -d]pyrimidine-4-amine,

(R)-6-((1-(Dimethylamino)hex-3-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole [3,4-d]pyrimidine-4-amine,

4-amino-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-7H-pyrrolo[2,3- d] pyrimidine-6-carbonitrile,

6-butoxy-1-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-butoxy-1-((2-(pyrrolidin-1-ylmethyl)pyridin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-((2-(Dimethylamino)pyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine,

4-amino-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-7H-pyrrolo[2,3 -d]pyrimidine-6-carbonitrile,

(R)-3-((4-Amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hexa-1-ol,

(R)-1-((4-amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hex-3-ol,

1-benzyl-6-((2-(methylamino)pyridin-4-yl)methoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

(S)-3-((4-Amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hexa-1-ol,

(S)-1-((4-amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hex-3-ol,

6-((4-Fluorobenzyl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine ,

1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-((tetrahydrofuran-3-yl)methoxy)-1H-pyrazolo[3,4-d]pyrimidine-4- amine,

6-((3-oxabicyclo[3.1.0]hex-6-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole [3,4-d]pyrimidine-4-amine,

(R)-6-((1-methoxyhex-3-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine,

2-butoxy-7-(4-(1-methylpiperidin-4-yl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

6-butoxy-1-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine 4-amine,

6-((2-Methylpyridin-4-yl)methoxy)-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine,

4-amino-2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile,

4-amino-2-((4,4-difluorocyclohexyl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl-7H-pyrrolo[2,3-d Pyrimidine-6-carbonitrile,

4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((2-(trifluoromethyl)pyridin-4-yl)methoxy)-7H-pyrrole [2,3-d]pyrimidine-6-carbonitrile,

6-Chloro-2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -amine,

4-amino-2-((2-methylpyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3 -d]pyrimidine-6-carbonitrile,

6-((5-Methylisoxazol-3-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d] pyrimidine-4-amine

2-(4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yloxy)pent-1- alcohol,

1-(4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yloxy)pent-2- alcohol,

1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(1-(thiazol-5-yl)butoxy)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine,

4-amino-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-2-(pyridin-4-ylmethoxy)-7H -pyrrolo[2,3-d]pyrimidine-6-carbonitrile,

6-((2-(Methylamino)pyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine,

N-(3-((4-Amino-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzyl)acetamide ,

4-amino-2-((4-fluorocyclohexyl-3-en-1-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole [2,3-d]pyrimidine-6-carbonitrile,

4-amino-2-(pyridin-4-ylmethoxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6 -carbonitrile,

(S)-6-(1-phenylbutoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine,

(R)-6-(1-phenylbutoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine,

1-(cyclohexylmethyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

6-(pyridin-4-ylmethoxy)-1-(6-(pyrrolidin-1-yl)hexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

(S)-4-amino-2-(3-hydroxyhexyloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine -6-carbonitrile,

(R)-4-amino-2-(3-hydroxyhexyloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine -6-carbonitrile,

(R)-3-((4-amino-1-((4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d] Pyrimidin-6-yl)oxy)hexan-1-ol,

1-((4-((3,3-Difluoropyrrolidin-1-yl)methyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[ 3,4-d]pyrimidine-4-amine,

6-(pyridin-4-ylmethoxy)-1-(8-(pyrrolidin-1-yl)octyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

(S)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)-1H-pyrazole And [3,4-d]pyrimidine-4-amine,

1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(tetrahydro-2H-pyran-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine 4-amine,

6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-methyl formate,

(R)-6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d]pyrimidine-4-carboxylic acid methyl ester,

(S)-6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d] Methyl pyrimidine-4-carboxylate.

Another aspect of the present invention provides a pharmaceutical composition comprising, as described above, Formula (I) (preferably Formula (I-1), Formula (I-2), Formula (I-3), Formula (I) -4), a 5-membered heterocyclic pyrimidine of the formula (I-5), the formula (I-6), the formula (I-7), the formula (I-8), or the formula (I-9)) A compound, a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope compound, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention may further comprise other pharmaceutically active ingredients, preferably a PD-1 antibody, a PD-L1 antibody or a PD-1 inhibitor, a PD-L1 inhibitor or a PD- 1/PD-L1 inhibitor.

Another aspect of the present invention provides a formula (I) as described above (preferably, formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula ( I-5), a five-membered heterocyclic pyrimidine compound represented by formula (I-6), formula (I-7), formula (I-8), or formula (I-9)), which is pharmaceutically acceptable Accepted salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites or prodrugs, or pharmaceutical compositions as described above, in the preparation of TLR ₇ receptor agonists use.

Another aspect of the present invention provides the above formula (I) (preferably formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5) a five-membered heterocyclic pyrimidine compound represented by formula (I-6), formula (I-7), formula (I-8), or formula (I-9)), or a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, isotope compound, metabolite or prodrug thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention, treatment and/or prevention of a disease use. The disease is a related disease that is treated by activating the TLR ₇ receptor to enhance immunity. In some embodiments, the disease is selected from a liver related disease, a tumor, or an AIDS.

Wherein, the liver related diseases are selected from the group consisting of viral hepatitis, autoimmune liver disease, drug-induced liver disease, liver disease liver damage, liver functional failure, chronic severe hepatitis, liver cirrhosis, liver abscess, fatty liver, primary liver cancer, Preferably, the liver related diseases are hepatitis B and hepatitis C.

Wherein the tumor is preferably selected from the group consisting of leukemia, lymphoma, melanoma or non-small cell lung cancer.

Another aspect of the invention also provides a method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a formula (I) as described above (preferably formula (I-1), formula (I) -2), Formula (I-3), Formula (I-4), Formula (I-5), Formula (I-6), Formula (I-7), Formula (I-8), or Formula (I) -9)) a five-membered heterocyclic pyrimidine compound, a pharmaceutically acceptable salt, a stereoisomer, a solvate, a polymorph, a tautomer, an isotope compound, a metabolite or a former A drug, or a pharmaceutical composition as described above, to activate the TLR ₇ receptor in its body. Among them, the disease is as described above.

Another aspect of the invention also provides a method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a) as described above, formula (I) (preferably formula (I-1), (I-2), Formula (I-3), Formula (I-4), Formula (I-5), Formula (I-6), Formula (I-7), Formula (I-8), or Formula (I-9)) 5-membered heterocyclic pyrimidine compound, pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope compound, metabolite thereof Or a prodrug and b) a PD-1 antibody, a PD-L1 antibody or a PD-1 inhibitor, a PD-L1 inhibitor or a PD-1/PD-L1 inhibitor. Among them, the disease is as described above. In some embodiments, the disease is preferably a tumor, further preferably selected from the group consisting of leukemia, lymphoma, melanoma or non-small cell lung cancer.

detailed description

The following detailed description of the invention is intended to be illustrative of the preferred embodiments of the invention, The invention is practiced to best suit the requirements of a particular application.

It will be appreciated that the substituents and substitutions on the compounds provided herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be synthesized by techniques known in the art and those described herein.

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention. In certain embodiments, preferred compounds are those which exhibit superior biological activity. Purified or partially purified isomers and stereoisomers, or racemic mixtures or mixtures of diastereomers of the compounds of the invention are also included within the scope of the invention. Purification and isolation of such materials can be accomplished by standard techniques known in the art.

The optically pure enantiomer can be obtained by resolution of the racemic mixture according to conventional methods, for example by using an optically active acid or base to form a diastereomeric salt, or by formation of a covalent diastereomer. . Mixtures of diastereomers can be separated into the individual diastereomers by methods known in the art (e.g., by chromatography or fractional crystallization) based on their physical and/or chemical differences. The optically active enantiomeric base or acid is then released from the separated diastereomeric salt. Another method for separating the racemic enantiomers can be carried out using chiral chromatography (eg, a chiral HPLC column), and the isolated chiral isomer can be subjected to conventional derivatization or derivatization prior to separation, depending on In what way, chiral isomers can be separated more efficiently. Enzymatic methods can also be used to isolate chiral isomers that are derivatized or not derivatized. Likewise, the optically pure compound of the present invention can be obtained by chiral synthesis using an optically active starting material.

Additionally, the compounds of the invention may exist in tautomeric forms. The invention includes all possible tautomers of the compounds of the invention, as well as single tautomers or any mixture of the tautomers in any ratio.

The compounds of the invention may exist in solvated forms, including hydrates or solvates, wherein the compounds of the invention comprise a polar solvent, such as water or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent (particularly water) may be present in stoichiometric or non-stoichiometric ratios. In the case of stoichiometric solvates (eg hydrates), it may be a hemi- solvate or hydrate, a (semi-) solvate or a hydrate, a solvate or a hydrate, respectively. , sesquisol or hydrate, solvate or hydrate, trisolvate or hydrate, tetrasolvate or hydrate, pentasolvate or hydrate, and the like. The invention includes all such hydrates or solvates.

Additionally, the compounds of the invention may exist in unsolvated as well as in free form. For example, it is in the form of a free base or a free acid or a zwitterion, or in the form of a salt. The salt may be any salt, which may be an organic or inorganic salt, especially any pharmaceutically acceptable organic or inorganic salt commonly used in pharmacy.

As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned. . Non-limiting examples of metal salts include, but are not limited to, alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts, aluminum salts, and the like. Non-limiting examples of salts formed with organic bases include, but are not limited to, with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, A salt formed by dicyclohexylamine or the like. Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Non-limiting examples of salts formed with organic acids include, but are not limited to, with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzene. a salt formed of a sulfonic acid, p-toluenesulfonic acid or the like. Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, and the like. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

In another aspect, the invention encompasses a method of preparing a compound of the invention, the method comprising the steps described in the experimental section herein.

The compound of the present invention can be administered orally or parenterally to a patient in the form of a conventional preparation, for example, a capsule, a microcapsule, a tablet, a granule, a powder, a lozenge, a pill, a suppository, an injection, and a mixture. Suspending agents, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable formulations can be prepared by conventional methods using conventional organic or inorganic additives such as, for example, sucrose, starch, mannitol, sorbitol, lactose, glucose, fiber. , talc, calcium phosphate or calcium carbonate), binders (eg, cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose Or starch), a disintegrant (for example, starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), lubricant (for example, hard Magnesium oleate, light anhydrous silicic acid, talc or sodium lauryl sulfate), flavoring agents (eg, citric acid, menthol, glycine or orange powder), preservatives (eg, sodium benzoate, sodium bisulfite, Methylparaben or propylparaben), stabilizer (eg citric acid, sodium citrate or acetic acid), suspending agent (eg methylcellulose, polyvinylpyrrolidone or aluminum stearate), dispersed Agent (for example, hydroxypropyl group) Cellulose), diluents (e.g., water), and base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). For example, an effective amount of the compound 4 in the pharmaceutical composition may be an amount that achieves the desired effect; for example, a subject weight of about 0.005 mg/kg in a unit dose for oral and parenteral administration to about Subject weight of 10 mg/kg.

The dosage of the compound to be administered to a subject is variable to a considerable extent and may be subject to the judgment of a health care professional.

For convenience, the compounds of the invention may be administered orally. In one embodiment, the compound is administered with water or with a meal when administered orally. In another embodiment, the compound is dispersed in water or fruit juice (eg, apple juice or orange juice) and administered orally as a suspension.

The compounds may also be intradermal, intramuscular, intraperitoneal, transdermal, intravenous, subcutaneous, intranasal, intradural, sublingual, intracerebral, intravaginal, transdermal, rectal, transmucosal, by inhalation or topical Administration to the ear, nose, eyes or skin. The mode of administration is judged by the health care professional and may depend in part on the location of the medical condition.

In one embodiment, provided herein are capsules containing the compound without additional carriers, excipients or vehicles.

The pharmaceutical composition of the present invention may be in the form of a tablet, a chewable tablet, a capsule, a solution, a parenteral solution, a troche, a suppository, a suspension, or the like. The compositions may be formulated as a suitable portion in a dosage unit containing a daily or daily dose, which may be a single tablet or capsule or a suitable volume of liquid. In one embodiment, the solution is prepared from a water soluble salt, such as a hydrochloride salt. Generally, all compositions are prepared according to known methods in medicinal chemistry. Capsules can be prepared by mixing the compound with a suitable carrier or diluent and filling the appropriate amount of the mixture into a capsule. Commonly used carriers and diluents include, but are not limited to, inert powdered materials such as various starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugar ratios such as sugar, mannitol and sucrose, flour and the like. Edible powder.

Tablets can be prepared by direct compression, wet granulation or dry granulation. The formulation is usually added with a diluent, a binder, a lubricant and a disintegrant as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are such as starch, gelatin and sugars (such as lactose, fructose, glucose, etc.). Natural and synthetic gums are also suitable, including gum arabic, alginate, methylcellulose, polyvinylpyrrolidone and the like. Polyethylene glycol, ethyl cellulose and waxes can also act as binders.

Lubricants may be required in the tablet formulation to prevent the tablet and punch from sticking to the mold. The lubricant may be selected from slippery solids such as talc, magnesium stearate and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrants swell upon wetting to break up the tablet and release the compound. They include starch, clay, cellulose, algin and gum. More specifically, for example, corn and potato starch, methyl cellulose, agar, bentonite, wood cellulose, powdered natural sponge, anion exchange resin, alginic acid, guar gum, citrus slag and carboxymethyl cellulose can be used. And sodium lauryl sulfate. The tablets may be coated with sugar as a flavoring and sealant, or coated as a film protectant to optimize the dissolution properties of the tablet. The composition may also be formulated as a chewable tablet, for example by adding some material, such as mannitol, to the formulation.

When it is desired to administer as a suppository, a typical matrix can be used. Cocoa butter is a traditional suppository base which can be altered by the addition of wax to slightly increase its melting point. Water miscible suppository bases, including, in particular, polyethylene glycols of various molecular weights are widely used.

The action of the compound can be delayed or extended by a suitable formulation. For example, slowly dissolving pellets of the compound can be prepared and added to a tablet or capsule or as a sustained release implantable device. The technique also includes preparing pellets of several different dissolution rates and filling the capsules with a mixture of pellets. Tablets or capsules can be coated with a film that resists dissolution during a predictable period. Even parenteral formulations can be formulated to be effective by dissolving or suspending the compound in an oily or emulsified vehicle which allows it to be slowly dispersed in the serum.

Related definitions:

Unless otherwise stated, the terms used herein are to be interpreted as having the same meaning of the art as commonly understood by one of ordinary skill in the art. It is to be further understood that the terms used herein are to be interpreted as having a meaning consistent with the context of the present specification and the related art, unless explicitly defined herein.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, the description including the occurrence or non-occurrence of the event or circumstance. For example, an ethyl group "optionally" substituted with halo, refers to an ethyl group may be unsubstituted (CH ₂ CH _3), monosubstituted (e.g., CH ₂ CH ₂ F), polysubstituted (e.g. CHFCH ₂ F, CH ₂ CHF _2, etc.) or completely substituted (CF ₂ CF ₃ ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.

As used herein, refers to the portion C _{m_n} having mn carbon atoms. For example, "C _3-10 cycloalkyl" means that the cycloalkyl group has 3 to 10 carbon atoms. The "C _0-6 alkylene group" means that the alkylene group has 0 to 6 carbon atoms, and when the alkylene group has 0 carbon atoms, the group is a bond.

The numerical range in this document refers to each integer in a given range. For example, "C _1-10 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 One carbon atom, nine carbon atoms or ten carbon atoms.

The term "optionally substituted" means that any one or more hydrogen atoms on a particular atom are optionally substituted with a substituent as long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are substituted, and the ketone substitution does not occur on the aryl group.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, the term "hetero" means a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), that is, an atom other than carbon and hydrogen or an atomic group containing the same, and the hetero atom is independently selected from the group consisting of oxygen, nitrogen, sulfur, Phosphorus, silicon, germanium, aluminum, boron. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.

The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

The term "hydroxy" refers to an -OH group.

The term "cyano" refers to a -CN group.

The term "mercapto" refers to a -SH group.

The term "amino" refers to a -NH2 group.

The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is attached to the remainder of the molecule by a single bond. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, Neopentyl, n-hexyl, 2-methylhexyl, -CH ₂ -cyclopropyl, and the like.

The term "alkylene" refers to a saturated straight or branched or cyclic hydrocarbon radical having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane. . Non-limiting examples of alkylene include, but are not limited to, methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylene (-CH _{2 )} CH ₂ -), 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), and the like.

The term "imino" refers to -NH-.

The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group having at least one double bond consisting of a carbon atom and a hydrogen atom. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

The term "alkynyl" means a straight or branched unsaturated aliphatic hydrocarbon group having at least one triple bond composed of a carbon atom and a hydrogen atom. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C = CH), 1- propynyl _{(-C = C-CH 3)} , 2- propynyl (-CH2-C = CH), 1 , 3-butadiynyl (-C=CC=CH), and the like.

The term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic cyclic hydrocarbon group consisting of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings. The cyclic hydrocarbon group may be a monocyclic, fused polycyclic, bridged or spiro ring structure. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl, and the like.

The term "heterocycloalkyl" refers to a non-aromatic monocyclic, fused polycyclic, bridged or spiro ring system wherein some of the ring atoms are selected from N, O, S(O)n (where n is 0) a hetero atom of 1 or 2), the remaining ring atoms being C. Such rings may be saturated or unsaturated (eg, having one or more double bonds), but do not have a fully conjugated π-electron system.

Examples of the 3-membered heterocyclic hydrocarbon group include, but are not limited to, an oxiranyl group, an ethylenethio group, a cycloalkylethane group, and examples of the 4-membered heterocyclic hydrocarbon group include, but are not limited to, azetidinyl, acetobutyl group, and thidium. Examples of the cyclic group, 5-membered heterocycloalkyl group include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, 1,1-dioxo Examples of thiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyridyl Cyclol, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thiazolidine, 1,4-dioxacyclyl, thiomorpholinyl, 1,2-, 1,4 Examples of -dithiaalkyl, dihydropyridyl, tetrahydropyridyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, 7-membered heterocycloalkyl include, but are not limited to, azacycloheptane Alkyl, oxetanyl, thiaheptanyl, oxazabicyclo[2.2.1]heptyl and azaspiro[3.3]heptyl, and the like.

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.

The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, fluorenyl, isodecyl and the like.

The term "pharmaceutically acceptable" is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.

In particular, the compounds of the invention can be prepared by a variety of synthetic methods well known to those skilled in the art. This includes the specific embodiments listed below, embodiments in combination with other chemical synthesis methods, and equivalent alternatives recognized in the art. Preferred embodiments include, but are not limited to, embodiments of the invention.

The chemical reaction of a particular embodiment of the invention is carried out in a suitable solvent which is suitable for the chemical changes of the invention and the reagents and materials required thereof. In order to obtain the compounds of the present invention, it will be necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes on an existing basis, if necessary.

An important consideration in any synthetic route in the art is the reactive functional group (such as the protecting group of the amino group in the present invention. We have borrowed from Greene and Wuts' Protective Groups In Organic Synthesis, Wiley and Sons, 1991, which is cited by the present invention. All references are incorporated into the present invention as a whole.

The compounds of formula I of the present invention can be prepared by those skilled in the art of organic synthesis by standard procedures common to the following Schemes 1 and 2.

Synthetic route 1

Among them, steps 1 and 2 can also be completed by the following steps

Synthetic route 2

Among them, steps 2 and 3 can also be completed by the following steps:

Among them, the introduction of R ₁ and R ₂ can be achieved by the following synthesis methods:

1. introducing R ₁ and R ₂ from the starting material of step 1 by suitable synthetic chemistry, and then carrying out the reaction of step 1;

2. From the intermediate obtained by Step 1, or Step 2, or Step 3, or Step 4, introduce R ₁ and R ₂ by a suitable synthetic chemistry, and then carry out the remaining steps to complete the synthesis of the final product.

The compound of the formula I-1 of the present invention can be prepared by a person skilled in the art of organic synthesis by the following standard methods common to the synthetic routes 3 and 4.

Synthetic route 3

Among them, steps 1 and 2 can also be completed by the following steps

Synthetic route 4

Among them, steps 2 and 3 can also be completed by the following steps:

Among them, the introduction of R ₁ can be achieved by the following synthesis methods:

1. Step 1 is introduced from the raw material ₁ by a suitable R & lt synthetic chemistry, and then to carry out the reaction of step 1; or

2. From the intermediate obtained by Step 1, or Step 2, or Step 3, or Step 4, introduce R ₁ by a suitable synthetic chemistry, and then carry out the remaining steps to complete the synthesis of the final product.

The compounds of formula 1-2 of the present invention can be prepared by those skilled in the art of organic synthesis by standard procedures common to the following Schemes 5 and 6.

Synthetic route 5

General Process 5:

Starting from 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine or the like (commercial reagent), alkylation with a halogenated hydrocarbon to introduce a 7-position substituent (see Scheme 5) ). Subsequently, it undergoes a nucleophilic substitution reaction with ammonia. Thus, an intermediate compound of 2-chloro-4-amine was obtained. Finally, it reacts with sodium alkoxide or potassium alkoxide, or other nucleophiles. Thus, the 2-chloro group in the substrate is replaced by an alkoxy group or other group (see Scheme 5).

The compound of formula 1-2 can also be prepared by standard procedures common to Scheme 6 below.

Synthetic route 6

Among them, steps 1 and 2 can also be completed by the following steps

Among them, the introduction of R ₁ can be achieved by the following synthesis methods:

1. Step 1 is introduced from the raw material ₁ by a suitable R & lt synthetic chemistry, and then to carry out the reaction of step 1; or

2. From the intermediate obtained by Step 1, or Step 2, or Step 3, or Step 4, introduce R ₁ by a suitable synthetic chemistry, and then carry out the remaining steps to complete the synthesis of the final product.

The compounds of the formula I-3 of the present invention can be prepared by those skilled in the art of organic synthesis by standard methods common to the following Schemes 7 and 8.

Synthetic route 7

General Process 7:

Starting from 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine or the like (commercial reagent), alkylation reaction with a halogenated hydrocarbon introduces introduction of a substituent at the N-1 position ( See synthetic route 7). Subsequently, it undergoes a nucleophilic substitution reaction with ammonia. An intermediate compound of 6-chloro-4-amine is obtained. Finally, it reacts with sodium alkoxide or potassium alkoxide, or other nucleophiles. The 6-chloro group in the substrate is replaced with an alkoxy group or other group (see Scheme 7).

Compounds of formula 1-3 can also be prepared by standard procedures common to Scheme 8 below.

Synthetic route 8

Among them, steps 1 and 2 can also be completed by the following steps

The compound of the formula I-4 of the present invention can be produced by a person skilled in the art of organic synthesis by a standard method common to the following Scheme 9.

Synthetic route 9

Among them, steps 1 and 2 can also be completed by the following steps

Among them, the introduction of R ₁ can be achieved by the following synthesis methods:

1. Step 1 is introduced from the raw material ₁ by a suitable R & lt synthetic chemistry, and then to carry out the reaction of step 1; or

2. From the intermediate obtained by Step 1, or Step 2, or Step 3, or Step 4, introduce R ₁ by a suitable synthetic chemistry, and then carry out the remaining steps to complete the synthesis of the final product.

The compounds of formula I-5 of the present invention can be prepared by those skilled in the art of organic synthesis by standard procedures common to Scheme 10 below.

Synthetic route 10

Among them, steps 1 and 2 can also be completed by the following steps

The compounds of formula I-6 of the present invention can be prepared by those skilled in the art of organic synthesis by standard procedures common to Scheme 11 below.

Synthetic route 11

Among them, steps 1 and 2 can also be completed by the following steps

Among them, the introduction of R ₁ can be achieved by the following synthesis methods:

1. Step 1 is introduced from the raw material ₁ by a suitable R & lt synthetic chemistry, and then to carry out the reaction of step 1; or

2. From the intermediate obtained by Step 1, or Step 2, or Step 3, or Step 4, introduce R ₁ by a suitable synthetic chemistry, and then carry out the remaining steps to complete the synthesis of the final product.

The compounds of formula I-7 of the present invention can be prepared by those skilled in the art of organic synthesis by standard procedures common to Scheme 12 below.

Synthetic route 12

Among them, steps 1 and 2 can also be completed by the following steps

For the sake of clarity, the invention is further illustrated by the examples. The examples are intended to be illustrative only, and are not intended to limit the scope of the invention. It will be appreciated by those skilled in the art that the order of some of the reaction steps for preparing the compounds of the present invention may vary, and it is also within the scope of the invention.

All solvents used in the present invention are commercially available and can be used without further purification. The reaction is generally carried out under inert nitrogen in an anhydrous solvent. Proton nuclear magnetic resonance data was recorded on an AVANCE III HD (300 MHz) spectrometer and the chemical shift was expressed in ppm (ppm) at the low field of tetramethylsilane. Mass spectra were measured on an Agilent 1200 Series Plus 6110 (&1956A). LC/MS or Shimadzu MS contains one DAD: SPD-M20A (LC) and Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ionization source (ESI) operating in either positive or negative mode.

The present invention uses the following abbreviations:

Aq

SEMC1 (2-(chloromethoxy)ethyl)trimethylsilane;

Eq equivalent;

1,3-DPPP 1,3-bis(diphenyl)propane;

DCM dichloromethane;

PE petroleum ether;

DMA N,N-dimethylacetamide;

DMF N,N-dimethylformamide;

NMP N-methylpyrrolidone;

EtOAc ethyl acetate;

i-PrOH isopropanol;

EtOH ethanol;

MeOH methanol;

ⁿ BuOH n-butanol;

THF tetrahydrofuran;

BOC tert-butoxycarbonyl;

HOAc acetic acid;

NaCNBH ₃ sodium cyanoborohydride;

LAH lithium aluminum hydride;

9-BBN 9-borobicyclononane;

MsC1 methanesulfonyl chloride;

RT room temperature;

O/N overnight;

Boc ₂ 0 di-tert-butyl dicarbonate;

TFA trifluoroacetic acid;

TFAA trifluoroacetic anhydride;

TEA triethylamine;

DIBAL-H diisobutylaluminum hydride;

NBS bromosuccinamide;

DPPF 1,1'-bis(diphenylphosphino)ferrocene;

Ph ₃ P triphenylphosphine;

Pd(0Ac) ₂ palladium acetate;

Pd(PPh ₃ P) ₂ Cl ₂ bis(triphenylphosphine)palladium chloride;

Pd ₂ (dba) ₃ tris(benzylideneacetone) dipalladium;

n-BuLi n-butyl lithium.

Compounds are named by hand or by Chem Draw software, and commercial compounds are listed under the supplier's catalogue.

High performance liquid chromatography with Shimadzu LC20AB system equipped with Shimadzu SIL-20A autosampler and Japan Shimadzu DAD: SPD-M20A detector with Shim-pack XR-ODS (2.2 μm packing, size 2.0x50mm) Column. 5-100AB_8 min method: Apply a linear gradient, start elution with 95% A (A is 0.05% TFA in water), and end the elution with 100% B (B is MeCN) for 8 minutes, then 100% B was eluted for 2 minutes. The column was equilibrated for 0.5 minutes to reach 100:5 with a total run time of 12.5 minutes. 10-100AB_3.4 min method: Apply a linear gradient, start elution with 90% A (A is 0.05% TFA in water), and end the elution with 100% B (B is acetonitrile) for 2.2 minutes. It was then eluted with 100% B for 0.7 minutes. The column was equilibrated for 0.2 minutes to 90:10 with a total run time of 3.4 minutes. The column temperature was 50 ° C and the flow rate was 0.8 mL/min. The diode array detector has a scanning wavelength of 200-400 nm.

Thin layer chromatography (TLC) was performed on silica gel GF254 of Sanpont-group. Spots were detected by ultraviolet light irradiation. In some cases, spots were also observed by other methods. In these cases, iodine (10 g silica gel was added). About 1g of iodine and thoroughly mixed), vanillin (dissolved in about 1g vanillin in 100mL 10% H2S04), ninhydrin (purchased from Aldrich) or special developer (completely mixed (NH ₄ ) ₆ Mo _{7 0 24 · 4H 2 0,5g (} NH 4) 2 Ce (IV) (N0 3) 6, 450mLH 2 0 and 50mL of concentrated H ₂ S0 ₄ prepared) launched lamina views compound. Flash column chromatography was performed on Silicycle's 40-63 [mu]m (230-400 mesh) silica gel using a similar procedure to that disclosed in Still, WC; Kahn, M.; and Mitra, M. Joumal of Organic Chemistry, 1978, 43, 2923-2925. Common solvents for flash column chromatography or thin layer chromatography are dichloromethane/methanol, ethyl acetate/methanol and hexane/ethyl acetate mixtures. Preparative chromatographic analysis was performed on a Gilson_281Prep LC322 system using a Gilson UV/VIS-156 detector using the Age11a Venusil ASB Prep C18, 150 x 21.2 mm; CHIRALPAKAD-3 0.46 cm*10 cm, 3 μm; X select C18 19mm*150mm; Phenomenex Gemini C18, 5m, 150x30mm; or Phenomenex Synergi C18, 4m, 150x30mm. At a flow rate of about 25mL / min, with a low gradient of acetonitrile / water elution compound, wherein water containing 0.05% TFA, 0.25% HC00H or 0.5% NH ₃ · H20, total run time of 8-15 minutes.

Example 1: 2-Butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Synthetic scheme

Step A: 4-((2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

To a solution of 2,4-dichloro-7Hpyrrole[2,3-d]pyrimidine (1.00 g, 5.30 mmol) in N,N-dimethylacetamide (40.0 ml) in a nitrogen atmosphere. Sodium hydride (60% wt, 0.21 g, 5.30 mmol) was added slowly in portions. After 30 minutes, 4-bromomethylbenzaldehyde (1.05 g, 5.30 mmol) was added. Subsequently, the reaction solution was stirred at room temperature overnight.

The reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride (10 ml). Then, water (20 ml) was added to the mixture, which was diluted and extracted with ethyl acetate (40 ml × 4). The combined organic layers were dried with anhydrous sodium The residue was purified with EtOAc EtOAc m. There was obtained 1.42 g of 4-((2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde as a white solid (yield: 87%).

MS (ESI) M / Z: 306 [M+H ⁺ ].

Step B: 2,4-Dichloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine

To 4-((2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (1.42 g, 4.60 mmol) in a nitrogen atmosphere at 0 °C Pyrrolidine (0.43 g, 5.98 mmol) was added to a solution of dichloromethane (50.0 mL). After stirring for 5 minutes, sodium borohydride (1.07 g, 5.06 mmol) was slowly added portionwise. Subsequently, the reaction solution was stirred at room temperature for 5 hours.

The reaction mixture was extracted with water (50 ml). The combined organic phases were dried over anhydrous sodium sulfate and then evaporated tolulululululululululululululululululululu )-7H-pyrrolo[2,3-d]pyrimidine. It was used directly in the next reaction without purification.

MS (ESI) M / Z: 361 [M+H ⁺ ].

Step C: 2-Chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a 100 ml high pressure reactor, 2,4-dichloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine (2.20 g) was added. , 6.10 mmol) of an isopropanol solution (2.00 M, 30.5 mL, 61.0 mmol) dissolved in ammonia. The reaction mixture was stirred with heating at 100 ° C overnight. The reaction system was cooled to room temperature, and concentrated under reduced pressure to remove isopropyl alcohol. 2.50 g of the crude product 2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, It was used directly in the next reaction without purification.

MS (ESI) M / Z: 342 [M+H ⁺ ].

Step D: 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a 30 ml high pressure reactor, 2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (400) A solution of milligrams (1.20 mmol) of n-butanol (20.00 ml) was added sequentially to sodium t-butoxide (1.15 g, 12.00 mmol), and the mixture was stirred and dissolved, and then heated under a nitrogen atmosphere at 150 ° C in an oil bath overnight.

The reaction was cooled to room temperature and concentrated under reduced pressure to remove n-butanol. N,N-dimethylformamide (4.0 ml) was added to dissolve to clarify, and the crude product was purified by preparative HPLC. The preparation conditions are as follows. Column: Xselect C18 19mm*150mm; mobile phase: water (0.05% TFA) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile increased from 10% to 80% in 7 minutes; detection wavelength: 254 nm. After purification, lyophilization at low temperature gave 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine as a gray semi-solid. 4-Amine trifluoroacetate (26.5 mg, 5.8% yield).

MS (ESI) M/Z: 380 [M+H ⁺ ].

¹ H NMR (300 MHz, Methanol-d ₄ , ppm): δ 7.49 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 3.6 Hz, 1H) ), 6.75 (d, J = 3.6 Hz, 1H), 5.39 (s, 2H), 4.52 (t, J = 6.5 Hz, 2H), 4.35 (s, 2H), 3.61-3.37 (m, 2H), 3.25 -3.00 (m, 2H), 2.28-2.08 (m, 2H), 2.05-1.93 (m, 2H), 1.90-1.77 (m, 2H), 1.57-1.44 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H).

¹⁹ F NMR (282 MHz, Methanol-d ₄ , ppm): δ-76.85, -77.05.

Examples 2 and 3: (S)-1-(4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2 -yloxy)butan-2-ol and (S)-2-(4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d Pyrimidine-2-yloxy)butan-1-ol

Synthetic scheme

Step A: (S)-1-(4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yloxy Butan-2-ol

Into a 30 ml high pressure reactor, 2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d was added in sequence. Pyrimidine-4-amine (0.20 g, 0.59 mmol, 1.00 equiv), (S)-butane-1,2-diol (5.0 mL) and potassium t-butoxide (0.20 g, 1.79 mmol, 3.00 eq. ). After stirring and dissolving, the reaction was heated at 150 ° C in an oil bath under a nitrogen atmosphere overnight.

Post-treatment: After the reaction system was cooled to room temperature, ice water (30 ml) was added to the reaction system to quench the reaction. The mixture was extracted with ethyl acetate (50 mL×3×) and the organic phases were combined. The organic phase was back-washed with saturated brine (100 mL×3×) then dried over anhydrous sodium sulfate. The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% TFA) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 100% in 7 minutes Detection wavelength: 254 nm. Lyophilized under reduced pressure to give 62 mg of (S)-1-(4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidin-2-yloxy)butan-2-ol and (S)-2-(4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2, 3-d]pyrimidin-2-yloxy)butan-1-ol. These two compounds were separated by a reversed phase column and were not effective. Subsequently, the 120 mg mixture was further purified under conditions of chiral resolution. Purification conditions were as follows, column: CHIRALPAKAD-3 0.46 cm * 10 cm, 3 μm; mobile phase: n-hexane (containing 0.1% diethylamine) and isopropanol; flow rate: 1.0 ml / min; gradient: acetonitrile in 10 minutes From 6% to 20%; detection wavelength: 254nm. The product was collected and concentrated under reduced pressure. 19.8 mg of (S)-1-(4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow oil -2-yloxy)butan-2-ol and 7.1 mg of (S)-2-(4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H- as a white solid Pyrrolo[2,3-d]pyrimidin-2-yloxy)butan-1-ol.

(S)-1-(4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yloxy) -2-ol

MS (ESI) M / Z: 396 [M+H ⁺ ].

¹ H NMR (300 MHz, Methanol-d ₄ , ppm): δ 7.32 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 6.88 (d, J = 3.6 Hz, 1H) ), 6.47 (d, J = 3.6 Hz, 1H), 5.27 (s, 2H), 4.32 - 4.17 (m, 2H), 3.87 - 3.81 (m, 3H), 2.75 (s, 4H), 1.86 (s, 4H), 1.72–1.43 (m, 2H), 1.02–0.88 (m, 3H).

E.e.%=99.46%

(S)-2-(4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yloxy) -1-ol

MS (ESI) M / Z: 396 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ , ppm): δ 7.34 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 3.6 Hz, 1H) ), 6.47 (d, J = 3.6 Hz, 1H), 5.27 (s, 2H), 5.12 - 5.04 (m, 1H), 3.89 (s, 2H), 3.84 - 3.64 (m, 2H), 2.83 (s, 4H), 1.92–1.79 (m, 4H), 1.77–1.63 (m, 2H), 1.00–0.89 (m, 3H).

E.e.%=100%

Example 4: 7-(4-(Pyrrolidin-1-ylmethyl)benzyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)-7H-pyrrolo[2 ,3-d]pyrimidine-4-amine

Synthetic scheme

Step A: 7-(4-(Pyrrolidin-1-ylmethyl)benzyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)-7H-pyrrolo[2, 3-d]pyrimidine-4-amine trifluoroacetate

Into a 30 ml high pressure reactor, 2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was added in sequence ( 0.200 g, 0.59 mmol, 1.00 equiv), (tetrahydro-2H-pyran-4-yl)methanol (10.0 mL) and potassium t-butoxide (0.200 g, 1.79 mmol, 3.00 eq.). After stirring and dissolving, the oil bath was heated at 150 ° C under an atmosphere of nitrogen for overnight reaction.

After the reaction system was cooled to room temperature, the reaction mixture was poured into ice water (30 ml) to quench the reaction. Ethyl acetate (50 ml x 3 times) was extracted. The combined organic layers were backwashed with saturated brine (50 mL×3×) and dried over anhydrous sodium sulfate. Concentration in vacuo and the residue obtained was purified by C18 column chromatography. Purification conditions were as follows, Xselect C1819mm*150mm; eluent: acetonitrile and water (where the aqueous phase contained 0.05% TFA); flow rate: 25 ml/min; gradient: acetonitrile increased from 10% to 100% in 8 minutes; Wavelength: 254 nm. Lyophilization under reduced pressure at low temperature gave 62.9 mg of 7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((tetrahydro-2H-pyran-4-yl)methoxyl as a pale green solid. Base)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (yield 20.0%).

MS (ESI) M / Z: 422 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6, ppm): δ8.18 (br, s, 2H), 7.47 (d, J = 8.1Hz, 2H), 7.33 (d, J = 8.1Hz, 2H), 7.19 (d, J = 3.6 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 5.35 (s, 2H), 4.32 (d, J = 5.7 Hz, 2H), 4.22 (d, J = 6.6 Hz) , 2H), 3.94–3.85 (m, 2H), 3.33–3.26 (m, 4H), 3.09–3.06 (m, 2H), 2.27–2.07 (m, 3H), 1.90–1.85 (m, 2H), 1.65 –1.61 (m, 2H), 1.38–1.21 (m, 2H).

¹⁹ F NMR (282 MHz, DMSO-d ₆ , ppm): δ-74.05.

Example 5: 2-Butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Synthetic scheme

Step A: 4-((4-Amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

2-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (500 mg, 2.96 mmol) was dissolved in N,N-dimethylformamide (20.0 mL). After stirring at 0 ° C, sodium hydride (213 mg, 60% by weight, 5.33 mmol) was slowly added portionwise. After the end of the addition, the reaction flask was slowly warmed to room temperature and stirred for 15 minutes, and then 4-formylbenzyl bromide (647 mg, 3.25 mmol) was slowly added. After stirring at room temperature for 0.5 hours, TLC monitoring showed the disappearance of starting material. The mixture was poured into ice water (20 mL) and quenched. The resulting solution was extracted with ethyl acetate (20 mL EtOAc). The combined organic layers were dried with anhydrous sodium The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether 50%) to afford 4-((4-amino-2-chloro-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)methyl)benzaldehyde (400 mg, 47.5%).

MS (ESI) M / Z: 287 [M+H ⁺ ].

Step B: 2-Chloro-7-(4-(piperidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

4-((4-Amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (200 mg, 0.70 mmol) was dissolved in 1,2-di Piperidine (178 mg, 2.10 mmol) was added to ethyl chloride (3.00 mL) at room temperature. After stirring at room temperature for half an hour, sodium triacetoxyborohydride (445 mg, 2.10 mmol) was added. After stirring at room temperature for 4 hours, TLC detection showed the disappearance of the starting material. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The residue was dried over anhydrous sodium sulfate and evaporated. Concentration under reduced pressure gave 2-chloro-7-(4-(piperidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (105) Mg, 42.4%).

MS (ESI) M / Z: 356 [M+H ⁺ ].

Step C: 2-butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

In a 10 ml high pressure reactor, the compound 2-chloro-7-(4-(piperidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( 100 mg, 0.282 mmol, potassium tert-butoxide (81 mg, 0.85 mmol) was dissolved in n-butanol (2.00 mL). The mixture was heated to 150 ° C in an oil bath under a nitrogen atmosphere and stirred overnight. After the reaction mixture was cooled to room temperature, the mixture was diluted with water (10 mL) The combined organic layers were dried with anhydrous sodium The obtained concentrate was purified by preparative high performance liquid chromatography; the conditions were as follows, column: Waters X-bridge C185um, 19 mm * 150 mm; mobile phase: water (containing 10 mM ammonium hydrogencarbonate) and acetonitrile; flow rate: 25 ml / min; gradient : Acetonitrile was raised from 25% to 60% in 8 minutes; detection wavelength: 254 nm, and the product was collected. Concentration gave 2-butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (28.6 mg) , 25.9%).

MS (ESI) M / Z: 394 [M+H ⁺ ].

¹ H NMR: (300 MHz, CD ₃ OD, ppm): δ 7.25 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 6.86 (d, J = 3.3 Hz, 1H) ), 6.46 (d, J = 3.3 Hz, 1H), 5.24 (s, 2H), 4.30 (t, J = 6.3 Hz, 2H), 3.46 (s, 2H), 2.42 - 2.32 (m, 4H), 1.78 -1.68 (m, 2H), 1.58-1.41 (m, 8H), 0.97 (t, J = 7.5 Hz, 3H).

Example 6: 4-Amino-2-butoxy-N-methyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine -6-carboxamide

Synthetic scheme

Step A: 4-Amino-2-butoxy-N-methyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine- 6-carboxamide trifluoroacetate

4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid at room temperature (30 mg, 0.071 mmol) was dissolved in N,N-dimethylformamide (2 mL), then EtOAc (2 M / EtOAc, EtOAc. -diisopropylethylamine (45.8 mg, 0.355 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluron hexafluorophosphate (40.4 mg , 0.106 mmol). After the addition was completed, the mixture was stirred at room temperature for 16 hours.

After the addition, ethyl acetate (25 ml) was added to the reaction mixture, and the mixture was washed with brine (15 ml × 2). The resulting residue was purified by preparative high performance liquid chromatography.

Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80 in 10 minutes %; detection wavelength: 254 nm. The product was collected, the product was collected and concentrated to dryness. 18.9 mg of 4-amino-2-butoxy-N-methyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3- d] Trifluoroacetate salt of pyrimidine-6-carboxamide (yield 48%).

MS (ESI) M / Z: 437 [M+H ⁺ ].

_{^{1 H NMR (300MHz, CD 3}} OD) δ7.43 (d, J = 8.1Hz, 2H), 7.32 (d, J = 8.1Hz, 2H), 7.23 (s, 1H), 5.79 (s, 2H), 4.52 (t, J = 6.4 Hz, 2H), 4.35 (s, 2H), 3.50-3.40 (m, 2H), 3.21-3.00 (m, 2H), 2.82 (s, 3H), 2.29-2.10 (m, 2H), 2.08-1.90 (m, 2H), 1.89-1.72 (m, 2H), 1.60-1.40 (m, 2H), 0.97 (t, J = 6.4 Hz, 3H). ¹⁹ F NMR (300 MHz, CD ₃ OD) δ - 77.31.

Example 7: 2-(Cyclopentylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Synthetic scheme

Step A: 2-(Cyclopentylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Into a 30 ml high pressure reactor, 2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d was added in sequence. Pyrimidine-4-amine (0.200 g, 0.59 mmol, 1.00 equiv), cyclopentylmethanol (5.0 mL) and potassium t-butoxide (0.200 g, 1.79 mmol, 3.00 eq.). After stirring to dissolve, the reaction was stirred at 150 ° C overnight under nitrogen.

After the reaction system was cooled to room temperature, the reaction solution was poured into ice water (30 ml). It was extracted with ethyl acetate (50 ml × 3 times). The organic phases were combined and washed with saturated brine (50 mL×3×). Dry over anhydrous sodium sulfate and concentrate in vacuo. The residue obtained was purified by C18 column chromatography under purified conditions: Xselect C18 19mm*150mm; eluent as acetonitrile and water (water containing 0.05% formic acid); flow rate: 25 ml/min; gradient: within 8 minutes Acetonitrile increased from 5% to 100%; detection wavelength: 254 nm. Lyophilization under reduced pressure at low temperature gave 68.9 mg of 2-(cyclopentylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2. , 3-d]pyrimidine-4-amine formate (yield 27.34%).

MS (ESI) M/Z: 406 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4, ppm): δ7.44 (d, J = 7.9Hz, 2H), 7.32 (d, J = 7.9Hz, 2H), 6.89 (d, J = 3.6Hz, 1H ), 6.48 (d, J = 3.6 Hz, 1H), 5.31 (s, 2H), 4.30 (s, 2H), 4.17 (d, J = 6.9 Hz, 2H), 3.27 (s, 4H), 2.42 - 2.27 (m, 1H), 2.13 (s, 4H), 1.85 - 1.81 (m, 2H), 1.76 - 1.59 (m, 4H), 1.49 - 1.31 (m, 2H).

Example 8: 2-(Pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -amine

Synthetic scheme

Step A: 2-(Pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4- amine

Into a 30 ml high pressure reactor, 2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was added in sequence ( 0.200 g, 0.59 mmol, 1.00 equiv), 4-pyridine methanol (1.27 g, 11.7 mmol, 20.00 eq.) and potassium t-butoxide (0.200 g, 1.79 mmol, 3.00 eq.). After the reaction solution was stirred and dissolved, it was heated to 100 ° C under a nitrogen atmosphere to react overnight.

After the reaction system was cooled to room temperature, the reaction solution was poured into ice water (30 ml). It was then extracted with ethyl acetate (50 ml × 3 times). The combined organic layers were backwashed with saturated brine (50 mL×3×) and dried over anhydrous sodium sulfate. Concentration in vacuo and the residue obtained was purified by C18 column chromatography. Purification conditions were as follows, Xselect C18 19mm*150mm; eluent was acetonitrile and water (aqueous phase containing 0.05% ammonia); flow rate: 25 ml/min; gradient: acetonitrile increased from 5% to 100% in 8 minutes; Wavelength: 254 nm. Lyophilization under reduced pressure at a low temperature gave 43.0 mg (yield 17.76%) of 2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl) as a yellow solid. -7H-pyrrolo[2,3-d]pyrimidine-4-amine.

MS (ESI) M / Z: 415 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6, ppm): δ8.52 (d, J = 6.0Hz, 2H), 7.39 (d, J = 6.0Hz, 2H), 7.18-7.08 (m, 6H), 6.99 (d, J = 3.6 Hz, 1H), 6.45 (d, J = 3.6 Hz, 1H), 5.39 (s, 2H), 5.15 (s, 2H), 3.49 (s, 2H), 2.36 (s, 4H) , 1.65 (s, 4H).

Example 9: 2-(Pyridin-3-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -amine

Synthetic scheme

Step A: 2-(Pyridin-3-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4- amine

Into a 30 ml high pressure reactor, 2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was added in sequence. (0.200 g, 0.59 mmol, 1.00 equiv), 3-pyridinemethanol (5.0 mL) and potassium t-butoxide (0.200 g, 1.79 mmol, 3.00 eq.). After stirring to dissolve, the reaction mixture was heated to 150 ° C under a nitrogen atmosphere and stirred overnight.

After the reaction system was cooled to room temperature, ice water (30 ml) was added to the reaction system to quench the reaction. Ethyl acetate (50 ml x 3 times) was extracted and the organic phases were combined. It was backwashed with saturated brine (50 ml × 3 times) and dried over anhydrous sodium sulfate. Concentration in vacuo and the residue obtained was purified by preparative EtOAc. Purification conditions were as follows, column: Xselect C18 19 mm * 150 mm; eluent: acetonitrile and water (aqueous phase containing 0.05% aqueous ammonia); flow rate: 25 ml / min; gradient: acetonitrile increased from 10% to 100 in 8 minutes %; detection wavelength: 254 nm. The mixture was lyophilized to give 68.9 mg of 2-(pyridin-3-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole as a yellow solid. 2,3-d]pyrimidine-4-amine (yield 28.5%).

MS (ESI) M / Z: 415 [M+H ⁺ ].

^{1 H NMR ppm (300MHz, DMSO} -d 6): δ8.67 (d, J = 1.5Hz, 1H), 8.51-8.49 (m, 1H), 7.84 (d, J = 7.8Hz, 1H), 7.37- 7.33(m,1H), 7.22–7.07(m,6H), 6.99(d,J=3.5Hz,1H), 6.47(d,J=3.5Hz,1H),5.35(s,2H), 5.19(s , 2H), 3.50 (s, 2H), 2.37 (s, 4H), 1.66 (s, 4H).

