CN115368382A - KRAS G12D inhibitor and its application in medicine - Google Patents

Abstract

The present invention relates to a novel compound having KRAS G12D modulating activity. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.

Description

KRAS G12D inhibitor and its application in medicine

technical field

The present invention relates to a novel compound having KRAS inhibitory activity, especially KRAS G12D inhibitory activity. The invention also relates to processes for the preparation of these compounds and pharmaceutical compositions containing them.

Background technique

Clinical data show that RAS is the gene with the highest mutation rate in human tumors. About 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, 43% of multiple myeloma, And 32% of lung adenocarcinomas have RAS gene mutations. The most common mutation of RAS is point mutation, which often occurs at codons 12, 13, and 61, and the mutation at codon 12 is the most common, such as G12C, G12D or G12V.

At present, the development of drugs targeting KRAS mutations is one of the current research hotspots for new drugs. KRAS G12C inhibitors AMG510 (WO2018217651A1) and MRTX849 (WO2019099524A1) have entered the late clinical stage; while MIRATI is leading the development of G12D inhibitors (WO2021041671A1).

Contents of the invention

The present invention provides a compound represented by general formula (I), its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt:

in,

R ₁ is independently selected from H, hydroxyl, C _1-6 alkyl, C _1-6 aminoalkyl, -N(R _a ) ₂ , -C(=NH)NH ₂ , -C(=NCH ₃ )NH _2. Carboxyl, C _1-6 carboxyalkyl, cyano, C _1-6 cyanoalkyl, halogen, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aldehyde, -CO ₂ R _a , -CO ₂ N(R _a ) ₂ , -(CH ₂ ) _0-3 C(=O)N(R _a ) ₂ , -C(=O)(CH ₂ ) _0-3 N(R _a ) ₂ or 5-6 membered heteroaryl, said R _a is independently selected from H or C _1-6 alkyl; preferably R ₁ is H;

_X1 is selected from N or CH;

X ₂ is selected from N or CR ₇ ;

R ₂ or R ₇ are independently selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino and nitro, and the C _{1 -6} alkyl, C _1-6 alkoxy, haloalkyl or hydroxyalkyl are optionally further selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, cyano, amino, One or more substituents in nitro, hydroxy and hydroxyalkyl;

Ring A is selected from C _3-6 cycloalkyl or 3-6 membered heterocyclyl;

R _is independently selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, hydroxy or hydroxyalkyl;

R ₄ is independently selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, -(CH ₂ ) _0-3 N(R _b ) ₂ , C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-14 aryl or 4-14 membered heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, Hydroxyalkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-14 aryl or 4-14 membered heteroaryl are optionally further selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, -(CH ₂ ) _0-3 N(R _b ) ₂ , C _3-14 cycloalkyl, 3-14 One or more substituents in heterocyclic group, C _6-14 aryl and 4-14 heteroaryl, said R _b is independently selected from H, C _1-6 alkyl or C _{1- 6} haloalkyl;

L ₁ is selected from -O-(CH ₂ ) _0-3 , -S-(CH ₂ ) _0-3 , -NH-(CH ₂ ) _0-3 or alkylene, said L ₁ is optionally further One or more halogen or C _1-6 alkyl substitution;

_L is selected from a bond or an alkylene group optionally further substituted by one or more halogen, C _1-6 alkyl or C _1-6 haloalkyl;

_R is selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, alkoxyalkyl, C _3-14 cycloalkyl and 3-14 membered heterocyclyl;

_R is selected from C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-14 aryl and 4-14 membered heteroaryl, the C _3-14 cycloalkyl, 3-14 membered heteroaryl Cyclic group, C _6-14 aryl and 4-14 membered heteroaryl are optionally further substituted by one or more R _c ; R _c is independently selected from H, =O, =S, oxo, cyano , halogen, C _1-6 alkyl, C _1-6 haloalkyl, -C _0-3 alkylene-OR _d , -OC(=O)C _1-6 alkyl, -C _0-3 alkylene -SR _d , -C _0-3 alkylene-N(R _d ) ₂ , -C _0-3 alkylene-S(=O)R _d , -C _0-3 alkylene-S(=O ) ₂ R _d , -C _0-3 alkylene-SR _d , -C _0-3 alkylene-S(R _d ) ₅ , -C _0-3 alkylene-C(=O)R _d , -C _0-3 alkylene-C(=O)OR _d , -C _0-3 alkylene-C(=O)N(R _d ) ₂ , C _2-6 alkenyl, C _2-6 alkyne Group, substituted or unsubstituted -C _0-3 alkylene-C _3-14 cycloalkyl, substituted or unsubstituted -C _0-3 alkylene-(3-14 membered heterocycloalkyl), substituted or unsubstituted -C _0-3 alkylene-C _6-14 aryl or substituted or unsubstituted -C _0-3 alkylene-(5-14 membered heteroaryl), each _R independently is H, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkyl;

m, n or p are each independently selected from 0, 1, 2, 3 or 4.

In some embodiments, formula (I) is selected from compounds represented by formula (IA),

in,

_R1 is H;

Ring A is selected from C _3-6 cycloalkyl or 3-6 membered heterocyclic group, preferably cyclopropyl;

R _is independently selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, hydroxy and hydroxyalkyl;

R ₄ is independently selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, -(CH ₂ ) _0-3 N(R _b ) ₂ , C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-14 aryl and 4-14 membered heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, Hydroxyalkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-14 aryl and 4-14 membered heteroaryl are optionally further selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, -(CH ₂ ) _0-3 N(R _b ) ₂ , C _3-14 cycloalkyl, 3-14 One or more substituents in heterocyclic group, C _6-14 aryl and 4-14 heteroaryl, said R _b is independently selected from H or C _1-6 alkyl;

L ₁ is selected from -O-(CH ₂ ) _1-3 , said L ₁ is optionally further substituted by one or more halogen or C _1-6 alkyl;

_L is selected from alkylene, which is optionally further substituted by one or more halogen or C _1-6 alkyl;

_R is selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, alkoxyalkyl, C _3-14 cycloalkyl and 3-14 membered heterocyclyl;

_R is selected from C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-14 aryl and 4-14 membered heteroaryl, the C _3-14 cycloalkyl, 3-14 membered heteroaryl Cyclic, C _6-14 aryl and 4-14 membered heteroaryl are optionally further substituted by one or more _R ; R _is independently selected from H, =O, =S, acyl, cyano, halogen , C _1-6 alkyl, C _1-6 haloalkyl, -C _0-3 alkylene-OR _d , -OC(=O)C _1-6 alkyl, -C _0-3 alkylene-SR _d , -C _0-3 alkylene-N(R _d ) ₂ , -C _0-3 alkylene-S(=O)R _d , -C _0-3 alkylene-S(=O) ₂ R _d , -C _0-3 alkylene-SR _d , -C _0-3 alkylene-S(R _d ) ₅ , -C _0-3 alkylene-C(=O)R _d , -C _0-3 alkylene-C(=O)OR _d , -C _0-3 alkylene-C(=O)N(R _d ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, Substituted or unsubstituted -C _0-3 alkylene -C _3-14 cycloalkyl, substituted or unsubstituted -C _0-3 alkylene -(3-14 membered heterocycloalkyl), substituted or unsubstituted Substituted -C _0-3 alkylene -C _6-14 aryl or substituted or unsubstituted -C _0-3 alkylene -(5-14 membered heteroaryl), each R _d is independently H , C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkyl;

p is selected from 0, 1, 2, 3 or 4.

In some embodiments, _R in formula (I) is selected from H.

In some embodiments, _R in formula (I) is selected from H, cyano or C _1-6 alkyl.

In some embodiments, R in formula (I) ₃ is selected from H or C _1-6 alkyl

In some embodiments, _X in formula (I) is selected from N.

In some embodiments, _X in formula (I) is selected from N.

In some embodiments, R _in formula (I) is selected from C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-14 aryl or 4-14 membered heteroaryl, the C _{3 -14} cycloalkyl, 3-14 membered heterocyclic group, C _6-14 aryl or 4-14 membered heteroaryl are optionally further selected from halogen, C _1-6 alkyl, haloalkyl, cyano replaced by one or more substituents.

In some embodiments, L ₁ in formula (I) is selected from -O-(CH ₂ ) _1-3 , and said L ₁ is optionally further substituted by one or more halogens or C _1-6 alkyl groups.

In some embodiments, p in formula (I) is selected from 0 or 1.

选自

In some embodiments, in formula (I)

selected from

In some embodiments, _R in formula (I) is selected from halogen, C _1-6 alkyl or C _1-6 alkoxy, preferably F.

In some embodiments, _R in formula (I) is selected from

In some embodiments, the compound shown in formula (I) is selected from:

1) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((3-methyl (Piperidin-1-yl)methyl)cyclopropyl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;

2) 4-(2-((1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;

3) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-((3- Haloperidin-1-yl)methyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;

4) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-((2- Methylpyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;

5) 4-(2-((1-((1-oxo-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-4-((1R , 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;

6) 190) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2, 2,2-Trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalene- 2-alcohol;

7) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((3-(difluoromethyl )piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;

8) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-((4- Haloperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;

9) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-((R) -3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;

10) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((4,4-difluoropiper Pyridin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;

11) 4-(2-((1-((7-azabicyclo[2.2.1]hept-7-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)- 3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;

12) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((6,6-difluoro- 3-Azabicyclo[3.1.0]hex-3-yl)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol ;

13) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((3-( Trifluoromethyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;

14) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;

15) 4-(2-((1-((2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methoxy)-4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;

16) 4-(2-((1-((3-azabicyclo[3.1.0]hex-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)- 3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol;

17) 4-(2-((1-((3-azabicyclo[3.1.0]hex-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)- 3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;

18) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine Base) cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;

19) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine Base)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

20) 4-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)morpholine

21) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;

22) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

23) 4-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl- 7-fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine;

24) 4-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-3 -Hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1-dioxide ;

25) 4-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)1,1-disulfide phylloline;

26) 4-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1-dioxide ;

27) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine base) cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2-ol;

28) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine base) cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol;

29) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine Base) cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;

30) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol;

31) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol;

32) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;

