CN115368382A - KRAS G12D inhibitor and application thereof in medicines - Google Patents

KRAS G12D inhibitor and application thereof in medicines Download PDF

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Publication number
CN115368382A
CN115368382A CN202210549066.0A CN202210549066A CN115368382A CN 115368382 A CN115368382 A CN 115368382A CN 202210549066 A CN202210549066 A CN 202210549066A CN 115368382 A CN115368382 A CN 115368382A
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pyrimidin
octan
methyl
diazabicyclo
cyclopropyl
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吴颢
陈小平
路渊
徐人奇
何将旗
王维
李波燕
湛波
王冬
王国建
兰宏
王家炳
丁列明
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Betta Pharmaceuticals Co Ltd
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Betta Pharmaceuticals Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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 application thereof in medicines
Technical Field
The present invention relates to novel compounds having KRAS inhibitory activity, in particular KRAS G12D inhibitory activity. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.
Background
Clinical data show that RAS is the gene with the highest mutation rate in human tumors, and RAS gene mutations are present in about 20-30% of all tumors, about 98% of pancreatic cancers, 52% of colon cancers, 43% of multiple myelomas, and 32% of lung adenocarcinomas. The most common mode of mutation in RAS is a point mutation, often occurring at codon 12, 13, 61, with mutations most common again at codon 12, such as G12C, G12D or G12V.
At present, drug research and development aiming at KRAS mutation is one of the current new drug research hotspots. KRAS G12C inhibitors AMG510 (WO 2018217651 A1) and MRTX849 (WO 2019099524 A1) have entered a late clinical stage; while MIRATI has advanced in the development of G12D inhibitors (WO 2021041671 A1).
Disclosure of Invention
The invention provides a compound shown as a general formula (I), a stereoisomer, a tautomer, a deuteron or a medicinal salt thereof:
Figure BDA0003653766850000011
wherein, the first and the second end of the pipe are connected with each other,
R 1 independently selected from H, hydroxy, C 1-6 Alkyl radical, C 1-6 Aminoalkyl, -N (R) a ) 2 、-C(＝NH)NH 2 、-C(＝NCH 3 )NH 2 Carboxyl group, C 1-6 Carboxyalkyl, cyano, C 1-6 Cyanoalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Aldehyde group, -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 Independently selected from H or C 1-6 An alkyl group; preferably R 1 Is H;
X 1 is selected from N or CH;
X 2 selected from N or CR 7 ；
R 2 Or R 7 Independently selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro, said C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl or hydroxyalkyl optionally further selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, and hydroxyalkyl;
ring A is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclyl;
R 3 independently selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxy or hydroxyalkyl;
R 4 independently selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, - (CH) 2 ) 0-3 N(R b ) 2 、C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl or 4-14 membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxyalkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl or 4-14 membered heteroaryl optionally further selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, - (CH) 2 ) 0-3 N(R b ) 2 、C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl, said R being substituted by one or more substituents b Independently selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
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 Optionally further substituted by one or more halogens or C 1-6 Alkyl substitution;
L 2 selected from a bond or an alkylene group, said alkylene group being optionally further substituted by one or more halogens, C 1-6 Alkyl or C 1-6 Haloalkyl substitution;
R 5 selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, C 3-14 Cycloalkyl and 3-14 membered heterocyclyl;
R 6 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl, said C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl optionally further substituted with one or more R c Substitution; r c Independently selected from H, = O, = S, oxo, cyano, halogen, C 1-6 Alkyl radical, 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 oxideradical-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 radical, C 2-6 Alkynyl, substituted or unsubstituted-C 0-3 alkylene-C 3-14 Cycloalkyl, substituted or unsubstituted-C 0-3 Alkylene- (3-to 14-membered heterocycloalkyl), substituted or unsubstituted-C 0-3 alkylene-C 6-14 Aryl or substituted or unsubstituted-C 0-3 Alkylene- (5-to 14-membered heteroaryl), each R d Independently H, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or C 1-6 A haloalkyl group;
m, n or p are each independently selected from 0, 1,2, 3 or 4.
In some embodiments, formula (I) is selected from compounds of formula (IA),
Figure BDA0003653766850000031
wherein the content of the first and second substances,
R 1 is H;
ring A is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, preferably cyclopropyl;
R 3 independently selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxy, and hydroxyalkyl;
R 4 independently selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, - (CH) 2 ) 0-3 N(R b ) 2 、C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxyalkyl, C 3-14 A cycloalkyl group, a,3-14 membered heterocyclic group, C 6-14 Aryl and 4-14 membered heteroaryl optionally further selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, - (CH) 2 ) 0-3 N(R b ) 2 、C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl, said R being substituted by one or more substituents b Independently selected from H or C 1-6 An alkyl group;
L 1 is selected from-O- (CH) 2 ) 1-3 Said L is 1 Optionally further substituted by one or more halogens or C 1-6 Alkyl substitution;
L 2 selected from alkylene, said alkylene optionally further substituted by one or more halogens or C 1-6 Alkyl substitution;
R 5 selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, C 3-14 Cycloalkyl and 3-14 membered heterocyclyl;
R 6 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl, said C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl optionally further substituted with one or more R c Substitution; r c Independently selected from H, = O, = S, acyl, cyano, halogen, C 1-6 Alkyl radical, 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 radical, C 2-6 Alkynyl, substituted or unsubstituted-C 0-3 alkylene-C 3-14 Cycloalkyl, substituted or unsubstituted-C 0-3 Alkylene- (3-to 14-membered heterocycloalkyl), substituted or unsubstituted-C 0-3 alkylene-C 6-14 Aryl or substituted or unsubstituted-C 0-3 Alkylene- (5-to 14-membered heteroaryl), each R d Independently H, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or C 1-6 A haloalkyl group;
p is selected from 0, 1,2, 3 or 4.
In some embodiments, R in formula (I) 1 Is selected from H.
In some embodiments, R in formula (I) 2 Selected from H, cyano or C 1-6 An alkyl group.
In some embodiments, R in formula (I) 3 Is selected from H or C 1-6 Alkyl radical
In some embodiments, X in formula (I) 1 Is selected from N.
In some embodiments, X in formula (I) 2 Is selected from N.
In some embodiments, R in formula (I) 4 Is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl or 4-14 membered heteroaryl, said C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl or 4-14 membered heteroaryl optionally further selected from halogen, C 1-6 Alkyl, haloalkyl, cyano, or a combination thereof.
In some embodiments, L in formula (I) 1 Is selected from-O- (CH) 2 ) 1-3 Said L is 1 Optionally further substituted by one or more halogens or C 1-6 Alkyl substitution.
In some embodiments, p in formula (I) is selected from 0 or 1.
In some embodiments, of formula (I)
Figure BDA0003653766850000041
Is selected from
Figure BDA0003653766850000042
Figure BDA0003653766850000043
In some embodiments, R in formula (I) 5 Selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, preferably F.