Examples 10 and 11: (S)-2-(2-pentyloxy)-7-(4-(pyrrolidin-1-methyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine 4-Amine and (R)-2-(2-pentyloxy)-7-(4-(pyrrolidin-1-methyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-amine

Synthetic scheme

Step A: (S) and (R)-2-(2-pentyloxy)-7-(4-(pyrrolidin-1-methyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-amine racemate

Into a 30 ml high pressure reactor, 2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d was added in sequence. Pyrimidine-4-amine (0.20 g, 0.59 mmol, 1.00 equiv), 2-pentanol (5.0 mL) and potassium t-butoxide (0.20 g, 1.79 mmol, 3.00 eq.). After the reaction mixture was stirred and dissolved, it was heated to 150 ° C under a nitrogen atmosphere and stirred overnight.

After the reaction system was cooled to room temperature, ice water (30 ml) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (100 mL×3×). The combined organic phases were back-washed with saturated brine (100 mL×3×) then dried over anhydrous sodium sulfate. The residue was taken up in EtOAc (3 mL) elute elute Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 100% in 7 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized to give 132 mg of 2-(2-pentyloxy)-7-(4-(pyrrolidin-1-methyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-amine.

The 132 mg racemic chirality was resolved. Purification conditions were as follows, column: CHIRALPAKAD-3 0.46 cm * 10 cm, 3 μm; mobile phase: n-hexane (containing 0.1% diethylamine) and isopropanol; flow rate: 1 ml / min; gradient: within 10 minutes, different Propanol increased from 6% to 20%; temperature: 25 degrees Celsius; detection wavelength: 254 nm. The product was collected and concentrated under reduced pressure to give 50.3 g of (S)-2-(2-pentyloxy)-7-(4-(pyrrolidin-1-methyl)benzyl)-7H- Pyrrolo[2,3-d]pyrimidin-4-amine (yield 22%) and 43.9 mg of (R)-2-(2-pentyloxy)-7-(4-(pyrrole) as a colorless oil Alkyl-1-methyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (yield 19.0%).

(S)-2-(2-pentyloxy)-7-(4-(pyrrolidin-1-methyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

MS (ESI) M / Z: 394 [M+H ⁺ ].

¹ H NMR (300 MHz, Chloroform-d ppm): δ 7.29 (d, J = 8.1 Hz, 2H), 7.21. (d, J = 7.8 Hz, 2H), 6.73 (d, J = 3.6 Hz, 1H), 6.25 (d, J = 3.6 Hz, 1H), 5.25 - 5.16 (m, 3H), 4.95 (s, 2H), 3.49 (s, 2H), 2.54 (s, 4H), 1.80 (s, 4H), 1.60– 1.39 (m, 4H), 1.32 (d, J = 6.3 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H).

Ee%=99.52%

(R)-2-(2-pentyloxy)-7-(4-(pyrrolidin-1-methyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

MS (ESI) M / Z: 394 [M+H ⁺ ].

¹ H NMR (300 MHz, Chloroform-d) δ 7.31 - 7.26 (m, 2H), 7.19 (d, J = 7.5 Hz, 2H), 6.73 (d, J = 3.6 Hz, 1H), 6.25 (d, J) = 3.6 Hz, 1H), 5.25 - 5.16 (m, 3H), 4.95 (s, 2H), 3.72 (d, J = 7.5 Hz, 2H), 2.55 (s, 4H), 1.80 (s, 4H), 1.74 –1.57 (m, 4H), 1.55-1.40 (m, 3H), 0.94 (t, J = 7.2 Hz, 3H).

Ee%=100.00%

Example 12: 4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)-7H- Pyrrolo[2,3-d]pyrimidine-6-carbonitrile

Synthetic scheme

Step A: 6-Bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)-7H-pyrrole And [2,3-d]pyrimidine-4-amine

6-Bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (990 mg, at room temperature 2.35 mmol) and potassium t-butoxide (792 mg, 7.059 mmol) were dissolved in 4-hydroxymethyltetrahydropyran (8.00 mL) and reacted at 150 ° C for 16 hours. After the reaction was completed, the cooled reaction mixture was concentrated to dryness and ethyl acetate (100 ml). The organic layer was washed with brine (50 mL EtOAc)EtOAc. The residue obtained was purified by high pressure chromatography under the following conditions. Column: X select C18 19mm*150mm; mobile phase: water (containing 10 mM ammonium bicarbonate) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile from 5% to 100% in 8 minutes; detection wavelength: 254 nm. The product was collected and concentrated to dryness to give 6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((tetrahydro-2H-pyran-4-yl) as a brown solid. Methoxy)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.00 g, yield 78%).

MS (ESI) M/Z: 500, 520 [M+H ⁺ ].

Step B: 4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)-7H-pyrrole And [2,3-d]pyrimidine-6-carbonitrile

6-Bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)-7H at room temperature - Pyrrolo[2,3-d]pyrimidin-4-amine (940 mg, 1.88 mmol) was dissolved in N,N-dimethylformamide (20.0 ml), then zinc cyanide was added sequentially to the mixture ( 154.4 mg, 1.31 mmol, tetrakis(triphenylphosphine)palladium (173.8 mg, 0.15 mmol) and 1,1-bis(diphenylphosphino)ferrocene (83.4 mg, 0.15 mmol). After the addition was completed, the reaction system was heated to 100 ° C and stirred under nitrogen for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and dissolved in ethyl acetate (500 ml). The organic layer was washed with brine (100 mL EtOAc)EtOAc. The obtained crude product was purified by preparative high performance liquid chromatography under the following conditions. Column: X-select C18, 19mm*150mm; mobile phase: water (0.05% formic acid) and acetonitrile; gradient: acetonitrile increased from 15% to 40% in 8 minutes; flow rate: 25 ml/min; detection wavelength: The product was collected at 254 nm and concentrated to dryness. 4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)- 7H-Pyro[2,3-d]pyrimidin-6-carbonitrilecarboxylate (295 mg, yield 35%).

MS (ESI) M / Z: 447 [M+H ⁺ ].

_{^{1 H NMR (300MHz, CD 3}} OD-d 4, ppm): δ7.48 (d, J = 8.1Hz, 2H), 7.37 (d, J = 7.8Hz, 2H), 7.30 (s, 1H), 5.45 (s, 2H), 4.29 (s, 2H), 4.23-4.04 (m, 2H), 3.98-3.93 (m, 2H), 3.54-3.34 (m, 2H), 3.31-3.07 (m, 4H), 2.15 -1.98 (m, 5H), 1.76-1.66 (m, 2H), 1.62-1.49 (m, 2H).

Example 13: 2-Butoxy-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Synthetic scheme

Step A: 4-((6-Bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

N,N-dimethylformamide (30.0 ml) and sodium hydride (450 mg, 11.23 mmol, 3.00 equivalent) were added to a 100 ml three-necked round bottom flask under a nitrogen atmosphere. After stirring uniformly, 6-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 3.74 mmol, 1.00 equivalent) was added to the reaction mixture. After stirring at room temperature for 30 minutes, the reaction mixture was stirred for 10 minutes under ice bath. Then, 4-(bromomethyl)benzaldehyde (890 mg, 4.49 mmol, 1.20 equivalent) was added thereto. The reaction was allowed to warm to room temperature and stirred overnight.

The reaction was quenched by the addition of ice water (150 ml). The resulting solution was extracted with ethyl acetate (3×100 mL). The mixture was washed with saturated aqueous sodium chloride (2×150 mL) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave a residue. The residue was purified by column chromatography [eluent ethyl acetate: petroleum ether ( 5% to 20%) to afford 1.12 g of 4-((6-bromo-2, 4-) Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (yield 77%).

MS (ESI) M/Z: 384, 386 [M+H ⁺ ].

Step B: 4-((4-Amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

Add 4-((6-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (1.12 g) to a 30 ml high pressure reactor. 2.92 mmol, 1.00 eq.), a solution of ammonia in isopropanol (2M, 30.0 mL). After the mixture was uniformly mixed, the reaction system was stirred at 90 ° C for 16 hours.

After the reaction system was cooled to room temperature, the reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent: methanol: methylene chloride (0% - 10%)). %) 4-((4-Amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde as a pale yellow solid.

MS (ESI) M/Z: 366, 368 [M+H ⁺ ].

Step C: 6-Bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a 100 ml three-necked flask was added 4-((4-amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl) under a nitrogen atmosphere in an ice bath. Benzaldehyde (0.85 g, 2.34 mmol, 1.00 equiv), dichloromethane (20.0 mL) and pyrrolidine (0.50 g, 7.02 mmol, 3.00 eq.). After stirring and stirring, sodium borohydride (1.49 g, 7.02 mmol, 3.00 equivalent) was slowly added in portions. After the addition was completed, the mixture was stirred at room temperature for 16 hours.

The reaction was quenched by ice water (50 mL). The combined organic phases were backwashed with saturated aqueous sodium chloride (2×50 mL) and dried over anhydrous sodium sulfate. The solvent was concentrated in vacuo and EtOAcqqqqqqqq Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 5% to 100 in 7 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized at low temperature and reduced pressure. 0.86 g of 6-bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a white solid (Yield 87%).

MS (ESI) M/Z: 422, 422 [M+H ⁺ ].

Step D: 6-Bromo-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Add 6-bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 to a 30 ml high pressure reactor. -Amine (0.10 mg, 0.23 mmol, 1.00 eq.), n-butanol (8.0 mL) and potassium t-butoxide (0.16 g, 1.43 mmol, 6.00 eq.). After mixing well, it was stirred at 150 ° C for 16 hours.

After the reaction system was cooled to room temperature, ice water (30 ml) was added to the reaction mixture. The resulting solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were back washed with saturated brine (3×50 mL) The solvent was concentrated in vacuo and the residue obtained was purified using preparative HPLC. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% TFA) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 10% to 70% in 7 minutes Detection wavelength: 254 nm. The product was collected and lyophilized to give 20.0 mg of 6-bromo-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2, 3-d]pyrimidine-4-amine (yield 18%).

MS (ESI) M/Z: 458, 460 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6, ppm): δ7.68 (br, s, 2H), 7.50 (d, J = 8.1Hz, 2H), 7.28 (d, J = 8.1Hz, 2H), 6.78 (s, 1H), 5.32 (s, 2H), 4.31 (d, J = 5.4 Hz, 2H), 4.24 (t, J = 6.6 Hz, 2H), 3.39 - 3.26 (m, 2H), 3.08 - 3.01 ( m, 2H), 2.08–1.87 (m, 2H), 1.84–1.81 (m, 2H), 1.70–1.60 (m, 2H), 1.45–1.32 (m, 2H), 0.95–0.88 (m, 3H).

¹⁹ F NMR (282 MHz, DMSO-d ₆ , ppm): δ - 74.2.

Example 14: 2-Butoxy-6-methyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Synthetic scheme

Step A: 2-butoxy-6-methyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Methyl 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (30 mg, 0.07 mmol) dissolved in tetrahydrofuran (1.0 mL). Thereafter, lithium aluminum hydride (8.0 mg, 0.21 mmol) was slowly added in portions at 0 °C. The resulting mixture was stirred under reflux with nitrogen for 5 hours. After the reaction was cooled to room temperature, the mixture was quenched with water (10 mL). The resulting reaction mixture was extracted with ethyl acetate (10 mL EtOAc). The organic phases were combined, dried over anhydrous sodium sulfate and evaporated. The obtained crude product was purified by preparative high performance liquid chromatography under the following conditions. Column: Waters X-bridge, C18, 5um, 19mm*150mm; mobile phase: water (containing 0.05% ammonium bicarbonate) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile from 25% liter in 8 minutes Up to 60%; detection wavelength: 254 nm], concentrated to give 2-butoxy-6-methyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole as a pale yellow solid And [2,3-d]pyrimidine-4-amine (4.9 mg, yield 18%).

MS (ESI) M / Z: 394 [M+H ⁺ ].

¹ H NMR: (300 MHz, CD ₃ OD, ppm): δ 7.28 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 6.20 (s, 1H), 5.30 (s) , 2H), 4.27 (t, J = 6.6 Hz, 2H), 3.68 (s, 2H), 2.64-2.60 (m, 4H), 2.20 (s, 3H), 1.85-1.80 (m, 4H), 1.79- 1.67 (m, 2H), 1.53-1.41 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H).

Example 15: 4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid Methyl ester

synthetic route

Step A: 6-Bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a 50 ml sealed tube, a solution of 6-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (4.00 g, 15.00 mmol) and ammonia in isopropanol (2.0 M, 22.5 ml, 45.0 mmol). Stir at 50 ° C for 16 hours. After the completion of the reaction, the cooled reaction system was concentrated to dryness. The product 6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (4.01 g, yield 97%) was obtained as a brown solid.

MS (ESI) M/Z: 247, 249 [M+H ⁺ ].

Step B: 4-((4-Amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

To a solution of 6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (4.00 g, 14.5 mmol) in anhydrous N,N-dimethylformamide (40.0 mL) in. Sodium hydride (582 mg, 14.5 mmol) was added portionwise at 0 °C. After stirring at 0 ° C for 1 hour, 4-(bromomethyl)benzaldehyde (2.89 g, 14.5 mmol) was added to the mixture. After the addition was completed, the reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride (20 mL). The resulting solution was extracted with ethyl acetate (200 mL×2). The combined organic phases were washed with brine (200 mL x 2). Dry over anhydrous sodium sulfate and concentrate to dryness to give 4-((4-amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl as a brown solid. ) benzaldehyde (4.80 g, yield 90.5%).

MS (ESI) M/Z: 367, 369 [M+H ⁺ ].

Step C: 6-Bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To 4-((4-amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (2.00 g, 5.45 mmol) at room temperature In a solution of dichloromethane (50.0 ml), acetic acid (20 mg) and pyrrolidine (0.45 ml) were sequentially added and stirred for 20 min. Sodium triacetoxyborohydride (4.06 g, 19.15 mmol) was then added to the reaction mixture at 0 °C. After the addition was completed, the reaction system was allowed to warm to room temperature and stirring was continued for 8 hours. After the reaction was completed, the reaction was quenched with a saturated aqueous solution of ammonium chloride. Extract with dichloromethane (100 mL x 3). The combined organic layers were washed with EtOAc EtOAc. The residue obtained was stirred and stirred with 20 ml of petroleum ether, and solid was precipitated after 2 minutes. Filter and collect the filter cake. The filter cake was dried to give 6-bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine as a brown solid. 4-amine (1.60 g, yield 69.5%).

MS (ESI) M/Z: 420,422 [M+H ⁺ ].

Step D: 6-Bromo-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

6-Bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.40 g) at room temperature 3.33 mmol) was dissolved in n-butanol (16.0 ml), and then potassium t-butoxide (1.12 g, 10.00 mmol) was added thereto. After the addition was completed, the reaction system was reacted at 150 ° C for 16 hours. After the reaction was completed, the reaction system was lowered to room temperature. Ethyl acetate (100 ml) was added thereto. Wash with saturated brine (100 ml x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to dry. Obtained 6-bromo-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a brown solid (1.42 g, yield 92%).

MS (ESI) M/Z: 458, 460 [M+H ⁺ ].

Step E: 4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-carboxylic acid ester

6-Bromo-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine at room temperature (1.40 g, 3.05 mmol) was dissolved in methanol (50.0 mL). Then, triethylamine (924 mg, 9.15 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (112 mg, 0.06 mmol) was sequentially added thereto. After the addition was completed, the reaction system was replaced with carbon monoxide. The temperature was raised to 100 ° C and stirred at a carbon monoxide pressure of 5 MPa for 16 hours. After the reaction was completed, the reaction system was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut The purification conditions are as follows. Column: Waters X-bridge, C18, 19mm*150mm; mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; gradient: acetonitrile from 50% to 60% acetonitrile in 8 minutes; flow rate: 25 ml/min Detection wavelength: 254 nm, product was collected and concentrated to dryness to give 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H as a pale yellow solid. Methyl pyrrolo[2,3-d]pyrimidine-6-carboxylate (1.00 g, yield 74%).

MS (ESI) M/Z: 438 [M+H ⁺ ].

¹ H NMR (300 MHz, CD ₃ OD-d ₄ , ppm): δ 7.37 (s, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 7.8 Hz, 2H), 5.71 (s, 2H), 4.34 (t, J = 6.6 Hz, 2H), 3.78 (s, 3H), 3.58 (s, 2H), 2.62-2.44 (m, 4H), 1.78-1.69 (m, 6H), 1.54-1.41 (m, 2H), 0.96 (t, J = 6.6 Hz, 3H).

Example 16: 4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-carboxaldehyde

Synthetic scheme

Step A: 4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-formaldehyde

To a 10 ml single-mouth bottle, add the compound (4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d Pyrimidin-6-yl)methanol (150 mg, 0.37 mmol) and dichloromethane (2.0 mL). After stirring and dissolved, manganese dioxide (96.0 mg, 1.10 mmol) was added thereto. The mixture was stirred at room temperature overnight. The reaction was filtered and the filter cake was washed with dichloromethane <RTIgt; The filtrate was concentrated under reduced pressure and the obtained crude product was purified by preparative HPLC. The purification conditions are as follows. Column: Waters X-bridge, C18, 5um, 19mm*150mm; mobile phase: water (containing 0.05% ammonium bicarbonate) and acetonitrile; gradient: acetonitrile from 25% to 60% in 8 minutes; flow rate: 25 ML/min; detection wavelength: 254 nm. The product was collected and concentrated to give 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxaldehyde (37.0 mg, yield 25%, white solid).

MS (ESI) M/Z: 408 [M+H ⁺ ].

_{^{1 H NMR (300MHz, CD 3}} OD, ppm): δ9.55 (s, 1H), 7.41 (s, 1H), 7.26-7.20 (m, 4H), 5.68 (s, 2H), 4.37 (t, J = 6.6 Hz, 2H), 3.62 (s, 2H), 2.60-2.52 (m, 4H), 1.89-1.69 (m, 6H), 1.52-1.42 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H).

Example 17: 2-Butoxy-6-(ethoxymethyl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole

[2,3-d]pyrimidine-4-amine

Synthetic scheme

Step A: (4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl) Methanol

Lithium tetrahydroaluminum (65.1 mg, 1.71 mmol) was added to 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H- at room temperature Methyl pyrrolo[2,3-d]pyrimidine-6-carboxylate (250 mg, 0.58 mmol) in tetrahydrofuran. Then, it was stirred at room temperature for 16 hours. After the TLC reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride (1.0 mL). Extract with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue obtained was purified by a reverse phase column, and purification conditions were as follows. Column: Waters X-bridge, C18, 5um, 19mm*150mm; mobile phase: water (containing 0.05% ammonium bicarbonate) and acetonitrile; gradient: acetonitrile from 25% to 60% in 8 minutes; flow rate: 25 ML/min; detection wavelength: 254 nm. The product fractions were collected and concentrated to dryness to give (4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2, 3-d]pyrimidin-6-yl)methanol (100 mg, yield 43%).

MS (ESI) M / Z: 410 [M+H ⁺ ].

Step B: 2-Butoxy-6-(ethoxymethyl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine 4-amine

Thionyl chloride (145 mg, 1.22 mmol) was added to (4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H- at room temperature A solution of pyrrolo[2,3-d]pyrimidin-6-yl)methanol (100 mg, 0.244 mmol) in dichloromethane (20 mL). After stirring at room temperature for 2 hours, ethanol (10 ml) was added dropwise to the reaction mixture, and the mixture was further stirred for 10 minutes. After the reaction was completed, the reaction system was concentrated to dryness. The residue obtained was purified by preparative high performance liquid chromatography under the following conditions. Column: Waters X-bridge, C18, 5um, 19mm*150mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; gradient: acetonitrile from 25% to 60% in 8 minutes; flow rate: 25 ml/ Minute; detection wavelength: 254 nm. The product was collected and concentrated to dryness. 2-butoxy-6-(ethoxymethyl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d as a white solid Pyrimidine-4-amine formate (10.9 mg, 9%)

MS (ESI) M/Z: 438 [M+H ⁺ ].

_{^{1 H NMR (300MHz, CD 3}} OD, ppm): δ7.43 (d, J = 7.7Hz, 2H), 7.22 (d, J = 7.7Hz, 2H), 6.51 (s, 1H), 5.42 (s, 2H), 4.50 (s, 2H), 4.42-4.25 (m, 4H), 3.47-3.40 (m, 2H), 3.32-3.27 (m, 4H), 2.05 (s, 4H), 1.75-1.66 (m, 2H), 1.52-1.40 (m, 2H), 1.08 (t, J = 7.5 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H).

Example 18: 1-(4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6 -yl)ethan-1-one

Synthetic scheme

Step A: 1-(2,4-Dichloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethanone

To a 250 ml three-necked flask was added 2,4-dichloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 30.58 mmol) under a nitrogen atmosphere. A solution of tetrahydrofuran (100.0 ml). After stirring at -78 ° C for 10 minutes, a solution of lithium diisopropylamide in tetrahydrofuran (1.6 mol/liter, 19.1 ml, 32.11 mmol) was added dropwise. After 1 hour, acetic anhydride (9.36 g, 91.68 mmol) was added dropwise. After the dropwise addition was completed, the reaction solution was slowly warmed to -40 ° C, and kept at this temperature, and stirred for 2 hours.

A saturated ammonium chloride solution (150 ml) was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate (100 ml × 2) and the organic phase was combined. The organic phase was washed with a saturated sodium chloride solution (100 ml × 2) then dried over anhydrous sodium sulfate and evaporated. The remaining solid residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3/1). The product was collected and concentrated under reduced vacuo to give 1. <RTIgt; <RTIgt; <RTIgt; <RTIgt; Ethyl ketone (yield 15%).

MS (ESI) M/Z: 370 [M+H ⁺ ].

Step B: 1-(2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethanone

To a 100 ml round bottom flask was added 1-(2,4-dichloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethanone (1.70 g) , 4.59 mmol) of a mixed solvent of tetrahydrofuran (18.0 ml) and water (6.0 ml). Then lithium hydroxide monohydrate (1.90 g, 45.9 mmol) was added. Subsequently, the reaction mixture was stirred at room temperature for 2 hours.

The reaction solution was allowed to stand, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL×2×). The combined organic phases were washed with a saturated sodium chloride solution (20 ml × 2), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. 1.06 g of 1-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethanone as a white solid was obtained. The crude product was used directly in the next step without purification.

MS (ESI) M/Z: 230 [M+H ⁺ ].

Step C: 4-((6-Acetyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

To a 100 mL round bottom flask was added 1-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethanone (1.75 g, 7.61 mmol) of N, N. - a solution of dimethylformamide (40.0 ml). Sodium hydride (0.34 g, 60% wt, 9.13 mmol) was added portionwise with stirring at 0 °C. After the addition was completed, the reaction solution was stirred at room temperature for 30 minutes. Then, 4-(bromomethyl)benzaldehyde (1.82 g, 9.13 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was stirred at room temperature overnight.

Water (50 ml) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 ml × 2). The combined organic phases were washed with a saturated sodium chloride solution (50 mL×2×) then dried over anhydrous sodium sulfate. 2.57 g (yield 97%) of 4-((6-acetyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzene as a yellow solid formaldehyde.

MS (ESI) M/Z: 348[M+H ⁺ ].

Step D: 4-((6-Acetyl-4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

Add 4-((6-acetyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (2.57 g) to a 500 mL round bottom flask , 7.38 mmol) and a solution of ammonia in isopropanol (2 mol/L, 100 mL, 200 mmol). The reaction mixture was stirred at room temperature overnight.

The reaction solution was concentrated. Water (100 ml) was added to the concentrated solid, stirred for 30 min and then filtered. The filter cake was washed with diethyl ether (20 mL x 2 times). The filter cake was dried to give 2.32 g (96%) of 4-((6-acetyl-4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl) as a yellow solid. Methyl)benzaldehyde.

MS (ESI) M / Z: 329 [M+H ⁺ ].

Step E: 1-(4-Amino-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl) Ethyl ketone

Add 4-((6-acetyl-4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (1.00) to a 100 mL round bottom flask. A solution of gram (3.04 mmol) and pyrrolidine (0.65 g, 9.1 mmol) in dichloromethane (20.0 mL). After the reaction mixture was stirred at room temperature for 30 minutes, it was cooled to 0 ° C and stirred for 10 minutes. Sodium borohydride acetate was added thereto. After the addition was completed, the reaction solution was stirred at room temperature for 3 hours.

Water (20 ml) was added to the reaction mixture, and the mixture was extracted with methylene chloride (20 ml × 2). The organic phase was washed with a saturated aqueous solution of sodium chloride (100 ml) and dried over anhydrous sodium sulfate. The obtained residue was purified by EtOAc EtOAcjjjjjjjjj Amino-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethanone.

MS (ESI) M/Z: 384[M+H ⁺ ].

Step F: 1-(4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6- Ketoacetate

Add 1-(4-amino-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine to a 10 mL sealed tube -6-yl)ethanone (150 mg, 0.39 mmol) and n-butanol (4.0 ml), then potassium t-butoxide (131.5 mg, 1.17 mmol). After mixing well, the reaction solution was stirred at 100 ° C overnight.

The reaction was concentrated and the residue was crystallised eluted eluting eluting Purification by preparative high performance liquid chromatography, the purification conditions are as follows. Column: X select C18 19mm*150mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile increased from 5% to 80% in 10 minutes; detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure to give 47.8 mg of 1-(4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H as a brown solid. Pyrrolo[2,3-d]pyrimidin-6-yl)ethanonecarboxylate (yield 26.2%).

MS (ESI) M / Z: 422 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ7.70-7.50 (m, 3H), 7.18 (d, J = 7.8Hz, 2H), 7.06 (d, J = 7.8Hz, 2H), 5.61 (s, 2H), 4.24 (t, J = 6.6 Hz, 2H), 3.51 (s, 2H), 2.48 - 2.31 (m, 7H), 1.74 - 1.57 (m, 6H), 1.49 - 1.30 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H).

Example 19: 2-Butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine 4-amine

Synthetic scheme

Step A: 2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

In a 500 ml three-neck round bottom flask, sodium hydride (6.42 g, 160.43 mmol), tetrahydrofuran (200 ml) and 2,4-dichloro-7H-pyrrole[2,3-d]pyrimidine were added in an ice water bath. (20.0 g, 106.95 mmol). After stirring at 0 ° C for 30 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (21.30 g, 128.34 mmol) was added. The reaction apparatus was then moved to room temperature and stirred for 2 hours, and the disappearance of the starting material was observed by TLC monitoring.

To the reaction system, 500 ml of ice water was added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (300 mL×3×). The combined organic phases were back-washed with water (100 mL x 2) then dried over anhydrous sodium sulfate and evaporated. 29.81 g of 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine were obtained. The compound was used directly in the next reaction without purification.

MS (ESI) M / Z: 318 [M+H ⁺ ].

Step B: 2,4-Dichloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

To a 250 ml three-neck round bottom flask was added bis(pinacolato)diboron (14.43 g, 56.78 mmol), 4,4-di-tert-butyl-2,2-dipyridine (0.83 g, 3.03). Millimol), 1,5-cyclooctadiene phosphonium chloride dimer (1.02 g, 1.51 mmol) and n-hexane (150 mL). After dissolution, it was stirred at 50 ° C for 10 minutes. Next, 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (12.00) was added to the mixture. Gram, 37.85 mmol) in tetrahydrofuran (50 mL). Subsequently, the reaction system was stirred at 90 °C. After 1 hour, LC-MS monitored the disappearance of the starting material and stopped heating.

The reaction solution was cooled to room temperature, and diluted with ice water (300 ml) was added to the reaction mixture. The organic phase was separated and the aqueous extracted with ethyl acetate (150 mL The combined organic phases were dried over anhydrous sodium sulfate and then evaporated. The solid residue obtained was purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane = 1 / 1). The product was collected and concentrated under reduced pressure to give 12.78 g of 2,4-dichloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl - 7-((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine.

MS (ESI) M / Z: 444 [M+H ⁺ ].

Step C: 2,4-Dichloro-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- D]pyrimidine

To a 250 ml three-neck round bottom flask, copper 2-thiophenecarboxylate (0.24 g, 1.08 mmol), 1,10-phenanthroline (0.48 g, 0.22 mmol), lithium hydroxide monohydrate (0.96 g) was added in that order. , 21.62 mmol, 1-(trifluoromethyl)-1,2-phenyliodo-3(1H)-one (4.21 g, 11.90 mmol) and 2,4-dichloro-6-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl) -7H-pyrrolo[2,3-d]pyrimidine (4.80 g, 10.81 mmol). Subsequently, the reaction apparatus was evacuated to replace nitrogen gas, and it was repeated three times. Then, dichloromethane (150 ml) was added. After the mixture was stirred and dissolved, the reaction mixture was stirred at 45 ° C for 10 hours.

The reaction solution was cooled to room temperature and concentrated under reduced pressure. The solid residue obtained was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1). The product was collected and concentrated under reduced pressure to give 3.21 g of 2,4-dichloro-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H. - Pyrrolo[2,3-d]pyrimidine.

MS (ESI) M/Z: 386 [M+H ⁺ ].

Step D: 2-Chloro-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 4-amine

2,4-Dichloro-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole was sequentially added to a 50 ml high pressure reactor. [2,3-d]pyrimidine (2.00 g, 5.20 mmol) and a solution of ammonia in isopropanol (20.0 mL, 2.0 M, 40.0 mmol). After the raw material was stirred and dissolved, it was stirred at 60 ° C for 10 hours.

The reaction solution was cooled to room temperature, and diluted with ice water (100 ml) was added to the reaction mixture. The mixture was extracted with ethyl acetate (100 mL×3×). The combined organic phases were backwashed with water (50 mL×3×) then dried over anhydrous sodium 1.25 g of 2-chloro-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3 as a white solid. -d]pyrimidine-4-amine. The compound was used directly in the next reaction without purification.

MS (ESI) M / Z: 367 [M+H ⁺ ].

Step E: 2-butoxy-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d Pyrimidine-4-amine

Potassium tert-butoxide (1.29 g, 11.48 mmol), tert-butanol (25 ml) and 2-chloro-6-(trifluoromethyl)-7- were sequentially added to a 50 ml high pressure reactor under a nitrogen atmosphere. ((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.05 g, 2.87 mmol). After stirring and dissolving, it was stirred at 150 ° C overnight.

After the reaction system was cooled to room temperature, ice water (100 ml) was added to the reaction system to quench the reaction. The mixture was extracted with ethyl acetate (100 mL×3×). The combined organic phases were back-washed with saturated brine (50 mL×3×) then dried over anhydrous sodium sulfate. 0.82 g of 2-butoxy-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2] , 3-d]pyrimidine-4-amine. The compound was used directly in the next reaction without purification.

MS (ESI) M / Z: 405 [M+H ⁺ ].

Step F: 2-butoxy-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

2-butoxy-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole was added sequentially to a 50 ml single-mouth bottle. [2,3-d]pyrimidin-4-amine (0.82 g, 2.03 mmol), trifluoroacetic acid (20 ml) and dichloromethane (20 ml). Stir at 60 ° C for 2 hours. Subsequently, the reaction liquid was concentrated under reduced pressure. Methanol (40 ml), water (20 ml) and potassium carbonate (1.38 g, 10.00 mmol) were added to the obtained brown residue. After stirring and dissolving, it was stirred at 60 ° C for 2 hours.

The reaction liquid was cooled to room temperature, and concentrated under reduced pressure to remove methanol in the reaction mixture. The resulting liquid was extracted with ethyl acetate (20 mL×3×) and the organic phases were combined. The organic phase was back-washed with saturated brine (20 mL×3×) then dried over anhydrous sodium sulfate. There was obtained 0.68 g of 2-butoxy-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a white solid.

MS (ESI) M/Z: 275 [M+H ⁺ ].

Step G: 4-((4-Amino-2-butoxy-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

To a 100 ml single-mouth bottle, potassium carbonate (0.91 g, 6.57 mmol), p-aldolyl bromide (0.52 g, 2.63 mmol), 2-butoxy-6-(trifluoromethyl)- 7H-Pyro[2,3-d]pyrimidin-4-amine (0.60 g, 2.19 mmol) and acetonitrile (50 mL). After stirring and stirring, stirring was continued for 10 hours at room temperature.

The reaction mixture was concentrated under reduced pressure. EtOAc m. The product fractions were collected and concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt; Base) methyl) benzaldehyde.

MS (ESI) M / Z: 393 [M+H ⁺ ].

Step H: 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-amine

Pyrrolidine (0.15 g, 2.11 mmol), 4-((4-amino-2-butoxy-6-(trifluoromethyl)-) was added sequentially to a 50 mL 3-neck round bottom flask under a nitrogen atmosphere. 7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (0.20 g, 0.51 mmol), methylene chloride (15.0 ml) and sodium borohydride (0.32 g, 1.53 mmol) ). After the raw material was stirred and dissolved, the reaction solution was stirred at room temperature for 10 hours.

Water (20 ml) was added to the reaction mixture for dilution. The lower organic phase was separated and the aqueous extracted with dichloromethane (20 mL x 3). The combined organic phases were back-washed with saturated brine (50 mL x 2) then dried over anhydrous sodium sulfate. The yellow solid was dissolved in dimethyl sulfoxide (5.0 mL) and purified using preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% TFA) and acetonitrile; flow rate: 30 ml / min; gradient: acetonitrile increased from 15% to 80% in 8 minutes; Detection wavelength: 254 nm. The product was collected, and lyophilized to give 43.1 mg of 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H as a white solid. Pyrrolo[2,3-d]pyrimidin-4-amine (yield 18.9%).

MS (ESI) M / Z: 448 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ9.81 (s, 1H), 7.65 (s, 2H), 7.45 (d, J = 8.1Hz, 1H), 7.25 (s, 1H), 7.15 (d, J = 8.1 Hz, 2H), 5.40 (s, 2H), 4.31 (d, J = 5.7 Hz, 2H), 4.22 (t, J = 6.6 Hz, 2H), 3.37 - 3.28 (m, 2H), 3.11 - 3.01 (m, 2H), 2.06–1.95 (m, 2H), 1.89–1.81 (m, 2H), 1.68–1.59 (m, 2H), 1.43–1.31 (m, 2H), 0.89 (t, J=7.2) Hz, 3H).

¹⁹ F NMR (300 MHz, DMSO-d ₆ ) δ-57.62, -74.23.

Example 20: 2-Butoxy-6-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Synthetic scheme

Step A: 2,4,6-Trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

Into a 250 ml single-necked flask, copper chloride (1.43 g, 10.6 mmol), 2,4-dichloro-6-(4,4,5,5-tetramethyl-1,3,2- was sequentially added. Dioxaborolan-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1.60 g) , 3.6 mmol), 20 ml of acetone and 20 ml of water. The reaction was stirred at 80 ° C for 2 hours. TLC monitoring found that the raw materials disappeared.

To the reaction system, ice water (100 ml) was added and the aqueous layer was extracted with ethyl acetate (100 ml × 3 times). The combined organic phases were concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt; , 3-d] pyrimidine. The crude product was used directly in the next reaction without purification.

MS (ESI) M / Z: 354 [M+H ⁺ ].

Step B: 2,6-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Add 2,4,6-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] to a 50 ml microwave tube. A solution of pyrimidine (0.97 g, 2.8 mmol) in isopropyl alcohol (20 mL, 2.0 M, 40.0 mmol). The reaction tube was sealed and heated at 60 ° C for 10 hours, and the disappearance of the starting material was monitored by LC-MS.

To the reaction system, ice water (50 ml) was added, and the aqueous layer was extracted with ethyl acetate (50 ml × 3 times). The organic phase was washed with water (20 ml × 3 times) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give &lt;RTI ID=0.&&&&&&&&&&&&&&&&&&&&&& Pyrimidine-4-amine, used directly in the next step without purification.

MS (ESI) M/Z: 333 [M+H ⁺ ].

Step C: 2-butoxy-6-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4- amine

Potassium tert-butoxide (1.26 g, 10.8 mmol), 20 ml of t-butanol, 2,6-dichloro-7-((2-(trimethylsilyl))B were sequentially added to a 50 ml microwave tube. Oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.90 g, 2.7 mmol). Then, after the reaction system was sealed, it was heated at 120 ° C for 10 hours, and the disappearance of the raw material was monitored by LC-MS.

100 ml of ice water was added to the reaction system, and the aqueous phase was extracted with ethyl acetate (100 ml × 3 times), and the organic phase was combined. The organic phase was washed with water (50 mL x 3 times). The organic phase was concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&& 3-d]pyrimidine-4-amine. It is used directly in the next step without purification.

MS (ESI) M / Z: 372 [M+H ⁺ ].

Step D: 2-butoxy-6-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a 100 ml single-mouth bottle, 2-butoxy-6-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole[2,3] was added sequentially. -d]pyrimidine-4-amine (1.02 g, 2.7 mmol) and trifluoroacetic acid 30 ml. The reaction system was stirred with heating at 60 ° C for 2 hours. The reaction solution was then concentrated under reduced pressure. To the obtained crude product, 30 ml of methanol, 20 ml of water and 1.54 g of potassium carbonate were added. After the raw materials were stirred and dissolved, the reaction mixture was heated and stirred at 50 ° C for two hours.

After the reaction solution was cooled to room temperature, water (50 ml) was added to the reaction mixture, and the mixture was evaporated. The aqueous phase obtained was extracted with ethyl acetate (100 mL×3×) and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and then evaporated. It is used directly in the next step without purification.

MS (ESI) M / Z: 241 [M+H ⁺ ].

Step E: 4-((4-Amino-2-butoxy-6-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

To a 100 ml single-mouth bottle, potassium carbonate (0.43 g, 3.1 mmol), p-aldehyde benzyl bromide (0.25 g, 1.3 mmol), 2-butoxy-6-chloro-7H-pyrrolo[ 2,3-d]pyrimidine-4-amine (0.25 g, 1.1 mmol) and 50 ml of acetonitrile. The reaction system was reacted at room temperature for 10 hours, and the disappearance of the starting material was monitored by LC-MS.

After the reaction mixture was concentrated under reduced pressure, the crude silica gel was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1/2). The product was collected and concentrated under reduced pressure to give 0.26 g of 4-((4-amino-2-butoxy-6-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzene. formaldehyde.

MS (ESI) M / Z: 359 [M+H ⁺ ].

Step F: 2-butoxy-6-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a 100 ml single-mouth bottle, pyrrolidine (0.09 g, 1.3 mmol), 4-((4-amino-2-butoxy-6-chloro-7H-pyrrolo[2,3-d] was added in sequence. Pyrimidin-7-yl)methyl)benzaldehyde (0.20 g, 0.6 mmol) and sodium borohydride acetate (0.36 g, 1.7 mmol). The reaction body solution was stirred at room temperature for 10 hours, and the material disappeared by LC-MS.

The reaction mixture was concentrated under reduced pressure to dryness crystals crystals Then, it was purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% TFA) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 20% to 70% in 8 minutes; Detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure to give 48 mg of 2-butoxy-6-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole as a white solid. 2,3-d]pyrimidine-4-amine (yield 20.9%).

MS (ESI) M / Z: 414 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ7.58 (br, s, 2H), 7.47 (d, J = 8.1Hz, 2H), 7.26 (d, J = 7.8Hz, 2H), 6.67 (s, 1H), 5.33 (s, 2H), 4.32 (d, J = 5.7 Hz, 2H), 4.26 (t, J = 6.6 Hz, 2H), 3.39 - 3.30 (m, 2H), 3.13 - 3.00 (m, 2H) ), 2.07-1.96 (m, 2H), 1.89-1.79 (m, 2H), 1.71 - 1.62 (m, 2H), 1.46 - 1.34 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H).

¹⁹ F NMR (300 MHz, DMSO-d ₆ ) δ-74.21.

Example 21: 4-Amino-2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d Pyrimidine-6-carbonitrile

Synthetic scheme

Step A: 6-Bromo-2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-amine

Add 6-bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 to a 50 ml three-necked flask. -Amine (300 mg, 0.71 mmol), acetonitrile (15.0 mL), potassium tert-butoxide (240 mg, 2.14 mmol) and pyridine-4-ylethanol (770 mg, 7.06 mmol). After the raw materials were uniformly mixed by stirring, the reaction was heated at 90 ° C overnight.

The reaction solution was concentrated under reduced pressure. The crude product was dissolved in 5 mL of N,N-dimethylformamide and purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% TFA) and acetonitrile; flow rate: 60 ml / min; gradient: acetonitrile from 10% to 90% in 30 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized to give 172 mg of 6-bromo-2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl) as a yellow oil. -7H-pyrrolo[2,3-d]pyrimidin-4-amine (yield 49%).

MS (ESI) M/Z: 495,495 [M+H ⁺ ].

Step B: 4-Amino-2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile

Add 6-bromo-2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2] to a 10 ml microwave tube. , 3-d]pyrimidin-4-amine (172 mg, 0.35 mmol), zinc cyanide (40.8 mL, 0.35 mmol), tetratriphenylphosphine palladium (40.4 mg, 0.035 mmol), 1,1' Bis(diphenylphosphino)ferrocene (19.4 mg, 0.035 mmol) and N,N-dimethylformamide (5.00 mL). The reaction mixture was heated to 160 ° C with microwave for 0.5 hour under nitrogen.

The reaction solution was cooled to room temperature, the reaction was filtered, and the filtrate was purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 15% to 80% in 7 minutes; Detection wavelength: 254 nm. The organic phase was collected and lyophilized to give 43.6 mg of 4-amino-2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl) as a white solid. -7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile formate (yield 22.5%).

MS (ESI) M/Z: 440 [M+H ⁺ ].

¹ H NMR: (300 MHz, CD ₃ OD, ppm) δ 8.58 - 8.49 (m, 2H), 7.51 (d, J = 5.4 Hz, 2H), 7.44 - 7.30 (m, 3H), 7.23 - 7.16 (m, 2H), 5.55 (s, 2H), 5.38 (s, 2H), 3.87 (s, 2H), 2.89 - 2.73 (m, 4H), 1.98 - 1.83 (m, 4H).

Examples 22 and 23: 1-((4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl) Oxy)butan-2-ol and 2-((4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2- Alkyloxybutan-1-ol

Synthetic scheme

Step A: 1-((4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)oxy) Butan-2-ol

Into a 30 ml high pressure reactor, 2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was added in sequence ( 0.20 g, 0.59 mmol, 1.00 equiv), butane-1,2-diol (5.0 ml) and potassium tert-butoxide (0.20 g, 1.79 mmol, 3.00 equiv), stirred and dissolved, and heated under nitrogen Stir at 150 ° C overnight.

After the reaction system was cooled to room temperature, ice water (30 ml) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (50 mL×3×) and the organic phases were combined. The organic phase was back-washed with saturated brine (100 mL×3×) then dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 5% to 100 in 7 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure. This gave 64 mg of 1-((4-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl as a yellow liquid. )oxy)butan-2-ol and 2-((4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2 a mixture of -yl)oxy)butan-1-ol. Subsequently, the 64 mg mixture was purified by hand-resolved conditions. Purification conditions were as follows, column: CHIRALPAKAD-3 0.46 cm * 10 cm, 3 μm; mobile phase: n-hexane (containing 0.1% diethylamine) and isopropanol; flow rate: 25.0 ml / min; gradient: within 10 minutes, gradient From 40% to 60% of isopropanol; detection wavelength: 254 nm. The product was collected and concentrated under reduced pressure. 19.8 mg of 1-((4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2- as a yellow oil 2-(4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2]-oxy)butan-2-ol and 12.9 mg of a yellow oil 2,3-d]pyrimidin-2-yl)oxy)butan-1-ol.

1-((4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)oxy)butane-2 -alcohol

MS (ESI) M / Z: 396 [M+H ⁺ ].

¹ H NMR (300 MHz, Methol-d ₄ , ppm) δ 7.43 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 3.6 Hz, 1H) , 6.49 (d, J = 3.6 Hz, 1H), 5.30 (s, 2H), 4.33 - 4.17 (m, 2H), 4.10 (s, 2H), 3.90 - 3.78 (m, 1H), 3.14 - 2.99 (m , 4H), 2.06 - 1.88 (m, 4H), 1.72 - 1.43 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).

2-((4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)oxy)butane-1 -alcohol

MS (ESI) M / Z: 396 [M+H ⁺ ].

¹ H NMR (300 MHz, Methanol-d ₄ , ppm) δ 7.38 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 3.6 Hz, 1H) , 6.47 (d, J = 3.6 Hz, 1H), 5.22 (s, 2H), 5.12 - 5.04 (m, 1H), 4.05 (s, 2H), 3.75 - 3.64 (m, 2H), 3.11 - 2.88 (m , 4H), 2.01 - 1.88 (m, 4H), 1.81 - 1.66 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H).

Example 24: 2-(oxetan-3-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d Pyrimidine-4-amine

Synthetic scheme

Step A: 2-(oxetan-3-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-amine

Into a 30 ml high pressure reactor, 2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d was added in sequence. Pyrimidine-4-amine (0.20 mg, 0.59 mmol, 1.00 equiv), 3-oxetanethanol (0.52 g, 5.93 mmol, 10.00 eq.), cesium carbonate (0.57 g, 1.76 mmol, 3.00 eq) And N,N-dimethylacetamide (10.0 ml). After stirring and dissolving, it was heated to 150 ° C in a nitrogen atmosphere and stirred overnight.

After the reaction system was cooled to room temperature, ice water (30 ml) was added to the reaction system to quench the reaction. The mixture was extracted with EtOAc (3×50 mL)EtOAc. The organic phase was back-washed with saturated brine (3.times.50 mL) then dried over anhydrous sodium sulfate. The residue was taken up in anhydrous methanol (4 mL) and purified and purified. The purification conditions were as follows: column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 100% in 7 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized to give 4.6 mg of <RTIgt; </RTI> <RTIgt; 2- ( </RTI> </RTI> - 7H-pyrrolo[2,3-d]pyrimidin-4-amine (yield 2%).

MS (ESI) M / Z: 394 [M+H ⁺ ].

¹ H NMR (300 MHz, Methanol-d ₄ , ppm) δ 7.30 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 3.6 Hz, 1H) , 6.47 (d, J = 3.6 Hz, 1H), 5.29 (s, 2H), 4.84 - 4.78 (m, 2H), 4.62 - 4.54 (m, 4H), 3.68 (s, 2H), 3.48 - 3.39 (m , 1H), 2.70–2.50 (m, 4H), 1.90–1.70 (m, 4H).

Example 25: 6-((4,4-Difluorocyclohexyl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine

synthetic route

Step A: 4,4-Difluorocyclohexane-1-carboxylic acid ethyl ester

To a stirred solution of diethylaminosulfur trifluoride (7.7 ml) in carbon tetrachloride (75.0 ml) was slowly added dropwise ethyl 4-oxocyclohexane-1-carboxylate (5.0). Gram, 29.0 mmol). Then, the reaction apparatus was stirred at room temperature for 16 hours.

The reaction mixture was poured into ice water (100 ml). The organic phase was back-washed with saturated brine (50 mL×2×) then dried over anhydrous sodium sulfate. 4.2 g of ethyl 4,4-difluorocyclohexane-1-carboxylate as a colorless liquid were obtained (yield: 75%). It is used directly in the next step without purification.

Step B: (4,4-difluorocyclohexyl)methanol

To a reaction flask placed under a nitrogen atmosphere in an ice water bath was added diethyl ether (100.0 ml) and lithium aluminum hydride (475 mg, 12.5 mmol). After stirring for 10 minutes, a solution of ethyl 4,4-difluorocyclohexane-1-carboxylate (2.00 g, 10.4 mmol) in diethyl ether (30 ml) was slowly added dropwise. After the completion of the dropwise addition, the reaction was allowed to proceed to room temperature and stirring was continued for 3 hours.

The system was transferred to an ice water bath, and a saturated aqueous solution of sodium hydroxide was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (50 mL×3×) and the organic phases were combined. The organic phase was washed with saturated brine (100 ml × 3×), then dried over anhydrous sodium sulfate and evaporated. 1.56 g of (4,4-difluorocyclohexyl)methanol (yield 100%) was obtained as a yellow liquid. The compound can be used directly in the next reaction without purification.

Step C: 6-((4,4-Difluorocyclohexyl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d]pyrimidine-4-amine

To a 10 ml high pressure reactor was added 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine sequentially ( 200 mg, 0.6 mmol, acetonitrile (2.0 ml), (4,4-difluorocyclohexyl)methanol (900 mg, 6.0 mmol) and potassium t-butoxide (201.6 mg, 1.8 mmol). After stirring and dissolving, the mixture was heated and stirred at 100 ° C for 16 hours under a nitrogen atmosphere.