33) 4-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-3 -Hydroxynaphthalene-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1-dioxide thing;

34) 4-((1-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(8- Fluoro-3-hydroxynaphthalen-1-yl)pyridyl[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1-dioxide ;

35) 4-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(7,8-two Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1- Dioxide;

36) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine Base)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol;

37) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine base)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol;

38) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine Base) cyclopropyl) methoxy) pyridin [4,3-d] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;

39) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol;

40) 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol;

41) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol;

42) 4-((1-((4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7- Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1- Dioxide;

43) 4-((1-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(7- Fluoro-3-hydroxy-8-methylnaphthalen-1-yl)pyridyl[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1, 1-dioxide;

44) 4-((1-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(3-chloro-2- Cyclopropyl-5-hydroxyphenyl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1-di oxide;

45) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine base) cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloronaphthalene-2-ol;

46) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine base)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol;

47) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloronaphth-2-ol;

48) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol;

49) 4-((1-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-chloro-3- Hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1-dioxide;

50) 4-((1-((4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-7-(8-chloro-7-fluoro -3-Hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)methyl)thiomorpholine 1,1-dioxide;

51) 4-(2-((1-((3-azabicyclo[3.1.0]hex-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)- 3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-alcohol;

52) 2-((1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)-3, 8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyridino[4,3-d]pyrimidine ;

53) 4-(2-((1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2-ol ;

54) 4-(2-((1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalene- 2-alcohol;

55) 4-(2-((1-((3-azabicyclo[3.1.0]hex-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)- 3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2- alcohol;

56) 4-(2-((1-((3-azabicyclo[3.1.0]hexaazol-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene- 2-alcohol;

57) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(pyrrolidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol;

58) 3-(2-((1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropyl phenol;

59) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxygen heterocycle-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;

60) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxygen heterocycle-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

61) 4-((3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxan-3-yl)methyl)morpholine;

62) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxoalkane-3-yl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;

63) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxolan-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

64) 4-((3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxetan-3-yl)methyl)thiomorpholine;

65) 4-((3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-3 -Hydroxynaphthalene-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxetan-3-yl)methyl)thiomorpholine 1 ,1-dioxide;

66) 4-((3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxan-3-yl)methyl)sulfur Morpholine 1,1-dioxide;

67) 4-((3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -Fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxan-3-yl)methyl)1,1-di Oxythiophene;

68) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2-ol;

69) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol;

70) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;

71) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol;

72) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxoalkane-3-yl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol;

73) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxoalkane-3-yl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;

74) 4-((3-((4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-7-(8-ethyl-3- Hydroxynaphthalene-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxan-3-yl)methyl)thiomorpholine 1,1-di oxide;

75) 4-((3-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(8- Fluoro-3-hydroxynaphthalen-1-yl)pyridyl[4,3-d]pyrimidin-2-yl)oxy)methyl)oxolan-3-yl)methyl)thiomorpholine 1 ,1-dioxide;

76) 4-((3-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(7,8-difluoro -3-Hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxolan-3-yl)methyl)thiomorph Phenyl 1,1-dioxide;

77) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol;

78) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol;

79) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxygen heterocycle-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol;

80) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxetan-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol;

81) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxa-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol;

82) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxoalk-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol;

83) 4-((3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7 -Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxolan-3-yl)methyl)thio Morpholine 1,1-dioxide;

84) 4-((3-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(7- Fluoro-3-hydroxy-8-methylnaphthalen-1-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxan-3-yl)methyl)sulfur Morpholine 1,1-dioxide;

85) 4-((3-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(3-chloro-2- Cyclopropyl-5-hydroxyphenyl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxolan-3-yl)methyl)1,1 - dioxythiophene;

86) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloronaphth-2-ol;

87) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol;

88) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxoalkane-3-yl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5-chloronaphth-2-ol;

89) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxolan-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol;

90) 4-((3-((4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-7-(8-chloro-3-hydroxy Naphthalene-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxan-3-yl)methyl)thiomorpholine 1,1-dioxide thing;

91) 4-((3-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-chloro-7- Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxolan-3-yl)methyl)thio Morpholine 1,1-dioxide;

92) 4-(2-((3-((3-azabicyclo[3.1.0]hexaazol-3-yl)oxy)oxan-3-yl)methoxy)-4-(( 1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 - Fluorinaphth-2-ol;

93) 2-((3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)oxacyclo-3-yl)methoxy)-4-((1R, 5S )-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyridin[4,3 -d] pyrimidine;

94) 4-(2-((3-((3-azabicyclo[3.1.0]hexaazol-3-yl)methyl)oxane-3-yl)methoxy)-4-((1R , 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2 -alcohol;

95) 4-(2-((3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)oxacyclo-3-yl)methoxy)-4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6 - Fluorinaphth-2-ol;

96) 4-(2-((3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)oxacyclo-3-yl)methoxy)-4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5,6-di Fluorin-2-ol;

97) 4-(2-((3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)oxacyclo-3-yl)methoxy)-4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl- 6-fluoronaphth-2-ol;

98) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(pyrrolidine- 1-ylmethyl)oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol;

99) 3-(2-((3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)oxacyclo-3-yl)methoxy)-4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4 - cyclopropylphenol;

100) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;

101) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

102) 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidine;

103) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalene-2-ol ;

104) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R, 5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene -2-ol;

105) 2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)-3, 8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyridino[4,3-d]pyrimidine ;

106)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbonitrile ;

107)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine- 3-carbonitrile;

108)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbonitrile ;

109) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol;

110) 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine-1 -ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol;

111) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;

112) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R, 5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2-ol ;

113) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol;

114) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R, 5S) -3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2- alcohol;

115)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbonitrile ;

116)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7 -(8-fluoro-3-hydroxynaphthalen-1-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbonitrile;

117)(R)-1-((1-((4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-7-(7,8 -Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbon Triamine;

118) 4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-2l4-isochromene -1-yl)-8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidine;

119) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol;

120) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol;

121) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene -2-ol;

122) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalene- 2-alcohol;

123) 3-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropyl phenol;

124)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine- 3-carbonitrile;

125)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7 -(7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine- 3-carbonitrile;

126)(R)-1-((1-((4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-7-(3-chloro -2-cyclopropyl-5-hydroxyphenyl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbon Triamine;

127) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5-chloronaphth-2-ol;

128) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol;

129) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloronaphthalene-2-ol;

130) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R, 5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalene- 2-alcohol;

131)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Chloro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbonitrile;

132)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3 - carbonitrile;

133) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalene-2-ol ;

134) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene -2-ol;

135) 2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)-3, 8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyridino[4,3-d]pyrimidine ;

136) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;

137) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol ;

138) 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2-((1-((((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidine;

139) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2-ol ;

140) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol;

141) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2 -alcohol;

142) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol;

143) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol;

144) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;

145) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene -2-ol;

146) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalene -2-ol;

147) 3-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropyl phenol;

148) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-((R) -3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ;

149) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol;

150) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol;

151) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloronaphthalene-2-ol;

152) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalene- 2-alcohol;

153) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphth-2-ol;

154) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol;

155) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;

156) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol ;

157) 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2-((1-((((R)-3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidine;

158)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3-carbonitrile ;

159)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine- 3-carbonitrile;

160)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3-carbonitrile ;

161) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol;

162) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol;

163) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;

164)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3-carbonitrile ;

165)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7 -(8-fluoro-3-hydroxynaphthalen-1-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3-carbonitrile;

166)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(7, 8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3- Carbonitrile;

167) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ;

168) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol ;

169) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol;

170)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine- 3-carbonitrile;

171)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7 -(7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine- 3-carbonitrile;

172)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(3- Chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3- Carbonitrile;

173) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphth-2-ol;

174) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol;

175)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Chloro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3-carbonitrile;

176)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3 - carbonitrile;

177) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((ethyl(2,2 ,2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;

178) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2,2, 2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -alcohol;

179)N-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl- 7-fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-N-ethyl-2,2, 2-trifluoro-1-amine;

180) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(pyrrolidine- 1-yl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;

181) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(pyrrolidine- 1-yl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

182) 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2-((1-(pyrrolidin-1-yl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidine;

183)4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2,2, 2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol;

184) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2,2, 2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol;

185)4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2,2, 2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol ;

186)4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((ethyl(2,2 ,2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene- 2-alcohol;

187)4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((ethyl(2,2 ,2-Trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalene- 2-alcohol;

188)3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2,2, 2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol; 189)4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2,2, 2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloronaphthalen-2-ol.

The present invention also provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises a therapeutically effective amount of at least one compound represented by formula (I), its stereoisomers, tautomers, deuterium Substitutes or pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient.

The present invention further provides a pharmaceutical composition, characterized in that the therapeutically effective amount of at least one compound represented by formula (I), its stereoisomer, tautomer, deuterium or drug The mass percentage of salt and pharmaceutically acceptable auxiliary materials is 0.0001:1-10.

The present invention provides the application of the compound represented by formula (I), its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt or pharmaceutical composition in the preparation of medicine.

The present invention further provides the preferred technical scheme of said application:

Preferably, the application is in the preparation of medicines for treating and/or preventing cancer.

Preferably, the application is the application of preparing medicines for treating diseases mediated by KRAS G12D. Preferably, said disease is cancer.

Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

The present invention also provides a method for treating and/or preventing diseases, comprising administering a therapeutically effective amount of at least one compound represented by structural formula (I), its stereoisomers, tautomers, deuterium Substitutes or pharmaceutically acceptable salts or pharmaceutical compositions containing them.

The present invention also provides a method for treating and/or preventing diseases mediated by KRAS G12D, comprising administering a therapeutically effective amount of at least one compound represented by structural formula (I), its stereoisomer, mutual variants, deuteriums or pharmaceutically acceptable salts or pharmaceutical compositions containing them.

The present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least one compound represented by structural formula (I), its stereoisomer, tautomer, deuterium or medicinal salt or a pharmaceutical composition containing it.

Preferably, in the above method, the KRAS G12D-mediated disease is cancer.

Unless otherwise stated, general chemical terms used in the structural formulae have their usual meanings.