In some embodiments, R in formula (I) 6 Is selected from
Figure BDA0003653766850000051
Figure BDA0003653766850000052
In some embodiments, the compound of formula (I) is selected from:
1) 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((1- ((3-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol;
2) 4- (2- ((1- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol;
3) 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((3-fluoropiperidin-1-yl) methyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol;
4) 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((2-methylpyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-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-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol;
6) 190) 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- ((ethyl (2, 2-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
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-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol;
8) 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((4-fluoropiperidin-1-yl) methyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
9) 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol;
10 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- ((4, 4-difluoropiperidin-1-yl) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-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] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-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) naphthalen-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) naphthalen-2-ol;
14 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-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-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-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] octan-3-yl) -8-fluoropyridine [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] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
18 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
19 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) 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] octan-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] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
22 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) 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] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) thiomorpholine;
24 4- ((1- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-3-hydroxynaphthalen-1-yl) -8-fluoropyrid [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] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) 1, 1-dithiomorpholine;
26 4- ((1- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-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] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
28 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
29 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) 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] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
31 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
32 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) 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] octan-3-yl) -7- (8-ethyl-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) thiomorpholine 1, 1-dioxide;
34 4- ((1- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) pyridinyl [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] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) 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] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) 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] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
39 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
40 4- (4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
41 3- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
42 4- ((1- ((4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl) pyridinyl [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] octan-3-yl) -7- (3-chloro-2-cyclopropyl-5-hydroxyphenyl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) thiomorpholine 1, 1-dioxide;
45 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
46 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) 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] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
48 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
49 4- ((1- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-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] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) 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] octan-3-yl) -8-fluoropyridin [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
52 2- ((1- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidine;
53 4- (2- ((1- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
54 4- (2- ((1- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
55 4- (2- ((1- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
56 4- (2- ((1- ((3-azabicyclo [3.1.0] hexaazen-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoropyridin [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
57 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
58 3- (2- ((1- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
59 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxetan-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
60 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxetan-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
61 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-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] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxoalk-3-yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
63 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxolane-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
64 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-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] octan-3-yl) -7- (8-ethynyl-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxirane-3-yl) methyl) thiomorpholine 1, 1-dioxide;
66 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxetan-3-yl) methyl) thiomorpholine 1, 1-dioxide;
67 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridin [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxetan-3-yl) methyl) 1, 1-dioxythiophene;
68 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
69 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
70 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
71 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
72 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxoalk-3-yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
73 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxoalk-3-yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
74 4- ((3- ((4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -7- (8-ethyl-3-hydroxynaphthalen-1-yl) -8-fluoropyridin [4,3-d ] pyrimidin-2-yl) oxy) methyl) tauro-3-yl) methyl) thiomorpholine 1, 1-dioxide;
75 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) pyridinyl [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxocyclopent-3-yl) methyl) thiomorpholine 1, 1-dioxide;
76 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxocyclopent-3-yl) methyl) thiomorpholine 1, 1-dioxide;
77 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
78 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
79 3- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxan-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
80 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxetan-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
81 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxa-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
82 3- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
83 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxocyclopent-3-yl) methyl) thiomorpholine 1, 1-dioxide;
84 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl) pyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxirane-3-yl) methyl) thiomorpholine 1, 1-dioxide;
85 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-2-cyclopropyl-5-hydroxyphenyl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxolane-3-yl) methyl) 1, 1-dioxythiophene;
86 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
87 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
88 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxoalk-3-yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
89 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxolane-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
90 4- ((3- ((4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -7- (8-chloro-3-hydroxynaphthalen-1-yl) -8-fluoropyridin [4,3-d ] pyrimidin-2-yl) oxy) methyl) tauro-3-yl) methyl) thiomorpholine 1, 1-dioxide;
91 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxocyclopent-3-yl) methyl) thiomorpholine 1, 1-dioxide;
92 4- (2- ((3- ((3-azabicyclo [3.1.0] hexanitro-3-yl) oxy) pyrrolidin-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
93 2- ((3- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) oxetan-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridin [4,3-d ] pyrimidine;
94 4- (2- ((3- ((3-azabicyclo [3.1.0] hexa-aza-3-yl) methyl) pyrrolidin-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
95 4- (2- ((3- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) oxetan-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridin [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
96 4- (2- ((3- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) oxetan-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridin [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
97 4- (2- ((3- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) oxetan-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridin [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
98 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (pyrrolidin-1-ylmethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
99 3- (2- ((3- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) oxa-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
100 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
101 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
102 4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidine;
103 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
104 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
105 2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidine;
106 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) pyrrolidine-3-carbonitrile;
109 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
110 4- (4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
111 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
112 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
113 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
114 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
115 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) pyridine [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] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) pyrrolidine-3-carbotriamine;
118 4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-2 l 4-isochromen-1-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidine;
119 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
120 3- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
121 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
122 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
123 3- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
124 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl) pyridine [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] octan-3-yl) -7- (3-chloro-2-cyclopropyl-5-hydroxyphenyl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) pyrrolidine-3-carbotriamine;
127 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
128 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
129 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
130 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
131 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) pyrrolidine-3-carbonitrile;
133 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
134 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
135 2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [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) pyridine [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] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((1- ((((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidine;
139 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
140 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
141 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
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) pyridinyl [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
145 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
146 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
147 3- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
148 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyridine [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) pyridine [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) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
151 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
152 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
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-chloronaphthalen-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) pyridine [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) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
157 4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((1- ((((R) -3-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidine;
158 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) piperidine-3-carbo-nitrile;
160 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [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) pyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
164 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) pyridine [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] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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) pyridine [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) pyridine [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) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
170 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) piperidine-3-carbo-nitrile;
171 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl) pyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) piperidine-3-carbo-nitrile;
172 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-2-cyclopropyl-5-hydroxyphenyl) -8-fluoropyridine [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-chloronaphthalen-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) pyridine [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] octan-3-yl) -7- (8-chloro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) piperidine-3-carbo-nitrile;
176 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) piperidine-3-carbo-nitrile;
177 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ((1- ((ethyl (2, 2-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [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-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
179 N- ((1- (((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) -N-ethyl-2, 2-trifluoro-1-amine;
180 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-yl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
181 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-yl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
182 4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((1- (pyrrolidin-1-yl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidine;
183 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- ((ethyl (2, 2-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [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-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [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-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
186 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ((1- ((ethyl (2, 2-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
187 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ((1- ((ethyl (2, 2-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
188 3- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- ((ethyl (2, 2-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [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-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol.
The invention also provides a pharmaceutical composition, which is characterized by comprising a therapeutically effective amount of at least one compound shown as the formula (I), a stereoisomer, a tautomer, a deuteron or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary material.
The invention further provides a pharmaceutical composition, which is characterized in that the mass percentage of the therapeutically effective amount of at least one compound shown as the formula (I), the stereoisomer, the tautomer, the deuteron or the pharmaceutically acceptable salt thereof and the pharmaceutically acceptable auxiliary materials is 0.0001.
The invention provides an application of a compound shown as a formula (I), a stereoisomer, a tautomer, a deuteron or a medicinal salt or a medicinal composition thereof in preparing a medicament.
The invention further provides a preferable technical scheme of the application:
preferably, the application is the application in preparing a medicament for treating and/or preventing cancer.
Preferably, the use is for the manufacture of a medicament for the treatment of a disease mediated by KRAS G12D. Preferably, the 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, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatobiliary cell carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, schwann cell tumor, lung squamous cell carcinoma, lichenification keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
The present invention also provides a method for treating and/or preventing diseases, which comprises administering a therapeutically effective amount of at least any one of the compounds represented by the structural formula (I), stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing the same, to a subject.