After the reaction system was cooled to room temperature, the reaction solution was concentrated. The residue was dissolved in N,N-dimethylformamide (4.0 mL). The preparation conditions were as follows, column: X select C18 19mm*150mm; mobile phase: water (0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile increased from 10% to 80% in 7 minutes Detection wavelength: 254 nm. The product was collected and lyophilized to give 25.2 mg of 6-((4,4-difluorocyclohexyl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl) as a pale yellow solid. Benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (yield 7.6%).

MS (ESI) M / Z: 467 [M+H ⁺ ].

¹⁹ F NMR (300 MHz, DMSO-d ₆ ) δ-73.5, -89.12 (d,J=246.9 Hz, 1F), -99.97 (tt, J = 300.0 Hz, 1F).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.98 (s, 1H), 7.90-7.50 (m, 2H), 7.28 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 5.36 (s, 2H), 4.17 (d, J = 6.9 Hz, 2H), 3.66 (s, 2H), 2.66-2.39 (m, 4H), 2.26-2.11 (m, 1H), 2.08-1.96 (m, 2H), 1.92-1.80 (m, 3H), 1.78-1.68 (m, 4H), 1.53-1.41 (m, 1H), 1.39-1.09 (m, 2H).

Example 26: 6-butoxy-1-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine

synthetic route

Step A: Methyl isoquinoline-6-carboxylate

6-Bromoisoquinoline (10.00 g, 48.0 mmol) was dissolved in a mixed solution of N,N-dimethylformamide (100.0 ml) and methanol (100.0 ml). Subsequently, sodium acetate (5.00 g, 61.0 mmol), triphenylphosphine (3.00 g, 11.4 mmol) and palladium acetate (2.80 g, 12.0 mmol) were sequentially added to the above solution. The mixture was placed in an autoclave with carbon monoxide (300 kPa). The reaction solution was heated to 100 ° C and stirred for 15 hours.

The reaction was filtered through EtOAc (EtOAc)EtOAc. The concentrated liquid was diluted with ethyl acetate (200 mL). The mixture was washed with brine (100 ml × 3×), then washed with water (100 ml×2×), then dried over sodium sulfate The obtained residue was purified to silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1).

MS (ESI) M/Z: 188 [M+H ⁺ ].

Step B: Methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate

To a solution of methyl iso-isoquinoline-6-carboxylate (8.9 g, 47.59 mmol) in methanol (100.0 mL), EtOAc (EtOAc) Then, the reaction apparatus was evacuated to replace hydrogen, and the reaction liquid was heated to 40 ° C under a hydrogen atmosphere (200 kPa), and stirred for 3 hours.

The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. 9.00 g of methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate was obtained. It is used directly in the next step without further purification.

MS (ESI) M / Z: 192 [M+H ⁺ ].

Step C: Methyl 2-isopropyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate

Methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate (1.90 g, 10.0 mmol) was dissolved in N,N-dimethylformamide (20.0 mL). . After stirring and mixing well, sodium hydride (600 mg, 60% wt, 15.0 mmol) was added in portions. The addition was completed and the mixture was stirred at room temperature for 1 hour. Then, 2-iodopropane (6.80 g, 40.0 mmol) was added to the reaction mixture, and stirring was continued at room temperature for 3 hours.

Under ice water bath, water (30 ml) was added to the reaction mixture for dilution. The mixture was extracted with ethyl acetate (30 mL×3×) and the organic phases were combined. The organic phase was washed with brine (50 mL×2×) then dried over anhydrous sodium sulfate. 2.12 g of methyl 2-isopropyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate were obtained. It is used directly in the next step without purification.

MS (ESI) M / Z: 234 [M+H ⁺ ].

Step D: (2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methanol

To a solution of lithium tetrahydroaluminum (1.30 g, 34.2 mmol) in tetrahydrofuran (40.0 ml), 2-isopropyl-1,2,3,4-tetrahydroisoquinoline-6 was slowly added dropwise under ice-water bath. A solution of methyl carboxylate in tetrahydrofuran (20.0 mL). The addition was completed, and the reaction solution was stirred at room temperature for 2 hours.

Water (30 ml) was slowly added dropwise to the reaction solution placed in an ice water bath. The mixture was filtered through celite, and the filtrate was collected. The residue was washed with ethyl acetate (20 mL×3×) and the filtrate was combined. The filtrate was allowed to stand and the upper organic phase was separated. The aqueous phase was extracted with ethyl acetate (40 mL×3×). The organic phase was washed with brine (50 ml×2×), then dried over anhydrous sodium sulfate. 5.98 g of (2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methanol as a colorless liquid were obtained, which was used in the next step without purification.

MS (ESI) M / Z: 206 [M+H ⁺ ].

Step E: 6-(Chloromethyl)-2-isopropyl-1,2,3,4-tetrahydroisoquinoline

To a reaction flask placed in an ice water bath was added (2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methanol (205 mg, 1.0 mmol). In a solution of 4.0 ml), then thionyl chloride (375 mg, 3.0 mmol) was slowly added dropwise thereto. After the dropwise addition was completed, the reaction solution was stirred at room temperature for 1 hour.

The reaction solution was concentrated under reduced pressure to give 236 mg (yield: chloromethyl)-2-isopropyl-1,2,3,4-tetrahydroisoquinoline as a brown-brown liquid.

MS (ESI) M / Z: 224 [M+H ⁺ ].

Step F: 6-Chloro-1-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-1H-pyrazolo[3,4-d Pyrimidine-4-amine

To a solution of 6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (170 mg, 1.0 mmol) in N,N-dimethylformamide (2.0 mL) Sodium hydride (160 mg, 60% by weight, 4.0 mmol) was added in portions to the solution. After the addition was completed, the reaction solution was stirred at room temperature for 1 hour. Then, 6-(chloromethyl)-2-isopropyl-1,2,3,4-tetrahydroisoquinoline (268 mg, 1.2 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hr.

The reaction mixture was quenched with water and the mixture was evaporated. The organic phase was washed with saturated brine (50 mL×3×) then dried over anhydrous sodium sulfate. Obtained 230 mg of 6-chloro-1-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-1H-pyrazole in the form of a yellow oil. 3,4-d]pyrimidine-4-amine. It is used directly in the next step without purification.

MS (ESI) M / Z: 357 [M+H ⁺ ].

Step G: 6-butoxy-1-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine

6-chloro-1-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-1H-pyrazole was sequentially added to a 10 ml high pressure reactor. [3,4-d]pyrimidin-4-amine (200 mg, 0.6 mmol), n-butanol (2.0 ml), potassium tert-butoxide (189 mg, 1.7 mmol). After the raw materials were uniformly mixed, the reaction liquid was stirred at 120 ° C for 16 hours.

The reaction solution was cooled to room temperature, and the reaction solution was concentrated. The residue was dissolved in EtOAc (EtOAc) (EtOAc) Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 20 ml / min; gradient: acetonitrile from 10% to 80% in 15 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure. The final product was obtained as 31.7 mg of 6-butoxy-1-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-1H-pyrene as a white solid. Zoxao[3,4-d]pyrimidin-4-amine (yield 13.0%).

MS (ESI) M / Z: 495 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ7.95 (s, 1H), 7.90-7.40 (m, 2H), 7.04-6.89 (m, 3H), 5.28 (s, 2H), 4.26 (t, J = 6.6 Hz, 2H), 3.57 (s, 2H), 2.86 - 2.78 (m, 1H), 2.77 - 2.61 (m, 4H), 1.72 - 1.62 (m, 2H), 1.47 - 1.35 (m, 2H), 1.03 (d, J = 6.5 Hz, 6H), 0.93 (t, J = 7.3 Hz, 3H).

Example 27: (4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl Methanol

Synthetic scheme

Step A: (4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl) Methanol

4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester ( 30 mg, 0.0685 mmol) was dissolved in tetrahydrofuran (1.00 mL). After stirring and dissolving, lithium aluminum hydride (8.0 mg, 0.211 mmol) was slowly added portionwise to the reaction mixture at 0 °C. The mixture was stirred at room temperature overnight under a nitrogen atmosphere.

The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The combined organic layers were dried over anhydrous sodium The residue obtained was taken up in EtOAc (2 mL). Purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 1% ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80 in 7 minutes %; detection wavelength: 254 nm. The product was collected and concentrated under reduced pressure to give (4-(4-(2-(ethyl)-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2, 3-d]pyrimidin-6-yl)methanol (yield 17.8%).

MS (ESI) M / Z: 410 [M+H ⁺ ].

_{^{1 H NMR (300MHz, CD 3}} OD) δ7.37 (d, J = 8.1Hz, 2H), 7.20 (d, J = 8.1Hz, 2H), 6.46 (s, 1H), 5.45 (s, 2H), 4.49 (s, 2H), 4.27 (t, J = 6.6 Hz, 2H), 4.08 (s, 2H), 3.09-2.99 (m, 4H), 2.02-1.92 (m, 4H), 1.76-1.68 (m, 2H), 1.56-1.48 (m, 2H), 0.96 (t, J = 6.6 Hz, 3H).

Example 28: 4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d Pyrimidine-6-carbonitrile

Synthetic scheme

Step A: 4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile trifluoroacetate

6-Bromo-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine was sequentially added to a 100 ml three-necked flask. 4-Amine (250 mg, 0.55 mmol), tetratriphenylphosphine palladium (63 mL, 0.06 mmol), 1,1-bis(diphenylphosphino)ferrocene (61 mL, 0.11 mmol) Zinc cyanide (98 ml, 1.10 mmol) and zinc powder (70 mg, 1.10 mmol). After the oil pump was vacuum-replaced with nitrogen three times, a solution of N,N-dimethylformamide (10.0 ml) was added to the reaction flask with a syringe. After stirring and mixing uniformly, the mixture was stirred under heating at 110 ° C overnight.

After the reaction system was cooled to room temperature, ice water (30 ml) was added to the reaction system to quench the reaction. The resulting solution was extracted with ethyl acetate (50 mL×3×). The combined organic layers were backwashed with saturated brine (100 mL×3×) and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by preparative HPLC. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80 in 10 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure. 98 mg of 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6,7-dihydro-5H-pyrrolo[2, 3-d]pyrimidine-6-carbonitrile trifluoroacetate (yield 34%).

MS (ESI) m / z: 405 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6, ppm): δ7.72 (br, s, 2H), 7.50-7.44 (m, 3H), 7.28 (d, J = 8.1Hz, 2H), 5.38 (s, 2H), 4.38–4.23 (m, 4H), 3.39–3.25 (m, 2H), 3.16–2.98 (m, 2H), 2.07–1.88 (m, 2H), 1.85–1.71 (m, 2H), 1.69– 1.58 (m, 2H), 1.69 - 1.33 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

¹⁹ F NMR (300 MHz, DMSO-d ₆ , ppm): δ-74.3.

Example 29: 1-((4-Methylenecyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Synthetic scheme

Step A: Synthesis of 1-((4-(bromomethyl)cyclohexyl)methyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine

In a 40 ml vial, 6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 1.18 mmol) of N,N-dimethylformamide (8.0 ml) In the solution, 1,4-bis(bromomethyl)cyclohexane (634 mg, 2.37 mmol) and potassium carbonate (490 mg, 3.55 mmol) were sequentially added, and the reaction mixture was stirred at 60 ° C for 16 hours.

Work-up: The solid was removed by filtration and the filtrate was purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 100% in 10 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized at low temperature. 1-((4-(Bromomethyl)cyclohexyl)methyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (172 mg, 41% yield)

MS (ESI) M/Z: 358 [M+H ⁺ ].

Step B: Synthesis of 1-((4-(bromomethyl)cyclohexyl)methyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine

1-((4-(Bromomethyl)cyclohexyl)methyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.42 m) under N2 Mol) was dissolved in N,N-dimethylformamide (5.0 mL). EtOAc (19 mg, 0.46 mmol). After the reaction was stirred for 30 minutes, the reaction was allowed to proceed to room temperature for 16 hours.

After the reaction was quenched with ice water, ethyl acetate (50 ml × 3) was evaporated. Filtration, the filtrate was removed under reduced pressure to remove the organic solvent, and the residue was purified by preparative high performance liquid chromatography column. The purification conditions were as follows: column: X select C18 19mm*150mm; mobile phase: water (containing 0.05% ammonium hydrogencarbonate) and acetonitrile Flow rate: 25 ml/min; gradient: acetonitrile was raised from 5% to 100% in 20 minutes; detection wavelength: 254 nm. The product was collected and lyophilized at low temperature. Obtained 1-((4-(bromomethyl)cyclohexyl)methyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 69% yield) ).

MS (ESI) M / Z: 278 [M+H ⁺ ].

Step C: Synthesis of 1-((4-methylenecyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

1-((4-(Bromomethyl)cyclohexyl)methyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine in a 10 mL sealed tube under nitrogen. (80 mg, 0.29 mmol) was dissolved in acetonitrile (5 mL), then 4-pyridinemethanol (494 mg, 2.89 mmol) and potassium t-butoxide (97 mg, 0.87 mmol). The reaction was carried out at 100 ° C for 16 hours.

After the reaction was quenched with ice water, ethyl acetate (50 ml × 3) was evaporated. Filtration, the filtrate was removed under reduced pressure to remove the organic solvent, and the residue was purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 75% in 8 minutes; Detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure to give 1-((4-methylenecyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4- d]pyrimidine-4-amine (7.2 mg, 7.1% yield).

MS (ESI) M / Z: 351 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 8.59 - 8.51 (m, 2H), 7.97 (s, 1H), 7.58 - 7.51 (m, 2H), 5.54 (s, 2H), 4.61 - 4.58 (m) , 2H), 4.11–4.08 (m, 2H), 2.29–2.16 (m, 2H), 2.13–1.88 (m, 3H), 1.62–1.58 (m, 2H), 1.09–0.96 (m, 2H).

Example 30: 6-((2-Methylpyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine

Synthetic scheme

Step A: 2-methyl-4-hydroxymethylpyridine

To a solution of 2-methyl-4-carboxypyridine (8.00 g, 58 mmol) in tetrahydrofuran (150 ml), a solution of lithium aluminum hydride (4.40 g, 11.6 mmol) . After the addition was completed, the reaction solution was moved to room temperature and stirred overnight.

Under ice-water bath, water (5.0 ml) and sodium hydroxide solution (4N, 5.0 ml, 20.0 mmol) were slowly added dropwise to the reaction mixture. Subsequently, anhydrous sodium sulfate (10.0 g) was added. After stirring for 10 minutes, the reaction was filtered through celite and filtrate was collected. The filter cake was washed with ethyl acetate (20 mL x 3). The filtrate was combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent 2.41 g of 2-methyl-4-hydroxymethylpyridine as a brown liquid were obtained (yield: 33.6%).

MS (ESI) M / Z: 124 [M+H ⁺ ].

Step B: 6-((2-Methylpyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine

To a 20 ml high pressure reactor was added 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine sequentially ( 150 mg, 0.44 mmol, acetonitrile (10.0 ml), 2-methyl-4-hydroxymethylpyridine (539 mg, 4.4 mmol) and potassium t-butoxide (147 mg, 1.31 mmol). After the reaction mixture was stirred and mixed uniformly, it was stirred at 100 ° C overnight.

The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue obtained was taken up in EtOAc (EtOAc)EtOAc. Preparative high performance liquid chromatography purification. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 70% in 8 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give 37.1 mg of 6-((2-methylpyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl) as a white solid. Benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (yield 19.7%).

MS (ESI) M/Z: 430 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ8.40 (d, J = 5.4Hz, 1H), 7.97 (s, 1H), 7.96-7.80 (m, 1H), 7.78-7.52 (m, 1H), 7.27 (s, 1H), 7.19 - 7.17 (m, 3H), 7.10 (d, J = 8.1 Hz, 2H), 5.39 (s, 2H), 5.32 (s, 2H), 3.49 (s, 2H), 2.44 (s, 3H), 2.37 (s, 4H), 1.66 (s, 4H).

Example 31:1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-((2-(trifluoromethyl)pyridin-4-yl)methoxy)-1H-pyrazole And [3,4-d]pyrimidine-4-amine

Synthetic scheme

Step A: (2-(Trifluoromethyl)pyridin-4-yl)methanol

A solution of 2-(trifluoromethyl)isonicotinic acid (5.00 g, 26 mmol) in tetrahydrofuran (500 mL) was stirred for 10 min. Thereto, lithium aluminum hydride (0.98 g, 26 mmol) was slowly added in portions. After the addition was completed, the reaction apparatus was moved to room temperature and stirred overnight.

Under ice-water bath, water (5.0 ml) and sodium hydroxide solution (4.0 N, 5.0 ml) were slowly added dropwise to the reaction mixture. Subsequently, anhydrous sodium sulfate (10.0 g) was added. After stirring for 10 minutes, the reaction was filtered through celite and filtrate was collected. The filter cake was washed with ethyl acetate (20 mL×3×). The residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 10:1). 1.80 g of (2-(trifluoromethyl)pyridin-4-yl)methanol was obtained (yield 39.04%).

MS (ESI) M / Z: 178 [M+H ⁺ ].

Step B: 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-((2-(trifluoromethyl)pyridin-4-yl)methoxy)-1H-pyrazole [3,4-d]pyrimidine-4-amine

To a 20 ml high pressure reactor was added 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine sequentially ( 150 mg, 0.44 mmol, acetonitrile (10.0 ml), (2-(trifluoromethyl)pyridin-4-yl)methanol (785 mg, 4.4 mmol) and potassium t-butoxide (147 mg, 1.31 mmol) ). The reaction mixture was stirred and mixed uniformly, and then stirred at 100 ° C overnight.

The reaction solution was cooled to room temperature, and the reaction solution was concentrated. The residue obtained was taken up in EtOAc (EtOAc) (EtOAc) Purification conditions are as follows, column: X select C1819mm*150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80% in 7 minutes; detection Wavelength: 254 nm. The product was collected, lyophilized under reduced pressure to give 69.5 mg of 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-((2-(trifluoromethyl)pyridine) as pale yellow solid. 4-yl)methoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (yield 32.8%).

MS (ES, M/Z): 484 [M+H ⁺ ].

^{1 H NMR (300MHz, Chloroform-} d, ppm): δ8.70 (d, J = 4.8Hz, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.59 (d, J = 4.2Hz, 1H), 7.30 (s, 1H), 7.26 (s, 1H), 7.20 (d, J = 7.8 Hz, 2H), 5.54 (s, 2H), 5.42 (s, 2H), 3.63 (s, 2H), 2.54 (s, 4H), 1.80 (s, 4H).

¹⁹ F NMR (300 MHz, Chloroform-d, ppm): δ - 67.9.

Example 32: 6-(2-Methoxypyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine

synthetic route

Step A: (2-methoxypyridin-4-yl)methanol

A solution of 2-methoxyisonicotinic acid (5.00 g, 33.0 mmol) in diethyl ether (50 mL) was stirred for 10 min. Thereto, lithium tetrahydroaluminum (1.90 g, 49.5 mmol) was slowly added in portions. After the addition was completed, the reaction apparatus was moved to room temperature and stirred for 1 hour.

Water (5.0 ml) and a sodium hydroxide solution (4.0 N, 10.0 ml) were slowly added dropwise to the reaction mixture in an ice water bath. Subsequently, anhydrous sodium sulfate (20.0 g) was added. After stirring for 10 minutes, the reaction was filtered through celite and filtrate was collected. The filter cake was washed with ethyl acetate (20 mL×3×). 3.80 g of (2-methoxypyridin-4-yl)methanol as a yellow liquid were obtained. The compound was used directly in the next step without purification.

MS (ESI) M/Z: 140 [M+H ⁺ ].

Step B: 6-((2-Methoxypyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine

To a 10 ml high pressure reactor was added 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine sequentially ( 200 mg, 0.6 mmol, acetonitrile (5.0 ml), (2-methoxypyridin-4-yl)methanol (690 mg, 6 mmol) and potassium t-butoxide (216 mg, 1.8 mmol). After stirring and mixing uniformly, the mixture was stirred at 100 ° C for 16 hours.

The reaction solution was cooled to room temperature, and the reaction solution was concentrated. The residue obtained was taken up in EtOAc (EtOAc)EtOAc. Preparative high performance liquid chromatography purification. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80 in 7 minutes %; detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure to give 43.5 mg of 6-((2-methoxypyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl) as a white solid. Benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (yield 13.0%).

MS (ESI) M/Z: 446[M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6, ppm): δ8.14 (d, J = 5.1Hz, 1H), 8.02 (s, 2H), 7.76 (s, 1H), 7.42 (d, J = 8.1Hz , 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 5.1 Hz, 1H), 6.82 (s, 1H), 5.57 (s, 4H), 4.31 (d, J = 5.4 Hz , 2H), 3.84 (s, 3H), 3.39 - 3.30 (m, 2H), 3.11 - 3.01 (m, 2H), 2.07 - 1.95 (m, 2H), 1.90 - 1.77 (m, 2H).

¹⁹ F NMR (300 MHz, DMSO-d ₆ , ppm): δ - 74.4.

Example 33: 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-(thiazol-5-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine

synthetic route

Step A: 5-Hydroxymethylthiazole

A solution of thiazole-5-carboxylate (3.14 g, 20.0 mmol) in tetrahydrofuran (100 mL) was stirred for 10 min. Lithium tetrahydroaluminum (760 mg, 20.0 mmol) was slowly added thereto in portions. After the addition was completed, the reaction apparatus was moved to room temperature and stirred for 2 hours.

Under ice-water bath, water (5.0 ml) and sodium hydroxide solution (4.0 N, 10.0 ml) were slowly added dropwise to the reaction mixture. Subsequently, anhydrous sodium sulfate (20.0 g) was added. After stirring for 10 minutes, the reaction was filtered through celite and filtrate was collected. The filter cake was washed with ethyl acetate (20 mL×3×). 2.16 g of a yellow liquid 5-hydroxymethylthiazole was obtained. The crude product can be used directly in the next reaction without purification.

MS (ESI) M / Z: 116 [M+H ⁺ ].

Step B: 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-(thiazol-5-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine trifluoroacetate

To a 10 ml high pressure reactor was added 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine sequentially ( 200 mg, 0.6 mmol, acetonitrile (2.0 ml), 5-hydroxymethylthiazole (690 mg, 6 mmol) and potassium t-butoxide (216 mg, 1.8 mmol). After stirring and mixing, the mixture was stirred at 100 ° C for 16 hours.

The reaction solution was cooled to room temperature, and the reaction solution was concentrated. The residue obtained was taken up in EtOAc (EtOAc)EtOAc. Preparative high performance liquid chromatography purification. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80 in 7 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 20.6 mg of the crude product as a yellow solid, 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(thiazol-5-ylmethoxy)-1H- Pyrazolo[3,4-d]pyrimidine-4-amine trifluoroacetate (yield 6.4%)

MS (ESI) M / Z: 422 [M+H ⁺ ].

¹⁹ F NMR (300 MHz, Methanol-d ₄ , ppm): δ - 77.0.

^{1 H NMR (300MHz, Methanol-} d 4, ppm): δ9.06 (s, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.52-7.40 (m, 4H), 5.81 (s, 2H), 5.60 (s, 2H), 4.38 (s, 2H), 3.54 - 3.47 (m, 2H), 3.23 - 3.14 (m, 2H), 2.21 - 2.15 (m, 2H), 2.07 - 1.97 (m, 2H).

Examples 34 and 35: (S)-6-(pent-2-yloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine and (R)-6-(pent-2-yloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[ 3,4-d]pyrimidine-4-amine

Synthetic scheme

Step A: (S)-6-(pent-2-yloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidin-4-amine and (R)-6-(pent-2-yloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine

To a 30 ml high pressure reactor, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine ( 620 mg, 1.81 mmol, 2-pentanol (15.0 mL), sodium tert-butoxide (1.01 g, 9.05 mmol). After stirring and dissolving, the mixture was stirred under heating at 150 ° C overnight.

After the reaction was cooled to room temperature. After the oil pump was concentrated under reduced pressure to remove 2-pentanol, it was dissolved in N,N-dimethylformamide (4.0 ml). The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 10% to 70% in 7 minutes; Detection wavelength: 254 nm. The product was collected, and after lyophilization, 185 mg of the title compound 6-(pent-2-yloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H as a white solid. -pyrazolo[3,4-d]pyrimidin-4-amine.

The racemate of 185 mg of white solid was resolved by chiral chromatography. The separation conditions were as follows, chiral column name: CHIRALPAK AD-3; chiral column size: 10*0.46 cm, 3.0 μm; mobile phase: n-hexane (containing 0.05% diethylamine) / ethanol = 70/30; flow rate: 1.00 ML/min; temperature: 25 ° C; detection wavelength: 254 nm. The product was collected and concentrated under reduced pressure to give (EtOAc, m. Pyrazolo[3,4-d]pyrimidin-4-amine (yield, 3.7%) and 31.8 mg of (S)-6-(pent-2-yloxy)-1-(4-) as a white solid (Pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (yield 4.5%).

(R)-6-(pent-2-yloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine

MS (ESI) M / Z: 495 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ , ppm): δ 7.94 (s, 1H), 7.31 - 7.22 (m, 4H), 5.41 (s, 2H), 5.36 - 5.22 (m, 1H), 3.62 ( s, 2H), 2.60–2.41 (m, 4H), 1.83–1.71 (m, 5H), 1.68–1.44 (m, 3H), 1.34 (d, J=6.2 Hz, 3H), 0.96 (t, J= 7.2 Hz, 3H).

Ee%=100%.

(S)-6-(pent-2-yloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine

¹ H NMR (300 MHz, Methanol-d ₄ , ppm): δ 7.94 (s, 1H), 7.30 - 7.21 (m, 4H), 5.41 (s, 2H), 5.36 - 5.24 (m, 1H), 3.60 ( s, 2H), 2.60–2.41 (m, 4H), 1.89–1.71 (m, 5H), 1.68–1.42 (m, 3H), 1.34 (d, J=6.2 Hz, 3H), 0.96 (t, J= 7.2 Hz, 3H).

MS (ESI) M / Z: 495 [M+H ⁺ ].

Ee%=99.5%.

Example 36: 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazolo[ 3,4-d]pyrimidine-4-amine

Synthetic scheme

Step A: 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazolo[3 ,4-d]pyrimidine-4-amine

To a 30 ml high pressure reactor, (tetrahydro-2H-pyran-4-yl)methanol (10 ml), 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl -1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.29 mmol) and potassium t-butoxide (97 mg, 0.87 mmol). After stirring and mixing well, the mixture was heated and stirred at 150 ° C overnight.

The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove solvent. N,N-dimethylformamide (2.00 ml) was added to the obtained solid residue to be purified. The crude product was purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80% in 7 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized to give 30.08 mg of 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-((tetrahydro-2H-pyran-4-yl) as a white solid. Methoxy)-1H-pyrazolo[3,4-d]pyrimidine-4-amine (yield 24.6%).

MS (ESI) M / Z: 422 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6, ppm): δ7.96 (s, 1H), 7.81-7.52 (m, 2H), 7.24 (d, J = 7.9Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 5.34 (s, 2H), 4.12 (d, J = 6.6 Hz, 2H), 3.87 - 3.76 (m, 2H), 3.50 (s, 2H), 3.31 - 3.26 (m, 2H), 2.37 (s, 4H), 2.08–1.97 (m, 1H), 1.76–1.53 (m, 6H), 1.44–1.21 (m, 2H).

Example 37: 6-(Pyridin-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine

Synthetic scheme

Step A: 6-(Pyridin-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine

In a 30 ml high pressure reactor, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was added in sequence. (160 mg, 0.47 mmol), acetonitrile (8.00 mL), 4-pyridinemethanol (512 mg, 4.7 mmol) and potassium tert-butoxide (263 mg, 2.53 mmol). After stirring and mixing well, it was stirred at 100 ° C overnight.

After the reaction mixture was cooled to room temperature, water (40 ml) was added to the reaction mixture to quench the reaction. Then, it was extracted with ethyl acetate (40 ml × 3 times). The organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, N,N-dimethylformamide (2.0 mL) was evaporated and evaporated. The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 10% to 80% in 7 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized to give 39.3 mg of 6-(pyridin-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyridin as a white solid. Zoxao[3,4-d]pyrimidin-4-amine (yield 20.1%).

MS (ESI) M / Z: 416 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6, ppm): δ8.54 (d, J = 5.7Hz, 2H), 7.97 (s, 1H), 7.91-7.64 (m, 2H), 7.40 (d, J = 5.7 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 7.8 Hz, 2H), 5.43 (s, 2H), 5.31 (s, 2H), 3.49 (s, 2H) , 2.37 (s, 4H), 1.66 (m, 4H).

Examples 38 and 39: 3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl )oxy)hexan-1-ol and 1-((4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)oxy)hexan-3-ol

Synthetic scheme

Step A: Hexane-1,3-diol

A solution of lithium aluminum hydride (4.81 g, 126.58 mmol) in tetrahydrofuran (200 ml) was added portionwise to a 500 ml three-necked flask under a nitrogen atmosphere. After stirring at -40 to -30 ° C for 10 minutes, ethyl butyrate (20.00 g, 126.58 mmol) was slowly added dropwise to the reaction mixture. After the dropwise addition was completed, the reaction apparatus was moved to room temperature and stirred for 2 hours.

Under ice-water bath, a saturated aqueous solution of ammonium chloride (200 ml) was slowly added dropwise to the reaction mixture. The resulting mixture was suction filtered under reduced pressure and the filtrate was collected. The filter cake was rinsed with ethyl acetate (20 mL x 2). The filtrates were combined and the upper organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 mL×3) and organic phases were combined. The organic layer was concentrated under reduced pressure. 6.53 g of hexane-1,3-diol as a colorless transparent liquid were obtained (yield: 43.7%).

Step B: 3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hex-1-ol formate and 1-((4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine - 6-yl)oxy)hexan-3-ol

In a 10 ml high pressure reactor, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was added in sequence. (150 mg, 0.44 mmol), hexane-1,3-diol (1.04 g, 8.8 mmol), potassium tert-butoxide (148 mg, 1.32 mmol) and acetonitrile (4.0 mL). After the raw materials were stirred and mixed uniformly, the reaction mixture was stirred with heating at 150 ° C overnight.

After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: Xselect C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 90% in 7 minutes; detection Wavelength: 254 nm. The product was collected and lyophilized to give EtOAc (EtOAc (EtOAc) Zoxao[3,4-d]pyrimidin-6-yl)oxy)hexan-1-ol formate and 35 mg of 1-((4-amino-1-(4-(pyrrolidine)-) as a white solid 1-Methylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexan-3-ol (96% purity, yield 18.8%).

22 mg (82% pure) of white solid 3-((4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)) as N,N-dimethylformamide (2.0 mL) The crude product of -1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexan-1-olcarboxylate was dissolved until clarified, and the mixture was again purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: Xselect C1819mm*150mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80% in 7 minutes; detection wavelength : 254 nm. The product was collected and lyophilized to give 10 mg of 3-((4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidin-6-yl)oxy)hexan-1-ol formate (yield 5.4%).

3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexyl- 1-alcohol formate

MS (ESI) M/Z: 425 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4): δ7.97 (s, 1H), 7.34-7.25 (m, 4H), 5.49-5.37 (m, 3H), 3.67-3.56 (m, 4H), 2.67- 2.50 (m, 4H), 1.98-1.91 (m, 2H), 1.89-1.76 (m, 4H), 1.76-1.62 (m, 2H), 1.52-1.36 (m, 2H), 0.95 (t, J = 7.3) Hz, 3H).

1-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexyl- 3-ol

MS (ESI) M/Z: 425 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ): δ 7.95 (s, 1H), 7.29 - 7.30 (m, 4H), 5.42 (s, 2H), 4.52 - 4.47 (m, 2H), 3.81 - 3.78 ( m,1H), 3.60 (s, 2H), 2.55–2.49 (m, 4H), 2.03–1.91 (m, 1H), 1.83–1.74 (m, 5H), 1.51–1.37 (m, 4H), 0.95– 0.91 (m, 3H).

Example 40: 6-(Pyridin-4-ylmethoxy)-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine

Synthetic scheme

Step A: 3-((4-Amino-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)

6-Chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.0 g, 23.5 mmol), 3-(bromomethyl)benzaldehyde (5.6 g, 28.2 mmol) and carbonic acid Potassium (6.5 g, 70.5 mmol) was added to N,N-dimethylformamide (100.0 mL).

Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 ml × 2). The combined organic phases were washed with aq. EtOAc (EtOAc m. The obtained solid residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc Zoxao[3,4-d]pyrimidin-1-yl)methyl)benzaldehyde (yield 31.3%).

MS (ESI) M / Z: 288 [M+H ⁺ ].

Step B: 6-Chloro-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

3-((4-Amino-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzaldehyde (2.0 g, 6.94 mmol) was dissolved in dichloromethane. 20.0 ml). Pyrrolidine (1.48 g, 20.83 mmol) was then added thereto. The reaction mixture was stirred at room temperature for 30 minutes. Then, sodium borohydride (2.2 g, 10.42 mmol) was added to the reaction mixture at 0 °C. Subsequently, the reaction apparatus was moved to room temperature and stirred for 3 hours.

Water (20 ml) was added to the reaction mixture to quench. The mixture was extracted with dichloromethane (20 mL×2×) and the organic phases were combined. The organic phase was washed with a saturated sodium chloride solution (30 ml × 2) and then dried over anhydrous sodium sulfate. The residue obtained was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to afford 340 mg of 6-chloro-1-(3-(pyrrolidine-1-yl) Benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (yield 14.2%).

MS (ESI) M / Z: 343 [M+H ⁺ ].

Step C: 6-(Pyridin-4-ylmethoxy)-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine

6-Chloro-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was added in sequence to a 10 mL high pressure reactor. 100 mg, 0.29 mmol, acetonitrile (4.0 mL), 4-pyridine methanol (317.2 mg, 0.92 mmol) and potassium t-butoxide (98.3 mg, 0.88 mmol). After stirring and mixing well, it was heated at 100 ° C overnight.

The reaction was concentrated and the residue was crystallised eluted elut elut The crude product was purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 5% to 75% in 10 minutes; Detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure to give 6.2 mg of 6-(pyridin-4-ylmethoxy)-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H- Pyrazolo[3,4-d]pyrimidin-4-amine (yield 5.1%).

MS (ESI) M / Z: 416 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6): δ8.54 (d, J = 6.0Hz, 2H), 7.98 (s, 1H), 7.96-7.60 (m, 2H), 7.41 (d, J = 6.0Hz , 2H), 7.26–7.12 (m, 3H), 7.05–6.95 (m, 1H), 5.43 (s, 2H), 5.34 (s, 2H), 3.49 (s, 2H), 2.45-2.30 (m, 4H) ), 1.70–1.59 (m, 4H).

Example 41: 6-(1-(Pyridin-4-yl)butoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d]pyrimidine-4-amine

Synthetic scheme

Step A: 1-(pyridin-4-yl)butan-1-ol

To a 100 ml three-neck round bottom flask, magnesium shavings (2.80 g, 116.7 mmol) and one elemental iodine granule were added. Vacuum was added to nitrogen, and tetrahydrofuran (50 ml) was added by a syringe. Subsequently, 5 to 10 drops of 1-bromopropane were added dropwise. Heat at 100 ° C until the solution changed from reddish brown to colorless and transparent. Next, the reaction mixture was stirred in an ice water bath for 10 minutes, and the remaining 1-bromopropane (11.50 g, 93.50 mmol) was slowly dropped, and stirred until the magnesium dust disappeared. The reaction system was cooled to minus 20 ° C, and 4-pyridinecarboxaldehyde (5.00 g, 46.7 mmol) was added dropwise. After the addition was completed, the reaction mixture was maintained at 0 ° C for 1 hour, and then naturally warmed to room temperature and stirred for 1 hour. TLC monitoring revealed the disappearance of 4-pyridine formaldehyde.

It was quenched with 50 ml of ice water and extracted with ethyl acetate (50 ml×3×). The organic phase was combined and washed with a saturated sodium chloride solution (50 ml × 2 times). It was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc: (Yield 64.3%).

Step B: 6-(1-(Pyridin-4-yl)butoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d Pyrimidine-4-amine formate

Add 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 to a 50 ml three-neck round bottom flask. -amine (100 mg, 0.29 mmol), acetonitrile (5.0 ml), 1-(pyridin-4-yl)butan-1-ol (880 mg, 5.83 mmol) and potassium t-butoxide (98 mg, 0.88 m Moore). The raw materials were stirred and mixed uniformly, and stirred at 80 ° C overnight.

The reaction mixture was concentrated under reduced vacuo. The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 10% to 90% in 7 minutes; Detection wavelength: 254 nm. Lyophilization at low temperature gave 58.9 mg of 6-(1-(pyridin-4-yl)butoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyridine as a white solid. Zoxao[3,4-d]pyrimidine-4-amine formate (yield 40.3%).

MS (ESI) M / Z: 458 [M+H ⁺ ] ⁺ .

^{1 H NMR (300MHz, Methanol-} d 4): δ8.51-8.39 (m, 2H), 7.93 (s, 1H), 7.54-7.43 (m, 2H), 7.31 (d, J = 7.8Hz, 2H) , 7.11 (d, J = 7.8 Hz, 2H), 6.06-6.01 (m, 1H), 5.54-5.19 (m, 2H), 4.17 (s, 2H), 3.21-3.06 (m, 4H), 2.17.76 (m, 6H), 1.67 - 1.36 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).

Examples 42 and 43: (R)-3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine -6-yl)oxy)hexan-1-ol and (S)-3-((4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[ 3,4-d]pyrimidin-6-yl)oxy)hexan-1-ol

Synthetic scheme

Step A: (S)-3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-6- Ethyl)hexan-1-ol

6-Chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was added sequentially to a 10 mL high pressure reactor. (300 mg, 0.88 mmol), potassium tert-butoxide (296 mg, 2.64 mmol), hexane-1,3-diol (2.08 g, 17.60 mmol) and acetonitrile (5.0 mL). After stirring and mixing well, it was stirred at 150 ° C overnight.

The reaction solution was cooled to room temperature and filtered. The filtrate obtained was purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80% in 7 minutes; Detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&& , 4-d]pyrimidin-6-yl)oxy)hexan-1-ol.

57 mg of racemate 3-((4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl )oxy)hexan-1-ol is subjected to chiral resolution. The separation conditions were as follows, chiral column name: CHIRAL AD; chiral column size: 0.46 cm * 10 cm, 5 um; mobile phase: n-hexane (containing 0.1% diethylamine) / ethanol = 70 / 30; flow rate: 1.00 ml / min Temperature: 25 ° C; detection wavelength: 254 nm. The product was collected and concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt; [3,4-d]pyrimidin-6-yl)oxy)hexan-1-ol (yield 4.9%) and 19.3 mg of (S)-3-(4-amino-1-(4) as a white solid -(Pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexan-1-ol (91% purity).

The crude product was purified by preparative high performance liquid chromatography, and the purification conditions were as follows. Column: X select C18 19 mm*150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; Gradient: Acetonitrile was raised from 10% to 80% in 7 minutes; detection wavelength: 254 nm. The product was collected, and lyophilized under reduced pressure to give 14.1 mg of colorless semi-solid (S)-3-((4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H- Pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexan-1-ol (yield 3.8%).

(R)-3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hexyl-1-ol, the absolute configuration of which is determined by SAR.

MS (ESI) M/Z: 425 [M+H ⁺ ].

¹ H NMR (300 MHz, Methanol-d ₄ ) δ 7.97 (s, 1H), 7.34-7.25 (m, 5H), 5.49-5.38 (m, 3H), 3.69-3.56 (m, 4H), 2.63-2.52 (m, 4H), 1.96-1.89 (m, 2H), 1.89-1.78 (m, 4H), 1.75-1.63 (m, 2H), 1.52-1.40 (m, 2H), 0.95 (t, J = 7.3 Hz) , 3H).

(S)-3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hexan-1-ol

MS (ESI) M/Z: 425 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 8.12 (s, 1H), 7.49-7.47 (m, 4H), 5.61-5.46 (m, 3H), 4.37 (s, 2H), 3.72-3.63 (m , 2H), 3.57-3.43 (m, 2H), 3.25-3.06 (m, 2H), 2.27-2.09 (m, 2H), 2.09-1.89 (m, 2H), 1.88-1.66 (m, 2H), 1.58 -1.38 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H).

¹⁹ F NMR (300 MHz, Methanol-d ₄ ) δ - 77.19.

Example 44: 2-butoxy-6-(5-methylthiazol-2-yl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2, 3-d]pyrimidine-4-amine

Synthetic scheme

Step A: 2-(2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-6- 5-methylthiazole

To a 250 ml single-necked flask, tetratriphenylphosphine palladium (1.26 g, 1.09 mmol), aqueous sodium carbonate solution (2.0 M, 6.3 ml, 12.6 mmol), 1,4-dioxane, was placed under a nitrogen atmosphere. Hexacyclic (100.0 ml), 2-bromo-5-methylthiazole (1.68 g, 9.44 mmol) and 2,4-dichloro-6-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.10 g, 4.73 mmol). After stirring and dissolved, the reaction solution was heated at 75 ° C for 2 hours.

After the reaction system was cooled to room temperature, ice water (200 ml) was added to the reaction liquid. The resulting mixture was extracted with ethyl acetate (100 mL×3×). The combined organic layers were dried over anhydrous sodium The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1). The product was collected and concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt; [2,3-d]pyrimidin-6-yl)-5-methylthiazole.

MS (ESI) M / Z: 415 [M+H ⁺ ].

Step B: 2-Chloro-6-(5-methylthiazol-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2, 3-d]pyrimidine-4-amine

2-(2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-] was added sequentially to a 50 ml high pressure reactor. d] Pyrimidine-6-yl)-5-methylthiazole (1.57 g, 3.79 mmol) and a solution of ammonia in isopropanol (30.0 mL, 2.0 mol/L, 60.0 mmol). After the raw material was stirred and dissolved, it was stirred at 60 ° C for 10 hours.

To the reaction system, ice water (100 ml) was added, and the aqueous phase was extracted with ethyl acetate (100 ml × 3 times), and the organic phase was combined. The organic phase was washed with water (50 ml×3×) then dried over anhydrous sodium sulfate and evaporated. 1.49 g of 2-chloro-6-(5-methylthiazol-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2] , 3-d]pyrimidine-4-amine.

MS (ESI) M / Z: 396 [M+H ⁺ ].

Step C: 2-butoxy-6-(5-methylthiazol-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-amine

Potassium tert-butoxide (1.25 g, 11.21 mmol), 30 ml of tert-butanol (30.0 ml) and 2-chloro-6-(5-methylthiazol-2-yl)- were sequentially added to a 50 ml high pressure reactor. 7-((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.10 g, 2.78 mmol). After stirring and mixing uniformly, the mixture was stirred at 120 ° C for 10 hours.

After the reaction system was cooled to room temperature, the reaction solution was poured into ice water (100 ml), and the reaction was quenched. The resulting mixture was extracted with ethyl acetate (100 mL×3×). The combined organic phases were washed with brine (50 mL×3×) then dried over anhydrous sodium sulfate. Yielding 0.95 g of 2-butoxy-6-(5-methylthiazol-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole [2,3-d]pyrimidine-4-amine. It is used directly in the next step without purification.

MS (ESI) M / Z: 434 [M+H ⁺ ].

Step D: 2-butoxy-6-(5-methylthiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a 100 ml single-mouth bottle, 2-butoxy-6-(5-methylthiazol-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl) was added in order. -7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.95 g, 2.19 mmol) and trifluoroacetic acid (30.0 mL). The reaction mixture was stirred at 60 ° C for 2 hours. Subsequently, the reaction liquid was concentrated under reduced pressure, and methanol (30.0 ml), water (20.0 ml) and potassium carbonate (1.38 g, 10.00 mmol) were added to the obtained brown liquid. After the raw materials were stirred and dissolved, they were further heated at 60 ° C for 2 hours.

The reaction solution was cooled to room temperature, and water (50 ml) was added to the mixture. Then, the mixture was concentrated under reduced pressure to remove methanol. The aqueous phase obtained was extracted with ethyl acetate (100 mL×3×). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. 1.05 g of the crude 2-butoxy-6-(5-methylthiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was obtained. It is used directly in the next step without purification.

MS (ESI) M / Z: 304 [M+H ⁺ ].

Step E: 4-((4-Amino-2-butoxy-6-(5-methylthiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl Benzaldehyde

To a 100 ml single-necked flask, potassium carbonate (0.34 g, 2.46 mmol), p-oxylbenzyl bromide (0.19 g, 0.98 mmol), 2-butoxy-6-(5-methylthiazole-2) was added in that order. -Base)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.25 g, 0.82 mmol) and acetonitrile (50.0 mL).

The reaction solution was suction filtered, and the filtrate was collected, and the filter cake was washed with ethyl acetate (20 ml x 2 times). The filtrate was combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1/2). The product was collected and concentrated under reduced pressure to give 0.27 g of 4-((4-amino-2-butoxy-6-(5-methylthiazol-2-yl)-7H-pyrrolo[2,3-d] Pyrimidin-7-yl)methyl)benzaldehyde.

MS (ESI) M / Z: 422 [M+H ⁺ ].

Step F: 2-butoxy-6-(5-methylthiazol-2-yl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3 -d]pyrimidine-4-amine

To a 100 ml single-mouth bottle, pyrrolidine (0.15 g, 2.11 mmol) was added in sequence, 4-((4-amino-2-butoxy-6-(5-methylthiazol-2-yl)-7H- Pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (0.20 g, 0.47 mmol) and sodium borohydride acetate (0.32 g, 1.41 mmol). The resulting mixture was stirred at room temperature for 10 hours.

The reaction mixture was concentrated under reduced pressure. EtOAc m. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 30 ml / min; gradient: acetonitrile from 20% to 80 in 9 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 20 mg of 2-butoxy-6-(5-methylthiazol-2-yl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl as a yellow solid. - 7H-pyrrolo[2,3-d]pyrimidin-4-amine (yield 8.9%).

MS (ESI) M / Z: 437 [M+H ⁺ ].

¹⁹ F NMR (300 MHz, CD ₃ OD) δ - 77.33.

_{^{1 H NMR (300MHz, CD 3}} OD) δ7.54 (s, 1H), 7.41 (d, J = 9.0Hz, 2H), 7.30 (d, J = 9.0Hz, 2H), 7.24 (s, 1H), 6.02(s,2H),4.55(t,J=6.5Hz,2H),4.32(s,2H),3.53-3.41(m,2H),3.21–3.08(m,2H),2.51(s,3H) , 2.26-2.09 (m, 2H), 2.08-1.91 (m, 2H), 1.89 - 1.75 (m, 2H), 1.60-1.43 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).

Examples 45 and 46: 6-((1-methoxypent-2-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[ 3,4-d]pyrimidine-4-amine and 6-((2-methoxypentyl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyridyl Oxazo[3,4-d]pyrimidin-4-amine

Synthetic scheme

Step A: Mixture of 1-methoxypentan-2-ol and 2-methoxypentan-1-ol

Sodium hydride (1.15 g, 60% wt, 48.08) was added slowly in portions to a solution of pentane-1,2-diol (5.00 g, 48.08 mmol) in tetrahydrofuran (100.0 mL). Millimoles). After stirring for 15 minutes, methyl iodide (8.19 g, 57.70 mmol) was slowly added dropwise to the reaction mixture. After the dropwise addition was completed, the reaction solution was moved to room temperature, and stirring was continued for 4 hours.

A saturated ammonium chloride solution (100 ml) was slowly added dropwise to the reaction mixture under ice water. The resulting mixture was allowed to stand, and the upper organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL×2×). Combine the organic phases. The combined organic phases were washed with water (50 mL×2×) then dried over anhydrous sodium sulfate. The obtained solid residue was purified by silica gel column chromatography (EtOAc /EtOAc The product was collected and concentrated under reduced pressure to give 2.13 g of a colorless transparent liquid as a mixture of 1-methoxypentan-2-ol and 2-methoxypentan-1-ol.

Step B: 6-((1-Methoxypentan-2-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine and 6-((2-methoxypentyl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole [3,4-d]pyrimidine-4-amine

Into a 10 ml high pressure reactor, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was added in sequence. (150 mg, 0.44 mmol), a mixture of 1-methoxypentan-2-ol and 2-methoxypentan-1-ol (1.04 g, 8.8 mmol), potassium t-butoxide (148 mg, 1.32 m) Mole) and acetonitrile (4.0 ml). The raw materials were stirred and mixed uniformly, and stirred at 150 ° C overnight.

The reaction liquid was cooled to room temperature, and the reaction liquid was concentrated under reduced pressure. The solid residue was dissolved in N,N-dimethylformamide (4.0 mL). Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 90 in 7 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 17.3 mg of 6-((1-methoxypentan-2-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl) as a white solid. -1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (yield 9.3%) and 14.5 mg of 6-((2-methoxypentyl)oxy group as a white solid. 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (yield: 7.8%).