For example, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine, unless otherwise specified.

In the present invention, unless otherwise specified, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups, preferably C _1-8 alkyl, more preferably C _1-6 alkyl. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and the like. Similarly, " _1-8 " in "C _1-8 alkyl" refers to a group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in a straight or branched chain group.

"Alkylene" refers to a linear or branched divalent saturated hydrocarbon group, preferably a C _1-8 alkylene group, more preferably a C _1-6 alkylene group. For example, methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

"Alkoxy" refers to the oxygen ether form of the aforementioned linear or branched alkyl, ie -O-alkyl, preferably C _1-8 alkoxy, more preferably C _1-6 alkoxy.

The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkoxy group is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" or "oxo" refers to "=O".

In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient may be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

The term "aryl", in the present invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic or condensed ring aromatic group including carbocyclic atoms. A C _6-14 aryl monocyclic or polycyclic aromatic ring group is preferred. More preferred are phenyl and naphthyl. Most preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl, where the ring bonded to the parent structure is an aryl ring, non-limiting examples include, but are not limited to, benzocyclopentyl.

The term "heterocyclyl", in the present invention, unless otherwise stated, refers to an unsubstituted or substituted stable ring system consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S, which is Saturated or partially saturated monocyclic or polycyclic 20-ring hydrocarbon substituents comprising 3 to 14 carbon atoms, wherein the nitrogen or sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatoms may be optionally quaternized . The heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro Oxadiazolyl. The heterocyclyl may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring bonded to the parent structure is the heterocyclyl.

The term "heteroaryl", in the present invention, unless otherwise stated, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-14-membered benzofused A heteroaromatic ring system or a polycyclic heteroaromatic ring system consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms can be optionally replaced by Oxygenated, the nitrogen heteroatoms can optionally be quaternized. Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene Thiadiazolyl, benzotriazolyladenine, quinolinyl or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclyl or cycloalkyl ring where the ring attached to the parent structure is a heteroaryl ring.

The term "cycloalkyl" refers to a ring system having at least one cycloalkyl group. C _3-14 cycloalkyl is preferred, where "C _3-14 " means that the cycloalkyl can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms . Cycloalkyl groups can include monocyclic and polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). Cycloalkyl groups in some embodiments include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, etc.; said cycloalkyl groups can also be fused to aryl, heterocyclyl or heteroaryl rings, where the parent structure The rings joined together are cycloalkyl groups.

The term "substituted" means that one or more hydrogen atoms in the group are respectively replaced by the same or different substituents. Typical substituents include, but are not limited to, H, halogen, -OR ^a , -OC(O)N(R ^a ) ₂ , -N(R ^a ) ₂ , -NR ^a C(O)R ^a , -NR ^a C (O)N(R ^a ) ₂ , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -S(=O)R ^a , -S(=O) ₂ R ^a , -SR ^a , -S(R ^a ) ₅ , -C(=O)R ^a , -C(=O)OR ^a , -C(=O)N(R ^a ) ₂ , C _1-6 alkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-14 aryl or 5-14 membered heteroaryl, the C _1-6 alkyl, C _3-14 cycloalkyl, 3- 14 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl are optionally further substituted by one or more R ^b ; R ^b is selected from H, halogen, cyano, C _1-6 alkyl , -C _0-6 alkylene-OR ^a , -C _0-6 alkylene-OC(O)N(R ^a ) ₂ , -C _0-6 alkylene-N(R ^a ) ₂ ,- C _0-6 alkylene-NR ^a C(O)R ^a , -C _0-6 alkylene-NR ^a C(O)N(R ^a ) ₂ , -C _0-6 alkylene-NR ^a S(O)R ^a , -C _0-6 alkylene-NR ^a S(O) ₂ R ^a , -C _0-6 alkylene-S(=O)R ^a , -C _0-6 alkylene -S(=O) ₂ R ^a , -C _0-6 alkylene-SR ^a , -C _0-6 alkylene-S(R ^a ) ₅ , -C _0-6 alkylene-C( =O)R ^a , -C _0-6 alkylene-C(=O)OR ^a , -C _0-6 alkylene-C(=O)N(R ^a ) ₂ , C _2-6 alkenyl , C _2-6 alkynyl, -C _0-6 alkylene-C _3-14 cycloalkyl, -C _0-6 alkylene-(3-14 membered heterocyclyl), -C _0-6 alkylene Alkyl-C _6-14 aryl or -C _0-6 alkylene-(5-14 membered heteroaryl), =O, =S, =CH ₂ , =CHF, =CF ₂ , =NCH ₃ , The C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-6 alkylene-C _3-14 cycloalkyl, -C _0-6 alkylene-( 3-14 membered heterocyclyl), -C _0-6 alkylene-C _6-14 aryl or -C _0-6 alkylene-(5-14 membered heteroaryl) can optionally also be replaced by 1 One or more R ^a replaced. Each R ^a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkane Base, C _1-6 haloalkyl, C 1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 heteroalkyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl.

In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy Butyl, isobutoxy, tert-butoxy, -SCH ₃ , -SC ₂ H ₅ , formaldehyde, -C(OCH ₃ ), cyano, nitro, -CF ₃ , -OCF ₃ , amino, dimethyl Amino, methylthio, sulfonyl and acetyl groups.

Examples of substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxolylmethyl and piperazinylmethyl.

Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxyl.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.

When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (superior and subvalent), ferric, ferrous, lithium, magnesium, manganese (superior and subvalent), potassium, sodium, zinc, and the like. Particular preference is given to the ammonium, calcium, magnesium, potassium and sodium salts. Nontoxic organic bases from which pharmaceutically acceptable salts can be derived include primary, secondary and tertiary amines, also cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine acid, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine Wait.

When the compound provided by the present invention is a base, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, Cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid, etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.

Since the compound shown in formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% purity, more suitable purity is at least 75%, particularly suitable purity is at least 98% (% is weight) Compare).

The prodrugs of the compounds of the present invention are included in the protection scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted in vivo into the desired compound. For example, any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present application, which can directly or indirectly provide the compound of the present application or its pharmaceutically active metabolite or Residues.

The compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and optical isomers. The present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.

When the compound represented by formula (I) has tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and their mixtures.

Substitution of compounds of formula (I) with heavier isotopes (eg deuterium) may afford certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.

When the compound represented by formula (I) and its pharmaceutically acceptable salts have solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent forming a solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.

The term "composition", in the present invention, is meant to include products comprising the specified amounts of each of the specified ingredients, as well as any product produced directly or indirectly from the combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients as well as processes for the preparation of the compounds of the invention are also part of the invention. Furthermore, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of the present invention.

The pharmaceutical composition provided by the present invention includes a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or adjuvants. Although the most suitable mode of administration of the active ingredient in any given case depends on the particular subject to be administered, the nature of the subject and the severity of the condition, the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and Pharmaceutical compositions for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration). The pharmaceutical compositions of the present invention may conveniently be presented in unit dosage forms and prepared by any methods of preparation well known in the art of pharmacy.

Synthetic scheme

经过取代反应得到化合物I-2；Step A: compound I-1 under alkaline conditions such as DIEA etc., with compound

Obtain compound I-2 through substitution reaction;

经过取代反应得到化合物I-3；Step B: Compound I-2 is reacted with strong base such as NaH etc., and compound

Obtain compound I-3 through substitution reaction;

在钯催化剂作用下如SphosPdG2，经过Suzuki偶联反应得到化合物I-4；Step C: Compound I-3 and

Under the action of palladium catalyst such as SphosPdG2, compound I-4 is obtained through Suzuki coupling reaction;

Step D: The target product I-5 can be obtained by removing the protecting group PG from compound I-4 under acidic conditions such as TFA.

Detailed ways

In order to make the above content more clear and definite, the present invention will use the following examples to further illustrate the technical solution of the present invention. The following examples are only used to illustrate specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the protection scope of the present invention. In the specific implementation of the present invention, technical means or methods that are not specifically described are conventional technical means or methods in the art.

Unless otherwise indicated, all parts and percentages herein are by weight and all temperatures are in degrees Celsius. The following abbreviations are used in the examples:

DIEA: N,N-Diisopropylethylamine;

DCM: dichloromethane;

Dioxane: dioxane;

ESI-MS: electrospray ionization mass spectrometry;

EtOH: ethanol;

MeOH: Methanol;

POCl ₃ : phosphorus oxychloride;

THF: Tetrahydrofuran;

TFA: trifluoroacetic acid;

DPPA: diphenylphosphoryl azide;

NIS: N-iodosuccinimide;

DMF: N,N-dimethylformamide;

CDI: N,N'-carbonyldiimidazole;

SphosPdG2: Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) Palladium(II)

Synthesis of Intermediate M:

Step 1: Synthesis of compound M-1

At room temperature, 2-chloro-3-fluoro-pyridine-4-carboxylic acid (54.00 g), toluene (390.00 mL), tert-butanol (390.00 mL), triethylamine (128.27 mL), powdered 4A were added sequentially Molecular sieve (90.00 mL) (pre-activated), under the protection of nitrogen, keep warm and reflux for half an hour (internal temperature 87°C). Then it was naturally cooled to room temperature, then DPPA (99.44 mL) was added, the temperature was raised to reflux, and the reaction was kept for 5 hours. Cool the reaction mixture to below 40°C, then add 500mL of EA to dilute; continue to cool to room temperature, filter with diatomaceous earth, and filter out the added molecular sieve; rinse the filter residue with 1500mL of EA for several times, and drain; collect the filtrate, and successively water 700mL , washed with 700 mL of saturated brine, and separated; dried the organic phase with anhydrous sodium sulfate; After dehydration, the target product M-1 (68.2 g, yield 89.88%) was finally obtained as a white solid. ESI-MS m/z: 247.1 [M+H] ⁺ .