The invention also provides a method for treating and/or preventing KRAS G12D mediated diseases, which comprises administering at least one compound shown in the structural formula (I), a stereoisomer, a tautomer, a deuteron or a medicinal salt thereof or a medicinal composition containing the compound to a treated object in a therapeutically effective amount.
The present invention also provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of at least any one of the compounds represented by structural formula (I), stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing the same.
Preferably, in the above method, the KRAS G12D mediated disease is cancer.
Unless otherwise indicated, general chemical terms used in the structural formulae have the usual meanings.
For example, the term "halogen" as used herein, unless otherwise specified, refers to fluorine, chlorine, bromine or iodine.
In the present invention, unless otherwise specified, "alkyl" includes straight or branched chain monovalent saturated hydrocarbon groups, preferably C 1-8 Alkyl, more preferably C 1-6 An alkyl group. For example, alkyl groups include 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-methylpentyl and the like. Similarly, "C 1-8 Of alkyl group " 1-8 "refers to a group comprising 1,2, 3, 4,5, 6, 7, or 8 carbon atoms arranged in a straight or branched chain.
"alkylene" means a straight or branched chain divalent saturated hydrocarbon radical, preferably C 1-8 Alkylene, more preferably C 1-6 An 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 hydroxyl groups, wherein alkyl is as defined above.
"alkoxy" means the oxygen ether form of the aforementioned straight or branched chain alkyl, i.e., -O-alkyl, preferably C 1-8 Alkoxy, more preferably C 1-6 An alkoxy group.
The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkoxy groups are as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "cyano" refers to — CN.
The term "nitro" means-NO 2 。
The term "oxo" or "oxo" means "= O".
In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition that includes "a" pharmaceutically acceptable excipient may be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.
The term "aryl", as used herein, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or fused ring aromatic group comprising carbocyclic atoms. Preferably C 6-14 Monocyclic or polycyclic aromatic ring groups of aryl groups. More preferably phenyl or naphthyl. Most preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples include, but are not limited to, benzocyclopentyl.
The term "heterocyclyl", as used herein, and unless otherwise specified, refers to an unsubstituted or substituted stabilizing ring system of carbon atoms and 1-3 heteroatoms selected from N, O and S which is a saturated or partially saturated monocyclic or polycyclic 20 cyclic hydrocarbon substituent comprising 3 to 14 carbon atoms wherein the nitrogen or sulfur heteroatom may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom to form a stable structure. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclyl group may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl.
The term "heteroaryl", in the context of the present invention, unless otherwise indicated, refers to an unsubstituted or substituted stable 5-or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-to 14-membered benzo-fused heteroaromatic ring system or polycyclic heteroaromatic ring system, which consists of carbon atoms and 1 to 4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heteroaryl group may be attached at 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, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolinyl, or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. Preferably C 3-14 Cycloalkyl radicals in which "C" is 3-14 By "it is meant that the cycloalkyl group may have 3, 4,5, 6, 7,8, 9, 10, 11, 12, 13, or 14 ring-forming atoms. Cycloalkyl groups can include monocyclic and polycyclic (e.g., 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, and the like; the cycloalkyl groups may also be fused to aryl, heterocyclyl, or heteroaryl rings, wherein the ring to which the parent structure is attached is cycloalkyl.
The term "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents, respectively. 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 radical, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl optionally further substituted with one or more R b Substitution; r b 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 radical, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-to 14-membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-to 14-membered heteroaryl), = O, = S, = CH 2 、＝CHF、＝CF 2 、＝NCH 3 Said C is 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl radicals、-C 0-6 Alkylene- (3-to 14-membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-to 14-membered heteroaryl) optionally may be further substituted by 1 or more R a And (4) substituting. Each R a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl group, 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, isobutoxy, tert-butoxy, -SCH 3 、-SC 2 H 5 Formaldehyde group, -C (OCH) 3 ) Cyano, nitro, -CF 3 、-OCF 3 Amino, dimethylamino, 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, dioxolanylmethyl, and piperazinylmethyl.
Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2, 3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.
The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
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 salts of aluminum, ammonium, calcium, copper (high and low), ferric, ferrous, lithium, magnesium, manganese (high and low), potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Non-toxic organic bases which can be derivatized to form pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compounds provided by the present invention are bases, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, oxalic, propionic, glycolic, hydroiodic, perchloric, cyclohexanesulfonic, salicylic, 2-naphthalenesulfonic, saccharinic, trifluoroacetic, tartaric, and p-toluenesulfonic acids and the like. Preferably citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. More preferably formic acid and hydrochloric acid.
Since the compounds of formula (I) are intended for pharmaceutical use, it is preferred to use them in a certain purity, for example, at least 60% pure, more suitably at least 75% pure, and especially at least 98% pure (% by weight).
Prodrugs of the compounds of the present invention are included within the scope of the invention. In general, the prodrug refers to a functional derivative that is readily converted in vivo to the desired compound. For example, any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present application, which upon administration to a subject is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite or residue thereof.
The compounds of the present invention may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers thereof, and pharmaceutically acceptable salts thereof.
When the compounds of formula (I) exist as tautomers, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise specified.
Certain therapeutic advantages may be provided when compounds of formula (I) are replaced with heavier isotopes such as deuterium, for example, which may be attributed to greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
When solvates or polymorphs of the compounds of formula (I) and pharmaceutically acceptable salts thereof exist, the present invention includes any possible solvates and polymorphs. The type of solvent for forming the 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," as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients as well as methods for preparing the compounds of the invention are also part of the present invention. In addition, some crystalline forms of the compounds may exist as polymorphs and as such are included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention.
The pharmaceutical composition provided by the invention comprises a compound (or a medicinal salt thereof) shown as a formula (I) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or auxiliary materials. Although the most suitable mode of administration of the active ingredient in any given case will depend on the particular host, host nature and severity of the condition being treated, the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular, intravenous) administration. The pharmaceutical compositions of the present invention may be conveniently prepared in unit dosage forms well known in the art and by any of the methods of preparation well known in the pharmaceutical arts.
Synthetic schemes
Figure BDA0003653766850000241
Step A: compound I-1 with compound I-1 under alkaline conditions such as DIEA and the like
Figure BDA0003653766850000242
Obtaining a compound I-2 through substitution reaction;
and B, step B: reacting compound I-2 with a strong base such as NaH or the like
Figure BDA0003653766850000251
Obtaining a compound I-3 through substitution reaction;
and C: compound I-3 with
Figure BDA0003653766850000252
Performing Suzuki coupling reaction on SphosPdG2 under the action of a palladium catalyst to obtain a compound I-4;
step D: the target product I-5 can be obtained by removing the protecting group PG from the compound I-4 under acidic conditions such as TFA.
Detailed Description
In order to make the above-mentioned contents clearer and clearer, the present invention will be further illustrated by the following examples. The following examples are intended only to illustrate specific embodiments of the present invention so as to enable those skilled in the art to understand the present invention, but not to limit the scope of the present invention. In the embodiments of the present invention, technical means or methods not specifically described are conventional in the art.