6-((1-methoxypent-2-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine MS (ESI) M/Z: 425 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 8.17 (s, 1H), 7.50 - 7.53 (m, 2H), 7.45 - 7.42 (m, 2H), 5.58 (s, 3H), 4.37 (s, 2H) ), 3.76–3.61 (m, 2H), 3.60–3.44 (m, 2H), 3.37 (s, 3H), 3.26–3.13 (m, 2H), 2.28–1.90 (m, 4H), 1.86–1.67 (m) , 2H), 1.61 - 1.44 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H).

¹⁹ F NMR (300 MHz, Methanol-d ₄ ) δ-76.85.

6-((2-Methoxypentyl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine MS (ESI) M/Z: 425 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 8.14 (s, 1H), 7.52 - 7.49 (m, 2H), 7.43 - 7.40 (m, 2H), 5.54 (s, 2H), 4.58 - 4.46 (m , 1H), 4.48–4.42 (m, 1H), 4.42 (s, 2H), 3.69–3.59 (m, 1H), 3.56–3.41 (m, 5H), 3.23–3.10 (m, 2H), 2.29–1.92 (m, 4H), 1.70 - 1.48 (m, 4H), 0.98 (t, J = 7.2 Hz, 3H).

Example 47: 4-Amino-7-(4-(piperidin-1-ylmethyl)benzyl)-2-(pyridin-4-ylmethoxy)-7H-pyrrolo[2,3-d Pyrimidine-6-carbonitrile

Synthetic scheme

Step A: 6-Bromo-2-chloro-7-(4-(piperidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

4-((4-Amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (770 mg, 2.10 m) in an ice water bath To a solution of methylene chloride (20.0 mL) was added EtOAc (EtOAc, EtOAc (EtOAc) Subsequently, the reaction solution was stirred to room temperature and stirred overnight.

The reaction solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (EtOAc) (EtOAc) Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 70 ml / min; gradient: acetonitrile from 10% to 80 in 30 minutes %; detection wavelength: 254 nm. The product was collected and concentrated under reduced vacuo afforded <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; -d]pyrimidine-4-amine (yield 32.8%).

MS (ESI) M/Z: 434, 436 [M+H ⁺ ].

Step B: 6-Bromo-7-(4-(piperidin-1-ylmethyl)benzyl)-2-(pyridin-4-ylmethoxy)-7H-pyrrolo[2,3-d] Pyrimidine-4-amine

6-Bromo-2-chloro-7-(4-(piperidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 was added sequentially to a 20 mL high pressure reactor. -Amine (300 mg, 0.69 mmol), 4-hydroxymethylpyridine (376 mg, 3.45 mmol), potassium tert-butoxide (232 mg, 2.07 mmol) and acetonitrile (15.0 mL). After stirring and mixing well, it was heated at 150 ° C overnight.

The reaction solution was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5.0 ml) and purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 60 ml / min; gradient: acetonitrile from 10% to 90 in 30 minutes %; detection wavelength: 254 nm. The product was collected and concentrated under reduced vacuo to give EtOAc (EtOAc: EtOAc (EtOAc) -7H-pyrrolo[2,3-d]pyrimidin-4-amine (yield 46.9%).

MS (ESI) M/Z: 507, 509 [M+H ⁺ ].

Step C: 4-Amino-7-(4-(piperidin-1-ylmethyl)benzyl)-2-(pyridin-4-ylmethoxy)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile trifluoroacetate

Under nitrogen, zinc cyanide (37.4 mg, 0.32 mmol), tetrakistriphenylphosphine palladium (37.1 mg, 0.032 mmol), 1,1-bis(diphenylphosphino)ferrocene (17.8) Mg, 0.032 mmol) and zinc powder (41.6 mg, 0.64 mmol) were added to 6-bromo-7-(4-(piperidin-1-ylmethyl)benzyl)-2-(pyridin-4-yl) A solution of oxy)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (164 mg, 0.32 mmol) in N,N-dimethylformamide (5.0 mL). After stirring and mixing uniformly, the reaction liquid was stirred at 100 ° C for 3 hours.

After the reaction system was cooled to room temperature, the reaction solution was suction filtered, and the filtrate was collected and purified by preparative high-performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 30 ml / min; gradient: acetonitrile from 10% to 80 in 10 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 27.7 mg of 4-amino-7-(4-(piperidin-1-ylmethyl)benzyl)-2-(pyridin-4-ylmethoxy)-7H as a white solid. Pyrrolo[2,3-d]pyrimidine-6-carbonitrile trifluoroacetate (yield 18.9%).

MS (ESI) M/Z: 454 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ8.73 (d, J = 4.8Hz, 2H), 7.97 (d, J = 4.8Hz, 2H), 7.46 (d, J = 8.0Hz, 2H), 7.35 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 5.72 (s, 2H), 5.45 (s, 2H), 4.28 (s, 2H), 3.50-3.39 (m, 2H), 3.12 2.88 (m, 2H), 2.01-1.38 (m, 6H).

Example 48: 1-Benzyl-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Synthetic scheme

Step A: 1-Benzyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a 50 ml three-necked flask, 6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (400 mg, 2.37 mmol), potassium carbonate (981 mg, 7.11 m) was added sequentially at room temperature. Mole), acetonitrile (20 mL) and benzyl bromide (480 mg, 2.84 mmol). The resulting mixture was stirred at room temperature overnight.

Work-up: The reaction solution was concentrated under reduced pressure. The obtained solid residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut elut -1H-pyrazolo[3,4-d]pyrimidin-4-amine (yield 51.5%).

MS (ESI) M / Z: 260 [M+H ⁺ ].

Step B: 1-Benzyl-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a 10 ml high pressure reactor, 1-benzyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.39 mmol), potassium t-butoxide ( 131 mg, 1.17 mmol, 4-pyridinemethanol (850 mg, 7.80 mmol) and acetonitrile (4.0 mL). After stirring and mixing well, the oil bath was heated at 150 ° C overnight.

Post-treatment: The reaction system was cooled to room temperature, and ice water (30 ml) was added to the reaction mixture to quench the reaction. The resulting mixture was extracted with ethyl acetate (50 mL × 3) The combined organic phases were back-washed with saturated brine (100 mL×3) then dried over anhydrous sodium sulfate. The residue was dissolved in EtOAc (EtOAc) (EtOAc) Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 100% in 7 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized at low temperature and reduced pressure. 7.5 mg of 1-benzyl-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine-4-amine formate as a brown solid (yield 5.8%) ).

MS (ESI) M/Z: 333 [M+H ⁺ ].

¹ H NMR (300 MHz, Chloroform-d) δ 8.72-8.63 (s, 2H), 7.87 (s, 1H), 7.53-7.47 (m, 2H), 7.28-7.11 (m, 5H), 5.80-5.68 ( m, 2H), 5.56 (s, 2H), 5.46 (s, 2H).

Example 49: 6-(Pyridin-4-ylmethoxy)-1-(5-(pyrrolidin-1-yl)pentyl)-1H-pyrazolo[3,4-d]pyrimidine-4- amine

Synthetic scheme

Step A: 1-(5-Bromopentyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

N-N-di- 6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 0.83 mmol) in an ice-water bath To a solution of methylformamide (5.0 ml) was added sodium hydride (36.4 mg, 0.91 mmol). After stirring at 0 ° C for 30 minutes, 1,5-dibromopentane (570 mg, 2.48 mmol) was added to the reaction mixture. Subsequently, the reaction solution was stirred at room temperature for 2 hours.

Ice water (10 ml) was added to the reaction mixture to quench the reaction. The resulting mixture was extracted with ethyl acetate (10 mL×3×). The organic phase was washed with saturated sodium chloride (10 mL×2×) then dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (EtOAc:EtOAc The product was collected and concentrated under reduced pressure to give &lt;RTIgt;&lt;&quot;&&&&&&&&&&&&&&&&&&&&&& 4-Amine (yield 30.9%).

MS (ESI) M/Z: 391, 393 [M+H ⁺ ].

Step B: 6-(Pyridin-4-ylmethoxy)-1-(5-(pyrrolidin-1-yl)pentyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To 1-(5-bromopentyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.23 mmol) Anhydrous potassium carbonate (96.1 mg, 0.70 mmol) was added to a solution of acetonitrile (5.0 mL). The resulting mixture was stirred at room temperature overnight.

The reaction solution was filtered, and the filtrate was collected, and the filter cake was washed with ethyl acetate (10 ml × 2 times). The filtrate was combined and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5.0 ml) and purified by preparative HPLC. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 80 ml / min; gradient: acetonitrile from 10% to 70 in 20 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 32.7 mg of 6-(pyridin-4-ylmethoxy)-1-(5-(pyrrolidin-1-yl)pentyl)-1H-pyrazolo[3. , 4-d]pyrimidin-4-amine (yield 33.6%).

MS (ESI) M / Z: 382 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ8.85 (d, J = 5.2Hz, 2H), 8.11 (d, J = 5.2Hz, 2H), 8.05 (s, 1H), 5.80 (s, 2H) , 4.29 (t, J = 6.7 Hz, 2H), 3.73 - 3.53 (m, 2H), 3.21-2.94 (m, 4H), 2.24-1.88 (m, 6H), 1.86-1.70 (m, 2H), 1.46 -1.22 (m, 2H).

¹⁹ F NMR (300 MHz, Methanol-d ₄ ,) δ-77.20.

Example 50: 4-Amino-2-((2-methoxypyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole And [2,3-d]pyrimidine-6-carbonitrile

synthetic route

Step A: 6-Bromo-2-((2-methoxypyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole [2,3-d]pyrimidine-4-amine

6-Bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 was added sequentially to a 10 mL high pressure reactor. -amine (150 mg, 0.36 mmol), (2-methoxypyridin-4-yl)methanol (500 mg, 3.60 mmol), acetonitrile (2.0 ml) and potassium t-butoxide (120 mg, 1.10 mmol) ). After stirring and dissolving, the reaction solution was heated at 120 ° C for 4 hours under a nitrogen atmosphere.

After the reaction system was cooled to room temperature, the reaction solution was concentrated under reduced pressure. Ethyl acetate (50 mL) was added to the concentrate. After the dissolution, the organic solution was washed with saturated brine (30 ml × 2×), then dried over anhydrous sodium sulfate and evaporated. Yield 200 mg of yellow liquid 6-bromo-2-((2-methoxypyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H- Pyrrolo[2,3-d]pyrimidin-4-amine (crude product). The compound was used directly in the next step without purification.

MS (ESI) M/Z: 523, 525 [M+H ⁺ ].

Step B: 4-Amino-2-((2-methoxypyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole [2,3-d]pyrimidine-6-carbonitrile

In a 10 ml two-neck round bottom flask, 6-bromo-2-((2-methoxypyridin-4-yl)methoxy)-7-(4-(pyrrolidine-1) was sequentially added under a nitrogen atmosphere. -ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (200 mg, crude), N,N-dimethylformamide (3.0 ml), zinc cyanide (93 mg, 0.8 mmol), tetrakistriphenylphosphine palladium (46 mg, 0.04 mmol), zinc powder (52 mg, 0.8 mmol) and 1,1-bis(diphenylphosphino)ferrocene (44 mg, 0.08 mmol). After the raw materials were uniformly mixed, the reaction liquid was stirred at 110 ° C for 16 hours.

After the reaction liquid was cooled to room temperature, the reaction liquid was filtered. The filtrate was collected and the filtrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80 in 7 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 33.0 mg of white solid 4-amino-2-((2-methoxypyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl) Benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-carbonitrile trifluoroacetate (15.7% yield in two steps).

MS (ESI) M/Z: 470 [M+H ⁺ ].

¹⁹ F NMR (300 MHz, DMSO-d ₆ ) δ - 74.50.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.13 (d, J = 5.1 Hz, 1H), 7.98 - 7.67 (m, 2H), 7.63 - 7.43 (m, 3H), 7.21. (d, J = 7.8 Hz, 2H), 7.00 (d, J = 4.2 Hz 1H), 6.80 (s, 1H), 5.38 (s, 2H), 5.36 (s, 2H), 4.32 (d, J = 5.6 Hz, 2H), 3.83 (s, 3H), 3.44 - 3.28 (m, 2H), 3.16 - 2.98 (m, 2H), 2.11 - 1.93 (m, 2H), 1.89 - 1.74 (m, 2H).

Examples 51 and 52: (S)-4-amino-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[ 2,3-d]pyrimidine-6-carbonitrile and (R)-4-amino-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl )-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

synthetic route

Step A: 6-Bromo-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine 4-amine

6-Bromo-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2] was added sequentially to a 10 mL high pressure reactor. , 3-d]pyrimidin-4-amine (150 mg, 0.36 mmol), pentan-2-ol (2.0 ml) and potassium t-butoxide (120 mg, 1.10 mmol). After the mixture was uniformly mixed, the reaction solution was heated at 120 ° C and stirred for 12 hours.

After the reaction system was cooled to room temperature, the reaction mixture was concentrated under reduced pressure to yield 180 mg of pale liquid. The compound was used directly in the next step without purification.

MS (ESI) M/Z: 472, 474 [M+H ⁺ ].

Step B: (S)-4-Amino-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3 -d]pyrimidine-6-carbonitrile and (R)-4-amino-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H -pyrrolo[2,3-d]pyrimidine-6-carbonitrile

6-Bromo-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl) was added sequentially to a 25 ml three-neck round bottom flask under a nitrogen atmosphere. -7H-pyrrolo[2,3-d]pyrimidin-4-amine (180 mg, 0.4 mmol), N,N-dimethylformamide (3.0 ml), zinc cyanide (93 mg, 0.8 mmol) ), tetrakistriphenylphosphine palladium (46 mg, 0.04 mmol), zinc powder (52 mg, 0.8 mmol) and 1,1-bis(diphenylphosphino)ferrocene (44 mg, 0.08 mmol) ). After stirring and mixing uniformly, the mixture was stirred at 110 ° C for 16 hours.

After the reaction solution was cooled to room temperature, it was filtered. The filtrate was collected and the filtrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80 in 7 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 33.5 mg of white 4-amino-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole. [2,3-d]pyrimidine-6-carbonitrile.

The 33.5 mg racemic chirality was resolved. The separation conditions were as follows, chiral column name: CHIRALPAK IC-3; chiral column size: 10 cm * 0.46 cm, 3.0 μm; mobile phase: n-hexane (containing 0.1% diethylamine): ethanol = 80: 20; flow rate: 1.00 ML/min; temperature: 25 ° C; detection wavelength: 254 nm. The product was collected and concentrated under reduced vacuo afforded EtOAc (EtOAc: EtOAc (EtOAc) Pyrazolo[3,4-d]pyrimidin-4-amine (yield, 4.9%) and 6.9 mg of white solid as (S)-6-(pent-2-yloxy)-1-(4- (Pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (yield 4.1%). The absolute configuration of the product was not determined.

(S)-4-amino-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile

MS (ESI) M / Z: 418 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 7.35-7.27 (m, 5H), 5.45 (s, 2H), 5.34-5.22 (m, 1H), 3.64 (s, 2H), 2.63-2.46 (m) , 4H), 1.86-1.72 (m, 5H), 1.68-1.38 (m, 3H), 1.34 (d, J = 6.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H).

(R)-4-amino-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile

MS (ESI) M / Z: 418 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ7.35-7.27 (m, 5H), 5.45 (s, 2H), 5.34-5.20 (m, 1H), 3.64 (s, 2H), 2.56-2.46 (m , 4H), 1.90-1.70 (m, 5H), 1.69-1.38 (m, 3H), 1.34 (d, J = 6.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H).

Example 53: 6-(Pyridin-2-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine

Synthetic scheme

Step A: 6-(Pyridin-2-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine

In a 30 ml high pressure reactor, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was added in sequence. (0.20 mg, 0.57 mmol), 2-pyridinemethanol (2.0 ml) and potassium t-butoxide (0.19 g, 1.70 mmol). After stirring and stirring, the reaction solution was stirred at 150 ° C overnight under a nitrogen atmosphere.

After the reaction system was cooled to room temperature, ice water (30 ml) was added to the reaction mixture to quench the reaction. The resulting mixture was extracted with ethyl acetate (50 mL×3×). The combined organic layers were washed with EtOAc EtOAc m. The residue was dissolved in N,N-dimethylformamide (4.0 mL). Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 30% in 6 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized to give 80.2 mg (yield of 6-(pyridin-2-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole as a pale yellow solid. [3,4-d]pyrimidine-4-amine (yield 33.8%).

MS (ESI) M / Z: 416 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ8.56 (d, J = 4.5Hz, 1H), 8.02 (s, 1H), 7.92-7.76 (m, 3H), 7.43 (d, J = 7.8Hz, 1H), 7.39–7.30 (m, 1H), 7.20–7.10 (m, 4H), 5.45 (s, 2H), 5.31 (s, 2H), 3.50 (s, 2H), 2.42–2.25 (m, 4H) , 1.80–1.56 (m, 4H).

Example 54: 6-(isoxazol-3-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine

Synthetic scheme

Step A: 6-(isoxazol-3-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine 4-amine

In a 30 ml high pressure reactor, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was added in sequence. (200 mg, 0.57 mmol), isoxazol-3-ylmethanol (190 mg, 1.92 mmol), potassium tert-butoxide (190 mg, 1.70 mmol) and anhydrous acetonitrile (5.0 mL). After stirring and dissolving, it was stirred at 150 ° C overnight under a nitrogen atmosphere.

After the reaction system was cooled to room temperature, ice water (30 ml) was added to the reaction mixture to quench the reaction. The resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with EtOAc EtOAc m. The residue was dissolved in N,N-dimethylformamide (4.0 mL). Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 100% in 7 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized to give 24.4 mg (yield. And [3,4-d]pyrimidine-4-amine (yield 10.5%).

MS (ESI) M/Z: 406 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ8.65 (s, 1H), 8.00 (s, 1H), 7.32-7.22 (m, 4H), 6.59 (s, 1H), 5.56 (s, 2H), 5.45 (s, 2H), 3.64 (s, 2H), 2.63 - 2.50 (m, 4H), 1.89 - 1.74 (m, 4H).

Example 55: 6-(pent-2-yloxy)-1-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine

Synthetic scheme

Step A: 6-(pent-2-yloxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine 4-amine

For details, see the synthesis of 6-butoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 6-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500.0 mg, 1.67 mmol) ), potassium tert-butoxide (280 mg, 2.5 mmol), pentan-2-ol (1.47 g, 16.7 mmol). 430 mg of a white solid are obtained as 6-(pent-2-yloxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine (yield 73.1%).

MS (ESI) M / Z: 352 [M+H ⁺ ].

Step B: 6-(pent-2-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

For details, see the synthesis of 6-butoxy-1H-pyrazolo[3,4-d]pyrimidine-4-amine. 6-(pent-2-yloxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4- Amine (430 mg, 1.23 mmol), trifluoroacetic acid (10.0 mL), methanol (20.0 mL), EtOAc (EtOAc) 196 mg of a white solid were obtained as 6-(pent-2-yloxy)-1H-pyrazolo[3,4-d]pyrimidine-4-amine (yield: 71.8%).

MS (ESI) M / Z: 222 [M+H ⁺ ].

Step C: 1-((trans-4-(bromomethyl)cyclohexyl)methyl)-6-(pent-2-yloxy)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine

See 1-((4-(Bromomethyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine for details. Synthesis. 6-(pent-2-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.45 mmol), acetonitrile (5.0 mL), trans-1,4 Bis(bromomethyl)cyclohexane (361 mg, 1.35 mmol) and anhydrous potassium carbonate (310 mg, 2.25 mmol). Obtained 77.0 mg of a white semisolid as 1-((trans-4-(bromomethyl)cyclohexyl)methyl)-6-(pent-2-yloxy)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine (yield 42%).

MS (ESI) M/Z: 410, 412 [M+H ⁺ ].

Step D: 6-(pent-2-yloxy)-1-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine

See 6-(pyridin-4-ylmethoxy)-1-((4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3,4-d] for details. Synthesis of pyrimidine-4-amine. 1-((trans-4-(bromomethyl)cyclohexyl)methyl)-6-(pent-2-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (77 mg, 0.19 mmol), acetonitrile (5.0 ml), potassium carbonate (138 mg, 1.0 mmol) and pyrrolidine (71 mg, 1.0 mmol). 34.0 mg of a white solid are obtained as 6-(pent-2-yloxy)-1-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazole [3,4-d]pyrimidine-4-amine (yield 44.7%).

MS (ESI) M / Z: 401 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 7.92 (s, 1H), 7.83 - 7.22 (m, 2H), 5.24 - 5.00 (m, 1H), 5.12 (d, J = 5.4 Hz, 2H), 2.34 (s, 4H), 2.15 (d, J = 6.9 Hz, 2H), 1.83 - 1.72 (m, 2H), 1.70 - 1.60 (m, 4H), 1.58 - 1.45 (m, 3H), 1.42 - 1.30 ( m, 3H), 1.29 - 1.19 (m, 4H), 1.06 - 0.71 (m, 8H).

Example 56: 3-(4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yloxy) Pent-1-ol

Synthetic scheme

Step A: 3-hydroxyvalerate ethyl ester

To a solution of ethyl propionylacetate (19.5 g, 130 mmol) in methanol (300.0 ml), sodium borohydride (2.57 g, 70 mmol). After the addition was completed, the reaction solution was further stirred at 0 ° C for 1 hour.

Work-up: Water (300 ml) was added to the reaction mixture. The resulting mixture was concentrated under reduced pressure to remove methanol. The residual aqueous phase was extracted with ethyl acetate (300 mL×3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride (200 ml, 3) and dried over anhydrous sodium sulfate. The residue after concentration was purified by silica gel column (eluent: petroleum ether / ethyl acetate = 3/1). The product was collected and concentrated to dryness under reduced pressure to yieldd 12.3 g of pale yellow liquid as ethyl 3-hydroxypentanoate (yield 62.21%).

Step B: ethyl 3-((tert-butyldimethylsilyl)oxy)pentanoate

To a solution of ethyl 3-hydroxyvalerate (7.3 g, 50 mmol) in dichloromethane (300.0 mL), EtOAc (10.2 g, 150 mmol) and tert. Silane (15.0 g, 100 mmol). Subsequently, the reaction solution was stirred at room temperature for 12 hours.

Work-up: Water (300 ml) was added to the reaction mixture to quench. The resulting mixture was allowed to stand for separation. The organic phase was separated and the aqueous extracted with dichloromethane (300 mL×3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride (200 ml, 3) and dried over anhydrous sodium sulfate. The residue obtained was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20/1). The product was collected and concentrated under reduced pressure to give EtOAc (yield: EtOAc (EtOAc)

Step C: 3-((tert-Butyldimethylsilyl)oxy)pentan-1-ol

Boron was added to a solution of ethyl 3-((tert-butyldimethylsilyl)oxy)pentanoate (6.0 g, 20 mmol) in tetrahydrofuran (150.0 mL) at 0 ° C under nitrogen. Sodium hydride (1.09 g, 30 mmol) and aluminum trichloride (1.22 g, 10 mmol). The raw materials were stirred and mixed uniformly, and stirred at room temperature for 16 hours.

Work-up: The reaction was quenched by the addition of ice brine (200 mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride (200 ml, 3) and dried over anhydrous sodium sulfate. The residue obtained was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3/1). The product was collected and concentrated under reduced pressure to give 4.6 g (yield: </ RTI> <RTIgt;

Step D: tert-Butyldimethyl((1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)oxy)silane

To a solution of 3-((tert-butyldimethylsilyl)oxy)pentan-1-ol (4.6 g, 20 mmol) in 3,4-dihydropyran (150.0 mL) at 0 °C p-Toluenesulfonic acid (180 mg, 1.05 mmol) was added. Subsequently, the reaction solution was further stirred at 0 ° C for 30 minutes.

Work-up: The reaction was quenched by the addition of saturated aqueous sodium carbonate (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride (100 mL? The residue obtained was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20/1). The product was collected and concentrated under reduced pressure to give 3.9 g of EtOAc (EtOAc: EtOAc (EtOAc) Silane (yield 61.14%).

Step E: 1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol

Add tert-butyldimethyl((1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)oxy)silane (3.9 g, 10 mmol) to four A solution of butyl ammonium fluoride in tetrahydrofuran (200 mmol, 1.0 mol/L, 200 mL). Subsequently, the reaction solution was stirred at room temperature for 16 hours.

Work-up: The reaction was quenched by the addition of saturated aqueous sodium carbonate (200 mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride (300 ml, 2) and dried over anhydrous sodium sulfate. The concentrated residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3/1). The product was collected and concentrated under reduced pressure to give diethyl ether (yield: EtOAc (EtOAc: EtOAc)

Step F: 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-((1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3- Ethyl)oxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

In a 10 ml high pressure reactor, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole[3,4-d] was added sequentially under a nitrogen atmosphere. Pyrimidin-4-amine (100 mg, 0.29 mmol), 1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol (548 mg, 2.92 mmol) and tert-butanol Potassium (108 mg, 0.97 mmol). The raw materials were stirred and mixed uniformly, and then stirred at 100 ° C for 3 hours.

After treatment: The reaction system is cooled to room temperature. N,N-dimethylformamide (3 ml) was added to the reaction mixture for dilution. The mixture was filtered and the filtrate was collected. The filtrate was purified by flash reverse phase chromatography. Mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile increased from 5% to 100% in 40 minutes; detection wavelength: 254 nm. The product was collected and the solvent was evaporated in vacuo to give white crystals (30g,jjjjjjjjjjjjj -yl)oxy)pentan-3-yl)oxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (yield 24.92%).

MS (ESI) M / Z: 495 [M+H ⁺ ].

Step G: 3-(4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yloxy)pentyl -1-ol

Into a 10 ml two-necked flask, 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-((1-((tetrahydro-2H-pyran-2-yl))oxy) was added sequentially. Pentyl-3-yl)oxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (36 mg, 0.07 mmol), methanol (3.0 ml) and p-toluenesulfonic acid (6) Mg, 0.04 mmol). Subsequently, the reaction solution was stirred at room temperature for 36 hours.

Work-up: The reaction was directly purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 90% in 16 minutes; Detection wavelength: 254 nm. The product was collected, and lyophilized under reduced pressure to give 14.8 mg of white solid 3-(4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d] Pyrimidine-6-yloxy)pentan-1-ol (yield 49.53%).

MS (ESI) M / Z: 411 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 7.97 (s, 1H), 7.38 - 7.27 (m, 4H), 5.44 (s, 2H), 5.38 - 5.30 (m, 1H), 3.70 - 3.62 (m) , 4H), 2.72 - 2.54 (m, 4H), 1.96 - 1.89 (m, 2H), 1.85 - 1.71 (m, 6H), 7.97 (t, J = 7.2 Hz, 3H).

Example 57: 6-(Pyridin-4-ylmethoxy)-1-((cis-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3 ,4-d]pyrimidine-4-amine

Synthetic scheme

Step A: cis-1,4-bis(bromomethyl)cyclohexane

See the synthesis of trans-1,4-bis(bromomethyl)cyclohexane for details. Cis-cyclohexane-1,4-diyldimethanol (10.0 g, 69.4 mmol), toluene (100 mL), phosphorus tribromide (18.8 g, 69.4 mmol). 14.5 g of a yellow oily liquid was obtained as cis-1,4-bis(bromomethyl)cyclohexane (yield: 77.3%).

Step B: 1-((cis-4-(Bromomethyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine 4-amine

See 1-((4-(Bromomethyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine for details. Synthesis. 6-(Pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 0.37 mmol), acetonitrile (3.0 mL), anhydrous 154 mg, 1.12 mmol). Obtained 85 mg of yellow solid 1-((cis-4-(bromomethyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazole[3,4- d] Pyrimidine-4-amine (yield 53.1%).

MS (ESI) M/Z: 431, 433 [M+H ⁺ ].

Step C: 6-(Pyridin-4-ylmethoxy)-1-((cis-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine

See 6-(pyridin-4-ylmethoxy)-1-((4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3,4-d] for details. Synthesis of pyrimidine-4-amine. 1-((cis-4-(bromomethyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine-4- Amine (85 mg, 0.20 mmol), acetonitrile (2.0 mL), tetrahydropyrrole (140 mg, 1.97 mmol) and anhydrous potassium carbonate (81.6 mg, 0.59 mmol). Yield 6.0 mg of the yellow oily compound as 6-(pyridin-4-ylmethoxy)-1-((cis-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyridyl Zoxao[3,4-d]pyrimidin-4-amine (yield 7.2%).

MS (ESI) M / Z: 422 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ8.84 (s, 2H), 8.19-8.08 (m, 2H), 8.04 (s, 1H), 5.78 (s, 2H), 4.23 (d, J = 7.6 Hz, 2H), 3.80–3.60 (m,, 2H), 3.21 (d, J = 7.2 Hz, 2H), 3.20–3.05 (m, 2H), 2.28–1.91 (m, 6H), 1.70–1.46 (m) , 6H), 1.45–1.30 (m, 2H).

Example 58: (S)-4-Amino-2-((1-hydroxyhex-3-yl)oxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H- Pyrrolo[2,3-d]pyrimidine-6-carbonitrile

Synthetic scheme

Step A: (S)-3-(4-Amino-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine- 2-yloxy)hexan-1-ol

In a 30 ml high pressure reactor, 6-bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-Amine (0.50 g, 1.19 mmol, 1.00 equiv), (S)-heptane-1,3-diol (1.57 g, 11.93 mmol, 10.00 eq; see (S)-3-((4- Synthesis of amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexan-1-ol 2 , Synthesis of 2,2-trifluoro) and potassium tert-butoxide (0.40 g, 3.67 mmol, 3.00 equivalent). After stirring and stirring, the reaction was stirred at 100 ° C for 3 hours.

Post-treatment: The reaction system was cooled to room temperature, and ice water (30 ml) was added to the reaction mixture to quench the reaction. The resulting mixture was extracted with ethyl acetate (50 mL×3×). The organic phase was back-washed with saturated brine (100 mL×3×) then dried over anhydrous sodium sulfate. The concentrated crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 5% to 100 in 7 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 68 mg of white solid as (S)-3-((4-amino-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl) -7H-pyrrolo[2,3-d]pyrimidin-2-yl)oxy)hexan-1-ol (yield 11.4%).

MS (ESI) M / Z: 502, 504 [M+H] ⁺ .

Step B: (S)-4-Amino-2-((1-hydroxyhex-3-yl)oxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole And [2,3-d]pyrimidine-6-carbonitrile

See 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine for details. Synthesis of -6-carbonitrile. (S)-3-((4-Amino-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2- Alkyloxy)hexanol (68 mg, 0.14 mmol, 1.00 equiv), zinc cyanide (31 mg, 0.27 mmol, 2.00 equiv), zinc powder (17 mg, 0.27 mmol, 2.00 equiv) 1,1'-bis(diphenylphosphino)ferrocene (15 mg, 0.03 mmol, 0.20 equivalent), tetratriphenylphosphine palladium (31 mg, 0.03 mmol, 0.20 equivalent) and N,N- Dimethylacetamide (3.0 ml). 4.4 mg of a white solid are obtained as (S)-4-amino-2-((1-hydroxyhex-3-yl)oxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl - 7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (yield 7.0%).

MS (ESI) M / Z: 449 [M+H] ⁺ .

¹ H NMR (300MHz, Methanol-d ₄ ) δ 7.36–7.25 (m, 5H), 5.48–5.34 (m, 3H), 3.69–3.65 (m, 4H), 2.68–2.51 (m, 4H), 1.98 -1.89 (m, 2H), 1.85 - 1.83 (m, 4H), 1.78 - 1.61 (m, 2H), 1.54 - 1.31 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H).

Example 59: (R)-4-Amino-2-(1-hydroxyhex-3-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole [2,3-d]pyrimidine-6-carbonitrile

Synthetic scheme

Step A: (R)-3-(4-Amino-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine- 2-yloxy)hexan-1-ol

See (S)-3-(4-Amino-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2 for details. Synthesis of -yloxy)hexan-1-ol, step A. 6-Bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.50 g, 1.19 mmol) , 1.00 equivalent), (R)-heptane-1,3-diol (1.57 g, 11.93 mmol, 10.00 equivalent; see (R)-3-((4-amino-1-(4-(pyrrolidine)) Synthesis of -1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yloxy) and potassium tert-butoxide (0.40 g, 3.67 mmol, 3.00 equiv) 72 mg of a white solid are obtained as (R)-3-(4-amino-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2, 3-d]pyrimidin-2-yloxy)hexan-1-ol (yield 12.1%).

MS (ESI) M / Z: 502, 504 [M+H] ⁺ .

Step B: (R)-4-Amino-2-(1-hydroxyhex-3-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[ 2,3-d]pyrimidine-6-carbonitrile

See 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine for details. Synthesis of -6-carbonitrile, step B. (S)-3-(4-Amino-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl Oxy)hexan-1-ol (72 mg, 0.14 mmol, 1.00 equiv), zinc cyanide (33 mg, 0.29 mmol, 2.00 equiv), zinc powder (18 mg, 0.29 mmol, 2.00 equiv), 1 , 1'-bis(diphenylphosphino)ferrocene (16 mg, 0.03 mmol, 0.20 equivalent), tetrakis(triphenylphosphine)palladium (33 mg, 0.03 mmol, 0.20 equivalent) and N,N- Dimethylacetamide (3.00 ml). Obtained 3.5 mg of a white solid as (R)-4-amino-2-(1-hydroxyhex-3-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)- 7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (yield 5.6%).

MS (ESI) M / Z: 449 [M+H] ⁺ .

¹ H NMR (300 MHz, Methanol-d ₄ ) δ 7.42-7.24 (m, 5H), 5.57-5.30 (m, 3H), 3.76-3.60 (m, 4H), 2.68-2.49 (m, 4H), 2.00 -1.99 (m, 2H), 1.97-1.88 (m, 4H), 1.78-1.63 (m, 2H), 1.52-1.38 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H).

Example 60: 6-(Pyridin-4-ylmethoxy)-1-(7-(pyrrolidin-1-yl)heptyl)-1H-pyrazolo[3,4-d]pyrimidine-4- amine

Synthetic scheme

Step A: 1-(7-Bromoheptyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

For details, see the synthesis of 1-(3-bromopropyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 6-(Pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.62 mmol), N,N-dimethylacetamide (8.0 ML), 1,7-dibromoheptane (450 mg, 1.86 mmol), potassium carbonate (257 mg, 1.86 mmol). Obtained 45 mg of white solid 1-(7-bromoheptyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (yield 17.3%) ).

MS (ESI) M / Z: 419, 421 [M+H ⁺ ].

Step B: 6-(Pyridin-4-ylmethoxy)-1-(7-(pyrrolidin-1-yl)heptyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

For details, see the synthesis of 6-(pyridin-4-ylmethoxy)-1-(6-(pyrrolidin-1-yl)hexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. . 1-(7-Bromoheptyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (45 mg, 0.11 mmol), N N-dimethylacetamide (5.0 ml), potassium carbonate (44 mg, 0.32 mmol) and pyrrolidine (23 mg, 0.32 mmol). 5.7 mg of light gray solid 6-(pyridin-4-ylmethoxy)-1-(7-(pyrrolidin-1-yl)heptyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine (yield 12.6%).

MS (ESI) M / Z: 410 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ8.57-8.52 (m, 2H), 7.97 (s, 1H), 7.54 (d, J = 6.0Hz, 2H), 5.54 (s, 2H), 4.24 ( t, J=6.9 Hz, 2H), 2.53–2.51 (m, 4H), 2.44–2.30 (m, 2H), 2.05–1.76 (m, 6H), 1.52–1.42 (m, 2H), 1.38–1.13 ( m, 6H).

Example 61: 6-((2-Methylpyridin-4-yl)methoxy)-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine

Synthetic scheme

Step A: 6-Chloro-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 1.18 mmol) in acetonitrile (5.0 mL), anhydrous potassium carbonate (342 mg, 2.48 m) Mole) and 4-chloromethylpyridine (670 mg, 2.48 mmol). The resulting reaction solution was stirred at 80 ° C overnight.

Work-up: The reaction system was cooled to room temperature, and water (10 mL) was then evaporated. The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and then evaporated. The residue was purified with EtOAc EtOAc EtOAcjjjjjjjj Pyrazolo[3,4-d]pyrimidin-4-amine (yield 78%).

MS (ESI) M / Z: 266 [M+H ⁺ ].

Step B: 6-((2-Methylpyridin-4-yl)methoxy)-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-4- amine

See 6-(pyridin-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4- Synthesis of amines. 6-Chloro-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (240 mg, 0.92 mmol), acetonitrile (10.0 mL), tert. Potassium alkoxide (309 mg, 2.76 mmol) and (2-methyl-pyridin-4-yl)methanol (340 mg, 2.76 mmol). Yield 17.8 mg of white solid 6-((2-methylpyridin-4-yl)methoxy)-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine (yield 5.6%).

MS (ESI) M/Z: 348[M+H ⁺ ].

¹ H NMR (300 MHz, Chloroform-d) δ 8.59 - 8.53 (m, 2H), 8.50 (d, J = 5.2 Hz, 1H), 7.90 (s, 1H), 7.32 (s, 1H), 7.23 (d) , J = 5.2 Hz, 1H), 7.15 - 7.09 (m, 2H), 5.53 (s, 2H), 5.49 (s, 2H), 5.45 (s, 2H), 2.61 (s, 3H).

Example 62: 6-(Pyridin-4-ylmethoxy)-1-(trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine

Synthetic scheme

Step A: trans-1,4-bis(bromomethyl)cyclohexane

See the synthesis of 1,4-dibromomethylcyclohexane for details. Trans-cyclohexane-1,4-diyldimethanol (10.0 g, 69.4 mmol), toluene (100 mL) and phosphorus tribromide (18.8 g, 69.4 mmol). 15.5 g of trans-1,4-bis(bromomethyl)cyclohexane as a yellow oil was obtained (yield: 82.7%).

Step B: 1-((trans-4-(bromomethyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine 4-amine

See 1-((4-(Bromomethyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine for details. Synthesis. 6-(Pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 0.83 mmol), acetonitrile (5.0 mL), anhydrous 154 mg, 1.12 mmol) and (1r,4r)-1,4-bis(bromomethyl)cyclohexane (670 mg, 2.48 mmol). Yield 190 mg of yellow solid 1-(((1r,4r)-4-(bromomethyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3, 4-d]pyrimidin-4-amine (yield 53.4%).

MS (ESI) M/Z: 431, 433 [M+H ⁺ ].

Step C: 6-(Pyridin-4-ylmethoxy)-1-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine

See 6-(pyridin-4-ylmethoxy)-1-((4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3,4-d] for details. Synthesis of pyrimidine-4-amine. 1-((trans-4-(bromomethyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine-4- Amine (190 mg, 0.44 mmol), acetonitrile (5.0 mL), tetrahydropyrrole (313 mg, 4.41 mmol), and anhydrous potassium carbonate (182.5 mg, 1.32 mmol). 28.0 mg of a yellow oily compound as 6-(pyridin-4-ylmethoxy)-1-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyridyl Zoxao[3,4-d]pyrimidin-4-amine (yield 15.0%).

MS (ESI) M / Z: 422 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 8.57–8.49 (m, 2H), 7.97 (s, 1H), 7.55–7.49 (m, 2H), 5.54 (s, 2H), 4.07 (d, J) =7.1 Hz, 2H), 3.24–2.89 (m, 4H), 2.87–2.58 (m, 2H), 2.04 – 1.93 (m, 4H), 1.90–1.70 (m, 3H), 1.65–1.49 (m, 3H) ), 1.05–0.85 (m, 4H).

Example 63: 6-(4-Fluoro-3-methoxybenzyloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d]pyrimidine-4-amine

Synthetic scheme

Step A: 6-(4-Fluoro-3-methoxybenzyloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d Pyrimidine-4-amine

See compound 6-(pyridin-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 for details. - Synthesis of amines. 6-Chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.46 mmol), ( 4-Fluoro-3-methoxyphenyl)methanol (682.2 mg, 4.37 mmol), potassium tert-butoxide (490 mg, 4.38 mmol) and acetonitrile (10.0 mL). 33.6 mg of white solid 6-(4-fluoro-3-methoxybenzyloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole[3,4 -d]pyrimidine-4-amine (yield 5.0%).

MS (ESI) M / Z: 463 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 8.07 (s, 1H), 7.46 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 8.5 Hz, 1H), 7.13 - 7.00 (m, 2H), 5.54 (s, 2H), 5.48 (s, 2H), 4.36 (s, 2H), 3.85 (s, 3H), 3.55 - 3.02 (m, 2H) ), 3.23–2.95 (m, 2H), 2.28–2.11 (m, 2H), 2.10–1.90 (m, 2H).

¹⁹ F NMR (300 MHz, Methanol-d ₄ ) δ - 138.0.

Examples 64 and 65: (S)-4-Amino-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[ 2,3-d]pyrimidine-6-carbonitrile and (R)-4-amino-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl )-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

Synthetic scheme

Step A: 3-((6-Bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

For details, see the synthesis of 4-((6-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidinyl)methyl)benzaldehyde. 6-Bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.06 g, 4.03 mmol), tetrahydrofuran (50.0 mL), sodium hydride (176 mg, 4.43 mmol) -(Bromomethyl)benzaldehyde (1.19 g, 6.05 mmol). 754.2 mg of pale yellow solid 3-((6-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (yield 48.9%) was obtained.

MS (ESI) M/Z: 384, 386 [M+H ⁺ ].

Step B: 3-((4-Amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

For details, see the synthesis of 4-((4-amino-6-bromo-2-chloro-7hydro-pyrrolo[2,3-d]pyrimidinyl)methyl)benzaldehyde. 3-((6-Bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (754.2 mg, 1.96 mmol) and isopropyl chloride Alcohol solution (2 mol/L, 32.1 mL, 62.8 mmol). 360.2 mg of a brown solid was obtained as 3-((4-amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (yield 45.6%) ).

MS (ESI) M/Z: 365, 367 [M+H ⁺ ].

Step C: 6-Bromo-2-chloro-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

For details, see the synthesis of 6-bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. 3-((4-Amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (360.3 mg, 0.99 mmol), methylene chloride (20.0 mL), pyrrolidine (210.1 mg, 2.97 mmol) and sodium borohydride (627.1 mg, 2.97 mmol). Obtained 290.3 mg of a pale yellow semisolid as 6-bromo-2-chloro-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -Amine (yield 70.0%).

MS (ESI) M/Z: 420,422 [M+H ⁺ ].

Step D: 6-Bromo-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine 4-amine

For details, see the synthesis of 6-bromo-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. 6-Bromo-2-chloro-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (280.3 mg, 0.67 mmol) , 2-pentanol (1.17 g, 13.3 mmol) and potassium t-butoxide (229.8 mg, 1.99 mmol). Yield 124.1 mg of a brown solid as 6-bromo-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3 -d]pyrimidine-4-amine (yield 39.4%).

MS (ESI) M/Z: 472, 474 [M+H ⁺ ].

Step E: (S)-4-Amino-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3 -d]pyrimidine-6-carbonitrile and (R)-4-amino-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H -pyrrolo[2,3-d]pyrimidine-6-carbonitrile

6-Bromo-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)- was sequentially added to a 20 ml high pressure reactor under a nitrogen atmosphere. 7H-pyrrolo[2,3-d]pyrimidin-4-amine (120 mg, 0.25 mmol), zinc cyanide (58.9 mg, 0.51 mmol), zinc powder (32.5 mg, 0.51 mmol), Iron (28.2 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium (58.8 mg, 0.05 mmol) and N,N-dimethylformamide (10.0 mL). Subsequently, the reaction solution was stirred at 130 ° C overnight.

After treatment: The reaction system is cooled to room temperature. Water (30 ml) was added to the reaction mixture to quench. The resulting mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with a saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. The residue obtained after concentration was dissolved in dimethyl sulfoxide (4.0 ml) and purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80% in 7 minutes; Detection wavelength: 254 nm. The product was collected, and lyophilized under reduced pressure to give 93 mg of brown solid 4-amino-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H. -pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

93 mg of the racemic 4-amino-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3- d] Pyrimidine-6-carbonitrile for chiral resolution. The separation conditions were as follows, chiral column name: Repaired CHIRAL AD; chiral column size: 0.46 cm * 10 cm, 5 um; mobile phase: n-hexane (containing 0.1% diethylamine) / ethanol = 90/10; flow rate: 1.00 ml / Minutes; temperature: 25 degrees Celsius; detection wavelength: 254 nm. The product was collected and concentrated under reduced pressure to give 4 <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (yield 40.5%) and 40.6 mg of white solid, identified as (R)-4-amino-2-(pent-2- Benzyl)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (yield 38.7%). The absolute configuration of the chemical structure has not been done. The identification of the current configuration is done by SAR data. Confirmation of the configuration by chemical method will be carried out after the submission of the application materials.

(S)-4-Amino-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile

MS (ESI) M/Z: 420 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) 7.41-7.18 (m, 5H), 5.40 (s, 2H), 5.40-5.22 (m, 1H), 3.69 (s, 2H), 2.71–2.53 (m, 4H) ), 1.88–1.76 (m, 4H), 1.76-1.65 (m, 1H), 1.65-1.49 (m, 1H), 1.49-1.37 (m, 2H), 1.33 (d, J = 6.0 Hz, 3H), 1.03-0.89 (m, 3H).

E.e.%=99.28%

Example 66: 6-((5-Methylisoxazol-3-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[ 3,4-d]pyrimidine-4-amine

Synthetic scheme

Step A: 6-((5-Methylisoxazol-3-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3 ,4-d]pyrimidine-4-amine

See compound 6-(pyridin-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 for details. - Synthesis of amines. (5-Methylisoxazol-3-yl)methanol (330 mg, 0.29 mmol), potassium tert-butoxide (97 mg, 0.87 mmol), and 6-chloro-1-(4-(pyrrolidine-1) -ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.29 mmol). 40.9 mg of a white solid are obtained as 6-((5-methylisoxazol-3-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyridyl Zoxao[3,4-d]pyrimidin-4-amine (yield 33.7%).

MS (ESI) M/Z: 420 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ8.00 (s, 1H), 7.35-7.26 (m, 4H), 6.24 (s, 1H), 5.47 (s, 2H), 5.46 (s, 2H), 3.77 (s, 2H), 2.83-2.70 (m, 4H), 2.42 (s, 3H), 2.91-1.81 (m, 4H).

Example 67: 6-Butoxy-1-(isoindoline-5-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Synthetic scheme

Step A: 2-(tert-butyl) 5-ethylisoindoline-2,5-dicarboxylate

To a solution of ethyl isoindoline-5-carboxylic acid ethyl ester hydrochloride (426 mg, 1.88 mmol) in tetrahydrofuran (30.0 ml), triethylamine (569 mg, 5.63 mmol), Di-tert-butyl ester (819 mg, 3.7559 mmol) and 4-dimethylaminopyridine (23 mg, 0.1878 mmol). The resulting reaction solution was reacted at room temperature for 6 hours.

After-treatment: Water (50 ml) was added to the reaction mixture for dilution. The resulting mixture was extracted with ethyl acetate (50 mL×3×). The combined organic phases were washed with water (20 ml×3×), then dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjj elut elut elut elut , 5-dicarboxylate (yield 87.7%).

MS (ESI) M / Z: 292 [M+H ⁺ ].

Step B: 5-Hydroxymethylisoindoline-2-carboxylic acid tert-butyl ester

To a solution of 2-(tert-butyl) 5-ethylisoindoline-2,5-dicarboxylate (480 mg, 1.65 mmol) in tetrahydrofuran (50.0 mL) at 0 ° C Lithium tetrahydroaluminum (32 mg, 0.8247 mmol) was added in portions. Subsequently, the reaction solution was slowly warmed to room temperature, and stirring was continued at room temperature for 2 hours.

Work-up: Ice water (50 ml) was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate (50 mL×3×). The combined organic phases were washed with water (20 mL×3×) then dried over anhydrous sodium sulfate The residue after concentration was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1). The product was collected and concentrated under reduced pressure to give 380 mg (yield: 92.5%) of 5-hydroxymethylisoindoline-2-carboxylic acid as a solid.

MS (ESI) M/Z: 250 [M+H ⁺ ].

Step C: 5-((Methylsulfonyloxy)methyl)isoindoline-2-carboxylic acid tert-butyl ester

To a solution of 5-hydroxymethylisoindoline-2-carboxylic acid tert-butyl ester (200 mg, 0.80 mmol) in dichloromethane (20.0 mL) EtOAc. , 2.42 mmol) and methanesulfonyl chloride (138 mg, 1.21 mmol). Subsequently, the reaction solution was slowly warmed to room temperature, and stirring was continued at room temperature for 3 hours.

