CN116057059A - Deuterated compounds useful as KRAS G12D inhibitors - Google Patents

Deuterated compounds useful as KRAS G12D inhibitors Download PDF

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CN116057059A
CN116057059A CN202280005756.8A CN202280005756A CN116057059A CN 116057059 A CN116057059 A CN 116057059A CN 202280005756 A CN202280005756 A CN 202280005756A CN 116057059 A CN116057059 A CN 116057059A
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methoxy
diazabicyclo
octane
pyrimidin
pyrrolizine
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CN116057059B (en
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方海权
刘晓雷
杨惠
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Shanghai Yizhongxing Biotechnology Co ltd
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Nanjing Suikun Intelligent Technology Co ltd
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    • C07—ORGANIC CHEMISTRY
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    • 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

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Abstract

Disclosed are deuterated compounds of formula (I) or deuterated compounds of formula (I'), or salts thereof, wherein R 1 To R 6 At least one of them is D (deuterium atom), and X 0 Y and R are defined herein. Also disclosed are methods of modulating or inhibiting the activity of KRAS G12D muteins using such compounds, as well as pharmaceutical compositions comprising such compounds. These compounds are also provided for use in the treatment of a variety of diseases or conditions, such as cancer.

Description

Deuterated compounds useful as KRAS G12D inhibitors
Technical Field
The present invention relates to deuterated compounds of formula (I) (deuterated compound) or deuterated compounds of formula (I'), or salts thereof, wherein R 1 To R 6 At least one of them is D (deuterium atom), and X 0 Y and R are defined herein. In this context, the compounds of formula (I) or the compounds of formula (I') and pharmaceutical compositions comprising such compounds are useful for the treatment of a variety of disorders (disorders) such as cancer. Also described are methods of inhibiting KRAS G12D activity, as well as methods of using the same for treating KRAS G12D-related disorders, and methods for preparing compounds of formula (I) or compounds of formula (I').
Background
The Kirsten rat sarcoma type 2viral gene homolog (Kirsten rat sarcoma 2viral oncogene homolog,KRAS) gene is a proto-oncogene (proto-oncogene) known as KRAS, which encodes a small GTPase transporter (small GTPase transductor protein). KRAS proteins switch between inactive and active forms via binding to Guanosine Triphosphate (GTP) and Guanosine Diphosphate (GDP), respectively (Alangeer et al, current Opin Pharmcol, 2013; phase 13: pages 394-401). GTPase-activated proteins (GTPase activating proteins, GAPs) help hydrolyze GTP by KRAS, while guanine nucleotide exchange factors (guanine nucleotide exchange factors, GAPs) catalyze GDP dissociation (Vetter et al, science 2001, 94:1299-1304) (K.Scheffzek et al, science,1997, 277:333-338). Under physiological conditions KRAS is predominantly GDP-bound. Upon activation by receptor tyrosine kinases such as the epidermal growth factor (epidermal growth factor, EGF) receptor, GEFs are recruited to KRAS and initiate the exchange of GDP with GTP. Activated KRAS interacts with effector proteins (effector proteins) and activates downstream cell signaling pathways including RAF-MEK-ERK pathway, PI3K-AKT-MTOR pathway, and RalGDS pathway, regulating a number of important cellular processes including cell differentiation, cell growth, and cell proliferation (Rajalingam, et al, biochim.Biophys.Acta, mol.Cell res. 1773, pages 1177-1195) (McCormick et al, curr. Opin. Biotechnol,1996, 7, 449-456). In the regulated KRAS cycle, signaling is turned off after GTP hydrolysis. Most often the mutation in KRAS is activated at codon 12, codon 13 and codon 61, compromising its own function or GAP-mediated GTPase function, which results in accumulation of KRAS-GTP, which is constitutively active (constitutively active), and which results in uncontrolled cell growth/proliferation leading to tumor formation (turigenesis) and tumor development (tumor development) (coxad et al, small GTPases,2010, pages (1) 2-27) (Prior IA et al, cancer Res,2012, volume 72, p (10) 2457-2467). About 15% of all human tumors contain (harbor) mutated KRAS. Among them, G12D mutations in KRAS occur most frequently and are found in-45% of pancreatic ductal adenocarcinoma patients, 13% of colorectal Cancer patients, 10% of rectal Cancer patients, 4% of non-small Cell lung Cancer patients, and 1.7% of all small Cell lung Cancer patients (A.G.Stephen et al, cancer Cell,2014, 25: pages 272-281).