Step 2: Synthesis of compound M-2

Dissolve compound M-1 (65.00g) in CH ₃ CN (82.00mL) at room temperature, cool in a water bath, slowly add hydrochloric acid (4M in dioxane) (38.43g), stir at room temperature for about 16 hours, white solid Precipitated, in a suspended state. The reaction mixture was filtered, and the filter cake was rinsed with a small amount of acetonitrile, sucked dry, and the filtrate was discarded. Collect the filter cake, add it to a mixture of 700mL saturated sodium bicarbonate aqueous solution and 700mL ethyl acetate, alkalinize, extract, and separate liquids; extract the water phase with 350 mL ethyl acetate, and separate liquids; combine the ethyl acetate phases, add saturated Wash with 300 mL of aqueous sodium chloride solution and separate; dry the organic phase with anhydrous sodium sulfate, filter, remove the desiccant, and concentrate to obtain the target product M-2 (36.3 g, yield 94.0%) in the form of light yellow solid powder. ESI-MS m/z: 147.1 [M+H] ⁺ .

Step 3: Synthesis of compound M-3

Compound M-2 (36.00g) was dissolved in acetonitrile (180.00mL) at room temperature, NIS (66.32g) and p-toluenesulfonic acid (2.12g) were added thereto, and heated at 70°C under nitrogen protection. The reaction liquid was cooled to 50°C, and 900 mL of water was added, and a powdery white solid powder was precipitated, which was beaten for half an hour; filtered, and the filter cake was rinsed with water and drained. Collect the filter cake, add 1200 mL of ethyl acetate to dissolve completely, then wash twice with 350 mL of saturated sodium sulfite aqueous solution, then wash with 350 mL of saturated brine, separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain light yellow Solid particles of the target product M-3 (63.2 g, yield 94.43%). ESI-MS m/z: 272.9 [M+H] ⁺ .

Step 4: Synthesis of Compound M-4

At room temperature, compound M-3 (57.50g) was dissolved in DMF (22.00mL), zinc cyanide (32.22g), tetrakistriphenylphosphine palladium (12.19g) and powdered 4A molecular sieves (20.00mL) were added Wherein, in a nitrogen atmosphere, heat and keep at 100° C. for about 7 hours to react. Remove the oil bath, cool down to room temperature naturally, and wait for post-processing. Diatomaceous earth was used to filter, and the reaction mixture was filtered and sucked dry; the filtrate was collected and concentrated at 60-70°C to obtain a crude light yellow solid. The filter residue was rinsed and dried with 500 mL of ethyl acetate; the rinsing liquid was collected, combined into the crude product, and concentrated again until no liquid was distilled out; 700 mL of ethyl acetate was added to dissolve and concentrate the obtained solid crude product, and then use 250 mL of saturated sodium chloride each time , washed 3 times, and separated. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain a light yellow solid. Add 160 mL of PE/EA=3/1 mixture, beat for half an hour, filter, and drain. The filter cake was collected, concentrated in a water bath at 45°C, and then pumped with a high vacuum oil pump to constant weight; finally the target product M-4 (36.1 g, yield 99.7%) was obtained as light yellow solid powder. ESI-MS m/z: 172.0 [M+H] ⁺ .

Step 5: Synthesis of compound M-5

At room temperature, add concentrated sulfuric acid (61.37mL) to a 500mL single-necked flask, cool in an ice-water bath to below 10°C, add compound M-4 (39.30g) in batches, and stir for 10 minutes after the addition is complete. Keep warm at 60°C with an oil bath, and react for about 1 hour. The reaction solution was cooled to room temperature, and then carefully added to 1100 mL of ice-water mixture, diluted and quenched, and a small amount of yellow solid precipitated out. After stirring for 10 minutes, filter; collect the filter cake, use 50mL saturated aqueous sodium bicarbonate solution, beat for 20 minutes, filter again, collect the filtrate twice, combine; then slowly add sodium carbonate solid, adjust the pH to about 7, there is off-white A solid powder precipitated out. Stir for half an hour, filter, and drain; rinse the filter cake with 100 mL of water each time, drain, and rinse twice in total. The filter cake was collected, put into a vacuum oven, and dried at 55° C. to constant weight to obtain the target product M-5 (33.6 g, yield 77.37%) in the form of beige solid powder. ESI-MS m/z: 190.0 [M+H] ⁺ .

Step 6: Synthesis of compound M-6

At room temperature, add tetrahydrofuran (470.00mL), after nitrogen replacement, under the protection of slight nitrogen flow, add sodium hydride (10.00g), heat with oil bath, keep warm at 40-45°C, stir for 15 minutes; then add compound M in batches -5 (18.95g), after the addition is completed, keep warm and mechanically stir for 20 minutes, then carefully add CDI (24.31g) in batches, after the addition is completed, stir for 15 minutes, heat the oil bath to heat up, and keep warm for reflux reaction. Cool the reaction solution to below 10°C in an ice-water bath, then add 500mL of saturated ammonium chloride aqueous solution, a light yellow solid precipitates, add 1000mL of water; then transfer to a 5L beaker, add 3000mL of water; stir for 1 hour, filter, and drain ; Collect the filter cake, put it in a vacuum oven, and dry it at 50-55° C. to constant weight to obtain the target product M-6 (18.3 g, yield 84.93%) in the form of light yellow solid powder. ESI-MS m/z: 216.0 [M+H] ⁺ .

Step 7: Synthesis of compound M-7

Compound M-6 (18.00 g) and DIEA (36.00 mL) were dissolved in POCl ₃ (180.00 mL) at room temperature, and heated at 100° C. for about 2.5 hours under nitrogen atmosphere. Concentrate under reduced pressure to remove phosphorus oxychloride, and use DCM 100mL to strip twice; dissolve the concentrated residue with 400mL dichloromethane, then dropwise add it to 500mL saturated aqueous sodium bicarbonate solution, and cool with ice water; after stirring for 15 minutes, separate liquid; water phase, then extracted with 300mL of dichloromethane, and separated; combined the dichloromethane phases, washed with 300mL of saturated aqueous sodium chloride solution, and separated; dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by silica gel column (PE/EA=90/10～75/25) The target product M-7 was obtained as off-white solid powder (10.95 g, yield 51.94%). ESI-MS m/z: 251.9 [M+H] ⁺ .

Step 8: Synthesis of Compound M

Compound M-7 (10.50 g) and DIEA (17.18 mL) were dissolved in DCM (120.00 mL) at room temperature, cooled in a water bath, and tert-butyl 3,8-diazabicyclo[3.2.1] was added in portions Octane-8-carboxylate (9.27 g), then stirred at room temperature for about 10 minutes. Add 120mL of dichloromethane, wash with 100mL of water, 100mL of saturated aqueous sodium chloride solution, and separate the liquids. Dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and pass the concentrate through a silica gel column (PE/EA=90/10～75 /25) and beating purification (40mLEA+160mLPE) to obtain the target intermediate M (15.9g, yield 89.26%) in the form of white solid powder.

Example 1: Compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(( Synthesis of 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)naphthalene-2-ol

Step 1: Synthesis of compound 1-1

At room temperature, add 1-methoxycarbonylcyclopropane-1-carboxylic acid (3.00g) into the reaction flask, add dichloromethane (130.00mL), cool down to 0°C, then add oxalyl chloride (7.05mL) and DMF (0.08mL), after the addition, continue to stir at this temperature for 10min, then react at 35°C for 3h. Spin the solvent to dryness, add dry dichloromethane (130.00 mL), cool to 0°C, add triethylamine (14.47 mL) and 3-methylpiperidine (2.47 g), and return to room temperature for 2 h. The solvent was spin-dried, and then purified by a silica gel column (DCM:EA=3:1) to obtain the target product 1-1 (4.00 g, yield 85.30%) as a yellow liquid.

Step 2: Synthesis of Compound 1-2

Compound 1-1 (4.00g) was dissolved in tetrahydrofuran (50.00mL) at room temperature, cooled to -10°C, and lithium aluminum hydride (1.35g) was added in batches. After the addition was complete, return to room temperature for 2 hours. Cool down to 0°C, add diethyl ether to dilute, then add 1.3mL water to quench the reaction, add 15% sodium hydroxide aqueous solution, add 3.9mL water, stir at room temperature for 10min, add anhydrous magnesium sulfate to dry, filter, and concentrate the mother liquor Purification with a silica gel column (DCM-DCM:MeOH=12:1) gave the target product 1-2 (2.30 g, yield 70.67%) as a pale yellow liquid.

Step 3: Synthesis of compounds 1-3

Dissolve compound 1-2 (256.79mg) in tetrahydrofuran (4.00mL) at room temperature, cool down to 0°C, add sodium hydride (50.44mg), stir at room temperature for 10min, and add intermediate M (300.00mg) , continue to react for 1h. Under ice bath, add water to quench the reaction, add EA and water to extract, dry and concentrate. Purification with a silica gel column gave the target product 1-3 (280.00 mg) as a yellow solid. ESI-MS m/z: 575.3 [M+H] ⁺ .

Step 4: Synthesis of compounds 1-4

At room temperature, compound 1-3 (150.00 mg), dimethyl tert-butyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborine-2 -yl)naphthalen-2-yl]oxysilane (200.50 mg), SphosPdG2 (18.78 mg), K ₃ PO ₄ (166.08 mg), 1,4-dioxane (3.00 mL) and water (0.40 mL) , after nitrogen replacement, react at 95°C for 2h under nitrogen protection. Add EA and water to extract, dry and concentrate. The concentrate was purified by Pre-TLC (DCM:MeOH=15:1) to obtain the target product 1-4 (120.00 mg, 57.73%) as a yellow solid. ESI-MS m/z: 797.5 [M+H] ⁺ .

Step 5: Synthesis of Compounds 1-5

Compound 1-4 (150.00 mg) was dissolved in THF (2.00 mL) and triethylamine trihydrofluoride (0.31 mL) at room temperature, and stirred at room temperature for 0.5 h. The reaction mixture was concentrated directly to the crude target product 1-5 as a yellow oil. ESI-MS m/z: 683.4 [M+H] ⁺ .