All parts and percentages herein are by weight and all temperatures are in degrees Celsius, unless otherwise indicated. The following abbreviations are used in the examples:
DIEA: n, N-diisopropylethylamine;
DCM is dichloromethane;
a Dioxane: dioxane;
ESI-MS: electrospray ionization mass spectrometry;
EtOH: ethanol;
MeOH: methanol;
POCl 3 : phosphorus oxychloride;
THF: tetrahydrofuran;
TFA: trifluoroacetic acid;
DPPA: diphenyl phosphorazidate;
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:
Figure BDA0003653766850000261
step 1: synthesis of Compound M-1
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 molecular sieve (90.00 mL) (preactivation) were added sequentially at room temperature, and the mixture was refluxed for half an hour (internal temperature 87 ℃) under nitrogen protection. Then naturally cooling to room temperature, then adding DPPA (99.44 mL), heating to reflux, and keeping the temperature for reaction for 5 hours. Cooling the reaction mixture to below 40 ℃, and then adding 500mL of EA for dilution; continue to useCooling to room temperature, assisting filtration with diatomite, and filtering to remove the added molecular sieve; washing filter residue with 1500mL of EA for multiple times, and pumping to dry; collecting the filtrate, washing with 700mL of water and 700mL of saturated saline solution in sequence, and separating the liquid; drying the organic phase with anhydrous sodium sulfate; filtration, removal of the drying agent, concentration, purification of the concentrate by column chromatography (PE/EA =30:1 to 20), concentration of the eluent, and final yield of the target product M-1 as a white solid (68.2 g, 89.88% yield). ESI-MS m/z:247.1[ 2 ] M + H] + 。
And 2, step: synthesis of Compound M-2
Compound M-1 (65.00 g) was dissolved in CH at room temperature 3 CN (82.00 mL), cooled in a water bath, added hydrochloric acid (4M in dioxane) (38.43 g) slowly, and stirred at room temperature for about 16 hours to react, white solid precipitated out and was in suspension. The reaction mixture was filtered and the filter cake was rinsed with a small amount of acetonitrile, drained and the filtrate discarded. Collecting the filter cake, adding the filter cake into a mixture of 700mL of saturated sodium bicarbonate aqueous solution and 700mL of ethyl acetate, alkalifying, extracting and separating liquid; extracting the water phase with 350mL of ethyl acetate, and separating the liquid; mixing ethyl acetate phases, adding 300mL of saturated sodium chloride aqueous solution for washing and liquid separation; the organic phase was dried over anhydrous sodium sulfate, filtered, the drying agent removed, and concentrated to give the title product M-2 (36.3 g, 94.0% yield) as a yellowish solid powder. ESI-MS m/z 147.1[ 2 ] M + H] + 。
And step 3: synthesis of Compound M-3
Compound M-2 (36.00 g) was dissolved in acetonitrile (180.00 mL) at room temperature, and NIS (66.32 g) and p-toluenesulfonic acid (2.12 g) were added thereto, and the mixture was heated and incubated at 70 ℃ under nitrogen. Cooling the reaction liquid to 50 ℃, adding 900mL of water, separating out white solid powder, and pulping for half an hour; filter and rinse the filter cake with water and pump dry. The filter cake was collected, added with 1200mL of ethyl acetate to dissolve completely, and then washed twice with 350mL of saturated aqueous sodium sulfite solution, then washed with 350mL of saturated brine, separated, dried the organic phase over anhydrous sodium sulfate, filtered, and concentrated to give M-3 as a pale yellow solid as a target product (63.2 g, 94.43% yield). ESI-MS m/z of 272.9[ 2 ], [ M + H ]] + 。
And 4, step 4: synthesis of Compound M-4
Compound M-3 (57.50 g) was dissolved in DMF (22.00 mL) at room temperature, and zinc cyanide (32.22 g), palladium tetratriphenylphosphine (12.19 g) and powdered 4A molecular sieve (20.00 mL) were added thereto, and the reaction was carried out under a nitrogen atmosphere with heating and incubation at 100 ℃ for about 7 hours. And removing the oil bath, naturally cooling to room temperature, and waiting for post-treatment. Filtering with diatomite, filtering the reaction mixture, and draining; collecting the filtrate, and concentrating at 60-70 deg.C to obtain light yellow solid crude product. Rinsing the filter residue by using 500mL of ethyl acetate, and draining; collecting rinsing liquid, combining the rinsing liquid with the crude product, and concentrating again until no liquid is distilled out; the crude solid was concentrated by dissolving in 700mL of ethyl acetate, and then washed 3 times with 250mL of saturated sodium chloride each time, followed by separation. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a pale yellow solid, 160mL of the mixture was added PE/EA =3/1, slurried for half an hour, filtered, and suction dried. Collecting filter cake, water bath at 45 deg.C, concentrating, and drawing with high vacuum oil pump to constant weight; the expected product M-4 was finally obtained as a pale yellow solid (36.1 g, 99.7% yield). ESI-MS m/z 172.0[ 2 ] M + H] + 。
And 5: synthesis of Compound M-5
Concentrated sulfuric acid (61.37 mL) was added to a 500mL single-neck flask at room temperature, the mixture was cooled to 10 ℃ or lower in an ice-water bath, and after the addition of the compound M-4 (39.30 g) in portions, the mixture was stirred for 10 minutes, and the mixture was kept at 60 ℃ in an oil bath under a nitrogen atmosphere to react for about 1 hour. The reaction was cooled to room temperature and then carefully added to 1100mL of ice-water mixture, and the mixture was diluted and quenched with a small amount of yellow solid. Stirring for 10min, and filtering; collecting filter cakes, pulping for 20 minutes by using 50mL of saturated sodium bicarbonate aqueous solution, filtering again, collecting two filtrates, and mixing; then sodium carbonate solid was slowly added to adjust the pH to about 7, and a white-like solid powder was precipitated. Stirring for half an hour, filtering, and draining; the filter cake was rinsed with 100mL of water each time, drained, and rinsed 2 times total. The filter cake was collected, placed in a vacuum oven and dried to constant weight at 55 ℃ to give the desired product M-5 (33.6 g, 77.37% yield) as a beige solid powder. ESI-MS m/z:190.0[ 2 ], [ M + H ]] + 。
Step 6: synthesis of Compound M-6
At room temperature, add tetrahydrofuranPyran (470.00 mL), after nitrogen replacement, adding sodium hydride (10.00 g) under the protection of micro nitrogen flow, heating by using an oil bath, keeping the temperature at 40-45 ℃, and stirring for 15 minutes; then, compound M-5 (18.95 g) was added in portions, and after the addition was completed, mechanical stirring was performed while maintaining the temperature for 20 minutes, then CDI (24.31 g) was carefully added in portions, and after the addition was completed, stirring was performed for 15 minutes, and then the mixture was heated in an oil bath, and the reaction was performed while maintaining the temperature and refluxing. Cooling the reaction solution to below 10 ℃ by using an ice water bath, then adding 500mL of saturated ammonium chloride aqueous solution to precipitate pale yellow solid, and adding 1000mL of water; then transferring the mixture to a 5L beaker, and adding 3000mL of water; stirring for 1 hour, filtering and pumping to dry; the filter cake was collected, placed in a vacuum oven and dried to constant weight at 50-55 ℃ to give the desired product M-6 (18.3 g, 84.93% yield) as a pale yellow solid powder. ESI-MS m/z:216.0[ 2 ], [ M + H ]] + 。
And 7: synthesis of Compound M-7
Compound M-6 (18.00 g) and DIEA (36.00 mL) were dissolved in POCl at room temperature 3 (180.00 mL) was reacted at 100 ℃ for about 2.5 hours under a nitrogen atmosphere by heating and holding. The mixture was concentrated under reduced pressure to remove phosphorus oxychloride, and was taken 2 times with 100mL of DCM; the concentrated residue was dissolved in 400mL of methylene chloride, added dropwise to 500mL of a saturated aqueous sodium bicarbonate solution, and cooled with ice water; stirring for 15 minutes, and then separating liquid; extracting and separating the water phase by using 300mL of dichloromethane; the dichloromethane phases are combined, washed by 300mL of saturated sodium chloride aqueous solution and separated; dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate purified by silica gel column (PE/EA = 90/10-75/25) to give the desired product M-7 as an off-white solid powder (10.95 g, 51.94% yield). ESI-MS m/z:251.9[ 2 ] M + H] + 。
And 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, tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (9.27 g) was added in portions, and the reaction was stirred at room temperature for about 10 minutes. And adding 120mL of dichloromethane, washing with 100mL of water and 100mL of saturated aqueous sodium chloride solution in sequence, separating, drying the organic phase by using anhydrous sodium sulfate, filtering, concentrating, and purifying the concentrate by using a silica gel column (PE/EA = 90/10-75/25) and pulping (40mL EA +160mL PE) to obtain a white solid powdery target intermediate M (15.9 g, yield 89.26%).