Despite some breakthrough in targeting KRAS G12C mutations, such as AMG 510 (sotoraib) of amene, MRTX 849 of Mirati, and more in recent years (D-1553, JAB-21822, GH35, GFH925, BPI-421286), compounds that inhibit KRAS activity remain highly desirable. High frequency of KRAS G12D mutations makes it an ideal drug target, but potent drugs targeting KRAS G12D mutant KRAS remain undirected in clinical trials.
Thus, there is a need to develop new therapeutic agents targeting KRAS G12D with sufficient potency and safety profile (safety profile) for use in KRAS G12D-mediated cancers. The present invention relates to a novel class of deuterated compounds that bind directly to KRAS G12D and block its activity. These deuterated compounds are provided for use as medicaments having desirable stability, bioavailability, therapeutic index (therapeutic index) and toxicity value (toxicity values) important for their pharmaceutical properties.
The kinetic isotope effect (Kinetic isotope effect, KIE) makes the C-D bond 6-10 times stronger than the C-H bond (Chemical Science,2012, 3, pages 3231-3236; J.Med. Chem.,2014, 57, 3595-3611). The D-free compounds of deuterated compounds comprise one or more C-H bonds substituted by one or more C-D bonds as weak metabolic sites (soft metabolite spot), which deuterated compounds will increase their resistance to metabolism (resistance) and thus improve DMPK (drug metabolism and pharmacokinetics) properties involving absorption, distribution, metabolism and secretion (ADME) and serve to increase half-life of the compounds, which compounds are administered to mammals, in particular humans (Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends pharmacol. Sci. 5, volume 12: pages 524-527 (1984)).
Summary of The Invention
The present disclosure relates to deuterated compounds of formula (I) or (I '), PROTAC compounds comprising a moiety of formula (I) or a moiety of formula (I'), or salts thereof, wherein R 1 To R 6 At least one of them is D (deuterium atom), and the deuterated compound of formula (I) or the deuterated compound of formula (I') is used as a modulator of KRAS G12D activity.
The present disclosure also relates to pharmaceutical compositions comprising the aforementioned deuterated compounds of formula (I) or formula (I '), a PROTAC compound comprising a moiety of formula (I) or a moiety of formula (I'), and/or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier (carrier).
The present disclosure also relates to a method of treating a disease or disorder associated with the activity of KRAS G12D, the method comprising: determining whether the subject has a KRAS G12D mutation; and if the subject is determined to have a KRAS G12D mutation, then administering to the subject a therapeutically effective amount of a compound of formula (I) or a compound of formula (I '), a PROTAC compound comprising a moiety of formula (I) or a moiety of formula (I'), and/or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The present disclosure also relates to processes and intermediates for preparing compounds of formula (I) or compounds of formula (I') and/or salts thereof.
The present disclosure also relates to compounds of formula (I) or compounds of formula (I '), PROTAC compounds comprising a moiety of formula (I) or a moiety of formula (I'), and/or pharmaceutically acceptable salts thereof, for use in therapy.
The present disclosure also relates to the use of a compound of formula (I) or a compound of formula (I'), and/or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of KRAS G12D-related disorders such as cancer. As a separate agent or in combination with other active ingredients.
The presently disclosed therapeutic compounds wherein the substituent R in the compound of formula (I) or the compound of formula (I') 1 Radicals to R 6 At least one of the groups is D.