Step 6: Synthesis of Compound 1

Compound 1-5 (120.00 mg) was dissolved in a mixed solution of DCM (1.00 mL) and TFA (1.00 mL) at room temperature, and reacted at room temperature for 0.5 h. The reaction mixture was concentrated, dissolved in DCM, adjusted to pH=8 by adding aqueous sodium bicarbonate solution under ice bath, extracted with DCM and MeOH, dried and concentrated. The concentrate was purified by Pre-TLC (DCM:MeOH:ammonia water=10:1:0.1) to obtain the target product 1 (53.00 mg, yield 51.77%) as a yellow solid. ESI-MS m/z: 583.3 [M+H] ⁺ . ¹ HNMR (500MHz,MeOD)δ8.95(d,J=3.2Hz,1H),7.70(d,J=8.2Hz,1H),7.49(d,J=8.4Hz,1H),7.36(t,J =7.5Hz,1H),7.24(s,1H),7.21(d,J=1.9Hz,1H),7.16(t,J=7.6Hz,1H),4.49(d,J=12.2Hz,2H), 4.37(dd,J=22.7,10.9Hz,2H),3.64–3.45(m,4H),3.39-3.26(m,1H),2.97(dd,J=29.7,10.3Hz,2H),2.39(dd, J=47.0,12.8Hz,2H), 1.88-1.46(m,10H),0.81(d,J=6.1Hz,4H),0.66(d,J=20.0Hz,2H),0.48(d,J=19.7 Hz, 2H).

Embodiment 2: Compound 4-(2-((1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R , 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol

Step 1: Synthesis of Compound 2-1

Dissolve compound 1-methoxycarbonylcyclopropane-1-carboxylic acid (3.00g) in dichloromethane (100.00mL) at room temperature, cool down to 0°C, then add oxalyl chloride (7.05mL) and DMF (0.08 mL), after adding and keeping warm, continue to stir for 10 min, then react at 35°C for 3 h. Spin the solvent to dryness, add dry dichloromethane (100.00mL), cool to 0°C, add triethylamine (14.47mL) and 3-azabicyclo[3.1.0]hexane (2.08g), and finally restore Reaction at room temperature for 2h. The reaction mixture was concentrated, and the concentrate was purified by a silica gel column (DCM:EA=3:1) to obtain the target product 2-1 (3.6 g, yield 82.66%) as a yellow liquid.

Step 2: Synthesis of compound 2-2

Dissolve compound 2-1 (4.00g) in tetrahydrofuran (50.00mL) at room temperature, cool down to -10°C, add lithium aluminum hydride (2.5M/THF) (1.41g) in batches, return to room temperature after addition Reaction 2h. Cool down to 0°C, dilute with diethyl ether first, add 1.4mL of water, add 1.4mL of 15% sodium hydroxide aqueous solution, and finally add 4.2mL of water, stir at room temperature for 10min, add anhydrous magnesium sulfate to dry, filter, concentrate, concentrate The product was purified by silica gel column (DCM～DCM:MeOH=12:1) to obtain the target product 2-2 (2.20 g, yield 76.46%) in the form of pale yellow liquid.

Refer to Example 1 for subsequent detailed reaction steps. Target product 2ESI-MS m/z: 567.3[M+H] ⁺ . ¹ H NMR (500MHz, MeOD) δ9.02(s, 1H), 7.73(d, J=8.3Hz, 1H), 7.52(d, J=8.4Hz, 1H), 7.39(t, J=7.5Hz, 1H), 7.27(d, J=2.0Hz, 1H), 7.21(dd, J=13.6, 4.7Hz, 2H), 4.55(t, J=18.1Hz, 2H), 4.36(s, 2H), 3.74– 3.52(m,4H),3.31(dt,J=3.1,1.6Hz,1H),3.07(d,J=8.8Hz,2H),2.52(s,2H),2.38(d,J=8.2Hz,2H ), 1.77(dd, J＝35.4, 6.3Hz, 4H), 1.44-1.27(m, 2H), 0.63(dt, J＝7.8, 4.6Hz, 3H), 0.56-0.39(m, 2H), 0.31( td, J = 7.6, 4.1 Hz, 1H).

Example 3: Compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-( Synthesis of (3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)naphthalene-2-ol

For the detailed synthesis steps of Example 3, refer to Example 1. ESI-MS m/z: 587.3 [M+H] ⁺ .

Example 4: Compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-( Synthesis of (2-methylpyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)naphthalene-2-ol

For the detailed synthesis steps of Example 4, refer to Example 1. ESI-MS m/z: 569.3 [M+H] ⁺ .

Example 5: Compound 4-(2-((1-((1-oxo-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-4- ((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2- Alcohol synthesis

For the detailed synthesis steps of Example 5, refer to Example 1. ESI-MS m/z: 611.3 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO) δ9.96(s, 1H), 9.16(s, 1H), 7.80(d, J=8.2Hz, 1H), 7.56(d, J=8.6Hz, 1H), 7.44( t,J=7.5Hz,1H),7.29(d,J=2.2Hz,1H),7.25(d,J=7.1Hz,1H),7.22(d,J=2.4Hz,1H),5.47(s, 1H), 4.46(d, J=7.2Hz, 4H), 3.67-3.52(m, 4H), 3.30(s, 2H), 2.88(s, 2H), 2.52(s, 2H), 2.43(t, J =6.3Hz,2H),2.31(s,2H),2.11(s,2H),1.64(s,4H),1.24(s,2H),0.40(t,J=4.8Hz,2H),0.21(t , J=4.8Hz, 2H).

Example 6: Compound 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-2-((1-((ethyl(2 ,2,2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalene Synthesis of -2-ol

For the detailed synthesis steps of Example 6, refer to Example 1. ESI-MS m/z: 663.2 [M+H] ⁺ .

Example 7: Compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((3-(two Synthesis of Fluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol

For the detailed synthesis steps of Example 7, refer to Example 1. ESI-MS m/z: 619.3 [M+H] ⁺ .

Example 8: Compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-( Synthesis of (4-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol

For the detailed synthesis steps of Example 8, refer to Example 1. ESI-MS m/z: 611.3 [M+H] ⁺ . ¹ H NMR (500MHz, MeOD) δ9.08(s, 1H), 7.84(d, J=7.5Hz, 1H), 7.52(dd, J=7.1, 1.0Hz, 1H), 7.41(dd, J=8.1 ,7.3Hz,1H),7.35(d,J=2.5Hz,1H),7.16(d,J=2.5Hz,1H),5.06-4.87(m,2H),4.84-4.82(m,4H),4.51 (s,2H),4.29-4.27(m,2H),3.99-3.92(m,2H),3.92-3.75(m,2H),3.40-3.30(m,2H),3.29-3.16(m,2H) ,3.04(s,1H),2.24-2.21(m,2H),2.17-1.93(m,3H).

Example 9: Compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-( Synthesis of (R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol

For the detailed synthesis steps of Example 9, refer to Example 1. ESI-MS m/z: 573.3 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ8.84(s, 1H), 7.56(dd, J=17.7, 8.2Hz, 2H), 7.34-7.22(m, 2H), 7.21-7.04(m, 2H), 5.10(d, J=56.0Hz, 1H), 4.44-4.24(m, 4H), 3.46(d, J=19.6Hz, 3H), 3.34(t, J=17.3Hz, 2H), 2.93-2.71(m ,3H),2.63(d,J=12.5Hz,1H),2.49(dd,J=16.8,10.4Hz,2H),2.02(dddt,J=30.1,21.1,13.9,7.0Hz,2H),1.75- 1.49 (m, 4H), 0.63 (d, J=19.7Hz, 2H), 0.46 (s, 2H).

Example 10: Compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((4,4- Synthesis of difluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol

For the detailed synthesis steps of Example 10, refer to Example 1. ESI-MS m/z: 605.3 [M+H] ⁺ .

Example 11: Compound 4-(2-((1-((7-azabicyclo[2.2.1]hept-7-yl)methyl)cyclopropyl)methoxy)-4-((1R, Synthesis of 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol

For the detailed synthesis steps of Example 11, refer to Example 1. ESI-MS m/z: 581.3 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO) δ9.22(s, 1H), 8.25(s, 1H), 7.84(d, J=8.3Hz, 1H), 7.58(d, J=8.4Hz, 1H), 7.48( t,J=7.5Hz,1H),7.33(d,J=2.2Hz,1H),7.31-7.24(m,2H),4.55(d,J=12.1Hz,2H),4.40(s,2H), 3.78-3.69(m,4H),2.65(s,2H),1.76(s,8H),1.40(d,J＝7.1Hz,4H),1.27(s,2H),0.71(s,2H),0.60 (s,2H).

Example 12: Compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((6,6- Difluoro-3-azabicyclo[3.1.0]hex-3-yl)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene- Synthesis of 2-alcohols

For the detailed synthesis steps of Example 12, refer to Example 1. ESI-MS m/z: 603.3 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO) δ9.96(s, 1H), 9.16(s, 1H), 7.80(d, J=8.2Hz, 1H), 7.55(d, J=8.3Hz, 1H), 7.44( t,J=7.5Hz,1H),7.29(d,J=2.3Hz,1H),7.25(d,J=7.2Hz,1H),7.22(d,J=2.4Hz,1H),4.46(d, J＝11.8Hz, 2H), 4.25(s, 2H), 3.66-3.54(m, 4H), 3.05-2.98(m, 2H), 2.76(d, J＝9.2Hz, 2H), 2.43(s, 2H ),2.28(d,J=13.2Hz,2H),1.66(s,4H),1.24(s,1H),0.61(t,J=5.0Hz,2H),0.42(t,J=5.0Hz,2H ).

Example 13: Compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(( Synthesis of 3-(trifluoromethyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol

For the detailed synthesis steps of Example 13, refer to Example 1. ESI-MS m/z: 567.3 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO) δ9.97(s, 1H), 9.16(s, 1H), 7.80(d, J=8.3Hz, 1H), 7.55(d, J=8.3Hz, 1H), 7.44( t, J=7.5Hz, 1H), 7.29(d, J=2.1Hz, 1H), 7.24(d, J=7.3Hz, 1H), 7.22(d, J=2.4Hz, 1H), 4.45(d, J＝12.5Hz, 2H), 4.36(d, J＝10.8Hz, 1H), 4.20(d, J＝10.8Hz, 1H), 3.65-3.50(m, 4H), 3.10-2.95(m, 1H), 2.76(t, J=9.2Hz, 1H), 2.62-2.51(m, 4H), 2.31(d, J=12.3Hz, 1H), 2.04-1.90(m, 1H), 1.72(dd, J=13.0, 6.8Hz, 1H), 1.64(s, 4H), 1.23(s, 1H), 0.69-0.56(m, 2H), 0.48-0.38(m, 2H).