Work-up: Ice water (20 ml) was added to the reaction mixture. The resulting mixture was extracted with dichloromethane (50 mL×3×). The combined organic phases were washed with water (20 mL×3×) then dried over anhydrous sodium sulfate 282 mg of a colorless liquid were obtained as the crude product of 5-((methylsulfonyloxy)methyl)isoindoline-2-carboxylic acid (crude). This compound was used directly in the next reaction without purification.

MS (ESI) M / Z: 328 [M+H ⁺ ].

Step D: ((4-Amino-6-butoxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)isoindoline-2-carboxylic acid tert-butyl ester

To N-N-dimethylformamide (8.0 ml) to 6-butoxy-1H-pyrazolo[3,4-d]pyrimidin-4-amine (166 mg, 0.80 mmol) at 0 °C In the solution, sodium hydride (35 mg, 0.88 mmol) was added. After the obtained reaction liquid was stirred at 0 ° C for 30 minutes, 282 mg of tert-butyl 5-((methylsulfonyloxy)methyl)isoindoline-2-carboxylate (crude) was added to the reaction mixture. . After the addition was completed, the reaction solution was slowly warmed to room temperature, and stirring was continued at room temperature for 3 hours.

Work-up: The reaction was quenched by the addition of ice water (20 mL). The resulting mixture was extracted with ethyl acetate (50 mL×3×). The combined organic phases were washed with water (20 mL×3×) then dried over anhydrous sodium sulfate The concentrated crude product was dissolved in N,N-dimethylformamide (3 ml) and purified by medium-low-pressure liquid chromatography. The purification method was as follows, mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; flow rate: 45 ml/min; gradient: acetonitrile was increased from 10% to 100% in 36 minutes; detection wavelength: 254 nm. The product was collected and concentrated under reduced vacuo afforded <RTI ID=0.0>################################################################# - tert-butyl formate. (two-step yield 32.0%)

MS (ESI) M / Z: 437 [M+H ⁺ ].

Step E: 6-butoxy-1-(isoindoline-5-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To (4-amino-6-butoxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)isoindoline-2-carboxylic acid tert-butyl ester (112 mg, 0.26 To a solution of dichloromethane (6.0 mL) was added trifluoroacetic acid (2.0 mL). Subsequently, the resulting reaction solution was stirred at room temperature for 16 hours.

Work-up: The reaction solution was concentrated to dryness under vacuum. The residue was dissolved in N,N-dimethylformamide (3.0 ml) and purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 75% in 8 minutes; Detection wavelength: 254 nm. The product was collected, and lyophilized at low temperature to give 24.6 mg of white solid 6-butoxy-1-(isoindoline-5-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -Amine (yield 28.0%).

MS (ESI) M / Z: 339 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ7.97 (s, 1H), 7.28-7.17 (m, 3H), 5.44 (s, 2H), 4.61 (s, 1H), 4.39 (t, J = 6.6 Hz, 2H), 4.24 (s, 3H), 1.83 - 1.73 (m, 2H), 1.58 - 1.46 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H).

Example 68: 6-((2-Methylpyridin-4-yl)methoxy)-1-(pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine

Synthetic scheme

Step A: 6-Chloro-1-(pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

For details, see the synthesis of 6-chloro-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine. 6-Chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.59 mmol), acetonitrile (5.0 ml), anhydrous potassium carbonate (171 mg, 1.24 mmol) and 2 -Chloromethylpyridine (335 mg, 1.24 mmol). There was obtained 110 mg of a yellow solid 6-chloro-1-(pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (yield: 72%).

MS (ESI) M / Z: 266 [M+H ⁺ ].

Step B: 6-((2-Methylpyridin-4-yl)methoxy)-1-(pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-4- amine

See 6-(pyridin-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4- Synthesis of amines. 6-Chloro-1-(pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110 mg, 0.42 mmol), acetonitrile (5.0 mL), tert. Potassium alkoxide (174 mg, 1.26 mmol) and (2-methyl-pyridin-4-yl)methanol (155 mg, 1.26 mmol). Obtained 1.8 mg of white solid 6-((2-methylpyridin-4-yl)methoxy)-1-(pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine (yield 1.2%).

MS (ESI) M/Z: 348[M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ8.49 (d, J = 5.0Hz, 1H), 8.33 (d, J = 5.3Hz, 1H), 8.05 (s, 1H), 7.79-7.64 (m, 1H), 7.38 - 7.25 (m, 3H), 6.93 (d, J = 7.9 Hz, 1H), 5.57 (s, 2H), 5.46 (s, 2H), 2.50 (s, 3H).

Example 69: 6-Butoxy-1-((2-isopropylisoindoline-5-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Synthetic scheme

Step A: 6-Butoxy-1-((2-isopropylisoindoline-5-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Into a 25 ml single-neck round bottom flask, 6-butoxy-1-(isoindoline-5-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was added in sequence. (60 mg, 0.18 mmol), acetonitrile (5.0 ml), potassium carbonate (73 mg, 0.53 mmol) and iodoisopropane (91 mg, 0.53 mmol). After the reaction mixture was stirred well, it was stirred at 60 ° C for 16 hours.

Post treatment: The reaction system was cooled to room temperature, and the reaction liquid was filtered. The filtrate was collected and the filtrate was concentrated in vacuo to dryness. The residue obtained was dissolved in N,N-dimethylformamide (2.0 ml) and purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 85% in 8 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give 5.2 mg of white solid 6-butoxy-1-((2-isopropylisoindoline-5-yl)methyl)-1H-pyrazole [3, 4-d]pyrimidin-4-amine (yield 7.6%).

MS (ESI) M / Z: 381 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ7.96 (s, 1H), 7.23-7.17 (m, 3H), 5.43 (s, 2H), 4.39 (t, J = 6.6Hz, 2H), 3.95 ( s, 4H), 2.83–2.75 (m, 1H), 1.83–1.73 (m, 2H), 1.58–1.46 (m, 2H), 1.20 (d, J=6.3 Hz, 6H), 1.01 (t, J= 7.5 Hz, 3H).

Examples 70 and 71: (S)-2-(1-(pyridin-4-yl)butoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(III Fluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (R)-2-(1-(pyridin-4-yl)butoxy)-7-(4-(pyrrole) Alkyl-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Step A: 2-(1-(Pyridin-4-yl)butoxy)-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl) -7H-pyrrolo[2,3-d]pyrimidine-4-amine

For details, see 2-butoxy-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] Synthesis of pyrimidine-4-amine. Potassium tert-butoxide (0.65 g, 5.83 mmol), 1-(pyridin-4-yl)butan-1-ol (2.32 g, 15.28 mmol), 2-chloro-6-(trifluoromethyl)-7 -((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.70 g, 1.91 mmol) and acetonitrile (150 ml) ). 0.48 g of a brown solid 2-(1-(pyridin-4-yl)butoxy)-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)) Base)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (yield 52.3%).

MS (ESI) M / Z: 482 [M+H ⁺ ].

Step B: 2-(1-(Pyridin-4-yl)butoxy)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

For details, see the synthesis of 2-butoxy-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine. 2-(1-(Pyridin-4-yl)butoxy)-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- Pyrrolo[2,3-d]pyrimidin-4-amine (0.48 g, 0.99 mmol), trifluoroacetic acid (20 ml), dichloromethane (10 ml), methanol (40 ml), water (20 ml) Potassium carbonate (0.41 g, 2.99 mmol). Yield 290 mg of yellow solid 2-(1-(pyridin-4-yl)butoxy)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (yield 83.5%).

MS (ESI) M / Z: 352 [M+H ⁺ ].

Step C: 4-((4-Amino-2-(1-(pyridin-4-yl)butoxy)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)methyl)benzaldehyde

For details, see the synthesis of 4-((4-amino-2-butoxy-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde. Potassium carbonate (0.26 g, 2.48 mmol), aldehyde-benzyl bromide (0.18 g, 0.91 mmol), 2-(1-(pyridin-4-yl)butoxy)-6-(trifluoromethyl) -7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.29 g, 0.83 mmol) and acetonitrile (50 mL). 0.15 g of 4-((4-amino-2-(1-(pyridin-4-yl)butoxy)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)methyl)benzaldehyde (yield 38.5%).

MS (ESI) M/Z: 470 [M+H ⁺ ].

Step D: 2-(1-(Pyridin-4-yl)butoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H- Pyrrolo[2,3-d]pyrimidin-4-amine

For details, see 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-4 - Synthesis of amines. Pyrrolidine (0.027 g, 0.38 mmol), 4-((4-amino-2-(1-(pyridin-4-yl)butoxy)-6-(trifluoromethyl)-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (0.15 g, 0.32 mmol), dichloromethane (15.0 ml), and sodium borohydride (0.16 g, 1.61 mmol). Obtained 45 mg of white solid as 2-(1-(pyridin-4-yl)butoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl) )-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

The racemate was chiralized and the conditions were as follows. Column: CHIRAL Cellulose-SB 0.46 cm*15 cm, 5 um; mobile phase: n-hexane (containing 0.1% diethylamine) and ethanol; flow rate: 1 ml /min; Gradient: acetonitrile was increased from 10% to 22% in 10 minutes; detection wavelength: 254 nm. The product was collected and concentrated to dryness to dryness crystals crystalssssssssssssssssssssssssss -ylmethyl)benzyl)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (yield 3.8%) and 5.8 mg of a white solid. (R)-2-(1-(pyridin-4-yl)butoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H - Pyrrolo[2,3-d]pyrimidin-4-amine (3.5%). The absolute configuration of the chemical structure has not been done. The identification of the current configuration is done by SAR data. Confirmation of the configuration by chemical method will be carried out after the submission of the application materials.

(S)-2-(1-(Pyridin-4-yl)butoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H - pyrrolo[2,3-d]pyrimidin-4-amine.

MS (ESI) M/Z: 525 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ8.45 (d, J = 6.0Hz, 2H), 7.78-7.38 (m, 2H), 7.32 (d, J = 6.0Hz, 2H), 7.14 (d, J = 9.0 Hz, 3H), 6.90 (d, J = 7.8 Hz, 2H), 5.93 (m, 1H), 5.34 (d, J = 16.2 Hz, 1H), 5.16 (d, J = 16.2 Hz, 1H) , 3.51 (s, 2H), 2.46 - 2.35 (m, 4H), 1.89 - 1.75 (m, 2H), 1.71-1.63 (m, 4H), 1.42 - 1.21 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H).

Ee%=100%

(R)-2-(1-(pyridin-4-yl)butoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H - pyrrolo[2,3-d]pyrimidin-4-amine.

MS (ESI) M/Z: 525 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ8.45 (d, J = 6.0Hz, 2H), 7.78-7.38 (s, 2H), 7.32 (d, J = 6.0Hz, 2H), 7.14 (d, J = 9.0 Hz, 3H), 6.90 (d, J = 7.8 Hz, 2H), 5.93 (m, 1H), 5.34 (d, J = 16.2 Hz, 1H), 5.16 (d, J = 16.2 Hz, 1H) , 3.51 (s, 2H), 2.46 - 2.35 (m, 4H), 1.89 - 1.75 (m, 2H), 1.71 - 1.63 (m, 4H), 1.42 - 1.28 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H).

Ee%=100%

Example 72: 7-(4-(Pyrrolidin-1-ylmethyl)benzyl)-2-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)-7H-pyrrole [2,3-d]pyrimidine-4-amine

Synthetic scheme

Step A: 7-(4-(Pyrrolidin-1-ylmethyl)benzyl)-2-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)-7H-pyrrolo[ 2,3-d]pyrimidine-4-amine

For details, see the synthesis of 6-(pyridin-4-ylmethoxy)-1-(6-(pyrrolidin-1-yl)hexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. . Potassium tert-butoxide (194 mg, 1.7242 mmol), 2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -Amine (100 mg, 0.2873 mmol) and 1-(tetrahydro-2H-pyran-4-yl)ethanol (534 mg, 4.5978 mmol). 14.7 mg of colorless semisolid 7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)-7H Pyrrolo[2,3-d]pyrimidin-4-amine trifluoroacetate (yield 9.6%).

MS (ESI) M / Z: 436 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 8.16 (s, 1H), 7.67 - 7.43 (m, 4H), 5.55 (s, 2H), 5.43 - 5.20 (m, 1H), 4.37 (s, 2H) ), 4.01–3.96 (m, 2H), 3.49–3.32 (m, 4H), 3.19 (s, 2H), 2.28–2.13 (m, 2H), 2.02–1.89 (m, 3H), 1.84–1.75 (m) , 1H), 1.73 - 1.70 (m, 1H), 1.57 - 1.46 (m, 2H), 1.41 (d, J = 6.3 Hz, 3H).

Example 73: (R)-6-((1-(Dimethylamino)hex-3-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H -pyrazolo[3,4-d]pyrimidin-4-amine

Synthetic scheme

Step A: 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-((3R)-1-((tetrahydro-2H-pyran-2-yl)oxy)) -3-yl)oxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine was sequentially added to a 20 ml high pressure reactor under a nitrogen atmosphere. 4-Amine (900.0 mg, 2.36 mmol), (3R)-1-((tetrahydro-2H-pyran-2-yl)oxy)hexan-3-ol (531.1 mg, 23.6 mmol) Potassium butoxide (264.8 mg, 4.72 mmol). The resulting mixture was stirred at 110 ° C for 7 hours.

Work-up: The reaction was cooled to EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHH Methyl)benzyl)-6-(((3R)-1-((tetrahydro-2H-pyran-2-yl)oxy)hex-3-yl)oxy)-1H-pyrazole [3,4-d]pyrimidine-4-amine (18% yield)

MS (ESI) M/Z: 509 [M+H ⁺ ]

Step B: (R)-3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-6- Ethyl)hexan-1-ol

To 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-((3R)-1-((tetrahydro-2H-pyran-2-yl)oxy) under a nitrogen atmosphere A solution of hexyl-3-hexyloxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (240.0 mg, 0.42 mmol) in methanol (5 mL) And acetic acid (1.0 ml). The resulting mixture was stirred at 56 °C for 16 hours.

Work-up: The reaction mixture was concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt; Pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexan-1-ol. This compound was used directly in the next reaction without purification.

MS (ESI) M/Z: 425 [M+H ⁺ ]

Step C: (R)-6-((1-chlorohexane-3-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[ 3,4-d]pyrimidine-4-amine

To (R)-6-((1-chlorohexane-3-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)- under a nitrogen atmosphere at 0 °C To a solution of 1H-pyrazolo[3,4-d]pyrimidine-4-amine (180.0 mg, 0.38 mmol) was added chlorosulfoxide (5.0 mL). The resulting reaction solution was stirred at 50 ° C for 24 hours.

Work-up: The reaction mixture was concentrated under reduced pressure to give 20% (yel. Methyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. This compound was used directly in the next reaction without purification.

MS (ESI) M / Z: 443 [M+H ⁺ ].

Step D: (R)-6-((1-(Dimethylamino)hex-3-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H- Pyrazolo[3,4-d]pyrimidine-4-amine

Under a nitrogen atmosphere, (R)-6-((1-chlorohexane-3-yl)oxy)-1-(4-(pyrrolidin-1-yl) was added sequentially to a 20 ml high pressure reactor. Benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100.0 mg, 0.18 mmol), potassium carbonate (48.7 mg, 0.36 mmol), dimethylamine in tetrahydrofuran ( 2.0 mol/L, 8.0 mL). The reaction solution was stirred at 80 ° C for 48 hours.

Post-treatment: After the reaction was cooled to room temperature, the reaction solution was filtered to remove potassium carbonate, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by preparative high performance liquid chromatography. The preparation conditions were as follows, column: X Bridge C1819mm*150mm; mobile phase: water (0.1% formic acid) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile increased from 10% to 15% in 12 minutes; detection wavelength : 254 nm. The product was collected and lyophilized to give 45.5 mg of a yellow oily liquid (R)-6-((1-(dimethylamino)hex-3-yl)oxy)-1-(4-(pyrrolidin-1-) Methyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine formate (yield 46%).

MS (ESI) M / Z: 452 [M+H ⁺ ].

¹ H NMR (300 MHz, Methanol-d ₄ , ppm): δ 7.99 (s, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.33 (d, J = 7.6 Hz, 2H), 5.52 - 5.41 (m, 2H), 5.36–5.32 (m, 1H), 4.27 (s, 2H), 3.27–3.13 (m, 6H), 2.80 (s, 6H), 2.19–1.95 (m, 6H), 1.88–1.58 (m, 2H), 1.53 - 1.30 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

Ee%=100%

Example 74: 4-Amino-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidine-6-carbonitrile

Synthetic scheme

Step A: 6-Bromo-2-chloro-7-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-7H-pyrrolo[2,3 -d]pyrimidine-4-amine

To a 100 ml single-mouth bottle, potassium carbonate (1.62 g, 11.7 mmol), 6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.97 g, 3.9 m) was sequentially added. Mole), 7-(chloromethyl)-2-isopropyl-1,2,3,4-tetrahydroisoquinoline (0.96 g, 4.3 mmol) and acetonitrile (50 mL). The reaction mixture was stirred at 80 ° C for 1 hour.

Post-treatment: The reaction apparatus was cooled to room temperature, and the reaction liquid was concentrated under reduced pressure. The residue after concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1/4). The product was collected and concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt; -7H-pyrrolo[2,3-d]pyrimidine-4-amine.

MS (ESI) M/Z: 434, 436 [M+H ⁺ ].

Step B: 6-Bromo-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-amine

Potassium tert-butoxide (0.10 g, 0.9 mmol), 6-bromo-2-chloro-7-((2-isopropyl-1,2,3) was sequentially added to a 50 ml high pressure reactor under a nitrogen atmosphere. 4-tetrahydroisoquinolin-7-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.15 g, 0.3 mmol) and n-butanol (20.0 mL). Then, the reaction solution was stirred at 120 ° C for 10 hours.

After-treatment: After the reaction apparatus was cooled to room temperature, ice water (50 ml) was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate (50 mL×3×). The combined organic phases were washed with water (20 ml×3×) and then dried over anhydrous sodium sulfate. The concentrated residue was dissolved in dimethyl sulfoxide (4.0 mL) and purified and purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 30 ml / min; gradient: acetonitrile from 15% to 80% in 8 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized at low temperature and reduced pressure. 0.12 g of a brownish yellow solid 6-bromo-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-7H-pyrrole And [2,3-d]pyrimidine-4-amine.

MS (ESI) M/Z: 472, 474 [M+H ⁺ ].

Step C: 4-Amino-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-7H-pyrrolo[2 ,3-d]pyrimidine-6-carbonitrile trifluoroacetate

To a 30 ml single-mouth bottle, 6-bromo-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl) was added sequentially under a nitrogen atmosphere. Methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.12 g, 0.3 mmol), tri-dibenzylideneacetone dipalladium (0.06 g, 0.06 mmol), 1,1' - bisdiphenylphosphinoferrocene (0.04 g, 0.06 mmol), zinc cyanide (0.07 g, 0.6 mmol), zinc powder (0.04 g, 0.6 mmol) and N,N-dimethylformamide (6.00 ml). The reaction solution was stirred at 100 ° C for 10 hours.

Work-up: After the reaction apparatus was cooled to room temperature, the reaction liquid was filtered. The filtrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 30 ml / min; gradient: acetonitrile from 15% to 80 in 8 minutes %; detection wavelength: 254 nm. The product was collected, and lyophilized at low temperature to give 14.5 mg of white solid 4-amino-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl). Methyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile trifluoroacetate (yield 11.5%).

MS (ESI) M / Z: 418 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ8.01-7.52 (m, 2H), 7.45 (s, 1H), 7.35-7.11 (m, 2H), 6.96 (s, 1H), 5.34 (s, 2H ), 4.34 (d, J = 5.9 Hz, 2H), 4.26 (t, J = 6.6 Hz, 2H), 3.99 - 3.81 (m, 1H), 3.35 - 3.16 (m, 2H), 3.15 - 3.02 (m, 2H), 1.72 - 1.63 (m, 2H), 1.47 - 1.37 (m, 2H), 1.31 - 1.29 (d, 6H), 0.93 (t, J = 7.3 Hz, 3H).

Example 75: 6-Butoxy-1-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine

Synthetic scheme

Step A: 6-methylnicotinate methyl ester

To a 250 ml three-necked flask, 6-methylnicotinic acid (10.0 g, 73.0 mmol) and anhydrous methanol (80.0 ml) were sequentially added. After the raw material was stirred and dissolved, thionyl chloride (40.0 ml) was slowly added dropwise to the reaction mixture. The resulting reaction solution was stirred at 60 ° C overnight.

Work-up: After the reaction was cooled to room temperature, the reaction was concentrated under reduced pressure. The concentrated residue was diluted with water (50 ml) and then adjusted to pH 7 to 8 with aqueous sodium hydrogen carbonate. The resulting mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with aq. EtOAc (EtOAc)EtOAc. 9.89 g of light yellow solid 6-methylnicotinate methyl ester (yield 89.2%) was obtained.

MS (ESI) M / Z: 152 [M+H ⁺ ].

Step B: 6-(Bromomethyl)nicotinic acid methyl ester

To a 250 ml three-necked flask, methyl 6-methylnicotinate (9.89 g, 52.6 mmol), carbon tetrachloride (100.0 ml) and N-bromosuccinimide were sequentially added under a nitrogen atmosphere. 9.36 g, 52.6 mmol). The resulting mixture was stirred at 70 ° C for 4 hours.

Post-treatment: The reaction system was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Dichloromethane (100 ml) was added to the residue, and stirred at room temperature for 15 min. The mixture was suction filtered, and the filtrate was collected and evaporated. 10.1 g of a brown liquid, methyl 6-(bromomethyl)nicotinate (crude) was obtained. The crude product was used directly in the next step without purification.

MS (ESI) M/Z: 230, 232 [M+H ⁺ ].

Step C: 6-(pyrrolidin-1-ylmethyl)nicotinic acid methyl ester

Into a 250 ml round bottom flask, 6-(bromomethyl)nicotinic acid methyl ester (10.0 g, 43.5 mmol), acetonitrile (150.0 ml), pyrrolidine (9.26 g, 130.4 mmol) and anhydrous Potassium (18.0 g, 130.4 mmol). The reaction mixture was stirred at room temperature overnight.

Post-treatment: The reaction mixture was suction filtered, and the filtrate was collected, and the filter cake was washed with ethyl acetate (20 ml × 2 times). The combined filtrate was concentrated under reduced pressure in vacuo. The residue after concentration was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 5/1) to give 2.25 g of tan, semi-solid 6-(pyrrolidin-1-ylmethyl) nicotinic acid Methyl ester.

MS (ESI) M/Z: 220 [M+H ⁺ ].

Step D: (6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methanol

To a solution of 6-(pyrrolidin-1-ylmethyl)nicotinic acid methyl ester (1.0 g, 4.52 mmol) in tetrahydrofuran (30.0 ml) at 0 ° C, slowly add tetrahydro lithium aluminum (0.52) Gram, 13.6 mmol). After the addition was completed, the reaction apparatus was moved to room temperature and stirred overnight.

Work-up: quenched by adding water (10 mL) to the reaction mixture at 0 °C. The mixture was filtered and the filtrate was collected. The filtrate was extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with a saturated sodium chloride solution (50 ml) and dried over anhydrous sodium sulfate. The solvent was concentrated to give a crystal. m. m. The product was collected and concentrated to give 635 mg (yield: 72.8%) of brown solid (6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methanol.

MS (ESI) M / Z: 193 [M+H ⁺ ].

Step E: 5-(Chloromethyl)-2-(pyrrolidin-1-ylmethyl)pyridine hydrochloride

To a solution of 6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methanol (635.0 mg, 3.31 mmol) in dichloromethane (10.0 mL) 2.5 ml). The addition was completed and the resulting mixture was stirred at room temperature for 2 hours.

Work-up: The reaction mixture was concentrated in vacuo tolululululululululululululululululululululululululululu The crude product was used directly in the next step without purification.

MS (ESI) M / Z: 211 [M+H ⁺ ].

Step F: 6-Butoxy-1-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine

To N-N-dimethylformamide (15.0 ml) to 6-butoxy-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.72 mmol) at 0 °C In the solution, sodium hydride (86.6 mg, 2.16 mmol, 60% in oil) was slowly added in batches. After the resulting mixture was stirred at room temperature for 30 minutes, 5-(chloromethyl)-2-(pyrrolidin-1-ylmethyl)pyridine hydrochloride (214 mg, 0.86) was added to the reaction mixture at 0 °C. Millimoles). After the completion of the addition, the reaction solution was slowly warmed to room temperature and stirring was continued at room temperature for 5 hours.

Work-up: quenched by the addition of water (15 mL). The resulting mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with a saturated aqueous solution of sodium chloride (30 ml) and dried over anhydrous sodium sulfate. The residue obtained by concentration was dissolved in dimethyl sulfoxide (4 ml) and purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 75% in 80 minutes; Detection wavelength: 254 nm. The product was collected, and lyophilized under reduced pressure to give 40.4 mg of brown solid 6-butoxy-1-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-1H-pyrazole. [3,4-d]pyrimidine-4-amine (yield 14.6%).

MS (ESI) M / Z: 382 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ8.42 (d, J = 2.2Hz, 1H), 7.97 (s, 1H), 7.91-7.47 (m, 3H), 7.36 (d, J = 8.0Hz, 1H), 5.39 (s, 2H), 4.26 (t, J = 6.6 Hz, 2H), 3.65 (s, 2H), 2.43 (d, J = 6.0 Hz, 4H), 1.73-1.54 (m, 6H), 1.50–1.31 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

Example 76: 6-Butoxy-1-((2-(pyrrolidin-1-ylmethyl)pyridin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine

Synthetic scheme

Step A: 2-(pyrrolidin-1-ylmethyl)isonicotinate methyl ester

To a 50 ml round bottom three-necked flask, methyl 2-bromomethyl-4-pyridinecarboxylate (1.00 g, 4.37 mmol), acetonitrile (15.0 ml) and tetrahydropyrrole (621 mg, 8.74 mmol) were sequentially added. . The reaction mixture was stirred at room temperature for 30 minutes.

Work-up: The reaction mixture was evaporated to dryness crystals crystals The product was collected and concentrated under reduced pressure to give diethyl ether (yield: 33.3%).

MS (ESI) M / Z: 221 [M+H ⁺ ].

Step B: (2-(pyrrolidin-1-ylmethyl)pyridin-4-yl)methanol

To a solution of methyl 2-(pyrrolidin-1-ylmethyl)isonicotinate (320 mg, 1.45 mmol) in tetrahydrofuran (20 mL) EtOAc (EtOAc) Millimoles). During the addition, the temperature of the reaction solution was controlled to not exceed 10 °C. After the addition was completed, the reaction solution was further stirred under an ice water bath for 1 hour.

Work-up: The reaction was quenched by slowly dropwise adding water (5 ml) to the reaction mixture at 0 °C. Anhydrous sodium sulfate (50 g) was then added to the mixture and stirred for 15 minutes. The mixture was suction filtered, and the filtrate was collected and evaporated. The solid residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut Base pyridin-4-yl)methanol (yield 93.3%).

MS (ESI) M / Z: 193 [M+H ⁺ ].

Step C: 4-(Chloromethyl)-2-(pyrrolidin-1-ylmethyl)pyridine hydrochloride

Slowly add chlorination to a solution of (2-(pyrrolidin-1-ylmethyl)pyridin-4-yl)methanol (50 mg, 0.26 mmol) in dichloromethane (4 mL) Sulfoxide (92 mg, 0.78 mmol). After the dropwise addition was completed, the reaction solution was stirred at room temperature for 30 minutes.

Work-up: The reaction mixture was concentrated under reduced pressure to give 50 mg (yield: 50 mg) of 4-(chloromethyl)-2-(pyrrolidin-1-ylmethyl)pyridine hydrochloride. The crude product was used in the next step without purification.

MS (ESI) M / Z: 211 [M+H ⁺ ].

Step D: 6-Butoxy-1-((2-(pyrrolidin-1-ylmethyl)pyridin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine

To a solution of 6-butoxy-1H-pyrazolo[3,4-d]pyrimidin-4-amine (49 mg, 0.24 mmol) in tetrahydrofuran (10 mL) at 0 ° C Sodium hydride (9.5 mg, 60% wt, 0.24 mmol) was added. After stirring the reaction mixture for 15 minutes in an ice-water bath, 4-(chloromethyl)-2-(pyrrolidin-1-ylmethyl)pyridine hydrochloride (50 mg, 0.24 mmol). The solution was added dropwise to the reaction mixture. The dropwise addition was completed, and the reaction apparatus was stirred at room temperature for 4 hours.

Work-up: The reaction was quenched by the addition of water (40 mL). The resulting mixture was extracted with ethyl acetate (20 mL×3×). The combined organic phases were washed with brine (50 ml×1×), then dried over sodium sulfate and evaporated. The concentrated residue was dissolved in N,N-dimethylformamide (2 mL) and purified by preparative HPLC. Purification conditions were as follows, column: X timate C18 21.2 mm * 250 mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 100% in 7 minutes Detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give 29.9 mg of white solid 6-butoxy-1-((2-(pyrrolidin-1-ylmethyl)pyridin-4-yl)methyl)-1H-pyrazole. And [3,4-d]pyrimidine-4-amine trifluoroacetate (yield 25.2%).

MS (ESI) M / Z: 382 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d4) δ8.61 (d, J = 5.1Hz, 1H), 8.12 (s, 1H), 7.26 (d, J = 4.4Hz, 2H), 5.56 (s, 2H), 4.51 (s, 2H), 4.43 (t, J = 6.5 Hz, 2H), 3.76 - 3.37 (m, 4H), 2.10 - 1.98 (m, 4H), 1.82 - 1.73 (m, 2H), 1.55 - 1.43 ( m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

¹⁹ F NMR (282 MHz, Methanol-d 4) δ-77.2.

Example 77: 6-((2-(Dimethylamino)pyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole And [3,4-d]pyrimidine-4-amine

Synthetic scheme

Step A: 6-((2-(Dimethylamino)pyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole [3,4-d]pyrimidine-4-amine dicarboxylate

In a 100 ml high pressure reactor, 6-((2-chloropyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl group was added sequentially under a nitrogen atmosphere. -1H-pyrazolo[3,4-d]pyrimidin-4-amine (150.2 mg, 0.34 mmol) and dimethylamine alcohol solution (3.0 mol/L, 100 mL). After the raw materials were stirred and dissolved, the mixture was heated at 150 ° C in an oil bath under nitrogen atmosphere overnight.

Work-up: After the reaction was cooled to room temperature, the reaction mixture was concentrated. The residue obtained was dissolved in anhydrous methanol (4.0 ml) and purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 75% in 10 minutes; Detection wavelength: 254 nm. The product was collected, and lyophilized under reduced pressure to give 19.6 mg of brown solid 6-((2-(dimethylamino)pyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl) Benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dicarboxylate (yield 10.6%).

MS (ESI) M/Z: 459 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 8.00 (d, J = 5.5 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 6.79 (s, 1H), 6.68 (d, J = 5.3 Hz, 1H), 5.45 (d, J = 9.6 Hz, 4H), 4.31 (s, 2H), 3.26 - 3.19 (m, 4H), 3.08 (s, 6H), 2.17-1.98 (m, 4H).

Example 78: 4-Amino-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-7H-pyrrole [2,3-d]pyrimidine-6-carbonitrile

Synthetic scheme

Step A: 6-Bromo-2-chloro-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-7H-pyrrolo[2, 3-d]pyrimidine-4-amine

To a 100 ml single-mouth bottle, potassium carbonate (1.62 g, 11.7 mmol), 6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.97 g, 3.9 m) was sequentially added. Mole), 6-(chloromethyl)-2-isopropyl-1,2,3,4-tetrahydroisoquinoline (0.96 g, 4.3 mmol) and acetonitrile (50 mL). After the raw materials were stirred and mixed, they were heated at 80 ° C for 1 hour.

Post-treatment: The reaction system was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1/4). The product was collected and concentrated under reduced pressure to give &lt;RTI ID=0&&&&&&&&&&&&&&&&&&&&&&&&& )-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

MS (ESI) M / Z: 436 [M+H ⁺ ].

Step B: 6-Bromo-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-amine

To a 50 ml high pressure reactor, potassium tert-butoxide (0.10 g, 0.9 mmol), 6-bromo-2-chloro-7-((2-isopropyl-1,2, 3,4-Tetrahydroisoquinolin-6-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.15 g, 0.3 mmol) and n-butanol (20.0 mL) . After the raw materials were stirred and dissolved, they were heated at 120 ° C for 10 hours.

After-treatment: The reaction system was cooled to room temperature, and ice water (50 ml) was added to the mixture. The resulting mixture was extracted with ethyl acetate (50 mL×3×). The combined organic phases were washed with water (20 ml×3×), then dried over anhydrous sodium sulfate and evaporated. The obtained crude product was dissolved in N,N-dimethylformamide (4.0 ml) and purified by preparative HPLC. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80 in 7 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 0.13 g of brown-yellow solid 6-bromo-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl) Methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

MS (ESI) M/Z: 472, 474 [M+H ⁺ ].

Step C: 4-Amino-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidine-6-carbonitrile trifluoroacetate

In a 30 ml single-necked flask, 6-bromo-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinoline-6-) was added sequentially under a nitrogen atmosphere. Methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.12 g, 0.3 mmol), tris(dibenzylideneacetone)dipalladium (0.06 g, 0.06 mmol), Ferrocene (0.04 g, 0.06 mmol), zinc cyanide (0.07 g, 0.6 mmol), zinc powder (0.04 g, 0.6 mmol) and N,N-dimethylformamide (6.0 mL). Subsequently, the reaction liquid was heated to 100 ° C for 10 hours.

After-treatment: After the reaction system was cooled to room temperature, it was filtered, and the filtrate was collected. The filtrate was directly purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 30 ml / min; gradient: acetonitrile from 15% to 80 in 8 minutes %; detection wavelength: 254 nm. The product was collected, and lyophilized at low temperature to give 4.3 mg of white solid 4-amino-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl). )methyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile trifluoroacetate (yield 3.4%).

MS (ESI) M / Z: 418 [M+H ⁺ ].

¹⁹ F NMR (300 MHz, CD ₃ OD) δ-77.2.

¹ H NMR (300MHz, CD ₃ OD) δ 7.46 (s, 1H), 7.35 - 7.20 (m, 3H), 5.48 (s, 2H), 4.72 - 4.51 (m, 2H), 4.46 (s, 2H) , 3.77-3.65 (m, 2H), 3.60–3.47 (m, 1H), 3.26–3.13 (m, 2H), 1.89–1.79 (m, 2H), 1.60–1.23 (m, 8H), 1.02 (t, J = 9.0 Hz, 3H).

Examples 79 and 80: (R)-3-((4-Amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine -6-yl)oxy)hexan-1-ol and (R)-1-((4-amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[ 3,4-d]pyrimidin-6-yl)oxy)hexan-3-ol

Synthetic scheme

Step A: (R)-3-((4-Amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-6- And oxy)hexan-1-ol and (R)-1-((4-amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4 -d]pyrimidin-6-yl)oxy)hexan-3-ol

6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole[3,4-d] was sequentially added to a 10 ml high pressure reactor under a nitrogen atmosphere. Pyrimidine-4-amine (100 mg, 0.29 mmol), potassium tert-butoxide (97 mg, 0.87 mmol), (S)-hexane-1,3-diol (342 mg, 2.9 mmol). After the raw materials were stirred and mixed uniformly, the reaction liquid was stirred at 80 ° C for 4 hours.

Post-treatment: The reaction solution was filtered after the reaction apparatus was cooled to room temperature. The filtrate obtained was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X timate C18 21.2 mm * 250 mm; mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; flow rate: 25 ml / min; gradient: 35% acetonitrile, 20 minutes; detection wavelength: 254 nm. The product was collected and lyophilized to give 1.0 mg of a white solid (R)-3-((4-amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole [3 , 4-d]pyrimidin-6-yl)oxy)hexan-1-ol (yield 0.8%) and 2.8 mg of off-white solid (R)-1-((4-amino-1-(3-(pyrrole) Alkyl-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexan-3-ol (yield 2.3%).

(R)-3-((4-Amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hexyl-1-ol:

MS (ESI) M/Z: 425 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 7.95 (s, 1H), 7.31 - 7.19 (m, 4H), 5.42 - 5.38 (m, 3H), 3.67 - 3.61 (m, 2H), 3.54 (s , 2H), 2.58–2.45 (m, 4H), 1.93–1.89 (m, 2H), 1.74–1.59 (m, 6H), 1.47–1.31 (m, 2H), 0.92 (t, J=7.4 Hz, 3H) ).

Ee%=97.96%

(R)-1-((4-amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hex-3-ol:

MS (ESI) M/Z: 425 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 7.98 (s, 1H), 7.36 - 7.20 (m, 4H), 5.46 (s, 2H), 4.58 - 4.50 (m, 2H), 3.87 - 3.76 (m , 1H), 3.63 (s, 2H), 2.58–2.45 (m, 4H), 2.05–1.93 (m, 1H), 1.86–1.80 (m, 5H), 1.58–1.40 (m, 4H), 0.98–0.93 (m, 3H).

Ee%=96.82%

Example 81:1-Benzyl-6-((2-(methylamino)pyridin-4-yl)methoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Synthetic scheme

Step A: 1-Benzyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (400.0 ml, 2.35 mmol) in N,N-dimethylformamide (40 ml) In the middle, sodium hydride (188.2 mg, 4.71 mmol) was slowly added in portions. After the addition was completed, the reaction solution was stirred at room temperature for 30 minutes. Subsequently, benzyl chloride (270 mg, 2.11 mmol) of N,N-dimethylformamide (5.0 ml) was added to the reaction mixture at 0 °C. Finally, the reaction solution was slowly warmed to room temperature and stirred at room temperature for 4 hours.

After work-up: water (50 ml) was evaporated and evaporated. The combined organic phases were washed with a saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate The residue obtained was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 2/1) to afford 110 mg of yellow solid 1-benzyl-6-chloro-1H-pyrazole [3,4- d] Pyrimidine-4-amine (yield 18.0%).

MS (ESI) M / Z: 260 [M+H ⁺ ].

Step B: 1-Benzyl-6-((2-chloropyridin-4-yl)methoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

1-Benzyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110.0 mg, 0.42 mmol) was added sequentially to a 10 mL high-pressure reactor under a nitrogen atmosphere. Acetonitrile (5.0 ml), (2-chloropyridin-4-yl)methanol (607.2 mg, 4.25 mmol) and potassium t-butoxide (142.0 mg, 1.27 mmol). The raw materials were stirred and mixed uniformly, and then heated at 100 ° C overnight.

Post-treatment: The reaction system was cooled to room temperature, and the reaction solution was concentrated under reduced vacuum. The residue obtained was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 4/1). The product was collected and concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&& 4-amine (yield 63.2%).

MS (ESI) M / Z: 367 [M+H ⁺ ].

Step C: 1-Benzyl-6-((2-(methylamino)pyridin-4-yl)methoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

In a 100 ml high pressure reactor under nitrogen atmosphere, 1-benzyl-6-((2-chloropyridin-4-yl)methoxy)-1H-pyrazole[3,4-d] was added sequentially. Pyrimidine-4-amine (98.2 mg, 0.26 mmol) and a solution of methylamine in methanol (30% wt, 75 mL). After the raw material was stirred and dissolved, it was heated at 150 ° C for 36 hours.

Post-treatment: The reaction system was cooled to room temperature, and the reaction solution was concentrated under reduced vacuum. The residue was dissolved in anhydrous methanol (4.0 mL) and purified by preparative HPLC. Purification conditions are as follows, column: X select C1819mm*150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 75% in 80 minutes; detection Wavelength: 254 nm. The product was collected, and lyophilized under reduced pressure to give a white solid, 4-benzyl-6-((2-(methylamino)pyridin-4-yl)methoxy)-1H-pyrazolo[3,4- d] pyrimidin-4-amine (yield 4.3%).

MS (ESI) M/Z: 362 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 7.98 (s, 1H), 7.95 - 7.86 (m, 1H), 7.34 - 7.15 (m, 5H), 6.67 - 6.56 (m, 2H), 5.41 (d) , J = 4.4 Hz, 4H), 2.85 (s, 3H).

Examples 82 and 83: (S)-3-((4-Amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine -6-yl)oxy)hexan-1-ol and (S)-1-((4-amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[ 3,4-d]pyrimidin-6-yl)oxy)hexan-3-ol

Synthetic scheme

Step A: (S)-3-((4-Amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6- (yl)oxy)hexan-1-ol and (S)-1-((4-amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4 -d]pyrimidin-6-yl)oxy)hexan-3-ol

6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole[3,4-d] was sequentially added to a 10 ml high pressure reactor under a nitrogen atmosphere. Pyrimidine-4-amine (100 mg, 0.29 mmol), potassium t-butoxide (97 mg, 0.87 mmol), and (S)-hexane-1,3-diol (342 mg, 2.9 mmol). After stirring and mixing uniformly, the reaction liquid was stirred at 80 ° C for 4 hours.

Post-treatment: After the reaction apparatus was cooled to room temperature, the reaction liquid was filtered. The filtrate obtained was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X timate C18 21.2 mm * 250 mm; mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; flow rate: 25 ml / min; gradient: isocratic 35% acetonitrile, 20 minutes; detection wavelength: 254 nm . The product was collected and lyophilized to give 2.5 mg of a white solid (S)-3-((4-amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3 , 4-d]pyrimidin-6-yl)oxy)hexan-1-ol (yield 2.0%) and 6.0 mg of off-white solid (S)-1-((4-amino-1-(3-(pyrrole) Alkyl-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexan-3-ol (yield 4.9%).

(S)-3-((4-Amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hexyl-1-ol:

MS (ESI) M/Z: 425 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d4) δ 7.98 (s, 1H), 7.33 - 7.19 (m, 4H), 5.46 (s, 2H), 4.52 (t, J = 6.4 Hz, 2H), 3.90 - 3.74 (m, 1H), 3.61 (s, 2H), 2.52–2.38 (m, 4H), 2.04–1.94 (m, 1H), 1.86–1.79 (m, 5H), 1.63–1.37 (m, 4H), 0.95 (t, J = 6.7 Hz, 3H).

Ee%=99%

(S)-1-((4-amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hex-3-ol:

MS (ESI) M/Z: 425 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d4) δ 7.97 (s, 1H), 7.33 - 7.20 (m, 4H), 5.42 - 5.38 (m, 3H), 3.69 - 3.61 (m, 4H), 2.60 - 2.52 ( m, 4H), 1.96 - 1.89 (m, 2H), 1.74 - 1.61 (m, 6H), 1.57 - 1.37 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

Example 84: 6-((4-Fluorobenzyl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine 4-amine

Synthetic scheme

Step A: 6-((4-Fluorobenzyl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine trifluoroacetate

In a 10 ml sealed tube, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine was sequentially added under a nitrogen atmosphere. 4-Amine (100.0 mg, 0.29 mmol), acetonitrile (5.0 mL), 4-fluorobenzyl alcohol (368.2 mg, 2.9 mmol) and potassium tert-butoxide (98.2 mg, 0.87 mmol). The reaction mixture was stirred and mixed uniformly, and then stirred and heated at 100 ° C overnight.

Post-treatment: After the reaction system was cooled to room temperature, the reaction solution was concentrated under reduced pressure. The residue obtained was dissolved in N,N-dimethylformamide (4.0 ml), and purified by preparative high-performance liquid chromatography. The purification conditions were as follows: column: X select C18 19mm*150mm; mobile phase: water ( Containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile from 5% to 75% in 10 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give 50.0 mg of white solid 6-((4-fluorobenzyl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole. And [3,4-d]pyrimidine-4-amine trifluoroacetate (yield 32%).

MS (ESI) M / Z: 433 [M+H ⁺ ].

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.98 (s, 1H), 7.90-7.77 (m, 1H), 7.72 - 7.58 (m, 1H), 7.56 - 7.44 (m, 2H), 7.27 - 7.09 (m, 6H), 5.35 (d, J = 3.3 Hz, 4H), 3.51 (s, 2H), 2.45-2.32 (m, 4H), 1.72 - 1.61 (m, 4H).

¹⁹ F NMR (300 MHz, DMSO-d ₆ ) δ-114.7.

Example 85: 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-((tetrahydrofuran-3-yl)methoxy)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine

Synthetic scheme

Step A: Synthesis of 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-((tetrahydrofuran-3-yl)methoxy)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine

To a 30 ml sealed tube, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (in order) 0.15 g, 0.44 mmol, (tetrahydrofuran-3-yl)methanol (0.45 g, 4.4 mmol) and potassium t-butoxide (0.15 g, 1.32 mmol). The reaction apparatus was stirred at 100 ° C for 1.5 hours.

Work-up: The residue obtained by concentrating under reduced pressure was purified by silica gel column (eluent: methylene chloride/methanol = 10:1) to give 1-(4-(pyrrolidin-1-ylmethyl)benzyl - 6-((tetrahydrofuran-3-yl)methoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (11.4 mg, yield: 6.4%).

MS (ESI) M / Z: 409 [M+H ⁺ ].

¹ H NMR (300 MHz, Methanol-d ₄ ) δ 7.98 (s, 1H), 7.35 - 7.21 (q, J = 9.0, 4H), 5.42 (s, 2H), 4.21 - 4.46 (m, 2H), 3.71 –3.95 (m, 4H), 3.65 (s, 2H), 2.71–2.81 (m, 1H), 2.51– 2.61 (m, 4H), 2.08–2.09 (m, 1H), 1.73–1.85 (m, 5H) .

Example 86: 6-((3-oxabicyclo[3.1.0]hex-6-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H -pyrazolo[3,4-d]pyrimidin-4-amine

Synthetic scheme

Step A: Synthesis of (3-oxabicyclo[3.1.0]hex-6-yl)methanol

To a solution of 3-oxabicyclo[3.1.0]hexane-6-carboxylic acid (500 mg, 3.91 mmol) in tetrahydrofuran (5 mL) 3.91 ml, 7.81 mmol). The reaction was then stirred at room temperature overnight.

Post-treatment: The reaction was quenched with ice water (4 mL) at 0 °. Ethyl acetate (50 ml × 3) was evaporated. EtOAc m. 500 mg, crude).

Step B: Synthesis of 6-((3-oxabicyclo[3.1.0]hex-6-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H -pyrazolo[3,4-d]pyrimidin-4-amine

To 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.35 mmol) Potassium tert-butoxide (147 mg, 1.31 mmol), (3-oxabicyclo[3.1.0]hex-6-yl)methanol (500 mg, 3.5 mmol) was added to acetonitrile (0.5 mL). The above reaction solution was stirred at 100 ° C overnight.

Work-up: Filtration and purification of the filtrate by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 50 in 30 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 6-((3-oxabicyclo[3.1.0]hex-6-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl) as a colorless solid. Benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (12.6 mg, 3% yield).

MS (ESI) M/Z: 421 [M+H ⁺ ]

¹ H NMR (300MHz, Methanol-d ₄ ): δ 8.17 (d, J = 1.2 Hz, 1H), 7.76 - 7.26 (m, 4H), 5.55 (s, 2H), 4.46 (d, J = 7.5 Hz) , 2H), 4.36 (s, 2H), 3.85 (d, J = 8.4 Hz, 2H), 3.70 (dt, J = 8.4, 1.5 Hz, 2H), 3.47 (d, J = 5.8 Hz, 2H), 3.18 (d, J = 6.9 Hz, 2H), 2.18 - 1.99 (m, 4H), 1.85 - 1.81 (m, 2H), 1.29 (tt, J = 7.3, 3.4 Hz, 1H).

Example 87: (R)-6-((1-methoxyhex-3-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole And [3,4-d]pyrimidine-4-amine

Synthetic scheme

Step A: (R)-6-((1-Methoxyhex-3-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole [3,4-d]pyrimidine-4-amine

A 25 ml three-necked flask was taken, and (R)-3-((4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole[3] was added sequentially at 0 °C. , 4-d]pyrimidin-6-yl)oxy)hexan-1-ol (100 mg, 0.235 mmol), acetonitrile (10 ml), potassium carbonate (65 mg, 0.705 mmol), and iodomethane (33 mg) , 0.235 mmol). The resulting mixture was stirred at room temperature overnight.

Post treatment: The reaction solution was suction filtered under reduced pressure, and filtrate was collected. The filter cake was rinsed with acetonitrile (5.0 mL x 2 times). The combined filtrate was concentrated under reduced pressure. The concentrated residue was taken up in EtOAc (EtOAc) (EtOAc) Purification conditions were as follows, column: X timate C18 21.2 mm * 250 mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile: acetonitrile increased from 10% in 20 minutes 80%; detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure to give 63.2 mg of white (R)-6-((1-methoxyhex-3-yl)oxy)-1-(4-(pyrrolidin-1-yl) Benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine formate (yield 61.4%).