Example 1: synthesis of the compound 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((1- ((3-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol
Figure BDA0003653766850000281
Step 1: synthesis of Compound 1-1
1-Methoxycarbonylcyclopropane-1-carboxylic acid (3.00 g), dichloromethane (130.00 mL) and cooled to 0 ℃ were added to a reaction flask at room temperature, oxalyl chloride (7.05 mL) and DMF (0.08 mL) were added, and stirring was continued at this temperature for 10min, followed by reaction at 35 ℃ for 3h. The solvent was spun dry, dry dichloromethane (130.00 mL) was added, cooled to 0 deg.C, triethylamine (14.47 mL) and 3-methylpiperidine (2.47 g) were added, and the reaction was allowed to resume at room temperature for 2h. The solvent was spun dry and then purified over a silica gel column (DCM: EA =3 1) to give the target product 1-1 as a yellow liquid (4.00 g, 85.30% yield).
Step 2: synthesis of Compound 1-2
Compound 1-1 (4.00 g) was dissolved in tetrahydrofuran (50.00 mL) at room temperature, cooled to-10 ℃ and lithium aluminum hydride (1.35 g) was added in portions and allowed to react at room temperature for 2h. After cooling to 0 ℃, ether was added for dilution, and then 1.3mL of water was added for quenching reaction, 15% aqueous sodium hydroxide solution was added, 3.9mL of water was added, stirring was performed at room temperature for 10min, anhydrous magnesium sulfate was added for drying, filtration was performed, and the mother liquor was concentrated and purified by a silica gel column (DCM to DCM: meOH = 12) to obtain the objective product 1-2 (2.30 g, yield 70.67%) as a pale yellow liquid.
And step 3: synthesis of Compounds 1-3
Compound 1-2 (256.79 mg) was dissolved in tetrahydrofuran (4.00 mL) at room temperature, cooled to 0 deg.C, and sodium hydride (50.44 mg) was added thereto, followed by stirring at room temperature for 10min, to which intermediate M (300.00 mg) was added, followed by further reaction for 1h. Quenching the reaction by adding water under ice bath, adding EA and water, extracting, drying and concentrating. Purification on a silica gel column gave the desired product 1-3 (280.00) as a yellow solidmg)。ESI-MS m/z:575.3[M+H] + 。
And 4, step 4: synthesis of Compounds 1-4
Compound 1-3 (150.00 mg), dimethyl-tert-butyl- [4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-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) were replaced with nitrogen, and the mixture was reacted at 95 ℃ for 2 hours under nitrogen atmosphere. Adding EA and water, extracting, drying, and concentrating. The concentrate was purified by Pre-TLC (DCM: meOH = 15). ESI-MS m/z 797.5[ 2 ], [ M + H ]] + 。
And 5: synthesis of Compounds 1 to 5
Compounds 1-4 (150.00 mg) were dissolved in THF (2.00 mL) and triethylamine trihydrofluoride salt (0.31 mL) at room temperature, and the reaction was stirred at room temperature for 0.5h. The reaction mixture was directly concentrated to crude target product 1-5 as a yellow oil. ESI-MS m/z:683.4[ 2 ], [ M + H ]] + 。
Step 6: synthesis of Compound 1
Compounds 1-5 (120.00 mg) were dissolved in a mixed solution of DCM (1.00 mL) and TFA (1.00 mL) at room temperature and reacted for 0.5h at room temperature. The reaction mixture was concentrated, taken up in DCM, adjusted to pH =8 with aqueous sodium bicarbonate solution in ice bath, extracted with DCM and MeOH, dried and concentrated. The concentrate was purified by Pre-TLC (DCM: meOH: ammonia = 10). ESI-MS m/z:583.3[ 2 ], [ 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＝19.7Hz,2H)。
Example 2: synthesis of the compound 4- (2- ((1- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) cyclopropyl) methoxy) -4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol
Figure BDA0003653766850000301
Step 1: synthesis of Compound 2-1
Compound 1-methoxycarbonylcyclopropane-1-carboxylic acid (3.00 g) was dissolved in dichloromethane (100.00 mL) at room temperature, cooled to 0 ℃ and then oxalyl chloride (7.05 mL) and DMF (0.08 mL) were added and stirring was continued for 10min with incubation, followed by reaction at 35 ℃ for 3h. The solvent was spun dry, dry dichloromethane (100.00 mL) was added, cooled to 0 deg.C, triethylamine (14.47 mL) and 3-azabicyclo [3.1.0] hexane (2.08 g) were added and the reaction was allowed to return to room temperature for an additional 2h. The reaction mixture was concentrated and the concentrate was purified on a silica gel column (DCM: EA =3: 1) to give the target product 2-1 as a yellow liquid (3.6 g, yield 82.66%).
And 2, step: synthesis of Compound 2-2
Compound 2-1 (4.00 g) was dissolved in tetrahydrofuran (50.00 mL) at room temperature, cooled to-10 ℃ and lithium aluminum hydride (2.5M/THF) (1.41 g) was added in portions and allowed to react at room temperature for 2h. The temperature was reduced to 0 ℃, ether was added for dilution, 1.4mL of water was added, 1.4mL of 15% aqueous sodium hydroxide solution was added, 4.2mL of water was finally added, stirring was performed at room temperature for 10min, anhydrous magnesium sulfate was added for drying, filtration and concentration were performed, and the concentrate was purified by a silica gel column (DCM to DCM: meOH = 12) to obtain the objective product 2-2 (2.20 g, yield 76.46%) as a pale yellow liquid.