Example 14: Compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-( Synthesis of piperidin-1-ylmethyl)cyclopropyl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)naphthalene-2-ol

For the detailed synthesis steps of Example 14, refer to Example 1. ESI-MS m/z: 569.3 [M+H] ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) δ9.99(s, 1H), 9.17(s, 1H), 7.80(d, J=8.2Hz, 1H), 7.54(d, J=8.3Hz, 1H), 7.45 -42(m,1H),7.29(s,1H),7.27-7.19(m,2H),4.52-4.49(m,2H),4.31(s,2H),3.75-3.64(m,4H),2.44 -2.25 (m, 5H), 2.07-1.88 (m, 1H), 1.77-1.72 (m, 4H), 1.47-1.23 (d, 6H).

Examples 3-14 were synthesized with reference to the steps of Example 1. After the corresponding alcohol and intermediate M underwent a substitution reaction, they were subjected to Suzuki coupling with a borate ester, and then the TBS protecting group and Boc protecting group were removed to obtain the target product.

The corresponding synthetic intermediates are as follows:

The following examples are synthesized using the above method, or using a similar method using the corresponding intermediates.

Example 15: ¹ H NMR (500MHz, DMSO) δ9.21(s, 1H), 8.16(s, 1H), 7.81(d, J=8.3Hz, 1H), 7.54(d, J=8.4Hz, 1H ), 7.44(t, J=7.5Hz, 1H), 7.30(d, J=2.0Hz, 1H), 7.26-7.21(m, 2H), 4.64(d, J=13.1Hz, 2H), 4.34(dd ,J=21.7,10.6Hz,2H),4.11(s,2H),3.84(t,J=11.6Hz,4H),3.74(s,1H),3.54(d,J=7.6Hz,1H),2.93 (d,J=9.9Hz,1H),2.80(d,J=12.7Hz,1H),2.69-2.56(m,2H),1.91(s,4H),1.78(d,J=9.7Hz,1H) , 1.63 (d, J=9.5Hz, 1H), 0.64 (d, J=13.7Hz, 2H), 0.57 (d, J=9.7Hz, 1H), 0.49 (d, J=9.1Hz, 1H).

Example 16: ¹ H NMR (500MHz, CDCl ₃ ) δ8.89(s, 1H), 7.32(d, J=8.3Hz, 1H), 7.21(td, J=7.9, 5.2Hz, 1H), 7.16( s,1H),7.10(s,1H),6.81(dd,J=12.7,7.6Hz,1H),4.52(d,J=11.9Hz,1H),4.35(d,J=11.6Hz,1H), 4.29(s,2H),3.59(s,3H),3.48-3.37(m,1H),3.02(dd,J=8.4,4.7Hz,2H),2.43(d,J=12.7Hz,2H),2.27 (d,J=7.9Hz,2H),1.83-1.61(m,4H),1.31-1.19(m,2H),0.64(t,J=9.3Hz,1H),0.56(d,J=20.3Hz, 2H), 0.42 (d, J=20.2Hz, 2H), 0.23 (td, J=7.6, 4.0Hz, 1H).

Example 17: ¹ H NMR (500MHz, MeOD) δ9.04(s, 1H), 8.47(s, 1H), 7.83(d, J=8.2Hz, 1H), 7.51(d, J=7.0Hz, 1H ),7.44-7.38(m,1H),7.34(d,J=2.5Hz,1H),7.16(d,J=2.5Hz,1H),4.70(dd,J=26.3,13.2Hz,2H),4.48 (d,J=11.6Hz,1H),4.38(d,J=11.6Hz,1H),4.00(s,2H),3.90-3.79(m,2H),3.54(s,2H),3.12(s, 2H),3.04(s,1H),2.10-1.92(m,4H),1.73(s,2H),1.39-1.24(m,2H),0.86(dd,J＝12.5,6.8Hz,2H),0.76 (s,4H).

Pharmacological experiment

Pharmacological Experiment 1: Cell Proliferation Assay (AGS)

CRL-1739^TM)按1×10³/孔的细胞密度铺于低吸附96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓度20000、6666.67、2222.22、740.74、246.91、82.30、27.43、9.14、3.05、0nM(DMSO终浓度均为0.5％)加入96孔板中，37℃培养96h后向各孔加入50μL Cell-titer GLO工作液，震荡混匀后室温孵育10min，在多功能酶标仪读取Luminescence发光值，将发光值数据计算转换为抑制百分数。并根据以下公式，计算细胞增殖抑制百分数：The KRas-G12D mutant tumor cell AGS (

CRL-1739 ^TM ) were spread in a low-adsorption 96-well plate at a cell density of 1×10 ³ /well, and placed in a cell culture incubator for overnight culture. After the cells adhered to the wall, the compounds to be tested were added to the 96-well plate at the final concentrations of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, and 0 nM (the final concentration of DMSO was 0.5%), and incubated at 37 °C After 96 hours, add 50 μL of Cell-titer GLO working solution to each well, shake and mix well, and incubate at room temperature for 10 minutes. Read the Luminescence luminescence value on a multi-functional microplate reader, and convert the luminescence value data into inhibition percentage. And according to the following formula, calculate the percentage of inhibition of cell proliferation:

Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100

(“Maximum” from 0.1% DMSO control wells, “Blank” from blank control wells, “measured” from compound treated wells).

Curve fitting was performed using GraphPad Prism software and _IC50 values were obtained.

Table 1

Pharmacological Experiment 2: Cell Proliferation Experiment (NCI-H1975)

CRL-5908^TM)按1×10³/孔的细胞密度铺于低吸附96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓度20000、6666.67、2222.22、740.74、246.91、82.30、27.43、9.14、3.05、0nM(DMSO终浓度均为0.5％)加入96孔板中，37℃培养96h后向各孔加入50μL Cell-titer GLO工作液，震荡混匀后室温孵育10min，在多功能酶标仪读取Luminescence发光值，将发光值数据计算转换为抑制百分数。并根据以下公式，计算细胞增殖抑制百分数：The KRas-WT tumor cell NCI-H1975 (

CRL-5908 ^TM ) were spread in a low-adsorption 96-well plate at a cell density of 1×10 ³ /well, and placed in a cell culture incubator for overnight culture. After the cells adhered to the wall, the compounds to be tested were added to the 96-well plate at the final concentrations of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, and 0 nM (the final concentration of DMSO was 0.5%), and incubated at 37 °C After 96 hours, add 50 μL of Cell-titer GLO working solution to each well, shake and mix well, and incubate at room temperature for 10 minutes. Read the Luminescence luminescence value on a multi-functional microplate reader, and convert the luminescence value data into inhibition percentage. And according to the following formula, calculate the percentage of inhibition of cell proliferation:

Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100

(“Maximum” from 0.1% DMSO control wells, “Blank” from blank control wells, “measured” from compound treated wells).

Curve fitting was performed using GraphPad Prism software and _IC50 values were obtained.

Table 2

Pharmacological experiment 3: Cell p-ERK detection test

CRL-1739^TM)或Panc 04.03(

CRL-2555^TM)按5×10⁴/孔的细胞密度铺于96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓度10000nM、3333nM、1111nM、370.4nM、123.4nM、41.15nM、13.72nM、4.57nM、1.52nM、0.51nM、0.1％DMSO加入96孔板中，培养3h后，利用MSD(Meso Scale Discovery)电化学发光免疫检测试剂盒中的lysis buffer(50μL)提取96孔板中各处理细胞样品的蛋白裂解液，利用BCA方法对蛋白裂解液进行定量，并利用lysisbuffer将蛋白样品浓度稀释为0.1μg/μL。向MSD检测96孔板中加入25ul/孔的蛋白稀释液，室温孵育3h后加入25μL detection antibody solution，继续室温孵育1h，洗板后加入150μL 1×read buffer T。在SECTOR Imager上进行孔板读值，采集原始数据。Two kinds of KRas-G12D mutant tumor cells AGS (

CRL-1739 ^TM ) or Panc 04.03 (

CRL-2555 ^TM ) were plated in a 96-well plate at a cell density of 5×10 ⁴ /well, and placed in a cell culture incubator for overnight culture. After the cells adhered to the wall, the compounds to be tested were added to the 96-well plate according to the final concentration of 10000nM, 3333nM, 1111nM, 370.4nM, 123.4nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM, 0.51nM, 0.1% DMSO, and incubated After 3 hours, use the lysis buffer (50 μL) in the MSD (Meso Scale Discovery) electrochemiluminescence immunoassay kit to extract the protein lysate of each treated cell sample in the 96-well plate, use the BCA method to quantify the protein lysate, and use The lysisbuffer dilutes the protein sample concentration to 0.1μg/μL. Add 25ul/well protein diluent to the MSD detection 96-well plate, incubate at room temperature for 3h, add 25μL detection antibody solution, continue to incubate at room temperature for 1h, add 150μL 1×read buffer T after washing the plate. Plate readings were performed on a SECTOR Imager to acquire raw data.

Convert the readings to p-ERK% values according to the formula in the MSD assay method:

p-ERK% value=((2×phosphorylation signal value)/(phosphorylation signal value+total signal value))×100

Calculate the percent inhibition of p-ERK according to the following formula:

Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100

(“Maximum” from 0.1% DMSO control wells, “Blank” from blank control wells, “measured” from compound treated wells).

Curve fitting was performed using GraphPad Prism software and _IC50 values were obtained.

table 3

While the invention has been fully described by way of the embodiments thereof, it is to be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should all be included within the scope of the appended claims of the present invention.