MS (ESI) M / Z: 437 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ8.02 (s, 1H), 7.95-7.80 (m, 2H), 7.51 (d, J = 7.8Hz, 2H), 7.35 (d, J = 7.7Hz, 2H), 5.42 (s, 2H), 5.23–5.19 (m, 1H), 4.53 (s, 2H), 3.58–3.31 (m, 6H), 2.87 (s, 3H), 2.18–2.03 (m, 4H) , 1.81 - 1.72 (m, 2H), 1.59 - 1.54 (m, 2H), 1.43 - 1.23 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).

Example 88: 2-Butoxy-7-(4-(1-methylpiperidin-4-yl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Synthetic scheme

Step A: 4-(piperidin-4-yl)benzoic acid methyl ester hydrochloride

4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)benzoic acid (1.00 g, 3.28 mmol), methanol (20 ml) was added to a 250 ml single-neck round bottom flask under ice-cooling. ). After the raw material was stirred and dissolved, thionyl chloride (10 ml) was slowly added dropwise to the reaction mixture. The resulting reaction solution was stirred at room temperature for 2 hours.

Work-up: The reaction mixture was evaporated under reduced pressure to give THF (yield: </RTI> <RTIgt; The crude product was used directly in the next reaction without purification.

MS (ESI) M/Z: 220 [M+H ⁺ ].

Step B: Methyl 4-(1-methylpiperidin-4-yl)benzoate

Add 4-(piperidin-4-yl)benzoic acid methyl ester hydrochloride (620 mg, 2.83 mmol), 1,2-dichloromethane (15 ml) and poly. to a 50 ml three-neck round bottom flask. Formaldehyde (1.50 g, 50.0 mmol). After stirring for half an hour, sodium triacetoxyborohydride (1.50 g, 3.16 mmol) was slowly added to the reaction mixture in portions. After three hours, LC-MS monitoring showed complete reaction.

Post treatment: Dilute water (10 ml) into the reaction system. The resulting mixture was extracted with dichloromethane (20 mL×3×). The combined organic layers were dried over anhydrous sodium sulfate and then evaporated. The residue after concentration was purified through a silica gel column (eluent: methanol / methylene chloride = 1/10). The product was collected and concentrated under reduced pressure to give EtOAc (EtOAc:EtOAc:

MS (ESI) M / Z: 234 [M+H ⁺ ].

Step C: (4-(1-Methylpiperidin-4-yl)phenyl)methanol

The compound 4-(1-methylpiperidin-4-yl)benzoic acid methyl ester (620 mg, 2.66 mmol) and tetrahydrofuran (20 ml) were sequentially added to a 50 ml round bottom single-necked flask under a nitrogen atmosphere. . After stirring and dissolving, lithium aluminum hydride (320 mg, 8.20 mmol) was slowly added in portions to the above reaction solution at 0 °C. After stirring at room temperature for 3 hours, LC-MS monitoring showed the reaction was completed.

Post treatment: The reaction solution was slowly poured into ice water (20 ml). The resulting mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were dried over anhydrous sodium sulfate and then evaporated. The residue after concentration was purified through a silica gel column (eluent: methanol / methylene chloride = 1/10). The product was collected and concentrated under reduced vacuoielielielielieliel

MS (ESI) M / Z: 206 [M+H ⁺ ].

Step D: 4-(4-(Chloromethyl)phenyl)-1-methylpiperidine

4-(1-methylpiperidin-4-yl)phenyl)methanol (240 mg, 1.17 mmol), methylene chloride (5 mL) and EtOAc. Sulfoxide (1 ml). After stirring at 0 ° C for 1 hour, TLC monitoring showed the disappearance of the starting material.

Work-up: The reaction mixture was evaporated to dryness mjjjjjjjjjj

MS (ESI) M / Z: 206 [M+H ⁺ ].

Step E: 2-butoxy-7-(4-(1-methylpiperidin-4-yl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine trifluoroacetic acid salt

2-butoxy-7H-pyrrolo[2,3-d]pyrimidin-4-amine (20 mg, 0.097 mmol), N,N-di, was added sequentially to a 10 mL round bottom flask at 0 °C. Methylformamide (1.00 ml). After the raw materials were stirred and dissolved, sodium hydrogen (12 mg, 0.29 mmol) was slowly added in portions to the above reaction mixture. At the end of the addition, the reaction flask was stirred at room temperature for 15 minutes. A solution of 4-(4-(chloromethyl)phenyl)-1-methylpiperidine (26 mg, 0.112 mmol) in N,N-dimethylformamide (1 ml) was slowly added dropwise to the reaction mixture. . It was stirred at room temperature for 3 hours.

Work-up: The mixture was poured into ice water (5 mL). The combined organic layers were dried over anhydrous sodium sulfate and then evaporated. The concentrated residue was taken up in EtOAc (EtOAc m. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80% within 8 minutes Detection wavelength: 254 nm. The product was collected and concentrated under reduced pressure to give 30.5 mg of yellow semi-solid 2-butoxy-7-(4-(1-methylpiperidin-4-yl)benzyl)-7H-pyrrolo[2,3-d Pyrimidine-4-amine trifluoroacetate (yield 62.0%).

MS (ESI) M / Z: 394 [M+H ⁺ ].

¹ H NMR: (300 MHz, CD ₃ OD, ppm) δ 8.15 - 8.00 (m, 5H), 7.53 (d, J = 3.6 Hz, 1H), 6.07 (s, 2H), 5.29 - 5.15 (m, 2H) ), 4.43–4.28 (m, 2H), 3.90–3.80 (m, 2H), 3.70–3.53 (m, 4H), 2.78–2.48 (m, 6H), 2.27–1.17 (m, 2H), 1.74 (t) , J = 7.2 Hz, 3H).

Example 89: 6-butoxy-1-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine

Synthetic scheme

Step A: N-(4-bromoethyl)-trifluoroacetamide

2-(4-Bromophenyl)ethylamine (50.0 g, 250 mmol), dichloromethane (500.0 ml) and triethylamine (30.3 g, 300 m) were sequentially added to a 1000 ml three-necked flask under a nitrogen atmosphere. Molar), stir and mix evenly. Subsequently, trifluoroacetic anhydride (63.0 g, 300 mmol) was slowly added dropwise to the reaction mixture under ice-water bath. After the completion of the dropwise addition, the reaction solution was stirred at room temperature for 2 hours.

Work-up: Water (500 ml) was added to the reaction mixture. The mixture was allowed to stand for stratification, and the lower organic phase was separated. The organic phase was concentrated to dryness under reduced pressure to yield 7 <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;

MS (ESI) M/Z: 296, 298 [M+H ⁺ ].

Step B: 1-(7-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethyl ketone

N-(4-Bromoethyl)-trifluoroacetamide (72.5 g, 0.25 mol) was added to a mixed solution of concentrated sulfuric acid (419.0 ml) and glacial acetic acid (628.2 ml). After stirring and mixing uniformly, paraformaldehyde (22.1 g, 0.74 mol) was added portionwise to the reaction liquid. Then, it was stirred at room temperature overnight.

Work-up: The reaction solution was poured into ice water (1200 ml). The resulting mixture was extracted with ethyl acetate (1000 mL × 2). The organic phase was washed with aq. aq. The residue was purified by silica gel column chromatography eluting The product was collected and concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&&& 95.2%).

MS (ESI) M/Z: 308, 310 [M+H ⁺ ].

Step C: 2-Trifluoroacetyl-tetrahydroisoquinoline-7-carbonitrile

1-(7-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethyl ketone (32.0) was added to a 1000 mL round bottom flask under nitrogen atmosphere. Grams, 104.2 mmol), cuprous cyanide (18.6 g, 207.2 mmol) and methylpyrrolidin-2-one (300.0 mL). After the raw materials were stirred and dissolved, the reaction liquid was heated at 170 ° C for 4 hours.

Post-treatment: The reaction solution was cooled to room temperature, and the reaction solution was poured into ice water (500 ml) and then evaporated. The resulting mixture was extracted with ethyl acetate (300 mL × 2) The organic phase was washed with a saturated sodium chloride solution (500 ml), dried over anhydrous sodium sulfate 24.7 g of a yellow solid 2-trifluoroacetyl-tetrahydroisoquinoline-7-carbonitrile were obtained. It is used directly in the next step without purification.

MS (ESI) M / Z: 495 [M+H ⁺ ].

Step D: 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile

Into a 500 ml round bottom flask, 2-trifluoroacetyl-tetrahydroisoquinolin-7-carbonitrile (24.7 g, 96.8 mmol), anhydrous potassium carbonate (24.7 g, 179.0 mmol), methanol (200.0 ml) and water (40.0 ml). Stir at room temperature for 2 hours.

Post-treatment: The reaction solution was concentrated under reduced pressure and diluted with water (100 ml). The resulting mixture was extracted with ethyl acetate (100 mL×2×) and the organic phases were combined. The organic phase was washed with a saturated aqueous solution of sodium chloride (100 ml) and dried over anhydrous sodium sulfate. 12.6 g of a yellow solid 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile were obtained. It is used directly in the next step without purification.

MS (ESI) M/Z: 159 [M+H ⁺ ].

Step E: 2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile

To a solution of 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile (12.6 g, 79.2 mmol) in N,N-dimethylformamide (150.0 mL) Sodium hydride (4.7 g, 60% wt, 118.8 mmol) was added in portions. Subsequently, the reaction apparatus was moved to room temperature and stirred. After half an hour, the reaction solution was again transferred to an ice water bath, and iodoisopropane (53.8 g, 316.4 mmol) was slowly added. The addition was completed and the reaction was stirred at room temperature overnight.

After work-up: Water (100 ml) was added to the mixture and the mixture was evaporated. The organic phase was washed with a saturated sodium chloride solution (200 ml), dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAcjjjjjjjjjjjjj - Tetrahydroisoquinoline-7-carbonitrile.

MS (ESI) M / Z: 201 [M+H ⁺ ].

Step F: 2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7-formaldehyde

A solution of diisobutylaluminum hydride in toluene (1.5 M, 10.0 mL, 15.0 mmol) was slowly dropped into 2-isopropyl-1,2,3,4-tetrahydrogen at -10 ° C under a nitrogen atmosphere. Quinoline-7-carbonitrile (2.01 g, 10.0 mmol) in tetrahydrofuran (20.0 mL). After the dropwise addition was completed, the reaction apparatus was moved to an ice water bath, and stirring was continued for 4 hours.

Post-treatment: Under ice-water bath, water (30 ml) was slowly added dropwise to the reaction mixture to quench. The resulting mixture was extracted with ethyl acetate (30 mL × 2) The organic phase was washed with a saturated sodium chloride solution (50 ml), dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAcjjjjjjjj 1.93 g of a yellow oily liquid 2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7-carbaldehyde was obtained (yield: 95.1%).

MS (ESI) M / Z: 204 [M+H ⁺ ].

Step G: (2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methanol

To a solution of 2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-carbaldehyde (500.0 mg, 2.45 mmol) in dry ethanol (10.0 mL) Sodium borohydride (47.2 mg, 1.23 mmol) was added slowly. After the addition was completed, the reaction apparatus was moved to room temperature and stirred for 3 hours.

Post-treatment: Under ice-water bath, water (10 ml) was slowly added dropwise to the reaction mixture to quench. The mixture was concentrated under reduced pressure to remove ethanol. The concentrate was diluted with water (20 mL) andEtOAcEtOAc The organic phase was washed with a saturated sodium chloride solution (15 ml), dried over anhydrous sodium sulfate 527 mg of white solid (2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methanol were obtained. It is used directly in the next step without purification.

MS (ESI) M / Z: 206 [M+H ⁺ ].

Step H: 7-(Chloromethyl)-2-isopropyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

In a solution of (2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methanol (520 mg, 2.55 mmol) in dichloromethane (10.0 mL) Thionyl chloride (953 mg, 8.01 mmol) was added dropwise. After the dropwise addition was completed, the reaction apparatus was stirred at room temperature for 2 hours.

Work-up: The reaction was concentrated to give </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; It is used directly in the next step without purification.

MS (ESI) M / Z: 260 [M+H ⁺ ].

Step I: 6-Chloro-1-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine

To a solution of 6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (300.0 mg, 1.76 mmol) in N,N-dimethylformamide (10.0). Sodium hydride (282.3 mg, 60% wt, 7.05 mmol) was added in portions to the solution. Next, the reaction apparatus was moved to room temperature and stirred. After half an hour, 7-(chloromethyl)-2-isopropyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (542.2 mg, 2.11 mmol) was added to the reaction mixture. ). The addition was completed and the reaction was stirred at room temperature overnight.

After work-up: water (10 ml) was added and the mixture was evaporated. The organic phase was washed with a saturated sodium chloride solution (30 ml), dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography eluting The product was collected and concentrated under reduced pressure to give 164 mg (yield: 6-chloro-1-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-1H-py Zoxao[3,4-d]pyrimidin-4-amine (yield 25.6%).

MS (ESI) M / Z: 357 [M+H ⁺ ].

Step J: 6-butoxy-1-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-1H-pyrazolo[3,4- d]pyrimidine-4-amine

Into a 20 ml high pressure reactor, 6-chloro-1-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-1H-pyrazole was added in sequence. [3,4-d]pyrimidine-4-amine (150.0 mg, 0.42 mmol), n-butanol (15.0 ml) and potassium tert-butoxide (142.1 mg, 1.26 mmol). After the raw materials were uniformly mixed, the reaction liquid was stirred at 100 ° C overnight.

Work-up: The reaction mixture was concentrated. EtOAc m. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% NH ₃ · H ₂ O) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 5% in 10 minutes Increased to 75%; detection wavelength: 254nm. The product was collected and lyophilized under reduced pressure to give 15.2 mg of white solid 6-butoxy-1-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine (yield 9.1%).

MS (ESI) M / Z: 495 [M+H ⁺ ].

¹ H NMR (300 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.18 (d, J = 7.9 Hz, 1H), 7.14 - 7.01 (m, 2H), 5.42 (s, 2H), 5.33 (s) , 2H), 4.41 (t, J = 6.6 Hz, 2H), 3.94 - 3.76 (m, 1H), 3.21-2.76 (m, 4H), 1.89 - 1.73 (m, 2H), 1.62 - 1.47 (m, 4H) ), 1.38 - 1.13 (s, 6H), 1.01 (t, J = 7.4 Hz, 3H).

Example 90: 6-((2-Methylpyridin-4-yl)methoxy)-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine

Synthetic scheme

Step A: 6-((2-Methylpyridin-4-yl)methoxy)-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine

Into a 10 ml high pressure reactor, 6-chloro-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was added in sequence. (150 mg, 0.44 mmol), acetonitrile (5.0 mL), (2-methyl-pyridin-4-yl)methanol (539 mg, 4.42 mmol) and potassium tert-butoxide (147 mg, 1.31 mmol). After stirring and stirring, the reaction solution was stirred at 150 ° C overnight.

Post-treatment: The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (EtOAc) (EtOAc) Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 5% to 75% in 10 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized to give 11.3 mg of brown solid 6-((2-methylpyridin-4-yl)methoxy)-1-(3-(pyrrolidin-1-ylmethyl)benzyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine (yield 6%).

MS (ESI) M/Z: 430 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ8.40 (d, J = 5.1Hz, 1H), 7.98 (s, 1H), 7.95-7.60 (m, 2H), 7.27 (s, 1H), 7.26- 7.14 (m, 4H), 7.04–6.96 (m, 1H), 5.38 (s, 2H), 5.34 (s, 2H), 3.49 (s, 2H), 2.45 (s, 3H), 2.40–2.30 (m, 4H), 1.69-1.61 (m, 4H).

Example 91: 4-Amino-2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

Synthetic scheme

Step A: 3-((6-Bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

N,N-dimethylformamide to 6-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.00 g, 7.49 mmol) in a nitrogen atmosphere under ice-water bath Sodium hydride (329.6 mg, 60% by weight, 8.24 mmol) was added in portions (50.0 mL). After stirring for 0.5 hour, 3-(bromomethyl)benzaldehyde (1.64 g, 8.24 mmol) was added to the reaction mixture. Subsequently, the reaction apparatus was moved to room temperature and stirred for 0.5 hour, and the reaction was confirmed by LCMS.

Work-up: A saturated ammonium chloride solution (50 ml) was slowly added to the reaction mixture to quench the reaction. The resulting mixture was extracted with ethyl acetate (100 mL×3×). The organic phase was washed with a saturated sodium chloride solution (50 mL × 2), then dried over anhydrous sodium sulfate Ethyl acetate (10 ml) was added to the concentrated solid residue, and stirred for 10 min. The filter cake was collected and dried to give 1.60 g of a yellow solid 3-((6-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde ( The yield was 55.6%).

MS (ESI) M/Z: 384, 386 [M+H ⁺ ].

Step B: 3-((4-Amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

To a 20 ml high pressure sealed tube, 3-((6-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (1.60 g) was added in sequence. , 4.16 mmol) and a solution of ammonia in isopropanol (15.0 mL, 2.0 M, 30.0 mmol). After stirring and dissolving, the reaction solution was stirred at 120 ° C overnight.

Work-up: The reaction solution was cooled to room temperature, and the reaction solution was concentrated to dryness. The concentrate was dissolved in dichloromethane (30 mL). The organic solution was washed with saturated brine (30 ml × 2×), then dried over anhydrous sodium sulfate and evaporated. 1.50 g of a yellow solid 3-((4-amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (yield: 99%) was obtained. This compound can be used directly in the next reaction without further purification.

MS (ESI) M/Z: 365, 367 [M+H ⁺ ].

Step C: 6-Bromo-2-chloro-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

3-((4-Amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (770 mg, 2.12 m) in an ice water bath Mole), pyrrolidine (448 mg, 6.31 mmol) and sodium triacetoxyborohydride (892 mg, 4.21 mmol) were dissolved in dichloromethane (50 mL). The reaction was carried out at room temperature overnight.

Work-up: The reaction solution was concentrated to dryness under reduced pressure. The residue was taken up in EtOAc (EtOAc m. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 60 ml / min; gradient: acetonitrile from 0% to 100 in 30 minutes %; detection wavelength: 254 nm. The product was collected and concentrated to dryness <RTI ID=0.0></RTI></RTIjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj d]pyrimidine-4-amine (yield 33.9%).

MS (ESI) M/Z: 420,422 [M+H ⁺ ].

Step D: 6-Bromo-2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

6-Bromo-2-chloro-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 was added sequentially to a 20 mL high pressure reactor. -Amine (300 mg, 0.71 mmol), n-butanol (15.0 mL) and potassium t-butoxide (240 mg, 2.14 mmol). After stirring and stirring, the reaction solution was stirred at 90 ° C overnight.

Post-treatment: The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (50 mL). The organic solution was washed with saturated brine (30 ml × 2 times), dried over anhydrous sodium sulfate and evaporated to dryness. Yield 210 mg of 6-bromo-2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a yellow oil (Yield 64.4%).

MS (ESI) M/Z: 458, 460 [M+H ⁺ ].

Step E: 4-Amino-2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile Fluoroacetate

Add 6-bromo-2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine to a 10 ml microwave tube. 4-amine (210 mg, 0.46 mmol), zinc cyanide (53.7 ml, 0.46 mmol), tetratriphenylphosphine palladium (53.1 mg, 0.046 mmol), 1,1-bis(diphenylphosphine) Ferrocene (25.5 mg, 0.046 mmol) and N,N-dimethylformamide (5.00 mL). The reaction solution was heated under microwave atmosphere to 120 ° C for 20 minutes.

Work-up: The reaction was filtered and the filtrate was collected. The filtrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 30 ml / min; gradient: acetonitrile from 10% to 75 in 7 minutes %; detection wavelength: 254 nm. The organic phase was collected and lyophilized to give 24.1 mg of white 4-amino-2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3 -d] Pyrimidine-6-carbonitrile trifluoroacetate (yield 10%).

MS (ESI) M / Z: 405 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 7.63 - 7.45 (m, 4H), 7.45 - 7.33 (m, 1H), 5.55 (s, 2H), 4.56 (t, J = 6.5 Hz, 2H), 4.40 (s, 2H), 3.51–3.40 (m, 2H), 3.17–3.07 (m, 2H), 2.31–1.92 (m, 4H), 1.90–1.78 (m, 2H), 1.64–1.37 (m, 2H) ), 1.00 (t, J = 7.4 Hz, 3H).

Example 92: 4-Amino-2-((4,4-difluorocyclohexyl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl-7H-pyrrolo[2 ,3-d]pyrimidine-6-carbonitrile

synthetic route

Step A: 6-Bromo-2-((4,4-difluorocyclohexyl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-amine

6-Bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 was added sequentially to a 10 mL high pressure reactor. -Amine (150 mg, 0.36 mmol) acetonitrile (4.0 mL), (4,4-difluorocyclohexyl)methanol (540 mg, 3.6 mmol) and potassium t-butoxide (120 mg, 1.10 mmol). After the raw materials were uniformly mixed, the reaction solution was heated at 120 ° C for 4 hours.

Post-treatment: The reaction system was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (30 ml). Yield 180 mg of yellow liquid 6-bromo-2-((4,4-difluorocyclohexyl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole [2,3-d]pyrimidine-4-amine (crude product). This compound was used directly in the next step without purification.

MS (ESI) M/Z: 534, 538 [M+H ⁺ ].

Step B: 4-Amino-2-((4,4-difluorocyclohexyl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl-7H-pyrrolo[2, 3-d]pyrimidine-6-carbonitrile trifluoroacetate

In a 25 ml three-neck round bottom flask, 6-bromo-2-((4,4-difluorocyclohexyl)methoxy)-7-(4-(pyrrolidin-1-yl) was sequentially added under a nitrogen atmosphere. Benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (180 mg, crude), N,N-dimethylformamide (3.0 ml), zinc cyanide (93 mg , 0.8 mmol, tetrakistriphenylphosphine palladium (46 mg, 0.04 mmol), zinc powder (52 mg, 0.8 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (44 Mg, 0.08 mmol). After stirring and mixing uniformly, the mixture was stirred at 110 ° C for 16 hours.

After-treatment: The reaction solution was cooled to room temperature and filtered. The filtrate obtained was purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% TFA) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80% in 7 minutes; Detection wavelength: 254 nm. The product was collected, and lyophilized under reduced pressure to give a white solid (yield: 4-amino-2-((4,4-difluorocyclohexyl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl). Benzyl-7H-pyrrolo[2,3-d]pyrimidin-6-carbonitrile trifluoroacetate (two-step yield 12.7%).

MS (ESI) M / Z: 481 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ7.44 (d, J = 5.1Hz, 2H), 7.38-7.27 (m, 3H), 5.42 (s, 2H), 4.27 (d, J = 6.0Hz, 2H), 3.75 (s, 2H), 2.78 - 2.61 (m, 4H), 2.17 - 2.01 (m, 2H), 1.98 - 1.70 (m, 9H), 1.55 - 1.38 (m, 2H).

¹ F NMR (300 MHz, Methanol-d ₄ ) δ - 92.76 (d, J = 251.7 Hz, 1F), -103.47 (d, J = 251.7 Hz, 1F).

Example 93: 4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((2-(trifluoromethyl)pyridin-4-yl)methoxy)- 7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

Synthetic scheme

Step A: 6-Bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methoxy)-7H -pyrrolo[2,3-d]pyrimidin-4-amine trifluoroacetate

In a 30 ml high pressure reactor under nitrogen atmosphere, 6-bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole[2,3 was sequentially added. -d]pyrimidin-4-amine (0.20 g, 0.48 mmol, 1.00 eq.), (6-(trifluoromethyl)pyridin-3-yl)methanol (0.85 g, 4.77 mmol, 10.00 eq.) Acetonitrile (4.00 ml) and potassium t-butoxide (0.21 g, 1.91 mmol, 4.00 eq.). After the raw materials were stirred and mixed uniformly, the reaction solution was stirred at 100 ° C overnight.

Work-up: The reaction system was cooled to room temperature and quenched by adding ice water (30 mL). The resulting mixture was extracted with ethyl acetate (50 mL×3). Combine the organic phases. The organic phase was back-washed with a saturated aqueous solution of sodium chloride (100 mL, 3) The residue was dissolved in N,N-dimethylformamide (4.0 mL). Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 100% in 7 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&&&&&& 3-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidin-4-amine trifluoroacetate (yield 25%).

MS (ES, M/Z): 561, 563 [M+H ⁺ ].

Step B: 4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((2-(trifluoromethyl)pyridin-4-yl)methoxy)-7H -pyrrolo[2,3-d]pyrimidin-6-nitrile trifluoroacetate & formate

Under a nitrogen atmosphere, 6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((6-(trifluoromethyl)pyridine) was added sequentially to a 25 ml three-necked flask. 3-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidin-4-amine trifluoroacetate (81 mg, 0.12 mmol, 1.00 equiv), zinc cyanide (34 mg, 0.29) Millimol, 2.00 equivalents), zinc (19 mg, 0.30 mmol, 2.00 equiv), 1,1-bis(diphenylphosphino)ferrocene (16 mg, 0.03 mmol, 0.20 equivalent), tetrakis (triphenyl) Palladium (33 mg, 0.03 mmol, 0.20 eq.) and N,N-dimethylformamide (5.00 mL). After the raw materials were stirred and dissolved, the reaction solution was stirred at 100 ° C for 3 hours.

Post-treatment: The reaction system was cooled to room temperature, and ice-cold (30 ml) was added to the reaction mixture to quench the reaction. The resulting mixture was extracted with ethyl acetate (50 mL × 3) The organic phase was backwashed with saturated brine (3.times.100 mL) then dried over anhydrous sodium sulfate. The residue was dissolved in N,N-dimethylformamide (4.0 mL). Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 25 ml / min; acetonitrile from 30% to 50% in 8 minutes; detection wavelength : 254 nm. The product was collected and lyophilized to give 18.8 mg of white solid 4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((2-(trifluoromethyl)pyridine) 4-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidin-6-nitrile trifluoroacetate & formate (yield 27%).

MS (ESI) M/Z: 508 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6, ppm) δ8.73 (d, J = 5.1Hz, 1H), 8.15 (s, 1H), 7.95-7.63 (m, 3H), 7.43 (s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 8.1 Hz, 2H), 5.55 (s, 2H), 5.30 (s, 2H), 3.73 (s, 2H), 2.67 - 2.55 (m) , 4H), 1.82–1.67 (m, 4H).

¹⁹ F NMR (282 MHz, DMSO-d ₆ , ppm) δ - 66.53.

Example 94: 6-Chloro-2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d Pyrimidine-4-amine

Synthetic scheme

Step A: 6-Chloro-2-(pyridin-4-ylmethoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3 -d]pyrimidine-4-amine

To a 100 ml high pressure reactor, potassium t-butoxide (1.37 g, 12.2 mmol), acetonitrile (50.0 ml), 4-pyridine methanol (3.85 g, 35.3 mmol) and 2,6-dichloro-7 were added in sequence. -((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.96 g, 2.8 mmol). After the raw materials were stirred and mixed uniformly, the reaction liquid was heated at 120 ° C and stirred for 10 hours.

Post-treatment: The reaction system was cooled to room temperature, and the reaction solution was poured into ice water (100 ml). The resulting mixture was extracted with ethyl acetate (100 mL×3×). The combined organic phases were washed with EtOAcq. Yield 1.08 g of yellow solid 6-chloro-2-(pyridin-4-ylmethoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2 , 3-d]pyrimidine-4-amine. It is used directly in the next step without purification.

MS (ESI) M/Z: 406 [M+H ⁺ ].

Step B: 6-Chloro-2-(pyridin-4-ylmethoxy)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a 100 ml single-mouth bottle, 6-chloro-2-(pyridin-4-ylmethoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- was added in sequence. Pyrrolo[2,3-d]pyrimidin-4-amine (1.08 g, 2.7 mmol) and trifluoroacetic acid (30.0 mL). The reaction solution was stirred with heating at 60 ° C for 2 hours. Subsequently, the reaction liquid was concentrated under reduced pressure. Methanol (30.0 ml), water (20.0 ml) and potassium carbonate (1.54 g) were added to the concentrated residue. After stirring and dissolved, the reaction solution was heated at 50 ° C for two hours.

Post-treatment: The reaction solution was cooled to room temperature, diluted with water (50 ml), and the mixture was concentrated in vacuo to remove methanol. The aqueous phase obtained was extracted with ethyl acetate (100 mL×3×). The combined organic layers were dried with anhydrous sodium 1.07 g of crude 6-chloro-2-(pyridin-4-ylmethoxy)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was obtained as a yellow solid. It is used directly in the next step without purification.

MS (ESI) M / Z: 276 [M+H ⁺ ].

Step C: 4-((4-Amino-6-chloro-2-(pyridin-4-ylmethoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

To a 100 ml single-mouth bottle, potassium carbonate (0.42 g, 3.0 mmol), p-aldehyde benzyl bromide (0.28 g, 1.1 mmol), 6-chloro-2-(pyridin-4-ylmethoxy) was added in order. -7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.28 g, 1.0 mmol) and acetonitrile (50.0 mL). The reaction mixture was stirred at room temperature for 10 hours.

Post treatment: The reaction solution was suction filtered, and the filtrate was collected. The filter cake was washed with ethyl acetate (20 mL x 2). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut 2-(Pyridin-4-ylmethoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde.

MS (ESI) M / Z: 394 [M+H ⁺ ].

Step D: 6-Chloro-2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-amine trifluoroacetate

To a 100 ml single-mouth bottle, pyrrolidine (0.05 g, 0.6 mmol), dichloromethane (20.0 ml) 4-((4-amino-6-chloro-2-(pyridin-4-ylmethoxy)) 7H-Pyrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (0.20 g, 0.5 mmol) and sodium borohydride (0.32 g, 1.5 mmol). The reaction mixture was stirred at room temperature for 10 hours.

Work-up: The reaction solution was concentrated under reduced pressure. The concentrated residue was dissolved in dimethyl sulfoxide (5.0 mL) and purified and purified by preparative HPLC. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 15% to 75 in 9 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 59 mg of pale-yellow solid 6-chloro-2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H- Pyrrolo[2,3-d]pyrimidin-4-amine trifluoroacetate (yield 26.3%).

MS (ESI) M / Z: 449 [M+H ⁺ ].

¹⁹ F NMR (300 MHz, DMSO-d ₆ ) δ-74.6.

^{1 H NMR (300MHz, DMSO-} d 6) δ8.79 (d, J = 5.9Hz, 2H), 7.90 (d, J = 5.9Hz, 2H), 7.78-7.50 (m, 2H), 7.41 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 6.67 (s, 1H), 5.60 (s, 2H), 5.28 (s, 2H), 4.31 (s, 2H), 3.43 - 3.00 (m, 4H), 2.14 - 1.79 (m, 4H).

Example 95: 4-Amino-2-((2-methylpyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole [2,3-d]pyrimidine-6-carbonitrile

Synthetic scheme

Step A: 6-Bromo-2-((2-methylpyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[ 2,3-d]pyrimidine-4-amine

In a 30 ml high pressure reactor, 6-bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-Amine (0.20 g, 0.48 mmol, 1.00 eq.), (2-methyl-pyridin-4-yl)methanol (0.59 g, 4.77 mmol, 10.00 eq.), anhydrous acetonitrile (4.00 mL) Potassium alkoxide (0.16 g, 1.43 mmol, 3.00 equivalent). After the raw materials were stirred and dissolved, the reaction solution was stirred at 100 ° C overnight.

Post-treatment: The reaction system was cooled to room temperature, and ice water (30 ml) was added to the reaction mixture to quench the reaction. The resulting mixture was extracted with ethyl acetate (3×100 mL). The organic phase was back-washed with saturated brine (100 mL × 3) then dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in anhydrous methanol (4.0 mL). Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 75% in 7 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&& Benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (yield 31%).

MS (ES, M/Z): 507, 509 [M+H ⁺ ].

Step B: 4-Amino-2-((2-methylpyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[ 2,3-d]pyrimidine-6-carbonitrile

In a 25 ml three-neck round bottom flask, 6-bromo-2-((2-methylpyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-yl) was added sequentially under a nitrogen atmosphere. Methyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (78 mg, 0.15 mmol, 1.00 equiv), zinc cyanide (36 mg, 0.31 mmol, 2.00 eq), Zinc (20 mg, 0.31 mmol, 2.00 equiv), 1,1-bis(diphenylphosphino)ferrocene (18 mg, 0.03 mmol, 0.20 equivalent), tetrakis(triphenylphosphine)palladium (36 mg) , 0.03 mmol, 0.20 equivalents) and N,N-dimethylformamide (5.0 mL). After the raw materials were stirred and dissolved, the reaction solution was stirred at 100 ° C for 3 hours.

Post-treatment: The reaction system was cooled to room temperature, and ice-cold (30 ml) was added to the reaction mixture to quench the reaction. The resulting mixture was extracted with ethyl acetate (50 mL × 3) The organic phase was backwashed with saturated brine (100 mL × 3) then dried over anhydrous sodium sulfate and evaporated The residue after concentration was dissolved in N,N-dimethylformamide (4.0 ml), and purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 100% in 7 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized to give 15.9 mg of 4-amino-2-((2-methylpyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl) as a white solid. Benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (yield 23%).

MS (ES, M/Z): 454 [M+H ⁺ ].

¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 8.39 (d, J = 5.1 Hz, 1H), 7.93 - 7.53 (m, 2H), 7.42 (s, 1H), 7.26 - 7.18 (m, 4H) ), 7.08 (d, J = 8.1 Hz, 2H), 5.40 (s, 2H), 5.29 (s, 2H), 3.50 (s, 2H), 2.51 (s, 3H), 2.42 - 2.30 (m, 4H) , 1.76–1.60 (m, 4H).

Example 96: 6-((5-Methylisoxazol-3-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[ 3,4-d]pyrimidine-4-amine

Synthetic scheme

Step A: Synthesis of 6-((5-methylisoxazol-3-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[ 3,4-d]pyrimidine-4-amine

See compound 6-(pyridin-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 for details. - Synthesis of amines. (5-Methylisoxazol-3-yl)methanol (330 mg, 0.29 mmol), potassium tert-butoxide (97 mg, 0.87 mmol), and 6-chloro-1-(4-(pyrrolidine-1) -ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.29 mmol). 40.9 mg of a white solid are obtained as 6-((5-methylisoxazol-3-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyridyl Zoxao[3,4-d]pyrimidin-4-amine (yield 33.7%).

MS (ESI) M/Z: 420 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ8.00 (s, 1H), 7.35-7.26 (m, 4H), 6.24 (s, 1H), 5.47 (s, 2H), 5.46 (s, 2H), 3.77 (s, 2H), 2.83-2.70 (m, 4H), 2.42 (s, 3H), 2.91-1.81 (m, 4H).

Examples 97 and 98: 2-(4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yloxy Pentyl-1-ol and 1-(4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl Oxy)pentan-2-ol

Synthetic scheme

Step A: 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-(1-(tetrahydro-2H-pyran-2-yloxy)pentan-2-yloxy) -1H-pyrazolo[3,4-d]pyrimidin-4-amine and 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(2-(tetrahydro-2H-pyridyl) a mixture of m--2-yloxy)pentyloxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Into a 10 ml high pressure reactor, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was added in sequence. (100 mg, 0.73 mmol), 1,2-pentanediol (490 mg, 4.72 mmol), potassium tert-butoxide (99 mg, 0.87 mmol) and acetonitrile (3.0 mL). After the raw materials were stirred and mixed uniformly, the oil bath was heated at 100 ° C overnight.

Post-treatment: The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (4.0 mL). Purification conditions are as follows, column: X select C1819mm*150mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 65% in 7 minutes; detection Wavelength: 254 nm. The product was collected and lyophilized to give 4.5 mg of white solid 1-(4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidin-6-yloxy)pentan-2-ol formate and 25.2 mg of white solid 2-(4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyridin Zoxao[3,4-d]pyrimidin-6-yloxy)pentan-1-ol formate (purity 80%).

25.2 mg of 2-(4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3] with N,N-dimethylformamide (2.0 ml) , 4-d]pyrimidin-6-yloxy)pentan-1-ol formate (purity 80%) was dissolved until clear, and the mixture was again purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 75 in 10 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 17.5 mg of white solid 2-(4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidin-6-yloxy)pentan-1-ol trifluoroacetate.

1-(4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yloxy)pent-2- Alcohol formate

MS (ESI) M / Z: 411 [M+H ⁺ ].

¹ H NMR (300 MHz, Methanol-d ₄ ) δ 8.00 (s, 1H), 7.51-7.33 (m, 4H), 5.49 (s, 2H), 4.51-4.15 (m, 4H), 4.07-3.89 (m) , 1H), 3.22 (s, 4H), 2.04 (s, 4H), 1.69-1.36 (m, 4H), 0.98 (t, J = 6.7 Hz, 3H).

Example 99: 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-(1-(thiazol-5-yl)butoxy)-1H-pyrazolo[3,4- d]pyrimidine-4-amine

Synthetic scheme

Step A: 1-(thiazol-5-yl)butan-1-ol

A solution of propylmagnesium bromide in tetrahydrofuran (2 mol/L, 44.2) was slowly added dropwise to a solution of thiazole-5-carbaldehyde (5.0 g, 44.2 mmol) in tetrahydrofuran (100 ml) in a nitrogen atmosphere at -78 °C. ML, 88.4 mmol). After the addition was completed, the reaction solution was transferred to an ice water bath and stirred for 2 hours.

Post-treatment: Saturated ammonium chloride solution (150 ml) was slowly added dropwise to the reaction mixture under ice-water bath. The resulting mixture was extracted with ethyl acetate (100 mL × 2). Combine the organic phases. The organic phase was washed with a saturated sodium chloride solution (100 ml × 2), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 4.32 g of colorless liquid 1-(thiazol-5-yl)butene-1- Alcohol (yield 61%).

MS (ESI) M/Z: 158 [M+H ⁺ ].

Step B: 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-(1-(thiazol-5-yl)butoxy)-1H-pyrazolo[3,4-d Pyrimidine-4-amine

To a 10 ml high pressure reactor, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4- Amine (100 mg, 0.29 mmol), 1-(thiazol-5-yl)butan-1-ol, acetonitrile (5.0 mL) and potassium t-butoxide (97.9 mg, 0.88 mmol). After the raw materials were uniformly mixed, the reaction liquid was stirred at 100 ° C overnight.

Post-treatment: The reaction system was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (EtOAc) (EtOAc) Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80% in 7 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized at low temperature and reduced pressure. 13.6 mg of 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(1-(thiazol-5-yl)butoxy)-1H-pyrazole[3,4] -d]pyrimidine-4-amine (yield 10.0%).

MS (ES, M/Z): 464 [M+H] ⁺

¹ H NMR (300 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.93 (s, 1H), 7.82 (s, 1H), 7.43 - 7.32 (m, 2H), 7.29 (s, 2H), 6.44 (t, J = 6.9 Hz, 1H), 5.48 (s, 2H), 5.37 (s, 2H), 3.81 - 3.60 (m, 2H), 2.82 - 2.50 (m, 4H), 2.31-2.14 (m, 1H) ), 2.07 - 1.92 (m, 1H), 1.91 - 1.78 (m, 4H), 1.55 - 1.38 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).

Example 100: 4-Amino-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-2-(pyridin-4-ylmethoxy) -7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

Synthetic scheme

Step A: 6-Bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a 250 ml sealed tube, 6-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (4.00 g, 15.0 mmol) and an isopropanol solution of ammonia (100 ml) were added in sequence. , 250 mmol, 2 mol/L). Subsequently, the reaction apparatus was stirred at 120 ° C for 24 hours.

Post-treatment: The reaction apparatus was cooled to room temperature, and the reaction liquid was concentrated under reduced pressure. Dichloromethane (50 ml) and water (50 ml) were added to the residue, and stirred at room temperature for 10 min. The reaction solution was allowed to stand for separation, and the lower organic phase was separated. The organic phase was dried over anhydrous sodium sulfate and evaporated. 0.97 g of a yellow solid 6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine was obtained.

MS (ESI) M/Z: 247, 249 [M+H ⁺ ].

Step B: 6-Bromo-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-2-(pyridin-4-ylmethoxy) )-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a 100 ml single-mouth bottle, potassium carbonate (1.62 g, 11.7 mmol), 6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.97 g, 3.9 m) was sequentially added. Mole), 7-(chloromethyl)-2-isopropyl-1,2,3,4-tetrahydroisoquinoline (0.96 g, 4.3 mmol) and acetonitrile (50 mL). Subsequently, the reaction mixture was stirred at 80 ° C for 1 hour.

Post-treatment: The reaction apparatus was cooled to room temperature, and the reaction liquid was concentrated under reduced pressure. The solid residue obtained was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1/4). The product was collected and concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&& )-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

MS (ESI) M/Z: 434, 436 [M+H ⁺ ].

Step C: 6-Bromo-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-7H-pyrrolo[2 ,3-d]pyrimidine-4-amine

Potassium tert-butoxide (0.10 g, 0.9 mmol), 6-bromo-2-chloro-7-((2-isopropyl-1,2,3) was sequentially added to a 50 ml high pressure reactor under a nitrogen atmosphere. ,4-tetrahydroisoquinolin-6-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.15 g, 0.3 mmol), pyridin-4-ylmethanol (0.32 Grams, 3.0 mmol) and acetonitrile (30 mL). Then, the reaction apparatus was heated at 100 ° C for 10 hours.

Post-treatment: The reaction apparatus was cooled to room temperature, and the reaction liquid was concentrated under reduced pressure. The concentrated crude product was dissolved in dimethyl sulfoxide (4.0 ml) to clarified and purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 30 ml / min; gradient: acetonitrile from 15% to 80% in 8 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized at low temperature and reduced pressure. 0.11 g of a brownish yellow solid 6-bromo-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-7H-pyrrole And [2,3-d]pyrimidine-4-amine.

MS (ESI) M/Z: 507, 509 [M+H ⁺ ].

Step D: 4-Amino-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-2-(pyridin-4-ylmethoxy) )-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

In a N ₂ atmosphere, 6-bromo-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquino-7-) was added sequentially to a 30 ml single-necked flask. Methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.11 g, 0.2 mmol), tri-dibenzylideneacetone dipalladium (0.04 g, 0.04 mmol), 1, 1'-bisdiphenylphosphinoferrocene (0.03 g, 0.04 mmol), zinc cyanide (0.05 g, 0.4 mmol), zinc powder (0.03 g, 0.4 mmol) and N,N-dimethyl Formamide (6 ml). The reaction solution was stirred at 100 ° C for 10 hours.

Post-treatment: The reaction apparatus was cooled to room temperature with a reaction apparatus, and the reaction liquid was filtered. The filtrate was purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 30 ml / min; gradient: acetonitrile from 25% to 75% in 8 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized at low temperature to give 2 mg of white solid 4-amino-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-2. -(Pyridin-4-ylmethoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (yield 2.2%).

MS (ESI) M/Z: 454 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d6) δ8.54 (d, J = 6.0Hz 2H), 7.92-7.59 (m, 2H), 7.49-7.32 (m, 3H), 7.00-6.79 (m, 3H), 5.43 (s, 2H), 5.24 (s, 2H), 3.57 (s, 2H), 2.70 - 2.57 (m, 4H), 1.03 (d, J = 6.5 Hz, 6H).

Example 101: 6-((2-(Methylamino)pyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole [3,4-d]pyrimidine-4-amine

Synthetic scheme

Step A: 6-((2-Chloropyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d]pyrimidine-4-amine

In a 50 ml high pressure reactor, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was added in sequence. (250.0 mg, 0.73 mmol), acetonitrile (25.0 ml), (2-chloropyridin-4-yl)methanol (1.04 g, 7.29 mmol) and potassium t-butoxide (245.2 mg, 2.19 mmol). After the raw materials were uniformly mixed, the reaction liquid was stirred at 100 ° C overnight.

Work-up: The reaction system was cooled to room temperature and then quenched by adding water (15 mL). The resulting mixture was extracted with ethyl acetate (25 mL×2×). The combined organic phases were washed with a saturated sodium chloride solution (50 mL×2×) then dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc EtOAc The product was collected and concentrated under reduced pressure to give 230.2 mg (yield: 6-((2-chloropyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine (yield 70.1%).

MS (ES, M/Z): 450 [M+H ⁺ ].

Step B: 6-((2-(Methylamino)pyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[ 3,4-d]pyrimidine-4-amine formate

To a 100 ml high pressure reactor, 6-((2-chloropyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrene was added in sequence. Zoxao[3,4-d]pyrimidin-4-amine (153.5 mg, 0.34 mmol) and a solution of methylamine in methanol (30% wt, 75.0 mL). After the raw materials were stirred and dissolved, the reaction mixture was further stirred at 150 ° C for 36 hours.

Work-up: The reaction system was cooled to room temperature, and the reaction solution was concentrated. The residue was taken up in anhydrous methanol (4 mL) and purified and purified. Purification conditions are as follows, column: X select C1819mm*150mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 75% in 7 minutes; detection Wavelength: 254 nm. The product was collected and lyophilized at low temperature and reduced pressure. Yield 22.6 mg of brown solid 6-((2-(methylamino)pyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole And [3,4-d]pyrimidine-4-amine formate (yield 11.4%).

MS (ES, M/Z): 445 [M+H ⁺ ].

¹ H NMR (300 MHz, Methanol-d ₄ ) δ 7.99 (s, 1H), 7.89 (d, J = 5.7 Hz, 1H), 7.41 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 6.66 (d, J = 5.2 Hz, 1H), 6.65 (s, 1H), 5.46 (s, 2H), 5.42 (s, 2H), 4.31 (s, 2H), 3.31 - 3.21 ( m, 4H), 2.88 (s, 3H), 2.13 - 2.02 (m, 4H).

Example 102: N-(3-((4-Amino-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzyl Acetamide

Synthetic scheme

Step A: (3-(Aminomethyl)phenyl)methanol

To a solution of 3-formylbenzonitrile (5.0 g, 38.2 mmol) in tetrahydrofuran (150.0 mL) was added EtOAc (4. . The reaction solution was stirred in an ice water bath for half an hour and then stirred at room temperature overnight.

Work-up: Water (10 ml) was slowly added dropwise to the reaction mixture at 0 °C. Then, anhydrous sodium sulfate (20 g) was added to the above mixture, and stirred for 20 minutes. The reaction mixture was filtered to remove a white solid, and filtrate was collected. The filtrate was dried over anhydrous sodium sulfate and evaporated. 2.87 g of a pale yellow liquid (3-(aminomethyl)phenyl)methanol (yield 54.9%) was obtained.

MS (ESI) M / Z: 138 [M+H ⁺ ].

Step B: 3-(Acetylaminomethyl)benzyl acetate

To a solution of (3-(aminomethyl)phenyl)methanol (2.87 g, 20.28 mmol) in dichloromethane (100.0 mL), m. Moore) and stir for 10 minutes. Then, acetic anhydride (6.21 g, 60.87 mmol) was slowly added dropwise to the reaction mixture. After the dropwise addition was completed, the reaction solution was stirred to room temperature and stirred overnight.

After work-up: Water (20 ml) was added to the mixture, and the mixture was extracted with dichloromethane (100 ml × 2). The combined organic phases were washed with EtOAc (EtOAc m. 3.12 g of a yellow liquid 3-(acetylaminomethyl)benzyl acetate (yield 67.4%) was obtained.

MS (ESI) M / Z: 222 [M+H ⁺ ].

Step C: N-(3-(hydroxymethyl)benzyl)acetamide

To a mixed solution of 3-(acetylaminomethyl)benzyl acetate (3.12 g, 13.96 mmol) in methanol (30.0 mL) and water (10.0 mL), 5.86 g, 139.6 mmol). The resulting reaction solution was stirred at room temperature overnight.

Post-treatment: Water (100 ml) was added to the reaction mixture for dilution, and the reaction mixture was concentrated under reduced pressure to remove methanol. The concentrated aqueous solution was extracted with ethyl acetate (50 mL×2×). The combined organic phases were washed with EtOAc (EtOAc m. There was obtained 1.7 g of a white solid N-(3-(hydroxymethyl)benzyl)acetamide (yield: 67.5%).

MS (ESI) M/Z: 180 [M+H ⁺ ].

Step D: N-(3-(Chloromethyl)benzyl)acetamide hydrochloride

To a solution of N-(3-(hydroxymethyl)benzyl)acetamide (1.7 g, 5.58 mmol) in dichloromethane (30.0 mL), EtOAc (1. , 13.90 mmol). After the dropwise addition was completed, the reaction solution was stirred to room temperature and stirred overnight.