The subsequent detailed reaction steps refer to example 1. Target product 2ESI-MS m/z:567.3[ 2 ] 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＝7.6,4.1Hz,1H)。
Example 3: synthesis of the compound 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((3-fluoropiperidin-1-yl) methyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol
Figure BDA0003653766850000311
Detailed synthetic procedure for example 3 reference is made to example 1.ESI-MS m/z of 587.3[ 2 ], M + H] + 。
Example 4: synthesis of the compound 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((2-methylpyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol
Figure BDA0003653766850000312
Detailed synthetic procedure for example 4 reference is made to example 1.ESI-MS m/z 569.3[ 2 ], [ M + H ]] + 。
Example 5: synthesis of the 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] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol
Figure BDA0003653766850000321
Detailed synthetic procedure for example 5 reference is made to example 1.ESI-MS m/z:611.3[ 2 ] 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: synthesis of the compound 4- (4- ((1R, 5S) -3, 8-diazacyclo [3.2.1] octyl-3-yl) -2- ((1- ((ethyl (2, 2-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
Figure BDA0003653766850000322
Detailed synthetic procedure for example 6 reference is made to example 1.ESI-MS m/z:663.2[ 2 ], [ M + H ]] + 。
Example 7: synthesis of the compound 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- ((3- (difluoromethyl) piperidin-1-yl) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol
Figure BDA0003653766850000323
Detailed synthetic procedure for example 7 reference is made to example 1.ESI-MS m/z:619.3[ 2 ] M + H] + 。
Example 8: synthesis of the compound 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((4-fluoropiperidin-1-yl) methyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol
Figure BDA0003653766850000331
Detailed synthetic procedure for example 8 reference is made to example 1.ESI-MS m/z:611.3[ 2 ] 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: synthesis of the compound 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol
Figure BDA0003653766850000332
Detailed synthetic procedure for example 9 reference is made to example 1.ESI-MS m/z:573.3[ 2 ], [ 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: synthesis of the compound 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- ((4, 4-difluoropiperidin-1-yl) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol
Figure BDA0003653766850000341
Detailed synthetic procedure for example 10 reference is made to example 1.ESI-MS m/z 605.3[ 2 ] M + H] + 。
Example 11: synthesis of the compound 4- (2- ((1- ((7-azabicyclo [2.2.1] hept-7-yl) methyl) cyclopropyl) methoxy) -4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol
Figure BDA0003653766850000342
Detailed synthetic procedure for example 11 reference is made to example 1.ESI-MS m/z:581.3[ 2 ] 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: synthesis of the 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) naphthalen-2-ol
Figure BDA0003653766850000343
Detailed synthetic procedure for example 12 reference is made to example 1.ESI-MS m/z 603.3[ 2 ] 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: synthesis of the compound 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) naphthalen-2-ol
Figure BDA0003653766850000351
Detailed synthetic procedure for example 13 reference is made to example 1.ESI-MS m/z 567.3[ 2 ], [ 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: synthesis of the compound 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol
Figure BDA0003653766850000352
Detailed synthetic procedure for example 14 reference is made to example 1.ESI-MS m/z 569.3[ 2 ], [ 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 the synthesis was performed according to the procedure of reference example 1, the corresponding alcohol was subjected to substitution reaction with intermediate M, and then subjected to Suzuki coupling with borate, followed by removal of the TBS protecting group and the Boc protecting group to obtain the target product.
The corresponding synthetic intermediates are shown in the following table:
Figure BDA0003653766850000361
Figure BDA0003653766850000371
the following examples were synthesized using the methods described above, or analogous methods using the corresponding intermediates.
Figure BDA0003653766850000372
Figure BDA0003653766850000381
Figure BDA0003653766850000391
Figure BDA0003653766850000401
Figure BDA0003653766850000411
Figure BDA0003653766850000421
Figure BDA0003653766850000431
Figure BDA0003653766850000441
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 experiments
Pharmacological experiment 1: cell proliferation Assay (AGS)
AGS (KRas-G12D mutant tumor cells) (II)
Figure BDA0003653766850000452
CRL-1739 TM ) By 1 × 10 3 Cell density per well was plated on low adsorption 96-well plates and incubated overnight in a cell incubator. After the cells adhere to the wall, adding a compound to be detected into a 96-well plate according to the final concentration of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05 and 0nM (the final concentration of DMSO is 0.5%), culturing at 37 ℃ for 96 hours, adding 50 mu L of Cell-titer GLO working solution into each well, shaking and mixing uniformly, incubating at room temperature for 10min, reading a Luminescence value of Luminescence in a multifunctional microplate reader, and calculating and converting the Luminescence value data into inhibition percentage. And calculating the percentage of inhibition of cell proliferation according to the following formula:
percent inhibition = (max-measured)/(max-Blank) × 100
("maximum" from 0.1% DMSO control well, "Blank" from Blank control well, "measured" from compound treated well).
Curve fitting and IC acquisition were performed using GraphPad Prism software 50 The value is obtained.
TABLE 1
Figure BDA0003653766850000451
Figure BDA0003653766850000461
Pharmacological experiment 2: cell proliferation assay (NCI-H1975)
KRas-WT tumor cells NCI-H1975 (
Figure BDA0003653766850000462
CRL-5908 TM ) By 1 × 10 3 Cell density per well was plated on low adsorption 96-well plates and incubated overnight in a cell incubator. After the cells adhere to the wall, adding a compound to be detected into a 96-well plate according to the final concentration of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05 and 0nM (the final concentration of DMSO is 0.5%), culturing at 37 ℃ for 96 hours, adding 50 mu L of Cell-titer GLO working solution into each well, shaking and mixing uniformly, incubating at room temperature for 10min, reading a Luminescence value of Luminescence in a multifunctional microplate reader, and calculating and converting the Luminescence value data into inhibition percentage. And calculating the percentage of inhibition of cell proliferation according to the following formula:
percent inhibition = (max-measured)/(max-Blank) × 100
("maximum" from 0.1% DMSO control well, "Blank" from Blank control well, "measured" from compound treated well).
Curve fitting and IC acquisition were performed using GraphPad Prism software 50 The value is obtained.
TABLE 2
Figure BDA0003653766850000463
Pharmacological experiment 3: cellular p-ERK detection assay
Two KRas-G12D mutant tumor cells AGS (
Figure BDA0003653766850000464
CRL-1739 TM ) Or Panc 04.03 (
Figure BDA0003653766850000465
CRL-2555 TM ) By 5X 10 4 Cell density per well was plated in 96-well plates and incubated overnight in a cell incubator. After the cells were attached, the test compound was added to a 96-well plate at final concentrations of 10000nM, 3333nM, 1111nM, 370.4nM, 123.4nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM, 0.51nM, 0.1% DMSO, and after 3h of incubation,the protein lysate of each treated cell sample in the 96-well plate was extracted using lysis buffer (50. Mu.L) in the MSD (Meso Scale Discovery) electrochemiluminescence immunoassay kit, the protein lysate was quantified using the BCA method, and the protein sample concentration was diluted to 0.1. Mu.g/. Mu.L using the lysis buffer. Adding 25 ul/well of protein diluent into a 96-well MSD detection plate, incubating at room temperature for 3h, adding 25 muL of detection antibody solution, continuing to incubate at room temperature for 1h, washing the plate, and adding 150 muL of 1 × read buffer T. Plate readings were performed on a SECTOR Imager and raw data was collected.
The reading was converted to a p-ERK% value according to the formula in the MSD detection method:
p-ERK% value = ((2 × phosphorylation signal value)/(phosphorylation signal value + total signal value)) × 100
Percent p-ERK inhibition was calculated according to the following formula:
percent inhibition = (max-measured)/(max-Blank) × 100
("maximum" from 0.1% DMSO control well, "Blank" from Blank control well, "measured" from compound treated well).
Curve fitting and IC acquisition were performed using GraphPad Prism software 50 The value is obtained.
TABLE 3
Figure BDA0003653766850000471
While the present invention has been fully described by way of 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 are intended to be included within the scope of the appended claims.