The present disclosure relates to at least one compound of formula (I) or (I'):
Figure BDA0004093773770000031
wherein:
m is selected from integers from 1 to 4;
X 0 h, D, halogen, C 1-4 Alkyl, C 1-4 A hydroxyalkyl group; each of which may be substituted with a 3-to 7-membered heterocyclic ring having one or more heteroatoms independently selected from N, O or S, and at least one of which is N, the heteroatoms being directly attached to C 1-4 Alkyl or C 1-4 One of the C atoms of the hydroxyalkyl group; 3-to 7-membered heterocycles are additionally optionally substituted by-CH 3 or-N (CH) 3 ) 2 Substitution;
y is C or N;
R 1 、R 2 independently selected from H, D, -CH 3 ；R 1 、R 2 And R is 1 And R is 2 The C atom attached to may form a 3-to 5-membered cycloalkyl, 3-to 5-membered heterocycloalkyl;
R 3 is H, D, C 1-3 Alkyl, C 1-3 A hydroxyalkyl group; each of which may be substituted with a 3-to 7-membered heterocyclic ring having one or more heteroatoms independently selected from N, O or S, and at least one of which is N, the heteroatoms being directly attached to C 1-4 Alkyl or C 1-4 One of the C atoms of the hydroxyalkyl group; 3-to 7-membered heterocycles are additionally optionally substituted by-CH 3 or-N (CH) 3 ) 2 Substitution;
R 1 to R 6 At least one of them is D;
R 4 to R 6 Selected from H, -OH, -NH 2 D and F;
r is independently:
Figure BDA0004093773770000041
wherein:
n is 0, 1 or 2;
q is an integer from 0 to 3;
X 1 is H, -CH 2 CN、C 1-3 Alkyl, C 1-3 An alkoxy group;
X 2 is a 6-to 10-membered aryl or a 5-to 10-membered heteroaryl, said 6-to 10-membered aryl being selected from phenyl or naphthyl, wherein phenyl or naphthyl is optionally substituted with one or more R 2x Substitution; the 5-to 10-membered heteroaryl is optionally substituted with one or more R 2x Substitution;
R 2x independently selected from F, cl, -OH, -NH 2 、C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Deuterated alkynyl, cyano, (C) 1-3 Alkoxy) C 1-3 Alkyl, (C) 1-3 Alkoxy) C 1-3 Alkoxy, (C) 1-3 Hydroxyalkoxy) C 1-3 An alkoxy group;
X 3 independently selected from F, cl, C 1-3 Alkyl or C 1-3 An alkoxy group;
Figure BDA0004093773770000042
is a single bond or a double bond;
5 x is N or CR 7 Wherein
i) When (when) 5 When X is N, the number of the N-type fluorescent lamp,
Figure BDA0004093773770000043
is a double bond;
ii) when 5 X is CR 7 In the time-course of which the first and second contact surfaces,
Figure BDA0004093773770000044
is a single bond or a double bond;
R 7 is H, halogen, -CH 3 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein two R 7 Along with two R 7 The C atom to which it is attached may form oxo (=o), two R 7 Forming a lactam together with the N atom on the ring; 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycle;
w is O or NR w Wherein R is w Is H, C 1-3 An alkyl group.
In one embodiment, there is provided a deuterated compound of formula (I) having the structure of formula (II-a) wherein n, W, X 0 To X 3 、R 1 To R 6 Defined in the first aspect as:
Figure BDA0004093773770000051
in one embodiment, there is provided a deuterated compound of formula (I) having the structure of formula (II-b) wherein W, X 0 To X 3 、R 1 To R 6 Defined in the first aspect as:
Figure BDA0004093773770000052
in another embodiment, there is provided a deuterated compound of formula (I) having the structure of formula (III-a) wherein m, n, W, X 0 To X 3 、Y、R 1 To R 5 Defined in the first aspect as:
Figure BDA0004093773770000053
in another embodiment, there is provided a deuterated compound of formula (I) having the structure of formula (III-b) wherein m, W, X 0 To X 3 、R 1 To R 5 Defined in the first aspect as:
Figure BDA0004093773770000061
in another embodiment, there is provided a deuterated compound of formula (I) having the structure of formula (IV-a) wherein n, q,
Figure BDA0004093773770000062
W、X 0 To X 2 、 5 X、R 1 To R 7 Defined in the first aspect as:
Figure BDA0004093773770000063
in another embodiment, there is provided a deuterated compound of formula (I) having the structure of formula (IV-b) wherein q,
Figure BDA0004093773770000064