Work-up: The reaction mixture was concentrated under reduced pressure to give 1.5 g (yield: 67.6%) of pale yellow solid N-(3-(chloromethyl)benzyl)acetamide hydrochloride.

MS (ESI) M / Z: 198 [M+H ⁺ ].

Step E: 6-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 6-chloro -2-((2-(Trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-d]pyrimidin-4-amine

Slowly add hydrogenation to a solution of 6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (7.50 g, 44.1 mmol) in tetrahydrofuran (150.0 ml) in a nitrogen atmosphere Sodium (2.32 g, 60% wt, 52.9 mmol). The reaction was stirred at room temperature for 30 minutes. Subsequently, 2-(trimethylsilyl)ethoxymethyl chloride (8.83 g, 57.3 mmol) was slowly added dropwise to the reaction mixture at 0 °C. The resulting reaction solution was stirred at room temperature overnight.

Work-up: The reaction mixture was quenched with water (100 ml). The combined organic phases were washed with EtOAc (EtOAc m. Obtained 6.5 g of a yellow liquid as 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine And a mixture of 6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-d]pyrimidin-4-amine.

MS (ESI) M/Z: 300 [M+H ⁺ ].

Step F: 6-(Pyridin-4-ylmethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d] Pyrimidin-4-amine and 6-(pyridin-4-ylmethoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4 -d]pyrimidine-4-amine

6-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4 was added sequentially to a 250 ml high pressure reactor. a mixture of an amine and 6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-d]pyrimidin-4-amine (6.5 Gram, 21.67 mmol, acetonitrile (100.0 mL), potassium tert-butoxide (7.29 g, 65.1 mmol) and 4-pyridine methanol (11.8 g, 108.3 mmol). After stirring and mixing well, the reaction solution was stirred at 100 ° C overnight.

Work-up: The reaction system was cooled to room temperature, and the reaction solution was concentrated. Water (100 ml) was added to the concentrate, and the mixture was extracted with ethyl acetate (150 ml × 2). The combined organic phases were washed with EtOAc (EtOAc m. 4.32 g of a yellow liquid are obtained as 6-(pyridin-4-ylmethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3, 4-d]pyrimidin-4-amine and 6-(pyridin-4-ylmethoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazole A mixture of [3,4-d]pyrimidine-4-amine.

MS (ESI) M/Z: 373 [M+H ⁺ ].

Step G: 6-(Pyridin-4-ylmethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine

6-(Pyridin-4-ylmethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine and 6-(pyridin-4-ylmethoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-d A mixture of pyrimidine-4-amine (4.32 g, 11.58 mmol) was dissolved in trifluoroacetic acid (40 mL).

Work-up: The reaction solution was concentrated under reduced pressure. To the concentrated residue was added saturated sodium bicarbonate solution and the solution was adjusted to pH. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with EtOAc (EtOAc m. Petroleum ether (50 ml) and ethyl acetate (5 ml) were added and the mixture was stirred for 30 min. The mixture was suction filtered, and the cake was collected and dried to give 1.25 g of a yellow solid 6-(pyridin-4-ylmethoxy)-1-((2-(trimethylsilyl)ethoxy) Methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.

MS (ESI) M / Z: 243 [M+H ⁺ ].

Step H: N-(3-((4-Amino-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzyl Acetamide

To 6-(pyridin-4-ylmethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine- N-(3-(Chloromethyl)benzyl)acetamide hydrochloride (240 mg, 0.99 mmol) in anhydrous EtOAc (20.0 mL) Potassium carbonate (340.7 mg, 2.47 mmol). The reaction mixture was stirred at 70 ° C for 5 hours.

Post-treatment: The reaction system was cooled to room temperature, and the reaction solution was suction filtered to collect a filtrate. The filter cake was washed with ethyl acetate (20 mL x 2). The combined filtrate was concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (4 ml) and purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 5% to 75% in 10 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized to give 17.3 mg of white solid N-(3-((4-amino-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine-1 -yl)methyl)benzyl)acetamide (yield 5.2%).

MS (ESI) M/Z: 404 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ8.55 (d, J = 6.0Hz, 2H), 8.36-8.23 (m, 1H), 7.99 (s, 1H), 7.90-7.60 (m, 2H), 7.42 (d, J = 6.0 Hz, 2H), 7.26 - 7.10 (m, 3H), 7.01 (d, J = 7.4 Hz, 1H), 5.43 (s, 2H), 5.33 (s, 2H), 4.18 (d) , J = 6.0 Hz, 2H), 1.83 (s, 3H).

Example 103: 4-Amino-2-((4-fluorocyclohexyl-3-en-1-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)- 7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

synthetic route

Step A: 6-Bromo-2-((4-fluorocyclohexyl-3-en-1-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H -pyrrolo[2,3-d]pyrimidin-4-amine

6-Bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 was added sequentially to a 10 mL high pressure reactor. -amine (150 mg, 0.36 mmol) acetonitrile (4.0 ml), (4-fluorocyclohexyl-3-en-1-yl)methanol (468 mg, 3.6 mmol) and potassium t-butoxide (120 mg, 1.10) Millimoles). Subsequently, the reaction solution was stirred at 110 ° C for 12 hours.

Post-treatment: The reaction system was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (50 mL). The obtained organic phase was washed with saturated brine (30 ml×2×), then dried over anhydrous sodium sulfate The crude product obtained was purified by column chromatography (eluent: dichloromethane / methanol = 10/1). The product was collected and concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt; Methyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (yield 70%).

MS (ESI) M/Z: 514, 516 [M+H ⁺ ].

Step B: 4-Amino-2-((4-fluorocyclohexyl-3-en-1-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H -pyrrolo[2,3-d]pyrimidine-6-carbonitrile trifluoroacetate

6-Bromo-2-((4-fluorocyclohexyl-3-en-1-yl)methoxy)-7-(4-(pyrrolidine) was sequentially added to a 25 ml three-neck round bottom flask under a nitrogen atmosphere. -1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (130 mg, 0.25 mmol), N,N-dimethylformamide (3.0 ml), Zinc cyanide (93 mg, 0.8 mmol), tetrakistriphenylphosphine palladium (46 mg, 0.04 mmol), zinc powder (52 mg, 0.8 mmol) and 1,1'-bis(diphenylphosphino) Ferrocene (44 mg, 0.08 mmol). Subsequently, the reaction was stirred at 110 ° C for 16 hours.

Post treatment: The reaction system was cooled to room temperature, and the reaction liquid was filtered. The filtrate obtained was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80 in 7 minutes %; detection wavelength: 254 nm. The product was collected, and lyophilized under reduced pressure to give 24.6 mg of white solid, m., 4-amino-2-((4-fluorocyclohexyl-3-en-1-yl)methoxy)-7-(4-(pyrrolidine) -1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile trifluoroacetate (yield 21.3%).

MS (ESI) M / Z: 461 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 7.45–7.21 (m, 5H), 7.38–7.27 (m, 3H), 5.43 (s, 2H), 5.27–5.11 (m, 2H), 4.42–4.18 (m, 2H), 3.79 (s, 2H), 2.79–2.52 (m, 4H), 2.49–2.17 (m, 3H), 2.13–1.91 (m, 3H), 1.90–1.88 (m, 4H), 1.68 – 1.50 (m, 1H).

¹ F NMR (300 MHz, Methanol-d ₄ ) δ - 104.3.

Example 104: 4-Amino-2-(pyridin-4-ylmethoxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d Pyrimidine-6-carbonitrile

Synthetic scheme

Step A: 3-((6-Bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

To a solution of 6-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 3.75 mmol) in tetrahydrofuran (30 mL) at 0 ° C Sodium hydride (164.8 mg, 4.12 mmol) was added. After the addition was completed, the reaction apparatus was moved to room temperature and stirred for half an hour. Subsequently, a solution of 3-(bromomethyl)benzaldehyde (820 mg, 4.12 mmol) in tetrahydrofuran (10 ml) was added dropwise at 0 °C. After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred overnight.

After work-up: Water (40 ml) was added to the mixture and the mixture was evaporated. The combined organic phases were dried over anhydrous sodium sulfate and then evaporated. To the residue after concentration was added ethyl acetate (10 ml) and stirred for 10 min. The mixture was suction filtered under reduced pressure, and the cake was evaporated and dried to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&& )methyl)benzaldehyde (yield 41.6%).

MS (ESI) M/Z: 384, 386 [M+H ⁺ ].

Step B: 3-((4-Amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde

3-((6-Bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (600 mg, 1.56 mmol) was dissolved in ammonia Isopropanol (10 ml, 2 mol/L, 20 mmol) in solution. After the reaction solution was stirred and dissolved, it was stirred at 120 ° C overnight.

Post-treatment: The reaction system was allowed to reach room temperature, and the reaction solution was concentrated to dryness under reduced pressure. The concentrated residue was taken up in dichloromethane (50 mL). The obtained organic phase was back-washed with water (50 ml × 2 times), then dried over anhydrous sodium sulfate and evaporated. There was obtained 450 mg of a yellow solid 3-((4-amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (yield 78.9%). The crude product was used directly in the next step without purification.

MS (ESI) M/Z: 365, 367 [M+H ⁺ ].

Step C: 6-(Pyridin-4-ylmethoxy)-1-((4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3,4-d Pyrimidine-4-amine

3-((4-Amino-6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzaldehyde (450 mg, 1.23) at 0 ° C Millimol) and pyrrolidine (262 mg, 3.69 mmol) were dissolved in 5 mL of dichloromethane. Subsequently, sodium triacetoxyborohydride (782 mg, 3.69 mmol) was added to the reaction liquid. The resulting reaction solution was allowed to react at room temperature overnight.

Post-treatment: The phase reaction solution was quenched by the addition of pure water (10 ml). The resulting mixture was extracted with dichloromethane (10 mL×3×). The combined organic phases were washed with aq. EtOAc (EtOAc (EtOAc) Yield 400 mg of yellow solid 6-(pyridin-4-ylmethoxy)-1-((4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine (yield 77.2%).

MS (ESI) M/Z: 420,422 [M+H ⁺ ].

Step D: 6-Bromo-2-(pyridin-4-ylmethoxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-amine

Under the nitrogen atmosphere, 6-(pyridin-4-ylmethoxy)-1-((4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3] , 4-d]pyrimidin-4-amine (400 mg, 0.95 mmol), 4-hydroxymethylpyridine (310 mg, 2.84 mmol) and potassium t-butoxide (320 mg, 2.85 mmol) dissolved in 10 ml In acetonitrile. The resulting reaction solution was stirred at 90 ° C overnight.

Work-up: The reaction solution was filtered, and the filtrate was collected and concentrated. The residue was concentrated and purified with EtOAc (EtOAc) Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 80 ml / min; gradient: acetonitrile from 20% to 80 in 20 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 324 mg of brown solid 6-bromo-2-(pyridin-4-ylmethoxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole And [2,3-d]pyrimidine-4-amine (yield 69.2%).

MS (ESI) M/Z: 495,495 [M+H ⁺ ].

Step E: 4-Amino-2-(pyridin-4-ylmethoxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile trifluoroacetate

Under a nitrogen atmosphere, 6-bromo-2-(pyridin-4-ylmethoxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2, 3-d]pyrimidine-4-amine (324 mg, 0.66 mmol), zinc cyanide (77 mg, 0.66 mmol), tetratriphenylphosphine palladium (76.1 mg, 0.066 mmol), 1,1'- Bis(diphenylphosphino)ferrocene (36.6 mg, 0.066 mmol) and zinc powder (85.5 mg, 1.32 mmol) were dissolved in N,N-dimethylformamide (5.0 mL). The resulting mixture was reacted at 110 ° C for 3 hours.

Post-treatment: The reaction system was cooled to room temperature, and the reaction solution was filtered under reduced pressure. The filtrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 80 ml / min; gradient: acetonitrile from 10% to 70 in 20 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 47.0 mg (yield: 4,7 mg,yield 4-amino-2-(pyridin-4-ylmethoxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)- 7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile trifluoroacetate (yield 16.3%).

MS (ESI) M/Z: 440 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d4): δ8.81 (d, J = 6.0Hz, 2H), 8.11 (d, J = 6.0Hz, 2H), 7.59-7.41 (m, 3H), 7.38 (s, 1H), 7.24 (d, J = 6.7 Hz, 1H), 5.78 (s, 2H), 5.48 (s, 2H), 4.38 (s, 2H), 3.51 - 3.41 (m, 2H), 3.29 - 3.11 (m , 2H), 2.35–1.88 (m, 4H).

Examples 105 and 106: (S)-6-(1-phenylbutoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine and (R)-6-(1-phenylbutoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[ 3,4-d]pyrimidine-4-amine

Synthetic scheme

Step A: (S)-6-(1-Phenylbutoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine

6-(1-Phenylbutoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine ( 100 mg, 0.22 mmol) was dissolved in absolute ethanol (5.0 mL) and chiral resolved by chiral separation. Purification conditions were as follows, column: CHIRALPAK AD-3 0.46 cm * 10 cm, 3 μm; mobile phase: n-hexane (containing 0.1% diethylamine) and ethanol; flow rate: 1 ml / min; gradient: within 10 minutes, maintain positive The concentration of the alkane was 50%; the detection wavelength was 254 nm. The peak peak time is about 2.6 min, and the peak peak time is about 3 min. The two fractions were separately collected and concentrated to dryness under reduced pressure.

The pre-peak was collected and concentrated to dryness under reduced pressure. Obtained 12.3 mg of a white solid as (S)-6-(1-phenylbutoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine (yield 12.3%).

MS (ESI) M / Z: 467 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ8.48 (d, J = 5.3Hz, 2H), 7.93 (s, 1H), 7.49 (d, J = 5.2Hz, 2H), 7.22 (d, J = 7.7 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 6.21 - 5.95 (m, 1H), 5.45 - 5.21 (m, 2H), 3.61 (s, 2H), 2.60 - 2.40 (m, 4H) ), 2.11 - 1.66 (m, 6H), 1.61 - 1.44 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

E.e.%=99.64%

The post-peak was collected and concentrated to dryness under reduced pressure. 15 mg of 89% pure white solid were obtained. The white solid was dissolved in N,N-dimethylformamide (5 ml) and purified by preparative HPLC. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonium bicarbonate) and acetonitrile; flow rate: 80 ml / min; gradient: acetonitrile from 20% to 80 in 20 minutes %; detection wavelength: 254 nm. 5.9 mg of a white solid are obtained as (R)-6-(1-phenylbutoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine formate salt (yield 5.9%).

MS (ESI) M / Z: 467 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 8.74 - 8.36 (m, 2H), 7.94 (s, 1H), 7.48 (d, J = 5.2 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 6.15 - 6.00 (m, 1H), 5.58 - 5.21 (m, 2H), 4.17 (s, 2H), 3.25 - 3.00 (m, 4H), 2.07 -1.82 (m, 6H), 1.62 - 1.46 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).

E.e.%=99.86%

Example 107: 1-(Cyclohexylmethyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Synthetic scheme

Step A: 1-(Cyclohexylmethyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To 6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.6198 mmol) of N,N-dimethylacetamide ( In a solution of 8.0 ml), (bromomethyl)cyclohexane (327 mg, 1.860 mmol) and potassium carbonate (257 mg, 1.860 mmol) were sequentially added. The reaction solution was then stirred at 60 ° C for 16 hours.

Post-treatment: The reaction system was cooled to room temperature, the reaction solution was filtered, and the filtrate was collected. The filtrate was purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 75% in 8 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give 36.6 mg of white solid 1-(cyclohexylmethyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine (yield 17.4%).

MS (ESI) M / Z: 339 [M+H ⁺ ].

^{1 H NMR (300MHz, DMSO-} d 6) δ8.54 (d, J = 6.0Hz, 2H), 7.95 (s, 1H), 7.90-7.50 (m, 2H), 7.40 (d, J = 6.0Hz, 2H), 5.40 (s, 2H), 3.97 (d, J = 7.2 Hz, 2H), 1.81 - 1.73 (m, 1H), 1.57 (s, 3H), 1.47 - 1.28 (m, 2H), 1.09 (s , 3H), 0.90–0.83 (m, 2H).

Example 108: 6-(Pyridin-4-ylmethoxy)-1-(6-(pyrrolidin-1-yl)hexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Synthetic scheme

Step A: 1-(3-Bromopropyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To 6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.6198 mmol) of N,N-dimethylacetamide ( In a solution of 8.0 ml), 1,6-dibromohexane (450 mg, 1.860 mmol) and potassium carbonate (257 mg, 1.860 mmol) were sequentially added. The resulting mixture was stirred at 60 ° C for 16 hours.

流动相：水 (含有0.05％氨水)和乙腈；流速:50毫升/分钟；梯度：在40分钟内，乙腈从10％升到100％；检测波长：254nm。收集产物，低温减压冻干得到92毫克白色固体1-(3-溴丙基)-6-(吡啶-4-基甲氧基)-1H-吡唑并[3,4-d]嘧啶-4-胺(收率36.7％)。 Post-treatment: After the system was cooled to room temperature, the reaction solution was filtered and the filtrate was collected. The filtrate was purified by medium pressure liquid chromatography. Purification conditions are as follows, column: Flash Column C18 80g 20-35μm,

Mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; flow rate: 50 ml/min; gradient: acetonitrile increased from 10% to 100% in 40 minutes; detection wavelength: 254 nm. The product was collected, and lyophilized at low temperature to give 92 mg of white solid 1-(3-bromopropyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine (yield 36.7%).

MS (ESI) M / Z: 405, 407 [M+H ⁺ ].

Step B: 6-(Pyridin-4-ylmethoxy)-1-(6-(pyrrolidin-1-yl)hexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To 1-(3-bromopropyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (92 mg, 0.2277 mmol) Potassium carbonate (94 mg, 0.6831 mmol) and pyrrolidine (49 mg, 0.6831 mmol) were sequentially added to a solution of N,N-dimethylacetamide (5.0 ml). Subsequently, the resulting reaction solution was stirred at 60 ° C for 16 hours.

Post-treatment: The reaction system was cooled to room temperature, the reaction solution was filtered, and the filtrate was collected. The filtrate was purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 75% in 8 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give 17.6 mg (yield: 6-(pyridin-4-ylmethoxy)-1-(6-(pyrrolidin-1-yl)hexyl)-1H-pyrazolo[ 3,4-d]pyrimidine-4-amine (yield 19.5%).

MS (ESI) M / Z: 396 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 8.55 (d, J = 6.0 Hz, 2H), 7.97 (s, 1H), 7.54 (d, J = 6.0 Hz, 2H), 5.54 (s, 2H) , 4.25 (t, J = 6.9 Hz, 2H), 2.52 - 2.50 (m, 4H), 2.42 - 2.37 (m, 2H), 1.89 - 1.77 (m, 6H), 1.53 - 1.43 (m, 2H), 1.36 –1.28 (m, 4H).

Example 109: (S)-4-Amino-2-(3-hydroxyhexyloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3 -d]pyrimidine-6-carbonitrile

Synthetic scheme

Step A: (S)-1-((4-Amino-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine -2-yl)oxy)hexanol

In a 30 ml high pressure reactor, 6-bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-Amine (0.50 g, 1.19 mmol, 1.00 equiv), (S)-heptane-1,3-diol (1.57 g, 11.93 mmol, 10.00 eq.) and potassium t-butoxide (0.40 g, 3.67 m) Molar, 3.00 equivalents). After stirring and stirring, the reaction was stirred at 100 ° C for 3 hours.

Post-treatment: The reaction system was cooled to room temperature, and ice water (30 ml) was added to the reaction mixture to quench the reaction. The resulting mixture was extracted with ethyl acetate (50 mL×3×). The combined organic phases were back-washed with saturated brine (100 mL×3×) then dried over anhydrous sodium sulfate. The concentrated residue was purified by medium pressure liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 5% to 100 in 7 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 150 mg of white solid (S)-1-((4-amino-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H- Pyrrolo[2,3-d]pyrimidin-2-yl)oxy)hexan-3-ol.

MS (ESI) M/Z: 502, 504 [M+H ⁺ ].

Step B: (S)-4-Amino-2-(3-hydroxyhexyloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3- d]pyrimidine-6-carbonitrile

(S)-1-((4-Amino-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H was sequentially added to a 25 ml three-necked flask under a nitrogen atmosphere. -pyrrolo[2,3-d]pyrimidin-2-yl)oxy)hexan-3-ol (150 mg, 0.30 mmol, 1.00 equiv), zinc cyanide (69 mg, 0.60 mmol, 2.00 equiv) , zinc powder (38 mg, 0.60 mmol, 2.00 equiv), 1,1'-bis(diphenylphosphino)ferrocene (33 mg, 0.06 mmol, 0.20 equivalent), tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol, 0.20 eq.) and N,N-dimethylacetamide (5.00 mL). After the raw materials were stirred and dissolved, the reaction solution was stirred at 100 ° C for 3 hours.

Post-treatment: The reaction system was cooled to room temperature, and water (30 ml) was added to the reaction mixture for dilution. The resulting mixture was extracted with ethyl acetate (50 mL×3×). The combined organic phases were washed with saturated brine (100 mL×3×) then dried over anhydrous sodium sulfate. The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 100% in 7 minutes; Detection wavelength: 254 nm. It was lyophilized under reduced pressure to give 18.4 mg of (S)-4-amino-2-(3-hydroxyhexyloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H as a white solid. Pyrrolo[2,3-d]pyrimidine-6-carbonitrile (yield 14%).

MS (ESI) M / Z: 449 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 7.35 - 7.27 (m, 5H), 5.42 (s, 2H), 4.54 - 4.49 (m, 2H), 3.83 - 3.78 (m, 1H), 3.65 (s) , 2H), 2.57 (s, 4H), 2.04–1.93 (m, 1H), 1.87–1.75 (m, 5H), 1.58–1.34 (m, 4H), 1.01–0.90 (m, 3H).

Example 110: (R)-4-Amino-2-(3-hydroxyhexyloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3 -d]pyrimidine-6-carbonitrile

Synthetic scheme

Step A: (R)-1-(4-Amino-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine- 2-yloxy)hexyl-3-ol

Into a 30 ml high pressure reactor, 6-bromo-2-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-Amine (0.50 g, 1.19 mmol, 1.00 equiv), (R)-heptane-1,3-diol (1.57 g, 11.93 mmol, 10.00 eq.) and potassium t-butoxide (0.40 g, 3.67 m) Molar, 3.00 equivalents). After stirring to dissolve, the reaction was heated to 100 ° C and stirred for 3 hours.

Post-treatment: The reaction system was cooled to room temperature, and diluted with ice water (30 ml). The resulting mixture was extracted with ethyl acetate (50 mL×3×). The combined organic phases were washed with saturated brine (100 mL×3×) then dried over anhydrous sodium sulfate. The resulting concentrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 5% to 100 in 7 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 120 mg of (R)-1-(4-amino-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yloxy)hexyl-3-ol (yield 20%).

MS (ESI) M/Z: 502, 504 [M+H ⁺ ].

Step B: (R)-4-Amino-2-(1-hydroxyhex-3-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[ 2,3-d]pyrimidine-6-carbonitrile

In a 25 ml three-necked flask, (R)-1-(4-amino-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H- was added sequentially under a nitrogen atmosphere. Pyrrolo[2,3-d]pyrimidin-2-yloxy)hexyl-3-ol (120 mg, 0.24 mmol, 1.00 equiv), zinc cyanide (56 mg, 0.48 mmol, 2.00 equiv), zinc Powder (31 mg, 0.48 mmol, 2.00 equiv), 1,1'-bis(diphenylphosphino)ferrocene (27 mg, 0.05 mmol, 0.20 equivalent), tetrakis(triphenylphosphine)palladium (55) Mill, 0.05 mmol, 0.20 equivalents) and N,N-dimethylacetamide (5.00 mL). After the raw material was stirred and dissolved, the reaction liquid was heated to 100 ° C and stirred for 3 hours.

Post-treatment: The reaction system was cooled to room temperature, and diluted with ice water (30 ml). The resulting mixture was extracted with ethyl acetate (50 mL×3×). The combined organic phases were washed with saturated brine (100 mL×3×) then dried over anhydrous sodium sulfate. The concentrated residue was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 100% in 7 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give 10.2 <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

MS (ESI) M / Z: 449 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 7.35 - 7.23 (m, 5H), 5.41 (s, 2H), 4.86 - 4.46 (m2H), 3.83 - 3.80 (m, 1H), 3.64 (s, 2H) ), 2.55 (s, 4H), 2.04 - 1.93 (m, 1H), 1.84 - 1.75 (m, 5H), 1.52 - 1.31 (m, 4H), 0.97 - 0.93 (m, 3H).

Example 111: (R)-3-((4-Amino-1-((4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)methyl)-1H-pyrazolo[3, 4-d]pyrimidin-6-yl)oxy)hexan-1-ol

Synthetic scheme

Step A: 2-((4-Amino-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)isonicotinate

To a 50 ml round bottom three-necked flask was added 6-chloro-1H-pyrazolo[3,4-D]pyrimidin-4-amine (500 mg, 2.96 mmol), acetonitrile (30 ml), potassium carbonate (1.23 g, 8.88 mmol) and methyl 2-bromomethyl-4-pyridinecarboxylate (678 mg, 2.96 mmol). The resulting mixture was stirred at room temperature overnight.

Post treatment: The reaction solution was suction filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure. EtOAc m. The product was collected and concentrated under reduced pressure to give EtOAc (yield: (Yield 33.7%).

MS (ESI) M / Z: 319 [M+H ⁺ ].

Step B: (2-((4-Amino-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyridin-4-yl)methanol

To methyl 2-((4-amino-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)isonicotinate (317 mg, 0.99 m) at zero degrees Celsius To a solution of the hexanes (30 ml), lithium aluminum hydride (38 mg, 0.99 mmol) was slowly added. Subsequently, the reaction solution was further stirred at zero degrees Celsius for 4 hours.

Post-treatment: The reaction was quenched by slowly adding water (5 ml) to the reaction solution at zero degrees Celsius. Subsequently, anhydrous sodium sulfate (10.0 g) was added to the above mixture and stirred for 15 minutes. The resulting mixture was suction filtered, and the filtrate was collected and evaporated. The solid residue after concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2/1). The product was collected and concentrated under reduced vacuo to yieldd <RTI ID=0.0>#</RTI> </RTI> <RTIgt; -Based methanol (yield 73.1%).

MS (ESI) M / Z: 291 [M+H ⁺ ].

Step C: 6-Chloro-1-((4-(chloromethyl)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

(2-((4-Amino-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyridin-4-yl)methanol (200 mg at zero degrees Celsius) , 0.69 mmol) was slowly added to thionyl chloride (15 mL). The resulting reaction solution was stirred at zero degrees Celsius for 1 hour.

Work-up: The reaction solution was concentrated directly under reduced pressure to give 220 mg of yellow semi-solid (220 mg) 6-chloro-1-((4-(chloromethyl)pyridin-2-yl)methyl)-1H-pyrazole And [3,4-d]pyrimidine-4-amine. The crude product obtained was used in the next step without purification.

MS (ESI) M / Z: 309 [M+H ⁺ ].

Step D: 6-Butoxy-1-((2-(pyrrolidin-1-ylmethyl)pyridin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine

Add 6-chloro-1-((4-(chloromethyl)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine to a 25 ml three-necked flask (220 mg, 0.71 mmol), acetonitrile (15 ml), potassium carbonate (2.13 mmol) and tetrahydropyrrole (76 mg, 1.07 mmol). The resulting mixture was stirred at room temperature overnight.

Work-up: The reaction solution was filtered, the filtrate was collected and concentrated. The solid residue obtained after concentration was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 8/1). The product was collected and concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt; , 4-d]pyrimidine-4-amine (yield 69.8%).

MS (ESI) M/Z: 344 [M+H ⁺ ].

Step E: 1-((4-(Pyrrolidin-1-ylmethyl)pyridin-2-yl)methyl)-6-(((3R)-1-((tetrahydro-2H-pyran-2) -yl)oxy)hexyl-3-yl)oxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Into a 10 ml high pressure reactor, 6-chloro-1-((4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)methyl)-1H-pyrazole [3,4-] was added in sequence. d]pyrimidine-4-amine (120 mg, 0.35 mmol), potassium t-butoxide (118 mg, 1.05 mmol), and (3R)-1-((tetrahydro-2H-pyran-2-yl)oxy Hex-3-ol (7.7 mg, 3.5 mmol). The resulting reaction solution was stirred at 100 ° C overnight.

Post-treatment: The reaction system was cooled to room temperature, and N,N-dimethylformamide (3 ml) and water (0.5 ml) were added to the mixture to dissolve. The resulting solution was purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: Xselect C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80% in 20 minutes; detection Wavelength: 254 nm. The product was collected and concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&& Tetrahydro-2H-pyran-2-yl)oxy)hexyl-3-yl)oxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (yield 43.8%).

MS (ESI) M/Z: 510 [M+H ⁺ ].

Step F: (R)-3-((4-Amino-1-((4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)methyl)-1H-pyrazolo[3,4 -d]pyrimidin-6-yl)oxy)hexan-1-ol

Into a 10 ml single-necked flask, 1-((4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)methyl)-6-(((3R)-1-((tetrahydro-)- 2H-pyran-2-yl)oxy)hexyl-3-yl)oxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (78 mg, 0.15 mmol), p-toluene Acid (14 mg, 0.08 mmol) and methanol (5 mL). The resulting reaction solution was stirred at room temperature for 5 hours.

Post-treatment: The reaction solution was filtered, and the filtrate was directly purified by preparative high-performance liquid chromatography. Purification conditions are as follows, column: Xselect C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80% in 20 minutes; detection Wavelength: 254 nm. The product was collected and concentrated under reduced pressure to give 16.5 mg (yield. -1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexan-1-ol (yield 25.9%).

MS (ESI) M / Z: 426 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ8.45 (d, J = 5.1Hz, 1H), 8.03 (s, 1H), 7.33-7.31 (m, 1H), 7.00 (s, 1H), 5.58 ( s, 2H), 5.41–5.33 (m, 1H), 3.65–3.56 (m, 4H), 2.68–2.40 (m, 4H), 1.91–1.85 (m, 2H), 1.83–1.73 (m, 4H), 1.68–1.57 (m, 2H), 1.49–1.31 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H).

Example 112: 1-((4-((3,3-Difluoropyrrolidin-1-yl)methyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H- Pyrazolo[3,4-d]pyrimidine-4-amine

Synthetic scheme

Step A: 1-((4-((3,3-Difluoropyrrolidin-1-yl)methyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyridyl Zoxa[3,4-d]pyrimidine-4-amine formate

To 1-((4-(bromomethyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine ( To a solution of 50 mg (0.116 mmol) in acetonitrile (3.0 ml), 3,3-difluoropyrrole hydrochloride (50 mg, 0.351 mmol) and anhydrous potassium carbonate (48 mg, 0.348 mmol). Subsequently, the reaction solution was stirred at 100 ° C for 18 hours.

Work-up: After the reaction system was cooled to room temperature, the reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was concentrated and purified with EtOAc (EtOAc) Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 80 ml / min; gradient: acetonitrile from 20% to 80% in 20 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized to give 17.1 mg of white solid 1-((4-((3,3-difluoropyrrolidin-1-yl)methyl)cyclohexyl)methyl)-6-(pyridin-4-yl) Methoxy)-1H-pyrazolo[3,4-d]pyrimidine-4-amine formate (yield 29.5%).

MS (ESI) M / Z: 458 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ): δ 8.60–8.53 (m, 2H), 7.96 (s, 1H), 7.54–7.52 (m, 2H), 5.54 (s, 2H), 4.10–4.05 ( m, 2H), 3.10–2.95 (m, 2H), 2.86–2.70 (m, 2H), 2.40–2.22 (m, 4H), 1.83–1.79 (m, 3H), 1.55–1.36 (m, 3H), 1.04–0.77 (m, 4H).

¹ F NMR (300 MHz, Methanol-d ₄ ): δ-97.08.

Example 113: 6-(Pyridin-4-ylmethoxy)-1-(8-(pyrrolidin-1-yl)octyl)-1H-pyrazolo[3,4-d]pyrimidine-4- amine

Synthetic scheme

Step A: 1-(8-Bromooctyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 2.96 mmol) in N,N-dimethylacetamide (30.0 mL) . 1,6-Dibromohexane (2.40 g, 8.88 mmol), potassium carbonate (1.22 g, 8.88 mmol) was added in that order. The resulting mixture was heated at 60 ° C for 16 hours.

流动相：水(含有0.05％氨水)和乙腈；流速:50毫升/分钟；梯度：在40分钟内，乙腈从5％升到100％； 检测波长：254nm。收集产物，减压浓缩除去溶剂，得到270毫克白色固体1-(8-溴辛基)-6-氯-1H-吡唑并[3,4-d]嘧啶-4-胺(收率25％)。 Post treatment: The reaction solution was cooled to room temperature, and the reaction liquid was filtered, and the filtrate was purified by medium pressure liquid chromatography. Purification conditions are as follows, column: Flash Column C18 120g 20-35μm,

Mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; flow rate: 50 ml/min; gradient: acetonitrile increased from 5% to 100% in 40 minutes; detection wavelength: 254 nm. The product was collected, and the solvent was evaporated, evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjj ).

MS (ESI) M/Z: 360, 362 [M+H ⁺ ].

Step B: 6-Chloro-1-(8-(pyrrolidin-1-yl)octyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

N,N-di to 1-(8-bromooctyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (270 mg, 0.75 mmol) at room temperature Potassium carbonate (311 mg, 2.26 mmol) and pyrrolidine (160 mg, 2.26 mmol) were added sequentially to methyl acetamide (20.0 mL). The reaction solution was then stirred at 60 ° C for 16 hours.

流动相：水(含有0.05％氨水)和乙腈；流速:50毫升/分钟；梯度：在40分钟内，乙腈从5％升到100％；检测波长：254nm。收集产物，减压浓缩除去溶剂，得到136毫克白色固体6-氯-1-(8-(吡咯烷-1-基)辛基)-1H-吡唑并[3,4-d]嘧啶-4-胺(收率51.6％)。 Post treatment: The reaction system was cooled to room temperature, and the reaction liquid was filtered. The filtrate was taken and the filtrate was purified by medium pressure liquid chromatography. Purification conditions are as follows, column: Flash Column C18 120g 20-35μm,

Mobile phase: water (containing 0.05% aqueous ammonia) and acetonitrile; flow rate: 50 ml/min; gradient: acetonitrile increased from 5% to 100% in 40 minutes; detection wavelength: 254 nm. The product was collected, and the solvent was evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -Amine (yield 51.6%).

MS (ESI) M / Z: 351 [M+H ⁺ ].

Step C: 6-(Pyridin-4-ylmethoxy)-1-(8-(pyrrolidin-1-yl)octyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

See compound 6-(pyridin-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 for details. - Synthesis of amines. 6-Chloro-1-(8-(pyrrolidin-1-yl)octyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (136 mg, 0.39 mmol), acetonitrile (10.0) (ml), pyridin-4-ylmethanol (425 mg, 3.90 mmol) and potassium t-butoxide (131.0 mg, 1.17 mmol). 80.7 mg of white solid 6-(pyridin-4-ylmethoxy)-1-(8-(pyrrolidin-1-yl)octyl)-1H-pyrazolo[3,4-d]pyrimidine-4 was obtained. - Amine (yield 48.9%).

MS (ESI) M / Z: 422 [M+H ⁺ ].

¹ H NMR (300MHz, Methanol-d ₄ ) δ 8.58 - 8.52 (m, 2H), 7.97 (s, 1H), 7.54 (d, J = 6.3 Hz, 2H), 5.54 (s, 2H), 4.24 ( t, J=6.9 Hz, 2H), 2.55–2.53 (m, 4H), 2.47–2.41 (m, 2H), 1.88–1.73 (m, 6H), 1.53–1.48 (m, 2H), 1.28–1.20 ( m, 8H).

Example 114: (S)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine

Synthetic scheme

Step A: (S)-1-(tetrahydro-2H-pyran-4-yl)ethanol

(S)-2-Methyl-CBS-oxazolborane (7.8 ml, 2 M in toluene) was added dropwise to borane dimethyl sulfide (43.0 mL, 86.0 mmol) under nitrogen atmosphere at -10 °C. In a solution of tetrahydrofuran (100.0 ml). Subsequently, 1-(tetrahydro-2H-pyran-4-yl)ethanone (10.0 g, 78.1 mmol) was added dropwise to the above reaction mixture. During the dropwise addition, the temperature of the reaction solution was controlled to not exceed 0 °C. After the dropwise addition was completed, the temperature of the reaction solution was maintained at 0 to 5 ° C for 10 minutes. TLC monitors the disappearance of raw materials.

Post-treatment: Hydrochloric acid (2N, 100 mL) was slowly added to the reaction mixture at 0 ° C, and stirring was continued for 1 hour. Subsequently, sodium chloride was added to the mixture until the solution was saturated. Next, methyl tert-butyl ether (300 ml) was added to the above mixture, and the mixture was stirred for 5 minutes and then filtered. The filter cake was washed with methyl tert-butyl ether (100 mL). The filtrate was allowed to stand for separation, the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (50 ml x 5 times) until the target product was not detected in the aqueous phase. The combined organic phases were washed with brine (100 mL)EtOAc. The concentrated crude product was purified by silica gel column chromatography (EtOAcEtOAcEtOAc The product was collected and concentrated under reduced pressure to give 4.6 g (yel. The e.e. value of this compound was determined by the e.e. value of the product in step B to be 64.85%.

¹ H NMR (300 MHz, Chloroform-d) δ 4.06 - 3.91 (m, 2H), 3.52 (p, J = 6.2 Hz, 1H), 3.35 (tt, J = 11.6, 2.0 Hz, 2H), 2.09 (s) , 1H), 1.82 - 1.68 (m, 1H), 1.58 - 1.22 (m, 4H), 1.15 (d, J = 6.3 Hz, 3H).

Step B: (S)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)-1H -pyrazolo[3,4-d]pyrimidin-4-amine

6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine was sequentially added to a 10 ml high pressure reactor under nitrogen atmosphere. 4-Amine (150 mg, 0.44 mmol), (S)-1-(tetrahydro-2H-pyran-4-yl)ethanol (600 mg, 4.62 mmol) and potassium t-butoxide (100 mg mg) , 0.89 mmol). Subsequently, the reaction was stirred at 100 ° C for 10 hours.

Work-up: After the reaction mixture was cooled to room temperature, the reaction mixture was filtered, and the filter cake was washed with N, N-dimethylformamide (5.0 ml). The filtrate was collected and the filtrate was purified by preparative high performance liquid chromatography. Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 75% in 8 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give 52 mg of white solid. The compound had an e.e. value of 64.85% by detection.

52 mg of white solid (S)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethoxy) -1H-pyrazolo[3,4-d]pyrimidin-4-amine (ee = 64.85%) was resolved by chiral chromatography. The separation conditions were as follows, chiral column name: CHIRALPAK IC-3; chiral column size: 10 cm * 0.46 cm, 3.0 μm; mobile phase: n-hexane (containing 0.01% diethylamine) / ethanol = 50 / 50; flow rate: 1.00 ML/min; temperature: 25 ° C; detection wavelength: 254 nm. The product was collected and concentrated under reduced pressure to give 39.0 mg of white (S)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(1-(tetrahydro-2H-pyran-4-) Ethyl)ethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.

MS (ESI) M / Z: 437 [M+H ⁺ ].

E.e.=96.94%

¹ H NMR (300MHz, Methanol-d ₄ ) δ 7.97 (s, 1H), 7.33 - 7.24 (m, 4H), 5.44 (s, 2H), 5.15 (m, 1H), 4.00 - 3.96 (m, 2H) ), 3.65 (s, 2H), 3.51–3.33 (m, 2H), 2.57 (s, 4H), 1.90–1.80 (m, 6H), 1.68–1.64 (m, 1H), 1.56–1.39 (m, 2H) ), 1.33 (d, J = 6.3 Hz, 3H).

Example 115: Synthesis of 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(tetrahydro-2H-pyran-4-yloxy)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine

Synthetic scheme

Step A: Synthesis of 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(tetrahydro-2H-pyran-4-yloxy)-1H-pyrazole[3,4 -d]pyrimidine-4-amine

To a 30 ml sealed tube, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (in order) 0.15 g, 0.44 mmol, tetrahydro-2H-pyran-4-ol (0.45 g, 4.4 mmol) and potassium t-butoxide (0.15 g, 1.32 mmol). The reaction apparatus was stirred at 100 ° C for 1.5 hours.

Work-up: The residue obtained by concentrating under reduced pressure was purified by silica gel column (eluent: methylene chloride/methanol = 10:1) to give 1-(4-(pyrrolidin-1-ylmethyl)benzyl - 6-(tetrahydro-2H-pyran-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20.7 mg, yield: 11.6%).

MS (ESI) M / Z: 409 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ7.98 (s, 1H), 7.36-7.20 (q, J = 8.1,4H), 5.44 (s, 2H), 5.29 (m, 1H), 3.99 (m , 2H), 3.72–3.55 (m, 4H), 2.55 (m, 4H), 2.10 (m, 2H), 1.81 (m, 6H).

Example 116: Synthesis of 6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-carboxylic acid methyl ester

Synthetic scheme

Step A: Synthesis of 4-hydroxymethyloxirane

Add oxacycloheptane-4-carboxylic acid (500 mg, 3.47 mmol) to a 40 mL vial, dissolve in tetrahydrofuran (5 mL), stir at 0 ° C for ten minutes, then slowly inject borane dimethyl sulfide ( 3.47 ml, 6.94 mmol), stirred at room temperature overnight.

Work-up: The reaction was quenched with EtOAc (EtOAc)EtOAc. Concentration under reduced pressure gave 4-hydroxymethyl oxane (500 mg) as a crude oil.

Step B: Synthesis of 6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d]pyrimidine-4-carboxylic acid methyl ester

To a solution of 4-hydroxymethyloxirane (500 mg, 3.85 mmol) in N,N-dimethylformamide (0.5 mL) Purity), stirred at room temperature for 20 minutes, then added 4-amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-6- The methane sulfinate (298 mg, 0.77 mmol) was protected with nitrogen and stirred at 40 ° C overnight.

Work-up: Filtration and purification of the filtrate by preparative high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 10% to 80 in 7 minutes %; detection wavelength: 254 nm. The product was collected and lyophilized to give 6-(oxetane-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole as a white solid. [3,4-d]pyrimidine-4-carboxylic acid methyl ester (110 mg, 30% yield)

MS (ESI) M / Z: 437 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ8.46 (s, 1H), 7.99 (s, 1H), 7.71-7.14 (m, 4H), 5.49 (s, 2H), 4.33 (s, 2H), 4.25 (d, J = 6.7 Hz, 2H), 3.94 - 3.77 (m, 2H), 3.75 - 3.62 (m, 2H), 3.29 (t, J = 4.0 Hz, 3H), 2.23 - 1.36 (m, 11H) .

Examples 117 and 118: Synthesis of (R)6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole And [3,4-d]pyrimidine-4-carboxylic acid methyl ester and (S)6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl) Benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4-carboxylic acid methyl ester

Synthetic scheme

Step A: Synthesis of (R)6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3 , 4-d]pyrimidine-4-carboxylic acid methyl ester and (S)6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl )-1H-pyrazolo[3,4-d]pyrimidine-4-carboxylic acid methyl ester

80 mg of the racemate 6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-carboxylic acid methyl ester was subjected to chiral resolution. The separation conditions were as follows, chiral column name: Repaired CHIRALPAK ID; chiral column size: 0.46 cm * 5 cm, 3 um; mobile phase: n-hexane (containing 0.1% diethylamine) / ethanol = 85 / 15; flow rate: 1.00 ml / Minutes; temperature: 25 degrees Celsius; detection wavelength: 254 nm. The product was collected and concentrated under reduced pressure to give two white solids, m. Benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4-carboxylic acid methyl ester (10.8 mg, 2.5% yield) and (S)6-(oxetan-4-ylmethoxy) Methyl 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4-carboxylate (6.2 mg, 1.4% yield)

Assuming (R)6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4 -d]Methylpyrimidine-4-carboxylate, the absolute configuration of which is not determined.

MS (ESI) M/Z: 437 [M+H ⁺ ]

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.98 (s, 1H), 7.47 - 6.99 (m, 4H), 5.45 (s, 2H), 4.25 (d, J = 6.7 Hz, 2H), 3.99- 3.78 (m, 2H), 3.75–3.60 (m, 4H), 2.58–2.56 (m, 4H), 2.14 (dd, J=6.7, 3.3 Hz, 1H), 2.04–1.92 (m, 2H), 1.92– 1.68 (m, 5H), 1.67–1.25 (m, 3H).

Ee%>99%

Assume that (S)6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4 -d]Methylpyrimidine-4-carboxylate, the absolute configuration of which is not determined.

MS (ESI) M/Z: 437 [M+H ⁺ ]

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.98 (s, 1H), 7.47 - 7.08 (m, 4H), 5.45 (s, 2H), 4.25 (d, J = 6.7 Hz, 2H), 3.89 - 3.77 (m, 2H), 3.74–3.63 (m, 4H), 2.57 (br s, 4H), 2.23–2.05 (m, 1H), 2.05–1.91 (m, 2H), 1.90–1.68 (m, 5H) , 1.67–1.23 (m, 3H).

Ee%>96.8%

Example 119: 6-Isobutoxy-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Synthetic scheme

Step A: 6-Isobutoxy-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Take 10 ml of high pressure reactor and add 6-chloro-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine ( 80 mg, 0.23 mmol, isobutanol (539 mg, 4.42 mmol) and potassium t-butoxide (147 mg, 1.31 mmol). After the raw materials were uniformly mixed, the mixture was stirred under heating at 100 ° C for 3 hours.

Work-up: The reaction system was cooled to room temperature, and the reaction solution was concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (EtOAc) (EtOAc) Purification conditions are as follows, column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia water) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 5% to 75% in 80 minutes; Detection wavelength: 254 nm. The product was collected and lyophilized at low temperature to give 30.5 mg of white solid 6-isobutoxy-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d Pyrimidine-4-amine (yield 34.3%).

MS (ESI) M / Z: 381 [M+H ⁺ ].

^{1 H NMR (300MHz, Methanol-} d 4) δ7.97 (s, 1H), 7.36-7.21 (m, 4H), 5.44 (s, 2H), 4.16 (d, J = 6.6Hz, 2H), 3.65 ( s, 2H), 2.58 (d, J = 5.9 Hz, 4H), 2.19-1.98 (m, 1H), 1.92-1.72 (m, 4H), 1.05 (d, J = 6.7 Hz, 6H).

Example 120: 6-(Benzyloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Synthetic scheme

Step A: 6-(Benzyloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Into a 30 ml high pressure reactor, 6-chloro-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was added in sequence. (0.20 mg, 0.58 mmol, 1.00 equiv), benzyl alcohol (3.00 mL) and potassium t-butoxide (0.20 g, 1.76 mmol, 3.00 eq.). After the raw materials were stirred and dissolved, the reaction solution was stirred at 150 ° C overnight.

Post-treatment: The reaction system was cooled to room temperature, and ice water (30 ml) was added to the reaction system to quench the reaction. The mixture was extracted with EtOAc (3×50 mL)EtOAc. The organic phase was backwashed with saturated brine (50 mL × 3) then dried over anhydrous sodium sulfate The residue was dissolved in N,N-dimethylformamide (4.0 mL). The preparation conditions were as follows, column: X select C18 19mm*150mm; mobile phase: water (0.05% ammonia) and acetonitrile; flow rate: 25 ml/min; gradient: acetonitrile increased from 10% to 50% in 7 minutes; Wavelength: 254 nm. The product was collected and lyophilized to give 20.8 mg of white solid 6-(benzyloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d] Pyrimidine-4-amine (yield 8.6%).

MS (ES, M/Z): 415 [M+H ⁺ ].

¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 7.98 (s, 1H), 7.92 - 7.52 (m, 2H), 7.47 - 7.44 (m, 2H), 7.39 - 7.28 (m, 3H), 7.23 –7.13(m,4H), 5.37(s,2H), 5.35(s,2H), 3.51(s,2H), 2.48–2.31(m,4H),1.76–1.58(m,4H).

Effect Example 1: Screening of drug activity in HEK-Blue hTLR _7/8 cells

Experimental procedure

1. Cell plating:

a) advance HEK-Blue ^TM Detection detection reagent and PBS at 37 ℃ for preheating.

b) Discard the medium in the flask and wash once with pre-warmed PBS.

c) Add appropriate amount of PBS to the culture flask and leave at 37 ° C for 5 min.

d) Pat the culture flask to detach the cells, and terminate the digestion reaction with a medium containing 10% FBS.

e) Transfer the cell suspension to a 15 mL sterile centrifuge tube, centrifuge at 1000 rpm for 5 min.

f) The supernatant was discarded, with the HEK-Blue ^TM Detection detection reagent cells were resuspended and counted.

g) diluting the cell density in the HEK-Blue ^TM Detection detection reagent to 2.2X10 ⁵ / mL.

h) Inoculate 45 μL of the diluted cell suspension into a 384-well plate, ie 10,000 cells per well.