Claims (23)

1. A compound shown in general formula (I), its stereoisomers, tautomers, deuteriums or pharmaceutically acceptable salts:

in, R ₁ is independently selected from H, hydroxyl, C _1-6 alkyl, C _1-6 aminoalkyl, -N(R _a ) ₂ , -C(=NH)NH ₂ , -C(=NCH ₃ )NH _2. Carboxyl, C _1-6 carboxyalkyl, cyano, C _1-6 cyanoalkyl, halogen, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aldehyde, -CO ₂ R _a , -CO ₂ N(R _a ) ₂ , -(CH ₂ ) _0-3 C(=O)N(R _a ) ₂ , -C(=O)(CH ₂ ) _0-3 N(R _a ) ₂ or 5-6 membered heteroaryl, said R _a is independently selected from H or C _1-6 alkyl; preferably R ₁ is H; _X1 is selected from N or CH; X ₂ is selected from N or CR ₇ ; R ₂ or R ₇ are independently selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino and nitro, and the C _{1 -6} alkyl, C _1-6 alkoxy, haloalkyl or hydroxyalkyl are optionally further selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, cyano, amino, One or more substituents in nitro, hydroxy and hydroxyalkyl; Ring A is selected from C _3-6 cycloalkyl or 3-6 membered heterocyclyl; R _is independently selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, hydroxy or hydroxyalkyl; R ₄ is independently selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, -(CH ₂ ) _0-3 N(R _b ) ₂ , C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-14 aryl or 4-14 membered heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, Hydroxyalkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-14 aryl or 4-14 membered heteroaryl are optionally further selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, -(CH ₂ ) _0-3 N(R _b ) ₂ , C _3-14 cycloalkyl, 3-14 One or more substituents in heterocyclic group, C _6-14 aryl and 4-14 heteroaryl, said R _b is independently selected from H, C _1-6 alkyl or C _{1- 6} haloalkyl; L ₁ is selected from -O-(CH ₂ ) _0-3 , -S-(CH ₂ ) _0-3 , -NH-(CH ₂ ) _0-3 or alkylene, said L ₁ is optionally further One or more halogen or C _1-6 alkyl substitution; _L is selected from a bond or an alkylene group optionally further substituted by one or more halogen, C _1-6 alkyl or C _1-6 haloalkyl; _R is selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, alkoxyalkyl, C _3-14 cycloalkyl and 3-14 membered heterocyclyl; _R is selected from C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-14 aryl and 4-14 membered heteroaryl, the C _3-14 cycloalkyl, 3-14 membered heteroaryl Cyclic group, C _6-14 aryl and 4-14 membered heteroaryl are optionally further substituted by one or more R _c ; R _c is independently selected from H, =O, =S, oxo, cyano , halogen, C _1-6 alkyl, C _1-6 haloalkyl, -C _0-3 alkylene-OR _d , -OC(=O)C _1-6 alkyl, -C _0-3 alkylene -SR _d , -C _0-3 alkylene-N(R _d ) ₂ , -C _0-3 alkylene-S(=O)R _d , -C _0-3 alkylene-S(=O ) ₂ R _d , -C _0-3 alkylene-SR _d , -C _0-3 alkylene-S(R _d ) ₅ , -C _0-3 alkylene-C(=O)R _d , -C _0-3 alkylene-C(=O)OR _d , -C _0-3 alkylene-C(=O)N(R _d ) ₂ , C _2-6 alkenyl, C _2-6 alkyne Group, substituted or unsubstituted -C _0-3 alkylene-C _3-14 cycloalkyl, substituted or unsubstituted -C _0-3 alkylene-(3-14 membered heterocycloalkyl), substituted or unsubstituted -C _0-3 alkylene-C _6-14 aryl or substituted or unsubstituted -C _0-3 alkylene-(5-14 membered heteroaryl), each _R independently is H, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkyl; m, n or p are each independently selected from 0, 1, 2, 3 or 4. 2. according to the compound shown in the general formula (I) described in claim 1, its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, it is characterized in that, be selected from formula (IA) the compound shown,

in, _R1 is H; Ring A is selected from C _3-6 cycloalkyl or 3-6 membered heterocyclic group, preferably cyclopropyl; R _is independently selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, hydroxy and hydroxyalkyl; R ₄ is independently selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, -(CH ₂ ) _0-3 N(R _b ) ₂ , C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-14 aryl and 4-14 membered heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, Hydroxyalkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-14 aryl and 4-14 membered heteroaryl are optionally further selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, -(CH ₂ ) _0-3 N(R _b ) ₂ , C _3-14 cycloalkyl, 3-14 One or more substituents in heterocyclic group, C _6-14 aryl and 4-14 heteroaryl, said R _b is independently selected from H or C _1-6 alkyl; L ₁ is selected from -O-(CH ₂ ) _1-3 , said L ₁ is optionally further substituted by one or more halogen or C _1-6 alkyl; _L is selected from alkylene, which is optionally further substituted by one or more halogen or C _1-6 alkyl; _R is selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, alkoxyalkyl, C _3-14 cycloalkyl and 3-14 membered heterocyclyl; _R is selected from C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-14 aryl and 4-14 membered heteroaryl, the C _3-14 cycloalkyl, 3-14 membered heteroaryl Cyclic, C _6-14 aryl and 4-14 membered heteroaryl are optionally further substituted by one or more _R ; R _is independently selected from H, =O, =S, acyl, cyano, halogen , C _1-6 alkyl, C _1-6 haloalkyl, -C _0-3 alkylene-OR _d , -OC(=O)C _1-6 alkyl, -C _0-3 alkylene-SR _d , -C _0-3 alkylene-N(R _d ) ₂ , -C _0-3 alkylene-S(=O)R _d , -C _0-3 alkylene-S(=O) ₂ R _d , -C _0-3 alkylene-SR _d , -C _0-3 alkylene-S(R _d ) ₅ , -C _0-3 alkylene-C(=O)R _d , -C _0-3 alkylene-C(=O)OR _d , -C _0-3 alkylene-C(=O)N(R _d ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, Substituted or unsubstituted -C _0-3 alkylene -C _3-14 cycloalkyl, substituted or unsubstituted -C _0-3 alkylene -(3-14 membered heterocycloalkyl), substituted or unsubstituted Substituted -C _0-3 alkylene -C _6-14 aryl or substituted or unsubstituted -C _0-3 alkylene -(5-14 membered heteroaryl), each R _d is independently H , C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkyl; p is selected from 0, 1, 2, 3 or 4. 3. The compound represented by general formula (I) according to claim 1 or 2, its stereoisomers, tautomers, deuteriums or pharmaceutically acceptable salts, characterized in that R _is selected from H. 4. according to the compound shown in the general formula (I) described in any one of claim 1-3, its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, it is characterized in that, R _Selected From H, cyano or C _1-6 alkyl. 5. according to the compound shown in the general formula (I) described in any one of claim 1-4, its stereoisomer, tautomer, deuterium or medicinal salt, it is characterized in that, R _Selected From H or C _1-6 alkyl. 6. according to the compound shown in the general formula (I) described in any one of claim 1-5, its stereoisomer, tautomer, deuterated substance or medicinal salt, it is characterized in that, X _is selected from Since N. 7. according to the compound shown in the general formula (I) described in any one of claim 1-6, its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, it is characterized in that, X ₂ is selected from Since N. 8. according to the compound shown in the general formula (I) described in any one of claim 1-7, its stereoisomer, tautomer, deuterium or medicinal salt, it is characterized in that, R _Selected From C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-14 aryl or 4-14 membered heteroaryl, the C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-14 aryl or 4-14 membered heteroaryl is optionally further substituted by one or more substituents selected from halogen, C _1-6 alkyl, haloalkyl, and cyano. 9. according to the compound shown in the general formula (I) described in any one of claim 1-8, its stereoisomer, tautomer, deuterated substance or medicinal salt, it is characterized in that, L _is selected from From —O—(CH ₂ ) _1-3 , said L ₁ is optionally further substituted by one or more halogen or C _1-6 alkyl. 10. according to the compound shown in the general formula (I) described in any one of claim 1-9, its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, it is characterized in that, p is selected from 0 or 1. 11. according to the compound shown in the general formula (I) described in any one of claim 1-10, its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, it is characterized in that,

selected from

12. according to the compound shown in the general formula (I) described in any one of claim 1-11, its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, it is characterized in that, R _is selected from From halogen, C _1-6 alkyl or C _1-6 alkoxy, preferably F. 13. according to the compound shown in the general formula (I) described in any one of claim 1-12, its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, it is characterized in that, R _Selected since