W、X 0 To X 2 、 5 X and R 1 To R 7 Defined in the first aspect as:
Figure BDA0004093773770000065
in another embodiment, there is provided a deuterated compound of formula (I) having the structure of formula (V-a) wherein m, n, q,
Figure BDA0004093773770000066
W、X 0 To X 2 、 5 X、R 1 To R 5 And R is 7 Defined in the first aspect as:
Figure BDA0004093773770000071
in another embodiment, there is provided a deuterated compound of formula (I) having the structure of formula (V-b) wherein m, q,
Figure BDA0004093773770000072
W、X 0 To X 2 、 5 X、R 1 To R 5 And R is 7 Defined in the first aspect as:
Figure BDA0004093773770000073
Detailed Description
In one aspect, the present invention relates to at least one compound of formula (I), and PROTAC compounds comprising a moiety of formula (I)
Figure BDA0004093773770000074
Or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers thereof,
wherein:
X 0 is H, deuterium, halogen, OH, NH 2 、CN、C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 An alkoxy group; and each of which may independently be optionally unsubstituted or independently optionally substituted with a 3-to 7-membered heterocyclic ring having one or more heteroatoms independently selected from N, O or S, and at least one of which is N, the heteroatoms being directly attached to C 1-6 Alkyl or C 1-6 One of the C atoms of the hydroxyalkyl group; 3-to 7-membered heterocycles are additionally optionally substituted by-CH 3 or-N (CH) 3 ) 2 Substitution;
R 1 and R is 2 Each of which is independently selected from H, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
R 3 and R is 4 Each of which is independently selected from H, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-4 Alkyl or-C 1-4 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, halogen, -NH 2 、-NHC(O)NHC 1-6 Alkyl, -NHC (O) N (C) 1-6 Alkyl group 2 、-OH、-OC(O)NHC 1-6 Alkyl, -OC (O) N (C) 1-6 Alkyl group 2 、
Figure BDA0004093773770000083
-C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
R 5 And R is 6 Each of which is independently selected from H, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
and R is 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least one of which is deuterium;
r is independently:
Figure BDA0004093773770000081
wherein:
n is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
X 1 is H, -CH 2 CN、C 1-6 Alkyl or C 1-6 An alkoxy group;
X 2 is a 6-to 10-membered aryl or a 5-to 10-membered heteroaryl; and each of the 6-to 10-membered aryl or 5-to 10-membered heteroaryl is independently optionally unsubstituted or independently optionally substituted with one or more R 2x Substitution;
R 2x each of which is independently selected from halogen, -OH, -NH 2 、-CN、C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Deuterated alkynyl, cyano, (C) 1-6 Alkoxy) C 1-6 Alkyl, (C) 1-6 Alkoxy) C 1-6 Alkoxy, (C) 1-6 Hydroxyalkoxy) C 1-6 Alkoxy, 3-to 7-membered cycloalkyl or 3-to 7-membered heterocycloalkyl; and each of which is independently optionally unsubstituted or independently optionally substituted with one or more-NH' s 2 Halogen, deuterium, -CN, -OH, -C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
X 3 independently selected from H, halogen, C 1-6 Alkyl or C 1-6 An alkoxy group;
Figure BDA0004093773770000082
is a single bond or a double bond;
5 x is N or CR7, wherein
i) When (when) 5 X is N or 5 X is CR 7 In the time-course of which the first and second contact surfaces,
Figure BDA0004093773770000091
is a double bond;
ii) when 5 X is C (R) 7 ) 2 Or (b) 5 X is NR 7 In the time-course of which the first and second contact surfaces,
Figure BDA0004093773770000092
is a single bond;
R 7 independently H, halogen, -C 1-6 Alkyl or substituted by one or more halogens, deuterium, -OH or NH 2 substituted-C 1-6 An alkyl group; or (b)
Two R 7 Along with two R 7 The C atoms to which both are attached form oxo (=o), where oxo together with X 2 To which the N atom is attached to form a lactam, or
R 7 And R is 7 Together with the C atom to which they are each attached form a 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycle; or (b)
W is O or NR w And R is w Is H, deuterium or C 1-6 An alkyl group.