2. Drug treatment:

a) Test compound A 10 mM stock solution was prepared in DMSO.

b) Compound preparation

Test compound and control compound GS-9620:

The maximum concentration was diluted from 10 mM to 2 mM, then 3 fold dilutions, 10 gradients, and DMSO as a negative control. 2 μL of the diluted compound was added to 38 μL of HEK-Blue ^TM Detection Detection Reagent for 20-fold intermediate dilution.

c) Compound treatment of cells

5 μL of the intermediately diluted compound was added to a 384-well plate inoculated with 45 μL of cells, and the drug was diluted 10-fold with a final concentration of DMSO of 0.5%.

■ The final concentration of the test compound and the control compound is

10000, 3333, 1111, 370, 123, 41, 13, 4.6, 1.5, 0.5, 0.0 nM.

d) The 384-well plates were incubated for 16 hours at 37 ° C in a 5% CO ₂ incubator.

3. Detection

The light absorption of SEAP at 620 nm was measured using the instrument Envision. TLR ₇ /TLR ₈ activation experiment in human peripheral blood mononuclear cells

Experimental steps:

Step 1: Human blood collection

1. Aseptically collect 15 mL of blood from a donor.

2. 15 mL of blood can be tested for duplicate wells of 3 compounds.

Step 2: Separation of human peripheral blood mononuclear cells

1. The separation of PBMC should be separated within 2 hours after blood collection.

2. Add 6 mL of human blood separation solution to a 15 mL sterile centrifuge tube and equilibrate at room temperature.

3. Slowly add 5 mL of blood to the 6 mL separation solution to make it naturally stratified, and avoid adding it below the liquid level of the separation solution.

4. Centrifuge at room temperature for 30 minutes and centrifuge at 400 g.

5. Slowly remove the centrifuge tube after centrifugation and carefully remove the uppermost plasma layer.

6. After removing the plasma, transfer the monocyte-containing tunica layer to a new sterile 15 mL centrifuge tube.

7. Take 10 mL of PBS into a centrifuge tube containing monocytes and mix well.

8. Centrifuge at room temperature for 10 minutes and centrifuge at 300 g.

9. Discard the supernatant, resuspend the cells in 10 mL PBS, and mix well.

10. Centrifuge at room temperature for 10 minutes and centrifuge at 300 g.

11. Repeat steps 9, 10, discard the supernatant, and resuspend the cells in 1 mL medium at RPMI 1640 + 10% FBS + 1% PS.

12. The cell density was 1.5× ^{10 6} /mL, and the cell suspension was inoculated with 100 μL of a cell suspension of 150,000 cells per well.

13. Place the 96-well plate in a 37 ° C, 5% CO ₂ incubator.

Step 3: Dilute the test compound

1. The test compound was made into a 10 mM stock solution in DMSO.

2. The test compound was prepared by 3-fold gradient dilution from 10 mM to prepare 9 concentrations.

3. Control compound 14 concentrations (3 fold dilution or 1.5 fold dilution from stock).

4. DMSO is a negative control.

5. Perform a 10-fold intermediate dilution in the medium (5 μL of gradient dilution of the compound to 45 μL of medium).

Step 4: Compound treatment of cells

1. Add 98 μL of medium to each well to make a total volume of 198 μL.

2. Take 2 μL of the intermediate diluted compound (Step 3) to the corresponding 96-well plate. The final concentration of DMSO is 0.1%. The final concentration of the test compound is 10000, 3333, 1111, 370, 123, 41, 13, 4.6. 1.5, 0.0 nM. The final concentrations of the control compounds were 10,000, 3333, 2222, 1481, 987, 658, 219, 146, 98, 65, 43, 29, 19, 13, 0 nM.

Step 5: Cell incubation

The 96-well plate to which the compound was added was placed at 37 ° C for 20 hours in a 5% CO ₂ incubator.

Step 6: MSD test

1. Centrifuge the 96-well plate at room temperature for 5 minutes at a centrifuge speed of 1500 rpm.

2. Pipette the supernatant for MSD experiments.

TNF-α detection step in MSD experiment

Step 1: Preparation of standards and samples

1. Standard preparation: Add 250 μL of Diluent 2 to the standard dry powder, mix well, and use it after 5 minutes. Gradient dilutions were then performed, 7 gradients were diluted 4 times, and Diluent 2 was used as the zero point.

2. Sample preparation: The sample was centrifuged at room temperature for 5 minutes, the centrifugal speed was 1500 rpm, and the supernatant was aspirated for use.

3. Antibody preparation: The antibody stock concentration was 50X and the concentration was 1X. The antibody was diluted with Diluent 3.

4. Preparation of test solution: The concentration of the solution was 4X, the concentration was 2X, and it was diluted with distilled water.

5. Preparation of washing solution: The stock solution was 20X, and the concentration was 1X, which was diluted with distilled water.

Step 2: Steps for detecting TNF-α by MSD kit

1. Add sample: Add 50 μL sample to each well, standard or control, seal the sealing membrane, place the shaker at room temperature for 2 hours, and oscillate at 650 rpm.

2. Wash the plate: Wash the plate 3 times with 300 μL of 1X wash solution per well, and remove the last wash solution.

3. Add antibody: 25 μL of the prepared antibody was added to each well, the sealing membrane was sealed, and the shaker was placed at room temperature for 2 hours, and the shaking speed was 650 rpm.

4. Wash the plate: Wash the plate 3 times with 300 μL of 1X wash solution per well, and remove the last wash solution.

5. Detection: 150 μL of 2X test solution was added to each well and detected using an MSD instrument. It should be noted that the test solution can be detected without incubation.

IFN-α detection step in MSD experiment

Step 1: Preparation of standards and samples

1. Standard preparation: The standard stock solution was 1 μg/mL, the initial concentration was 2500 pg/mL, then the gradient was diluted, 4 gradients were diluted 7 times, and Diluent 2 was used as the zero point.

2. Sample preparation: The sample was centrifuged at room temperature for 5 minutes, the centrifugal speed was 1500 rpm, and the supernatant was aspirated for use.

3. Antibody preparation: The antibody stock concentration was 50X and the concentration was 1X. The antibody was diluted with Diluent 3.

4. Preparation of test solution: The concentration of the solution was 4X, the concentration was 2X, and it was diluted with distilled water.

5. Preparation of washing solution: The stock solution was 20X, and the concentration was 1X, which was diluted with distilled water.

Step 2: Steps for detecting IFN-α by MSD kit

1. Add Diluent 2: Add 25 μL of Diluent 2 to each well, shake at room temperature for 30 minutes, and shake at 650 rpm.

2. Add sample: Add 25 μL sample or standard to each well, seal the sealing membrane, place the shaker for 2 hours at room temperature, and oscillate at 650 rpm.

3. Wash the plate: Wash the plate 3 times with 300 μL of 1X wash solution per well, and remove the last wash solution.

4. Add antibody: Add 25 μL of the prepared antibody to each well, seal the sealing membrane, and place the shaker at room temperature for 2 hours at an oscillation speed of 650 rpm.

5. Wash the plate: Wash the plate 3 times with 300 μL of 1X wash solution per well, and remove the last wash solution.

6. Detection: 150 μL of 2X test solution was added to each well and detected using an MSD instrument. It should be noted that the test solution can be detected without incubation.

Table 1. Test results of in vitro biological activity

Table 2. hPBMC activity test results

The data in Tables 1 and 2 show that the compounds of the invention have high TLR ₇ activity and high TLR ₈ selectivity. Its high activity was also confirmed in the hPBMC assay.

While the invention has been described with respect to the preferred embodiments of the embodiments of the embodiments of the invention modify. Accordingly, the scope of the invention is defined by the appended claims.

Claims (20)

a five-membered heterocyclic pyrimidine compound represented by the formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate, a polymorph, a tautomer, an isotope compound, Metabolite or prodrug,

among them: X is selected from O, S or NR ₈ ; Y is selected from C or N; wherein When Y is C, R _{1 is} selected from H, CN, CF ₃ , halogen, hydrocarbyl acyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or quaternary to VIII a heteroaryl group, wherein the hydrocarbyl acyl group, C ₁ -C ₃ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, quaternary to octagonal heteroaryl group are each optionally R ₁₀ a substituent wherein the hetero atom in the four- to eight-membered heteroaryl group is selected from O, N or S; preferably, R _{1 is} selected from the group consisting of CN, CF ₃ , fluorine, chlorine, formyl, acetyl; When Y is N, R ₁ does not exist; Z is selected from C, N or S; wherein When Z is C, R _{2 is} selected from a hydrogen atom, a halogen or a C ₁ -C ₃ hydrocarbon group, preferably a hydrogen atom, a fluorine atom and a methyl group, wherein each of the C ₁ -C ₃ hydrocarbon groups is optionally substituted by R ₁₀ ; When Z is N or S, R ₂ is absent; and when Z is N, Y is only N; R ₃ is a C ₁ -C ₈ hydrocarbon group, preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5; A group may or may not be present, when A group is absent, R ₃ and R _{5 are} directly linked together; when A group is present, it is selected from C _3-10 cycloalkyl, C _3-10 heterocycle Hydrocarbyl, aryl, heterocyclic aryl, bicyclo[2.2.1]heptane-1,4-, bicyclo[1.1.1]pentane-1,3- or 7-oxobicyclo[2.2.1]heptane- 1,4-, wherein the C _3-10 cycloalkyl, C _3-10 heterocycloalkyl, aryl, heterocyclic aryl, bicyclo [2.2.1] heptane-1,4-, bicyclo [1.1.1 ] pentane-1,3- or 7-oxobicyclo[2.2.1]heptane-1,4- are each optionally substituted by one or more R ₁₀ ; preferably, the A group is selected from phenyl, pyridine , furan, thiophene, pyrrole, cyclohexane, cyclopentane, cyclobutane or cyclopropane, and optionally substituted by one or more R ₁₀ ; R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5; -N (R ₆₎ R ₇ may be present or absent, when present, R ₆ and R ₇ are each independently selected from hydrogen or C ₁ -C ₈ hydrocarbon group, each optionally substituted with ₁₀ R; R ₆ and R ₇ may be bonded to form a four- to eight-membered ring structure by a C atom or a hetero atom, wherein the hetero atom is O, S or N; optionally, a ring formed by R ₆ and R ₇ may also be bonded to A. The groups are fused together; preferably, -N(R ₆ )R _{7 is} selected from the group consisting of -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R- Piperazine-1-; optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the A group; optionally One of R ₆ or R ₇ may form a covalent bond with A to form a ring; R ₄ is absent or selected from a C ₁ -C ₈ alkyl group, a C ₂ -C ₈ alkenyl group or a C ₂ -C ₈ alkynyl group, wherein the C ₁ -C ₈ alkyl group, C ₂ -C ₈ alkenyl group Or C ₂ -C ₈ alkynyl are each optionally substituted by one or more R ₁₀ ; preferably, R ₄ is C _1-4 alkyl, each optionally substituted by R ₁₀ ; more preferably, R _{4 is} selected From -CH ₂ -, -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)--CH(CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)-, -CH(CH ₂ NR ₂ )-, -CH(CH ₂ CH ₂ NR ₂ )-; R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R may be selected from H, C ₁ -C ₈ alkyl, C _3- C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, may also be substituted by =0, —OH, —NH ₂ , —SH; When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached; The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R ₁₀ Preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyran, ring Oxypropane, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more independently selected R ₁₀ ; R ₉ is absent or selected from C ₁ -C ₈ hydrocarbyl groups, preferably a C ₃ -C ₅ alkyl group; wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally substituted with OR ₈ , SR ₈ or N(R ₈ ) ₂ ; R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ . A five-membered heterocyclic pyrimidine compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, a polymorph, a tautomer thereof, according to claim 1. a compound, a metabolite, a metabolite or a prodrug, wherein the structure of the five-membered heterocyclic pyrimidine compound represented by the formula (I) is as shown in the formula (I-1),

among them: X is selected from O, S or NR ₈ ; Y is selected from C or N; When Y is C, R1 is selected from H, CN, CF ₃ , halogen, hydrocarbyl acyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or quaternary to octa a heteroaryl group, wherein the hydrocarbyl acyl group, C ₁ -C ₃ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group or a quaternary to octavalent heteroaryl group is optionally substituted by R ₁₀ , Preferably, R _{1 is} selected from the group consisting of CN, CF 3 , fluorine, chlorine, bromine, formyl, acetyl; wherein the hetero atom in the four to eight membered heteroaryl is selected from O, N or S; When Y is N, R ₁ does not exist; R ₃ is a C ₁ -C ₈ hydrocarbon group, preferably -(CH ₂ ) n-; n is 1, 2, 3, 4 or 5; A group may or may not be present, when A group is absent, R ₃ and R _{5 are} directly linked together; when A group is present, it is selected from C _3-10 cycloalkyl, C _3-10 heterocycle Hydrocarbyl, aryl, heterocyclic aryl, bicyclo[2.2.1]heptane-1,4-, bicyclo[1.1.1]pentane-1,3- or 7-oxobicyclo[2.2.1]heptane- 1,4-, wherein the C _3-10 cycloalkyl, C _3-10 heterocycloalkyl, aryl, heterocyclic aryl, bicyclo [2.2.1] heptane-1,4-, bicyclo [1.1.1 ] pentane-1,3-, 7-oxobicyclo[2.2.1]heptane-1,4- are each optionally substituted by one or more R ₁₀ ; preferably, the A group is selected from phenyl, pyridine , furan, thiophene, pyrrole, cyclohexane, cyclopentane, cyclobutane and cyclopropane, and optionally substituted by one or more R ₁₀ ; R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5; -N (R ₆₎ R ₇ may be present or absent; when it is present, R ₆ and R ₇ are each independently selected from hydrogen or C ₁ -C ₈ hydrocarbon group, each optionally substituted with ₁₀ R; R ₆ and R ₇ may be bonded to form a four- to eight-membered ring structure by a C atom or a hetero atom, wherein the hetero atom is O, S, N; optionally, a ring formed of R ₆ and R ₇ may also be bonded to A. The groups are fused together; preferably, -N(R ₆ )R _{7 is} selected from -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R- Piperazine-1-; optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the A group; optionally One of R ₆ or R ₇ may form a covalent bond with A to form a ring; R ₄ is absent or selected from C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, wherein said C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl And a C ₂ -C ₈ alkynyl group is each optionally substituted by one or more R ₁₀ ; preferably, R ₄ is C _1-4 alkyl, optionally substituted by R ₁₀ ; more preferably, R _{4 is} selected from -CH ₂ -, -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH(CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)-, -CH(CH ₂ NR ₂ )-, -CH(CH ₂ CH ₂ NR ₂ )-; R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ , wherein R may be selected from H, C ₁ -C ₈ alkyl, C _{3 a} C ₈ cycloalkyl group, a 3-8 membered heterocycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, which may also be substituted by =O, -OH, -NH ₂ or -SH; When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached; The B group is present or absent. When the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from C ₃ -C ₁₀ cyclic hydrocarbon group, C ₃ -C ₁₀ hetero a cycloalkyl, aryl, heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl, heteroaryl is optionally substituted by one or more R ₁₀ ; Preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyran, epoxy Propane, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more independently selected R ₁₀ ; R ₉ is absent or selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally OR ₈ , SR ₈ , N(R ₈ ) ₂ substituted; R _{8 is} selected from hydrogen, C ₁ -C ₃ hydrocarbyl, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ . A five-membered heterocyclic pyrimidine compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, a polymorph, a tautomer thereof, according to claim 1. a compound, a metabolite, a metabolite or a prodrug, wherein the structure of the five-membered heterocyclic pyrimidine compound represented by the formula (I) is as shown in the formula (I-2),

among them: X is selected from O, S or NR ₈ ; R _{1 is} selected from the group consisting of H, CN, CF ₃ , halogen, hydrocarbyl acyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, quaternary to octagonal heteroaryl, wherein The hydrocarbyl acyl group, C ₁ -C ₃ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, tetra- to octa-heteroaryl group are optionally substituted by R ₁₀ , preferably, R ₁ Selected from CN, CF ₃ , fluorine, chlorine, bromine, formyl, acetyl; R _{3 is} selected from a C ₁ -C ₈ hydrocarbon group, preferably -(CH ₂ )n-; Wherein n is 1, 2, 3, 4 or 5; A group may or may not be present, when A group is absent, R ₃ and R _{5 are} directly linked together; when A group is present, it is selected from C _3-10 cycloalkyl, C _3-10 heterocycle Hydrocarbyl, aryl, heterocyclic aryl, bicyclo[2.2.1]heptane-1,4-, bicyclo[1.1.1]pentane-1,3- or 7-oxobicyclo[2.2.1]heptane- 1,4-, wherein the C _3-10 cycloalkyl, C _3-10 heterocycloalkyl, aryl, heterocyclic aryl, bicyclo [2.2.1] heptane-1,4-, bicyclo [1.1.1 ] pentane-1,3- or 7-oxobicyclo[2.2.1]heptane-1,4- are each optionally substituted by one or more R ₁₀ ; preferably, the A group is selected from phenyl, pyridine , furan, thiophene, pyrrole, cyclohexane, cyclopentane, cyclobutane and cyclopropane, and optionally substituted by one or more R ₁₀ ; R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5; -N (R ₆₎ R ₇ may be present or absent, when present, R ₆ and R ₇ are each independently selected from hydrogen or C ₁ -C ₈ hydrocarbon group, each optionally substituted with ₁₀ R; R ₆ and R ₇ may be bonded to form a four- to eight-membered ring structure by a C atom or a hetero atom, wherein the hetero atom is O, S, N; optionally, a ring formed of R ₆ and R ₇ may also be bonded to A. The groups are fused together; preferably, -N(R ₆ )R _{7 is} selected from -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R- Piperazine-1-; optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the A group; optionally One of R ₆ or R ₇ may form a covalent bond with A to form a ring; R _{4 is} selected from C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, wherein said C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ - The C ₈ alkynyl group is optionally substituted by one or more R ₁₀ ; preferably, R ₄ is C _1-4 alkyl, each optionally substituted by R ₁₀ ; more preferably, R _{4 is} selected from -CH ₂ - , -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH(CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)- , -CH(CH ₂ NR ₂ )- or -CH(CH ₂ CH ₂ NR ₂ )-; R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R may be selected from H, C ₁ -C ₈ alkyl, C _3- C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, may also be substituted by =0, —OH, —NH ₂ , —SH; When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached; The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl or heteroaryl is optionally independently selected by one or more R _{10 is} substituted; preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydrogen Pyran, propylene oxide, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted with one or more independently selected R ₁₀ ; R ₉ is absent or selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally OR ₈ , SR ₈ , N(R ₈ ) ₂ substituted; R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ . A five-membered heterocyclic pyrimidine compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, a polymorph, a tautomer thereof, according to claim 1. a compound, a metabolite, a metabolite or a prodrug, wherein the structure of the five-membered heterocyclic pyrimidine compound represented by the formula (I) is as shown in the formula (I-3),

among them: X is selected from O, S or NR ₈ ; R _{3 is} selected from a C ₁ -C ₈ hydrocarbon group, preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5; A group may or may not be present, when A group is absent, R ₃ and R _{5 are} directly linked together; when A group is present, it is selected from C _3-10 cycloalkyl, C _3-10 heterocycle Hydrocarbyl, aryl, heterocyclic aryl, bicyclo[2.2.1]heptane-1,4-, bicyclo[1.1.1]pentane-1,3- or 7-oxobicyclo[2.2.1]heptane- 1,4-, wherein the C _3-10 cycloalkyl, C _3-10 heterocycloalkyl, aryl, heterocyclic aryl, bicyclo [2.2.1] heptane-1,4-, bicyclo [1.1.1 ] pentane-1,3-, 7-oxobicyclo[2.2.1]heptane-1,4- is optionally substituted by one or more R ₁₀ ; preferably, the A group is selected from phenyl, pyridine, Furan, thiophene, pyrrole, cyclohexane, cyclopentane, cyclobutane and cyclopropane, and optionally substituted by one or more R ₁₀ ; R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5; -N (R ₆₎ R ₇ may be present or absent, when present, R ₆ and R ₇ are each independently selected from hydrogen or C ₁ -C ₈ hydrocarbon group, each optionally substituted with ₁₀ R; R ₆ and R ₇ may be bonded to form a four- to eight-membered ring structure through a C atom or a hetero atom, wherein the hetero atom is O, S, N; a ring formed by R ₆ and R ₇ may also be fused to the A group. Together; preferably, -N(R ₆ )R _{7 is} selected from -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R-piperazine-1 One of R ₆ or R ₇ may form a ring with R _{5 , and the} ring formed by R ₆ or R ₇ and R ₅ may be fused to the A group; optionally, in R ₆ or R ₇ One can form a covalent bond with A to form a ring; R ₄ is absent or selected from a C ₁ -C ₈ linear hydrocarbon group, each of which is optionally substituted by one or more R ₁₀ ; preferably, R ₄ is a C _1-4 linear alkyl group, optionally R _{10 is} substituted; more preferably, R _{4 is} selected from -CH ₂ -, -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH ( CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)-, -CH(CH ₂ NR ₂ )- or -CH(CH ₂ CH ₂ NR ₂ )-; R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R may be selected from H, C ₁ -C ₈ alkyl, C _3- C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, may also be substituted by =0, —OH, —NH ₂ , —SH; When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached; The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R ₁₀ Preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyran, ring Oxypropane, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more R ₁₀ ; when the B group is selected from a C ₃ -C ₁₀ cycloalkyl or aryl group, wherein C ₃ -C ₁₀ cycloalkyl, aryl optionally substituted by one or more R ₁₀ wherein R ₁₀ selected or contains a hydrogen atom, or the group necessarily contains one or more heteroatoms; preferably, B The group is selected from the group consisting of phenyl, cyclohexane, cyclopentane, cyclobutane and cyclopropane, the selected group of which may be substituted by one or more independently selected R ₁₀ , wherein R _{10 is} selected or included Hydrogen atom, or Group must contain one or more hetero atoms; When a B group is present, R ₉ is absent; when the B group is absent, R _{9 is} selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group Or C ₃ -C ₅ alkyl is optionally substituted by SR ₈ or N(R ₈ ) ₂ ; when R ₉ is methyl, R ₄ is not -CH(CH ₂ OCH ₃ )-; R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more R ₁₀ ; Wherein, when the -R ₄ -BR ₉ moiety is a butyl group, the A group is not a benzene ring, or -N(R ₆ )R _{7 is} present and one of R ₆ or R ₇ forms a ring with R ₅ and is R ₆ Or the ring formed by R ₇ and R ₅ is fused to the A group. A five-membered heterocyclic pyrimidine compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, a polymorph, a tautomer thereof, according to claim 1. a compound, a metabolite, a metabolite or a prodrug, wherein the structure of the five-membered heterocyclic pyrimidine compound represented by the formula (I) is as shown in the formula (I-4),

among them: R _{1 is} selected from H, CN, CF ₃ , halogen, hydrocarbyl acyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or quaternary to octagonal heteroaryl, wherein The hydrocarbyl acyl group, C ₁ -C ₃ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group or tetra- to 8-membered heteroaryl group is optionally substituted by R ₁₀ , preferably, R ₁ Selected from CN, CF ₃ , fluorine, chlorine, bromine, formyl, acetyl; X is selected from O, S or NR ₈ ; R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5; -N (R ₆₎ R ₇ may be present or absent, when present, R ₆ and R ₇ are each independently selected from hydrogen or C ₁ -C ₈ hydrocarbon group, each optionally substituted with ₁₀ R; R ₆ and R ₇ may be bonded to form a four- to eight-membered ring structure through a C atom or a hetero atom, wherein the hetero atom is O, S, N; a ring formed by R ₆ and R ₇ may also be fused with a benzene ring. Together; preferably, -N(R ₆ )R _{7 is} selected from -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R-piperazin-1- Optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the phenyl ring; optionally, R ₆ or R ₇ One of them may form a ring by forming a covalent bond with the benzene ring; R _{4 is} selected from C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, wherein said C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ - The C ₈ alkynyl groups are each optionally substituted by one or more R ₁₀ ; preferably, R ₄ is C _1-4 alkyl, optionally substituted by R ₁₀ ; more preferably, R _{4 is} selected from -CH ₂ - , -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH(CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)- , -CH(CH ₂ NR ₂ )-, -CH(CH ₂ CH ₂ NR ₂ )-; R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R may be selected from H, C ₁ -C ₈ alkyl, C _3- C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, which may also be substituted by =0, —OH, —NH ₂ , —SH; When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached; The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl, heterocyclic aryl are optionally independently selected by one or more R _{10 is} substituted; preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydrogen Pyran, propylene oxide, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more R ₁₀ ; R ₉ is absent or selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally OR ₈ , SR ₈ Or N(R ₈ ) ₂ substituted; R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ . A five-membered heterocyclic pyrimidine compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, a polymorph, a tautomer thereof, according to claim 1. a compound, a metabolite, a metabolite or a prodrug, wherein the structure of the five-membered heterocyclic pyrimidine compound represented by the formula (I) is as shown in the formula (I-5),

among them: X is selected from O, S or NR ₈ ; R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) _n -; wherein n is 1, 2, 3, 4 or 5; -N (R ₆₎ R ₇ may be present or absent, when present, R ₆ and R ₇ are each independently selected from hydrogen or C ₁ -C ₈ hydrocarbon group, each optionally substituted with ₁₀ R; R ₆ and R ₇ may be bonded to form a four- to eight-membered ring structure through a C atom or a hetero atom, wherein the hetero atom is O, S, N; a ring formed by R ₆ and R ₇ may also be fused with a benzene ring. Together; preferably, -N(R ₆ )R _{7 is} selected from -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R-piperazin-1- Optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the phenyl ring; optionally, R ₆ or R ₇ One of them may form a ring by forming a covalent bond with the benzene ring; R ₄ is absent or selected from a C ₁ -C ₈ linear hydrocarbon group, each of which is optionally substituted by one or more R ₁₀ ; preferably, R ₄ is a C _1-4 linear alkyl group, optionally R _{10 is} substituted; more preferably, R _{4 is} selected from -CH ₂ -, -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH ( CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)-, -CH(CH ₂ NR ₂ )- or -CH(CH ₂ CH ₂ NR ₂ )-; R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R is selected from H, C ₁ -C ₈ alkyl, C _{3 a} C ₈ cycloalkyl group, a 3-8 membered heterocycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, which may also be substituted by =O, -OH, -NH ₂ or -SH; When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached; The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R ₁₀ Preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyran, ring Oxypropane, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more R ₁₀ ; when the B group is selected from a C ₃ -C ₁₀ cycloalkyl or aryl group, wherein C ₃ -C ₁₀ cycloalkyl, aryl optionally substituted by one or more R ₁₀ wherein R ₁₀ selected or contains a hydrogen atom, or the group necessarily contains one or more heteroatoms; preferably, B The group is selected from the group consisting of phenyl, cyclohexane, cyclopentane, cyclobutane and cyclopropane, the selected group of which may be substituted by one or more independently selected R ₁₀ , wherein R _{10 is} selected or included Hydrogen atom, or Group must contain one or more hetero atoms; When a B group is present, R ₉ is absent; when the B group is absent, R _{9 is} selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group Or C ₃ -C ₅ alkyl optionally substituted by SR ₈ or N(R ₈ ) ₂ ; when R ₉ is methyl, R ₄ is not -CH(CH ₂ OCH ₃ )-; R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ ; Wherein, when the -R ₄ -BR ₉ moiety is a butyl group, the A group is not a benzene ring, or -N(R ₆ )R _{7 is} present and one of R ₆ or R ₇ forms a ring with R ₅ and is R ₆ Or the ring formed by R ₇ and R ₅ is fused to the A group. A five-membered heterocyclic pyrimidine compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, a polymorph, a tautomer thereof, according to claim 1. a compound, a metabolite, a metabolite or a prodrug, wherein the structure of the five-membered heterocyclic pyrimidine compound represented by the formula (I) is as shown in the formula (I-6),

among them: R _{1 is} selected from the group consisting of H, CN, CF ₃ , halogen, hydrocarbyl acyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, quaternary to octagonal heteroaryl, wherein The hydrocarbyl acyl group, C ₁ -C ₃ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, quaternary to octagonal heteroaryl group are each optionally substituted by R ₁₀ , preferably, R _{1 is} selected from the group consisting of CN, CF ₃ , fluorine, chlorine, bromine, formyl or acetyl; X is selected from O, S or NR ₈ ; R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5; -N(R ₆ )R ₇ may or may not be present, and when present, R ₆ and R ₇ are each independently selected from hydrogen or a C ₁ -C ₈ hydrocarbyl group, optionally substituted by R ₁₀ ; R ₆ and R ₇ may be bonded through a C atom or a hetero atom to form a four- to eight-membered ring structure, wherein the hetero atom is O, S, N; a ring formed by R ₆ and R ₇ may also be fused with a benzene ring. Preferably, -N(R ₆ )R _{7 is} selected from -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1- or 4-R-piperazine-1-; Optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the phenyl ring; optionally, R ₆ or R ₇ One of which can form a ring by forming a covalent bond with the benzene ring; R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; R may be selected from H, C ₁ -C ₈ alkyl, C _{3 a} C ₈ cycloalkyl group, a 3-8 membered heterocycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, which may also be substituted by =O, -OH, -NH ₂ or -SH; When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached; The B group may or may not be present. When the B group is absent, R ₉ and the adjacent group are directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cyclic hydrocarbon group, C ₃ a C ₁₀ Heterocyclic hydrocarbon group, an aryl group or a heterocyclic aryl group, wherein the C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ heterocycloalkylene group, aryl group or heterocyclic aryl group is optionally one or more R _{10 is} substituted; preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyridinium Methane, propylene oxide, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more independently selected R ₁₀ ; R ₉ is absent or selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally OR ₈ , SR ₈ Or N(R ₈ ) ₂ substituted; R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ . A five-membered heterocyclic pyrimidine compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, a polymorph, a tautomer thereof, according to claim 1. a compound, a metabolite, a metabolite or a prodrug, wherein the structure of the five-membered heterocyclic pyrimidine compound represented by the formula (I) is as shown in the formula (I-7),

among them: X is selected from O, S or NR ₈ ; R ₅ is absent or selected from a C ₁ -C ₈ hydrocarbon group; preferably -(CH ₂ ) n-; wherein n is 1, 2, 3, 4 or 5; -N(R ₆ )R ₇ may or may not be present, and when present, R ₆ and R ₇ are each independently selected from hydrogen or a C ₁ -C ₈ hydrocarbyl group, optionally substituted by R ₁₀ ; R ₆ and R ₇ may be formed by a C atom or a hetero atom to form a four- to eight-membered ring, wherein the hetero atom is O, S or N; a ring formed by R ₆ and R ₇ may also be fused with a benzene ring. Preferably, -N(R ₆ )R _{7 is} selected from the group consisting of -N(CH ₃ ) ₂ , tetrahydropyrrole-1-, piperidin-1-morpholine-1-, 4-R-piperazine-1-; Optionally, one of R ₆ or R ₇ may form a ring with R _{5 , and} a ring formed by R ₆ or R ₇ and R ₅ may be fused to the phenyl ring; optionally, R ₆ or R ₇ One of which can form a ring by forming a covalent bond with the benzene ring; R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R is selected from H, C ₁ -C ₈ alkyl, C _{3 a} C ₈ cycloalkyl group, a 3-8 membered heterocycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, which may also be substituted by =O, -OH, -NH ₂ or -SH; When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached; The B group may or may not be present. When the B group is absent, R ₉ and the adjacent group are directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cyclic hydrocarbon group, C ₃ a C ₁₀ Heterocyclic hydrocarbon group, an aryl group or a heterocyclic aryl group, wherein the C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ heterocycloalkylene group, aryl group or heterocyclic aryl group is optionally one or more R _{10 is} substituted; preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyridinium , propylene oxide, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more independently selected R ₁₀ ; when the B group is selected from a C ₃ -C ₁₀ cycloalkyl group Or an aryl group, wherein the C ₃ -C ₁₀ cycloalkyl group, aryl group is optionally substituted by one or more R ₁₀ groups, wherein the R ₁₀ selected group or contains a hydrogen atom, or the group necessarily contains one or more a hetero atom; preferably, the B group is selected from the group consisting of phenyl, cyclohexane, cyclopentane, cyclobutane and cyclopropane, the selected group of which may be substituted by one or more independently selected R ₁₀ , wherein R ₁₀ Group or a hydrogen atom, or a group containing one or more heteroatoms certain atoms. When a B group is present, R ₉ is absent; when the B group is absent, R _{9 is} selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group Or a C ₃ -C ₅ alkyl group is optionally substituted by OR ₈ , SR ₈ , N(R ₈ ) ₂ ; R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more R ₁₀ . A five-membered heterocyclic pyrimidine compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, a polymorph, a tautomer thereof, according to claim 1. a compound, a metabolite, a metabolite or a prodrug, wherein the structure of the five-membered heterocyclic pyrimidine compound represented by the formula (I) is as shown in the formula (I-8),

among them: R _{1 is} selected from H, CN, CF ₃ , halogen, hydrocarbyl acyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or quaternary to octagonal heteroaryl, wherein The hydrocarbyl acyl group, C ₁ -C ₃ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group or tetra- to 8-membered heteroaryl group is optionally substituted by R ₁₀ , preferably, R ₁ Selected from CN, CF ₃ , fluorine, chlorine, bromine, formyl, acetyl; X is selected from O, S or NR ₈ ; R _{6 is} selected from hydrogen or a C ₁ -C ₈ hydrocarbyl group, wherein the C ₁ -C ₈ hydrocarbyl group is optionally substituted with R ₁₀ ; R _{4 is} selected from C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, wherein said C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ - The C ₈ alkynyl groups are each optionally substituted by one or more R ₁₀ ; preferably, R ₄ is C _1-4 alkyl, optionally substituted by R ₁₀ ; more preferably, R _{4 is} selected from -CH ₂ - , -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH(CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)- , -CH(CH ₂ NR ₂ )-, -CH(CH ₂ CH ₂ NR ₂ )-; R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R may be selected from H, C ₁ -C ₈ alkyl, C _3- C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, which may also be substituted by =0, —OH, —NH ₂ , —SH; When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached; The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl, heterocyclic aryl are optionally independently selected by one or more R _{10 is} substituted; preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydrogen Pyran, propylene oxide, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more R ₁₀ ; R ₉ is absent or selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally OR ₈ , SR ₈ Or N(R ₈ ) ₂ substituted; R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ . A five-membered heterocyclic pyrimidine compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, a polymorph, a tautomer thereof, according to claim 1. a compound, a metabolite, a metabolite or a prodrug, wherein the structure of the five-membered heterocyclic pyrimidine compound represented by the formula (I) is as shown in the formula (I-9),

among them: X is selected from O, S or NR ₈ ; R _{6 is} selected from hydrogen or a C ₁ -C ₈ hydrocarbyl group, wherein the C ₁ -C ₈ hydrocarbyl group is optionally substituted with R ₁₀ ; R _{4 is} selected from C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, wherein said C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ - The C ₈ alkynyl groups are each optionally substituted by one or more R ₁₀ ; preferably, R ₄ is C _1-4 alkyl, optionally substituted by R ₁₀ ; more preferably, R _{4 is} selected from -CH ₂ - , -CH(CH ₃ )-, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ -n)-, -CH(CH ₂ OR)-, -CH(CH ₂ CH ₂ OR)- , -CH(CH ₂ NR ₂ )- or -CH(CH ₂ CH ₂ NR ₂ )-; R _{10 is} selected from the group consisting of halogen, cyano, -R, -OR, =O, -SR, -NR ₂ , =NR, -C(halogen) ₃ , -CR(halogen) ₂ , -CR ₂ (halogen), -OCN, -SCN, -N=C=O, -NCS, -NO, -NO ₂ , -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C( =O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(= O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NRR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR,- NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -C(=O)R, -C(=S)R, -C(= O) OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR) NRR, -NRC(=NR)NRR, or a C ₁ -C ₈ alkyl group optionally substituted by -OH, -SH, -NH ₂ ; wherein R is selected from H, C ₁ -C ₈ alkyl, C _{3 a} C ₈ cycloalkyl group, a 3-8 membered heterocycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, which may also be substituted by =O, -OH, -NH ₂ or -SH; When R _{10 is} selected from -NR ₂ , two independently selected R may form a four to six membered ring together with the N atom to which it is attached; The B group may or may not be present, and when the B group is absent, R ₄ and R _{9 are} directly linked together; when the B group is present, it is selected from a C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ a heterocycloalkyl, aryl or heterocyclic aryl group, wherein said C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R ₁₀ Preferably, the B group is selected from the group consisting of phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, pyran, tetrahydropyrrole, tetrahydropyrrole, tetrahydrofuran, dihydropyran, tetrahydropyran, ring Oxypropane, cyclohexane, cyclopentane, cyclobutane and cyclopropane, optionally substituted by one or more R ₁₀ ; R ₉ is absent or selected from a C ₁ -C ₈ hydrocarbyl group, preferably a C ₃ -C ₅ alkyl group, wherein the C ₁ -C ₈ hydrocarbyl group or C ₃ -C ₅ alkyl group is optionally OR ₈ , SR ₈ or N(R ₈ ) ₂ substituted; R _{8 is} selected from hydrogen or a C ₁ -C ₃ hydrocarbyl group, wherein the C ₁ -C ₃ hydrocarbyl group is optionally substituted with one or more independently selected R ₁₀ . The five-membered heterocyclic pyrimidine compound according to at least one of claims 1 to 10, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a polymorph, a tautomer thereof, Isotope compound, metabolite or prodrug, wherein The five-membered heterocyclic pyrimidine compound is selected from the group consisting of 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, (S)-1-(4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yloxy) -2-ol, (S)-2-(4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yloxy) - 1-Alcohol, 7-(4-(Pyrrolidin-1-ylmethyl)benzyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)-7H-pyrrolo[2,3-d Pyrimidine-4-amine, 2-butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 4-amino-2-butoxy-N-methyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-A Amide, 2-(cyclopentylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 2-(pyridin-3-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, (S)-2-(2-pentyloxy)-7-(4-(pyrrolidin-1-methyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, (R)-2-(2-pentyloxy)-7-(4-(pyrrolidin-1-methyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)-7H-pyrrolo[2 ,3-d]pyrimidine-6-carbonitrile, 2-butoxy-6-bromo-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 2-butoxy-6-methyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, Methyl 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate, 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-carboxaldehyde, 2-butoxy-6-(ethoxymethyl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4- amine, 1-(4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)B 1-ketone, 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine , 2-butoxy-6-chloro-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 4-amino-2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6 -carbonitrile, 1-((4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)oxy)butane-2 -alcohol, 2-((4-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)oxy)butane-1 -alcohol, 2-(oxetan-3-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -amine, 6-((4,4-Difluorocyclohexyl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine - 4-amine, 6-butoxy-1-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine, (4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol, 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6 -carbonitrile, 1-((4-Methylenecyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 6-((2-Methylpyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine, 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-((2-(trifluoromethyl)pyridin-4-yl)methoxy)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine, 6-(2-methoxypyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine, 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(thiazol-5-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, (S)-6-(pent-2-yloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine, (R)-6-(pent-2-yloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine, 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazolo[3,4- d]pyrimidine-4-amine, 6-(pyridin-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexyl- 1-alcohol, 1-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy)hexyl- 3-alcohol, 6-(pyridin-4-ylmethoxy)-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 6-(1-(pyridin-4-yl)butoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine, (R)-3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hexa-1-ol, (S)-3-((4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hexa-1-ol, 2-butoxy-6-(5-methylthiazol-2-yl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-amine, 6-((1-methoxypent-2-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidine- 4-amine, 6-((2-Methoxypentyl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine, 4-amino-7-(4-(piperidin-1-ylmethyl)benzyl)-2-(pyridin-4-ylmethoxy)-7H-pyrrolo[2,3-d]pyrimidine-6 -carbonitrile, 1-benzyl-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 6-(pyridin-4-ylmethoxy)-1-(5-(pyrrolidin-1-yl)pentyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 4-amino-2-((2-methoxypyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2, 3-d]pyrimidine-6-carbonitrile, (S)-4-amino-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile, (R)-4-amino-2-(pent-2-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile, 6-(pyridin-2-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 6-(isoxazol-3-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4- amine, 6-(pent-2-yloxy)-1-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine, 3-(4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yloxy)pent-1- alcohol, 6-(pyridin-4-ylmethoxy)-1-((cis-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3,4-d Pyrimidine-4-amine, (S)-4-amino-2-((1-hydroxyhex-3-yl)oxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2 ,3-d]pyrimidine-6-carbonitrile, (R)-4-amino-2-(1-hydroxyhex-3-yloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3 -d]pyrimidine-6-carbonitrile, 6-(pyridin-4-ylmethoxy)-1-(7-(pyrrolidin-1-yl)heptyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 6-((2-Methylpyridin-4-yl)methoxy)-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 6-(Pyridin-4-ylmethoxy)-1-(trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)methyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine, 6-(4-Fluoro-3-methoxybenzyloxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine, (S)-4-Amino-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile, (R)-4-amino-2-(pent-2-yloxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-6-carbonitrile, 6-((5-Methylisoxazol-3-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d]pyrimidine-4-amine, 6-butoxy-1-(isoindoline-5-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 6-((2-Methylpyridin-4-yl)methoxy)-1-(pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 6-butoxy-1-((2-isopropylisoindoline-5-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, (S)-2-(1-(Pyridin-4-yl)butoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H -pyrrolo[2,3-d]pyrimidin-4-amine, (R)-2-(1-(pyridin-4-yl)butoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(trifluoromethyl)-7H -pyrrolo[2,3-d]pyrimidin-4-amine, 7-(4-(Pyrrolidin-1-ylmethyl)benzyl)-2-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)-7H-pyrrolo[2,3 -d]pyrimidine-4-amine, (R)-6-((1-(Dimethylamino)hex-3-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole [3,4-d]pyrimidine-4-amine, 4-amino-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-7H-pyrrolo[2,3- d] pyrimidine-6-carbonitrile, 6-butoxy-1-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 6-butoxy-1-((2-(pyrrolidin-1-ylmethyl)pyridin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 6-((2-(Dimethylamino)pyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine, 4-amino-2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-7H-pyrrolo[2,3 -d]pyrimidine-6-carbonitrile, (R)-3-((4-Amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hexa-1-ol, (R)-1-((4-amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hex-3-ol, 1-benzyl-6-((2-(methylamino)pyridin-4-yl)methoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, (S)-3-((4-Amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hexa-1-ol, (S)-1-((4-amino-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)oxy Hex-3-ol, 6-((4-Fluorobenzyl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine , 1-(4-(Pyrrolidin-1-ylmethyl)benzyl)-6-((tetrahydrofuran-3-yl)methoxy)-1H-pyrazolo[3,4-d]pyrimidine-4- amine, 6-((3-oxabicyclo[3.1.0]hex-6-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazole [3,4-d]pyrimidine-4-amine, (R)-6-((1-methoxyhex-3-yl)oxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3, 4-d]pyrimidine-4-amine, 2-butoxy-7-(4-(1-methylpiperidin-4-yl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 6-butoxy-1-((2-isopropyl-1,2,3,4-tetrahydroisoquin-7-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine 4-amine, 6-((2-Methylpyridin-4-yl)methoxy)-1-(3-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine, 4-amino-2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, 4-amino-2-((4,4-difluorocyclohexyl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl-7H-pyrrolo[2,3-d Pyrimidine-6-carbonitrile, 4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-((2-(trifluoromethyl)pyridin-4-yl)methoxy)-7H-pyrrole [2,3-d]pyrimidine-6-carbonitrile, 6-Chloro-2-(pyridin-4-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -amine, 4-amino-2-((2-methylpyridin-4-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3 -d]pyrimidine-6-carbonitrile, 6-((5-Methylisoxazol-3-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d]pyrimidine-4-amine 2-(4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yloxy)pent-1- alcohol, 1-(4-Amino-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yloxy)pent-2- alcohol, 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(1-(thiazol-5-yl)butoxy)-1H-pyrazolo[3,4-d]pyrimidine- 4-amine, 4-amino-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-2-(pyridin-4-ylmethoxy)-7H -pyrrolo[2,3-d]pyrimidine-6-carbonitrile, 6-((2-(Methylamino)pyridin-4-yl)methoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4 -d]pyrimidine-4-amine, N-(3-((4-Amino-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzyl)acetamide , 4-amino-2-((4-fluorocyclohexyl-3-en-1-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrole [2,3-d]pyrimidine-6-carbonitrile, 4-amino-2-(pyridin-4-ylmethoxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6 -carbonitrile, (S)-6-(1-phenylbutoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine, (R)-6-(1-phenylbutoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine-4 -amine, 1-(cyclohexylmethyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 6-(pyridin-4-ylmethoxy)-1-(6-(pyrrolidin-1-yl)hexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, (S)-4-amino-2-(3-hydroxyhexyloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine -6-carbonitrile, (R)-4-amino-2-(3-hydroxyhexyloxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine -6-carbonitrile, (R)-3-((4-amino-1-((4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d] Pyrimidin-6-yl)oxy)hexan-1-ol, 1-((4-((3,3-Difluoropyrrolidin-1-yl)methyl)cyclohexyl)methyl)-6-(pyridin-4-ylmethoxy)-1H-pyrazolo[ 3,4-d]pyrimidine-4-amine, 6-(pyridin-4-ylmethoxy)-1-(8-(pyrrolidin-1-yl)octyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, (S)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)-1H-pyrazole And [3,4-d]pyrimidine-4-amine, 1-(4-(pyrrolidin-1-ylmethyl)benzyl)-6-(tetrahydro-2H-pyran-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine 4-amine, 6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-methyl formate, (R)-6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d]pyrimidine-4-carboxylic acid methyl ester, (S)-6-(oxetan-4-ylmethoxy)-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4- d] Methyl pyrimidine-4-carboxylate. A pharmaceutical composition comprising the five-membered heterocyclic pyrimidine compound according to at least one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, a polymorph a body, a tautomer, an isotope compound, a metabolite or a prodrug, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 12, further comprising another pharmaceutically active ingredient, which is a PD-1 antibody, a PD-L1 antibody or a PD-1 inhibitor, a PD-L1 inhibitor or a PD -1/PD-L1 inhibitor. A five-membered heterocyclic pyrimidine compound according to at least one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, a polymorph, a tautomer Use of a body, an isotope compound, a metabolite or a prodrug, or a pharmaceutical composition according to claim 12 for the preparation of a TLR ₇ receptor agonist. A five-membered heterocyclic pyrimidine compound according to at least one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate thereof, a polymorph, a tautomer Use of a body, an isotope compound, a metabolite or a prodrug, or a pharmaceutical composition according to claim 12 or 13 in a medicament for the prevention, treatment and/or prevention of a disease. Among them, the disease is a disease which is treated by activating the TLR ₇ receptor to enhance immunity. The use according to claim 15, wherein the disease is selected from a liver related disease, a tumor or AIDS. The use according to claim 16, wherein the liver-related disease is selected from the group consisting of viral hepatitis, autoimmune liver disease, drug-induced liver disease, liver disease liver damage, liver function failure, chronic severe hepatitis, liver cirrhosis, liver abscess And fatty liver, primary liver cancer, preferably the liver related diseases are hepatitis B and hepatitis C; the tumor is preferably selected from leukemia, lymphoma, melanoma or non-small cell lung cancer. A method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a five-membered heterocyclic pyrimidine compound according to at least one of claims 1 to 11, which is pharmaceutically acceptable a salt, stereoisomer, solvate, polymorph, tautomer, isotope compound, metabolite or prodrug, or a pharmaceutical composition according to claim 12 to activate TLR ₇ in vivo body. A method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a) a five-membered heterocyclic pyrimidine compound according to at least one of claims 1 to 11, which is pharmaceutically acceptable Accepted salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites or prodrugs, and b) PD-1 antibodies, PD-L1 antibodies or PD-1 inhibitors A PD-L1 inhibitor or a PD-1/PD-L1 inhibitor; wherein the disease is a disease which is treated by activating the TLR ₇ receptor to enhance immunity. The method of claim 19, wherein the disease is a tumor, preferably selected from the group consisting of leukemia, lymphoma, melanoma or non-small cell lung cancer.