Claims (23)

1. A compound of formula (I), a stereoisomer, a tautomer, a deuteride, or a pharmaceutically acceptable salt thereof:
Figure FDA0003653766840000011
wherein, the first and the second end of the pipe are connected with each other,
R 1 independently selected from H, hydroxy, C 1-6 Alkyl radical, C 1-6 Aminoalkyl, -N (R) a ) 2 、-C(＝NH)NH 2 、-C(＝NCH 3 )NH 2 Carboxyl group, C 1-6 Carboxyalkyl, cyano, C 1-6 Cyanoalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Aldehyde group, -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 Independently selected from H or C 1-6 An alkyl group; preferably R 1 Is H;
X 1 is selected from N or CH;
X 2 selected from N or CR 7 ；
R 2 Or R 7 Independently selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro, said C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl or hydroxyalkyl optionally further selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy and hydroxyalkyl;
ring A is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclyl;
R 3 independently selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxy or hydroxyalkyl;
R 4 independently selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, - (CH) 2 ) 0-3 N(R b ) 2 、C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl or 4-14 membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxyalkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl or 4-14 membered heteroaryl optionally further selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, - (CH) 2 ) 0-3 N(R b ) 2 、C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl, said R being substituted by one or more substituents b Independently selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
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 Optionally further substituted by one or more halogens or C 1-6 Alkyl substitution;
L 2 selected from a bond or an alkylene group, said alkylene group being optionally further substituted by one or more halogens, C 1-6 Alkyl or C 1-6 Haloalkyl substitution;
R 5 selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, C 3-14 Cycloalkyl and 3-14 membered heterocyclyl;
R 6 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl, said C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl optionally further substituted with one or more R c Substitution; r is c Independently selected from H, = O, = S, oxo, cyano, halogen, C 1-6 Alkyl radical, 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 radical, C 2-6 Alkynyl, substituted or unsubstituted-C 0-3 alkylene-C 3-14 Cycloalkyl, substituted or unsubstituted-C 0-3 Alkylene- (3-to 14-membered heterocycloalkyl), substituted or unsubstituted-C 0-3 alkylene-C 6-14 Aryl or substituted or unsubstituted-C 0-3 Alkylene- (5-to 14-membered heteroaryl), each R d Independently H, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or C 1-6 A haloalkyl group;
m, n or p are each independently selected from 0, 1,2, 3 or 4.
2. The compound represented by the general formula (I), a stereoisomer, a tautomer, a deuteron, or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from a compound represented by the formula (IA),
Figure FDA0003653766840000021
wherein, the first and the second end of the pipe are connected with each other,
R 1 is H;
ring A is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, preferably cyclopropyl;
R 3 independently selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxy, and hydroxyalkyl;
R 4 independently selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, - (CH) 2 ) 0-3 N(R b ) 2 、C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, hydroxyalkyl, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclic group,C 6-14 Aryl and 4-14 membered heteroaryl are optionally further selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, - (CH) 2 ) 0-3 N(R b ) 2 、C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl, said R being substituted by one or more substituents b Independently selected from H or C 1-6 An alkyl group;
L 1 is selected from-O- (CH) 2 ) 1-3 Said L is 1 Optionally further substituted by one or more halogens or C 1-6 Alkyl substitution;
L 2 selected from alkylene, said alkylene optionally further substituted by one or more halogens or C 1-6 Alkyl substitution;
R 5 selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, C 3-14 Cycloalkyl and 3-14 membered heterocyclyl;
R 6 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl, said C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 4-14 membered heteroaryl optionally further substituted with one or more R c Substitution; r c Independently selected from H, = O, = S, acyl, cyano, halogen, C 1-6 Alkyl radical, 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 radical, C 2-6 Alkynyl, substituted or unsubstituted-C 0-3 alkylene-C 3-14 Cycloalkyl, substituted or unsubstituted-C 0-3 Alkylene- (3-to 14-membered heterocycloalkyl), substituted or unsubstituted-C 0-3 alkylene-C 6-14 Aryl or substituted or unsubstituted-C 0-3 Alkylene- (5-to 14-membered heteroaryl), each R d Independently H, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or C 1-6 A haloalkyl group;
p is selected from 0, 1,2, 3 or 4.
3. The compound of formula (I), its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to claim 1 or 2, wherein R is 1 Is selected from H.
4. A compound of general formula (I), its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 1 to 3, wherein R 2 Selected from H, cyano or C 1-6 An alkyl group.
5. The compound of formula (I), its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 1-4, wherein R is 3 Is selected from H or C 1-6 An alkyl group.
6. The compound of formula (I), its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 1 to 5, wherein X is 1 Is selected from N.
7. The compound of formula (I), its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 1 to 6, wherein X is 2 Is selected from N.
8. A compound of general formula (I), a stereoisomer, a tautomer, a deutero-or a compound thereof according to any one of claims 1 to 7Pharmaceutically acceptable salts, characterized in that R 4 Is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl or 4-14 membered heteroaryl, said C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl or 4-14 membered heteroaryl optionally further selected from halogen, C 1-6 Alkyl, haloalkyl, cyano, or a combination thereof.
9. The compound of formula (I), its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 1 to 8, wherein L is 1 Is selected from-O- (CH) 2 ) 1-3 Said L is 1 Optionally further substituted by one or more halogens or C 1-6 Alkyl substitution.
10. The compound of general formula (I), its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any of claims 1 to 9, wherein p is selected from 0 or 1.
11. The compound of general formula (I), its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 1 to 10,
Figure FDA0003653766840000041
is selected from
Figure FDA0003653766840000042
Figure FDA0003653766840000043
12. The compound of formula (I), its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 1-11, wherein R is 5 Selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, preferably F.