In certain embodiments of formula (I), X 0 Is H, deuterium, F, cl, OH, NH 2 、CN、C 1-3 Alkyl, C 1-3 Hydroxyalkyl or C 1-3 Alkoxy, and each of which may independently be optionally unsubstituted or independently optionally substituted with a 3-to 7-membered heterocyclic ring having one or more heteroatoms independently selected from N, O or S, and at least one of which is N, the heteroatoms being directly attached to C 1-3 Alkyl or C 1-3 One of the C atoms of the hydroxyalkyl group; 3-to 7-membered heterocycles are additionally optionally substituted by-CH 3 or-N (CH) 3 ) 2 And (3) substitution.
In certain embodiments of formula (I), X 0 Is H, deuterium, F, cl, OH, NH 2 CN, methyl or methoxy.
In certain embodiments of formula (I), wherein X 0 Is H.
In certain embodiments of formula (I), R 1 And R is 2 In (a) and (b)Each independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
In certain embodiments of formula (I), R 1 And R is 2 Each of which is independently selected from H, deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy, and each of which is independently optionally unsubstituted or independently optionally deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy substitution.
In certain embodiments of formula (I), R 1 And R is 2 Independently selected from H or deuterium.
In certain embodiments of formula (I), R 3 And R is 4 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, F, cl, -NH 2 、-CN、-OH、-NHC(O)NHC 1-3 Alkyl, -NHC (O) N (C) 1-3 Alkyl group 2 、-OC(O)NHC 1-3 Alkyl, -CH 2 OC(O)N(C 1-3 Alkyl group 2 、
Figure BDA0004093773770000093
-C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
In certain embodiments of formula (I), R 3 And R is 4 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-CH 2 NHC(O)NHMe、-CH 2 NHC(O)N(Me) 2 、-OH、-CH 2 OH、-CH 2 OC(O)NHMe、-CH 2 OC(O)N(Me) 2 、
Figure BDA0004093773770000101
Methyl or methoxy, and each of which is independently optionallyUnsubstituted or independently optionally substituted with deuterium, F, cl, -NH 2 、NHC(O)NHMe、-NHC(O)N(Me) 2 、-OH、-OC(O)NHMe、-OC(O)N(Me) 2 、
Figure BDA0004093773770000102
Methyl or methoxy substitution.
In certain embodiments of formula (I), R 3 And R is 4 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-CH 2 NHC(O)NHMe、-CH 2 NHC(O)N(Me) 2 、-OH、-CH 2 OH、-CH 2 OC(O)NHMe、-CH 2 OC(O)N(Me) 2 、
Figure BDA0004093773770000103
Methyl or methoxy.
In certain embodiments of formula (I), R 3 And R is 4 Independently selected from H or deuterium.
In certain embodiments of formula (I), R 5 And R is 6 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
In certain embodiments of formula (I), R 5 And R is 6 Each of which is independently selected from H, deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy, and each of which is independently optionally unsubstituted or independently optionally deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy substitution.
In certain embodiments of formula (I), R 5 And R is 6 Independently selected from H, deuterium, OH, or F.
In certain embodiments of formula (I), R 1 、R 2 、R 3 、R 4 、R 5 And R is 5 At least one of which isDeuterium; and R is 5 Is deuterium.
In certain embodiments of formula (I), R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least one of which is deuterium; and R is 6 Is deuterium.
In certain embodiments of formula (I), R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least two of which are deuterium; and R is 1 And R is 2 Both are deuterium.
In certain embodiments of formula (I), R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least two of which are deuterium; and R is 3 And R is 4 Both are deuterium.
In certain embodiments of formula (I), R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least three of (a) are deuterium; and R is 1 And R is 2 Both are deuterium, and R 5 Deuterium or R6 is deuterium.
In certain embodiments of formula (I), R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least three of (a) are deuterium; and R is 3 And R is 4 Is deuterium, and R 5 Is deuterium or R 6 Is deuterium.
In certain embodiments of formula (I), R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least four of which are deuterium; and R is 1 And R is 2 Both are deuterium, and R 3 And R is 4 Both are deuterium.
In certain embodiments of formula (I), R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 Is deuterium; and R is 1 And R is 2 Both are deuterium, and R 3 And R is 4 Both are deuterium, and R 5 Is deuterium or R 6 Is deuterium.