14. A compound, its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, characterized in that the compound is selected from: 1) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((3-methyl (Piperidin-1-yl)methyl)cyclopropyl)methoxy)pyridinyl[4,3-d]pyrimidin-7-yl)naphthalene-2-ol; 2) 4-(2-((1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol; 3) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-((3- Haloperidin-1-yl)methyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)naphthalene-2-ol; 4) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-((2- Methylpyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)naphthalene-2-ol; 5) 4-(2-((1-((1-oxo-7-azaspiro[3.5]non-7-yl)methyl)cyclopropyl)methoxy)-4-((1R , 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol; 6) 190) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2, 2,2-Trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalene- 2-alcohol; 7) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((3-(difluoromethyl )piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol; 8) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-((4- Haloperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol; 9) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-((R) -3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol; 10) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((4,4-difluoropiper Pyridin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol; 11) 4-(2-((1-((7-azabicyclo[2.2.1]hept-7-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)- 3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol; 12) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((6,6-difluoro- 3-Azabicyclo[3.1.0]hex-3-yl)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol ; 13) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((3-( Trifluoromethyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol; 14) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)naphthalene-2-ol; 15) 4-(2-((1-((2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methoxy)-4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalene-2-ol; 16) 4-(2-((1-((3-azabicyclo[3.1.0]hex-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)- 3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol; 17) 4-(2-((1-((3-azabicyclo[3.1.0]hex-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)- 3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol; 18) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine Base) cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol; 19) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine Base)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 20) 4-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)morpholine 21) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol; 22) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 23) 4-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl- 7-fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine; 24) 4-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-3 -Hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1-dioxide ; 25) 4-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)1,1-disulfide phylloline; 26) 4-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1-dioxide ; 27) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine base) cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2-ol; 28) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine base) cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol; 29) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine Base) cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 30) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 31) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol; 32) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 33) 4-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-3 -Hydroxynaphthalene-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1-dioxide thing; 34) 4-((1-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(8- Fluoro-3-hydroxynaphthalen-1-yl)pyridyl[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1-dioxide ; 35) 4-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(7,8-two Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1- Dioxide; 36) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine Base)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 37) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine base)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol; 38) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine Base) cyclopropyl) methoxy) pyridin [4,3-d] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol; 39) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 40) 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol; 41) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol; 42) 4-((1-((4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7- Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1- Dioxide; 43) 4-((1-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(7- Fluoro-3-hydroxy-8-methylnaphthalen-1-yl)pyridyl[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1, 1-dioxide; 44) 4-((1-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(3-chloro-2- Cyclopropyl-5-hydroxyphenyl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1-di oxide; 45) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine base) cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloronaphthalene-2-ol; 46) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholine base)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol; 47) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloronaphth-2-ol; 48) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(thiomorpholine Methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol; 49) 4-((1-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-chloro-3- Hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)thiomorpholine 1,1-dioxide; 50) 4-((1-((4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-7-(8-chloro-7-fluoro -3-Hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)methyl)thiomorpholine 1,1-dioxide; 51) 4-(2-((1-((3-azabicyclo[3.1.0]hex-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)- 3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-alcohol; 52) 2-((1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)-3, 8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyridino[4,3-d]pyrimidine ; 53) 4-(2-((1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2-ol ; 54) 4-(2-((1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalene- 2-alcohol; 55) 4-(2-((1-((3-azabicyclo[3.1.0]hex-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)- 3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2- alcohol; 56) 4-(2-((1-((3-azabicyclo[3.1.0]hexaazol-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene- 2-alcohol; 57) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(pyrrolidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol; 58) 3-(2-((1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropyl phenol; 59) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxygen heterocycle-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol; 60) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxygen heterocycle-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 61) 4-((3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxan-3-yl)methyl)morpholine; 62) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxoalkane-3-yl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol; 63) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxolan-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 64) 4-((3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxetan-3-yl)methyl)thiomorpholine; 65) 4-((3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-3 -Hydroxynaphthalene-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxetan-3-yl)methyl)thiomorpholine 1 ,1-dioxide; 66) 4-((3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxan-3-yl)methyl)sulfur Morpholine 1,1-dioxide; 67) 4-((3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7 -Fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxan-3-yl)methyl)1,1-di Oxythiophene; 68) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2-ol; 69) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol; 70) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 71) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 72) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxoalkane-3-yl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol; 73) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxoalkane-3-yl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 74) 4-((3-((4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-7-(8-ethyl-3- Hydroxynaphthalene-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxan-3-yl)methyl)thiomorpholine 1,1-di oxide; 75) 4-((3-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(8- Fluoro-3-hydroxynaphthalen-1-yl)pyridyl[4,3-d]pyrimidin-2-yl)oxy)methyl)oxolan-3-yl)methyl)thiomorpholine 1 ,1-dioxide; 76) 4-((3-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(7,8-difluoro -3-Hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxolan-3-yl)methyl)thiomorph Phenyl 1,1-dioxide; 77) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 78) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol; 79) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxygen heterocycle-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol; 80) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxetan-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 81) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxa-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol; 82) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxoalk-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol; 83) 4-((3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7 -Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxolan-3-yl)methyl)thio Morpholine 1,1-dioxide; 84) 4-((3-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(7- Fluoro-3-hydroxy-8-methylnaphthalen-1-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxan-3-yl)methyl)sulfur Morpholine 1,1-dioxide; 85) 4-((3-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(3-chloro-2- Cyclopropyl-5-hydroxyphenyl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxolan-3-yl)methyl)1,1 - dioxythiophene; 86) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloronaphth-2-ol; 87) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(morpholine Base) oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol; 88) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxoalkane-3-yl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5-chloronaphth-2-ol; 89) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(thiomorpholine Methyl)oxolan-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol; 90) 4-((3-((4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-7-(8-chloro-3-hydroxy Naphthalene-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxan-3-yl)methyl)thiomorpholine 1,1-dioxide thing; 91) 4-((3-((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-chloro-7- Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)oxolan-3-yl)methyl)thio Morpholine 1,1-dioxide; 92) 4-(2-((3-((3-azabicyclo[3.1.0]hexaazol-3-yl)oxy)oxan-3-yl)methoxy)-4-(( 1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 - Fluorinaphth-2-ol; 93) 2-((3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)oxacyclo-3-yl)methoxy)-4-((1R, 5S )-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyridin[4,3 -d] pyrimidine; 94) 4-(2-((3-((3-azabicyclo[3.1.0]hexaazol-3-yl)methyl)oxane-3-yl)methoxy)-4-((1R , 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2 -alcohol; 95) 4-(2-((3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)oxacyclo-3-yl)methoxy)-4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6 - Fluorinaphth-2-ol; 96) 4-(2-((3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)oxacyclo-3-yl)methoxy)-4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5,6-di Fluorin-2-ol; 97) 4-(2-((3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)oxacyclo-3-yl)methoxy)-4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl- 6-fluoronaphth-2-ol; 98) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((3-(pyrrolidine- 1-ylmethyl)oxoalkane-3-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol; 99) 3-(2-((3-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)oxacyclo-3-yl)methoxy)-4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4 - cyclopropylphenol; 100) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol; 101) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 102) 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidine; 103) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalene-2-ol ; 104) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R, 5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene -2-ol; 105) 2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)-3, 8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyridino[4,3-d]pyrimidine ; 106)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbonitrile ; 107)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine- 3-carbonitrile; 108)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbonitrile ; 109) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 110) 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine-1 -ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol; 111) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 112) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R, 5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2-ol ; 113) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol; 114) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R, 5S) -3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2- alcohol; 115)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbonitrile ; 116)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7 -(8-fluoro-3-hydroxynaphthalen-1-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbonitrile; 117)(R)-1-((1-((4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-7-(7,8 -Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbon Triamine; 118) 4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-2l4-isochromene -1-yl)-8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidine; 119) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol; 120) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol; 121) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene -2-ol; 122) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalene- 2-alcohol; 123) 3-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropyl phenol; 124)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine- 3-carbonitrile; 125)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7 -(7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine- 3-carbonitrile; 126)(R)-1-((1-((4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-7-(3-chloro -2-cyclopropyl-5-hydroxyphenyl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbon Triamine; 127) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5-chloronaphth-2-ol; 128) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol; 129) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloronaphthalene-2-ol; 130) 4-(2-((1-((8-azabicyclo[3.2.1]octane-8-yl)methyl)cyclopropyl)methoxy)-4-((1R, 5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalene- 2-alcohol; 131)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Chloro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3-carbonitrile; 132)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidine-3 - carbonitrile; 133) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalene-2-ol ; 134) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene -2-ol; 135) 2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S)-3, 8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyridino[4,3-d]pyrimidine ; 136) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol; 137) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol ; 138) 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2-((1-((((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidine; 139) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2-ol ; 140) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol; 141) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2 -alcohol; 142) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 143) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol; 144) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 145) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene -2-ol; 146) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalene -2-ol; 147) 3-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropyl phenol; 148) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-((R) -3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ; 149) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol; 150) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol; 151) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloronaphthalene-2-ol; 152) 4-(2-((1-((3-azabicyclo[3.2.1]octane-3-yl)methyl)cyclopropyl)methoxy)-4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalene- 2-alcohol; 153) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphth-2-ol; 154) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol; 155) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol; 156) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol ; 157) 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2-((1-((((R)-3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidine; 158)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3-carbonitrile ; 159)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine- 3-carbonitrile; 160)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3-carbonitrile ; 161) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 162) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol; 163) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 164)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3-carbonitrile ; 165)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7 -(8-fluoro-3-hydroxynaphthalen-1-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3-carbonitrile; 166)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(7, 8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3- Carbonitrile; 167) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol ; 168) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalen-2-ol ; 169) 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol; 170)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine- 3-carbonitrile; 171)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7 -(7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine- 3-carbonitrile; 172)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(3- Chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3- Carbonitrile; 173) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphth-2-ol; 174) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((R)- 3-methylpiperidin-1-yl)methyl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalen-2-ol; 175)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Chloro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3-carbonitrile; 176)(R)-1-((1-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8- Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-3 - carbonitrile; 177) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((ethyl(2,2 ,2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol; 178) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2,2, 2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -alcohol; 179)N-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl- 7-fluoronaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-N-ethyl-2,2, 2-trifluoro-1-amine; 180) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(pyrrolidine- 1-yl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol; 181) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(pyrrolidine- 1-yl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 182) 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2-((1-(pyrrolidin-1-yl)cyclopropyl)methoxy)pyridin[4,3-d]pyrimidine; 183)4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2,2, 2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 184) 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2,2, 2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol; 185)4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2,2, 2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol ; 186)4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((ethyl(2,2 ,2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene- 2-alcohol; 187)4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((1-((ethyl(2,2 ,2-Trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-methylnaphthalene- 2-alcohol; 188)3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2,2, 2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol; 189)4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((ethyl(2,2, 2-trifluoroethyl)amino)methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-chloronaphthalen-2-ol. 15. A pharmaceutical composition, characterized in that, the pharmaceutical composition contains a therapeutically effective dose of the compound described in any one of claims 1-14, its stereoisomers, tautomers, deuterated Or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable auxiliary material. 16. The compound described in any one of claims 1-14, its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt or the application of the pharmaceutical composition described in claim 15 in the preparation of medicine . 17. The application according to claim 16, characterized in that the preparation of the medicament is an application in the preparation of a medicament for the treatment and/or prevention of diseases mediated by KRAS G12D. 18. The use according to claim 17, wherein the disease is selected from cancer. 19. The application according to claim 18, wherein the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small Cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid Carcinoma, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma. 20. A method for treating and/or preventing diseases, comprising administering a therapeutically effective amount of the compound, its stereoisomers, tautomers, and deuteriums according to any one of claims 1-14 to the subject Or pharmaceutically acceptable salt or the pharmaceutical composition described in claim 15. 21. The method according to claim 20, characterized in that the disease to be treated and/or prevented is a disease mediated by KRASG12D. 22. The method of claim 21, wherein the disease is selected from cancer. 23. The method according to claim 22, wherein the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small Cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid Carcinoma, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.