13. The compound of formula (I), its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 1-12, wherein R is 6 Is selected from
Figure FDA0003653766840000044
Figure FDA0003653766840000045
14. A compound, a stereoisomer, a tautomer, a deutero-compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
1) 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((1- ((3-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol;
2) 4- (2- ((1- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol;
3) 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((3-fluoropiperidin-1-yl) methyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol;
4) 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((2-methylpyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-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-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol;
6) 190) 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- ((ethyl (2, 2-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
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-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol;
8) 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((4-fluoropiperidin-1-yl) methyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
9) 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalen-2-ol;
10 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- ((4, 4-difluoropiperidin-1-yl) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-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] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-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) naphthalen-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) naphthalen-2-ol;
14 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) naphthalen-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-fluoropyridine [4,3-d ] pyrimidin-7-yl) naphthalen-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] octan-3-yl) -8-fluoropyridine [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] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
18 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
19 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
20 4- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-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] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
22 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) 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] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) thiomorpholine;
24 4- ((1- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-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] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) 1, 1-dithiomorpholine;
26 4- ((1- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
28 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
29 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) 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] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
31 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
32 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) 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] octan-3-yl) -7- (8-ethyl-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) thiomorpholine 1, 1-dioxide;
34 4- ((1- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) pyridinyl [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] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) 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] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) 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] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
39 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
40 4- (4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
41 3- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
42 4- ((1- ((4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl) pyridinyl [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] octan-3-yl) -7- (3-chloro-2-cyclopropyl-5-hydroxyphenyl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) thiomorpholine 1, 1-dioxide;
45 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
46 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) 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] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
48 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (thiomorpholinmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
49 4- ((1- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-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] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) 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] octan-3-yl) -8-fluoropyridin [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
52 2- ((1- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidine;
53 4- (2- ((1- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
54 4- (2- ((1- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
55 4- (2- ((1- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
56 4- (2- ((1- ((3-azabicyclo [3.1.0] hexaazen-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoropyridin [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
57 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
58 3- (2- ((1- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
59 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxetan-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
60 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxetan-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
61 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-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] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxoalk-3-yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
63 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxolanyl-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
64 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-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] octan-3-yl) -7- (8-ethynyl-3-hydroxynaphthalen-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] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxetan-3-yl) methyl) thiomorpholine 1, 1-dioxide;
67 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxiran-3-yl) methyl) 1, 1-dioxythiophene;
68 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
69 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
70 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
71 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
72 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxoalk-3-yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
73 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxoalk-3-yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
74 4- ((3- ((4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -7- (8-ethyl-3-hydroxynaphthalen-1-yl) -8-fluoropyridin [4,3-d ] pyrimidin-2-yl) oxy) methyl) tauro-3-yl) methyl) thiomorpholine 1, 1-dioxide;
75 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) pyridinyl [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxocyclopent-3-yl) methyl) thiomorpholine 1, 1-dioxide;
76 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxocyclopent-3-yl) methyl) thiomorpholine 1, 1-dioxide;
77 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
78 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
79 3- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxan-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
80 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxetan-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
81 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxa-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
82 3- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
83 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxocyclopent-3-yl) methyl) thiomorpholine 1, 1-dioxide;
84 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl) pyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxetan-3-yl) methyl) thiomorpholine 1, 1-dioxide;
85 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-2-cyclopropyl-5-hydroxyphenyl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxolane-3-yl) methyl) 1, 1-dioxythiophene;
86 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
87 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (morpholinomethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
88 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxoalk-3-yl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
89 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (thiomorpholinmethyl) oxolane-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
90 4- ((3- ((4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -7- (8-chloro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) pyrrolidin-3-yl) methyl) thiomorpholine 1, 1-dioxide;
91 4- ((3- ((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) oxocyclopent-3-yl) methyl) thiomorpholine 1, 1-dioxide;
92 4- (2- ((3- ((3-azabicyclo [3.1.0] hexazin-3-yl) oxy) pyrrolidin-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoropyridin [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
93 2- ((3- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) oxetan-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridin [4,3-d ] pyrimidine;
94 4- (2- ((3- ((3-azabicyclo [3.1.0] hexa-aza-3-yl) methyl) pyrrolidin-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
95 4- (2- ((3- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) oxetan-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridin [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
96 4- (2- ((3- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) oxetan-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridin [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
97 4- (2- ((3- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) oxetan-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridin [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
98 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((3- (pyrrolidin-1-ylmethyl) oxoalk-3-yl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
99 3- (2- ((3- ((3-azabicyclo [3.1.0] hex-3-yl) methyl) oxa-3-yl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
100 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
101 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
102 4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidine;
103 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
104 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
105 2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidine;
106 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) pyrrolidine-3-carbonitrile;
109 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
110 4- (4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
111 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
112 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
113 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoropyridin [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
114 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
115 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) pyridine [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] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) pyrrolidine-3-carbotriamine;
118 4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-2 l 4-isochromen-1-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidine;
119 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
120 3- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
121 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
122 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
123 3- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
124 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl) pyridine [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] octan-3-yl) -7- (3-chloro-2-cyclopropyl-5-hydroxyphenyl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) pyrrolidine-3-carbotriamine;
127 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
128 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (piperidin-1-ylmethyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
129 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
130 4- (2- ((1- ((8-azabicyclo [3.2.1] octan-8-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
131 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) pyrrolidine-3-carbonitrile;
133 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
134 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
135 2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [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) pyridine [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] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((1- ((((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidine;
139 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol;
140 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol;
141 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
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) pyridinyl [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
145 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
146 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
147 3- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
148 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyridine [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) pyridine [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) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
151 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol;
152 4- (2- ((1- ((3-azabicyclo [3.2.1] octan-3-yl) methyl) cyclopropyl) methoxy) -4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol;
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-chloronaphthalen-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) pyridine [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) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
157 4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((1- ((((R) -3-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidine;
158 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) piperidine-3-carbo-nitrile;
160 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) piperidine-3-carbo-nitrile;
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) pyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
164 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) pyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) piperidine-3-carbo-nitrile;
166 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) piperidine-3-carbo-nitrile;
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) pyridine [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) pyridine [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) pyridinyl [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
170 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) piperidine-3-carbo-nitrile;
171 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl) pyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) piperidine-3-carbonitrile;
172 (R) -1- ((1- ((4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-2-cyclopropyl-5-hydroxyphenyl) -8-fluoropyridine [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-chloronaphthalen-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) pyridine [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] octan-3-yl) -7- (8-chloro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [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] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) piperidine-3-carbo-nitrile;
177 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ((1- ((ethyl (2, 2-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [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-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
179 N- ((1- (((4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyridine [4,3-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) methyl) -N-ethyl-2, 2-trifluoro-1-amine;
180 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-yl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol;
181 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-yl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
182 4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ((1- (pyrrolidin-1-yl) cyclopropyl) methoxy) pyridine [4,3-d ] pyrimidine;
183 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- ((ethyl (2, 2-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [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-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [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-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
186 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ((1- ((ethyl (2, 2-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
187 4- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ((1- ((ethyl (2, 2-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -6-fluoro-5-methylnaphthalen-2-ol;
188 3- (4- ((1r, 5s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((1- ((ethyl (2, 2-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [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-trifluoroethyl) amino) methyl) cyclopropyl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-chloronaphthalen-2-ol.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-14, stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.
16. Use of a compound of any one of claims 1-14, a stereoisomer, a tautomer, a deutero-or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 15 for the preparation of a medicament.
17. The use of claim 16, wherein the manufacture of a medicament is for the manufacture of a medicament for the treatment and/or prevention of a disease mediated by KRAS G12D.
18. The use according to claim 17, wherein the disease is selected from cancer.
19. The use of 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, polymorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, schwann cell tumor, lung squamous cell carcinoma, lichenification, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
20. A method of treating and/or preventing a disease, comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1-14, a stereoisomer, tautomer, deuteron, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 15.
21. The method of claim 20, wherein the disease treated and/or prevented is a disease mediated by KRAS G12D.
22. The method of claim 21, wherein the disease is selected from cancer.
23. The method of 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, polymorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, schwann cell tumor, lung squamous cell carcinoma, licheniform keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
CN202210549066.0A 2021-05-21 2022-05-20 KRAS G12D inhibitor and application thereof in medicines Pending CN115368382A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024051852A1 (en) * 2022-09-09 2024-03-14 上海翰森生物医药科技有限公司 Pyrimidine-containing polycyclic biological inhibitor, preparation method therefor, and use thereof
WO2024123913A1 (en) * 2022-12-06 2024-06-13 Ranok Therapeutics (Hangzhou) Co. Ltd. Kras(g12v) inhibitors

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024051852A1 (en) * 2022-09-09 2024-03-14 上海翰森生物医药科技有限公司 Pyrimidine-containing polycyclic biological inhibitor, preparation method therefor, and use thereof
WO2024123913A1 (en) * 2022-12-06 2024-06-13 Ranok Therapeutics (Hangzhou) Co. Ltd. Kras(g12v) inhibitors

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