In certain embodiments of formula (I), R is independently:
Figure BDA0004093773770000111
in certain embodiments of formula (I), R is independently:
Figure BDA0004093773770000112
In certain embodiments of formula (I), R is independently:
Figure BDA0004093773770000113
in certain embodiments of formula (I), R is independently:
Figure BDA0004093773770000114
in certain embodiments of formula (I), n is 2.
In certain embodiments of formula (I), X 1 Is H, -CH 2 CN、C 1-3 Alkyl or C 1-3 An alkoxy group.
In certain embodiments of formula (I), X 1 Is H, -CH 2 CN, methyl or methoxy.
In certain embodiments of formula (I), X 1 Is H.
In certain embodiments of formula (I), X 2 Is phenyl, naphthyl or 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl; and each of phenyl, naphthyl or 5-to 10-membered heteroaryl is independently optionally unsubstituted or independently optionally substituted with 1R 2x 2R 2x Or 3R 2x And (3) substitution.
In certain embodiments of formula (I), X 2 Is phenyl, naphthyl or 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl or 8-membered heteroaryl; and each of phenyl, naphthyl, or 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, or 8-membered heteroaryl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
At a certain positionIn some embodiments of formula (I), X 2 Is phenyl or naphthyl, and each of the phenyl or naphthyl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
In certain embodiments of formula (I), X 2 Is phenyl, and phenyl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
In certain embodiments of formula (I), X 2 Is naphthyl, and naphthyl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
In certain embodiments of formula (I), R 2x Each of which is independently selected from F, cl, -OH, -NH 2 、-CN、C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Deuterated alkynyl, cyano, (C) 1-3 Alkoxy) C 1-3 Alkyl, (C) 1-3 Alkoxy) C 1-3 Alkoxy, (C) 1-3 Hydroxyalkoxy) C 1-3 Alkoxy, 3-or 4-membered cycloalkyl, or 3-or 4-membered heterocycloalkyl; and each of which is independently optionally unsubstituted or independently optionally substituted with 1, 2 or 3-NH 2 F, cl, deuterium, -CN, -OH, -C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
In certain embodiments of formula (I), R 2x Each of which is independently selected from F, cl, -OH, -NH 2 -CN, methyl, ethyl, methoxy, methyl substituted with 3F, methyl substituted with 3 Cl, ethyl substituted with 3F, vinyl, ethynyl substituted with deuterium, or cyano, 3 membered cycloalkyl, or 3 membered heterocycloalkyl; and each of which is independently optionally unsubstituted or independently optionally substituted with 1, 2 or 3-NH 2 F, cl, deuterium, -CN, -OH, methyl or methoxy substitution.
In certain embodiments of formula (I), R 2x Each of which is independently selected from F, cl, -OH, methyl substituted with 3F, vinylAn ethynyl group or a cyclopropyl group; and each of which is independently optionally unsubstituted or independently optionally substituted with 3F, 3 deuterium or methyl groups.
In certain embodiments of formula (I), X 3 Independently selected from H, F, cl, C 1-3 Alkyl or C 1-3 An alkoxy group.
In certain embodiments of formula (I), X 3 Independently selected from H, F, cl, methyl or methoxy.
In certain embodiments of formula (I), X 3 Independently selected from F.
In certain embodiments of formula (I),
Figure BDA0004093773770000121
is a single bond.
In certain embodiments of formula (I),
Figure BDA0004093773770000122
is a double bond.
In certain embodiments of formula (I), 5 x is N, and the number of the X is N,
Figure BDA0004093773770000123
is a double bond; or (b) 5 X is C (R) 7 ) 2 ，
Figure BDA0004093773770000124
Is a single bond.
In certain embodiments of formula (I), 5 x is CR 7 ，R 7 H, F, cl, -C independently 1-3 Alkyl or substituted by 1, 2 or 3F, cl, deuterium, -OH or NH 2 substituted-C 1-3 An alkyl group.
In certain embodiments of formula (I), 5 x is CR 7 ，R 7 Is independently H, F, cl, methyl or is substituted with 1, 2 or 3F, cl, deuterium, -OH or NH 2 Substituted methyl.
In certain embodiments of formula (I), R 7 And R is 7 Together with the C atoms to which they are each attached form a 3-membered ringAlkyl, 4-membered cycloalkyl, 5-membered cycloalkyl or 6-membered cycloalkyl, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle or 6-membered heterocycle.
In certain embodiments of formula (I), R 7 And R is 7 Together with the C atom to which they are each attached form a 5-or 6-membered cycloalkyl or a 5-or 6-membered heterocycle.
In certain embodiments of formula (I), two R 7 Along with two R 7 The C atoms to which both are attached form oxo (=o), where oxo together with X 2 The N atom attached to forms a 4-, 5-, or 6-membered lactam with one or two N.
In certain embodiments of formula (I), 5 x is N, and
Figure BDA0004093773770000131
is a double bond.
In certain embodiments of formula (I), W is NR w And R is w Is H, deuterium or C 1-3 An alkyl group.
In certain embodiments of formula (I), W is NR w And R is w Is H, deuterium, methyl or ethyl.
In certain embodiments of formula (I), W is NR w And R is w Is H.
In certain embodiments of formula (I), W is O.
In another aspect, the invention relates to at least one compound of formula (I '), or a PROTAC compound comprising a moiety of formula (I')
Figure BDA0004093773770000132
Or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers thereof,
wherein:
m is selected from 1, 2, 3 or 4.
X 0 Is H, deuterium, halogen, OH, NH 2 、CN、-NHC(O)NHC 1-6 Alkyl, -NHC(O)N(C 1-6 Alkyl group 2 、-OH、-OC(O)NHC 1-6 Alkyl, -OC (O) N (C) 1-6 Alkyl group 2 、
Figure BDA0004093773770000133
-C 1-6 Alkyl NHC (O) NHC 1-6 Alkyl, -C 1-6 Alkyl NHC (O) N (C) 1-6 Alkyl group 2 、-OH、-CH 2 OH、-CH 2 OC(O)NHC 1-6 Alkyl, -CH 2 OC(O)N(C 1-6 Alkyl group 2 、
Figure BDA0004093773770000134
C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, or C 1-6 An alkoxy group; and each of which may independently be optionally unsubstituted or independently optionally substituted with a 3-to 7-membered heterocyclic ring having one or more heteroatoms independently selected from N, O or S, and at least one of which is N, the heteroatoms being directly attached to C 1-6 Alkyl or C 1-6 One of the C atoms of the hydroxyalkyl group; 3-to 7-membered heterocycles are additionally optionally substituted by-CH 3 or-N (CH) 3 ) 2 Substitution;
y is C (R) N ) 2 Or NR (NR) N ；R N Each of which is independently H, deuterium, halogen, -NH 2 、-CN、-OH、-NHC(O)NHC 1-6 Alkyl, -NHC (O) N (C) 1-6 Alkyl group 2 、-OH、-OC(O)NHC 1-6 Alkyl, -OC (O) N (C) 1-6 Alkyl group 2 、
Figure BDA0004093773770000141
C 1-6 Alkyl NHC (O) NHC 1-6 Alkyl, -C 1-6 Alkyl NHC (O) N (C) 1-6 Alkyl group 2 、-OH、-C 1-6 Alkyl OH, -C 1-6 Alkyl OC (O) NHC 1-6 Alkyl, -C 1-6 Alkyl OC (O) N (C) 1-6 Alkyl group 2 、
Figure BDA0004093773770000142
C 1-6 Alkyl, -C 1-6 Alkoxy or +.>
Figure BDA0004093773770000143
R 1 And R is 2 Each of which is independently selected from H, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
R 3 and R is 4 Each of which is independently selected from H, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-4 Alkyl or-C 1-4 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
R 5 each of which is independently selected from H, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
and R is 1 、R 2 、R 3 、R 4 And R is 5 At least one of which is deuterium;
r is independently:
Figure BDA0004093773770000144
wherein:
n is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
X 1 is H, -CH 2 CN、C 1-6 Alkyl or C 1-6 An alkoxy group;
X 2 is 6 yuan to10 membered aryl or 5 to 10 membered heteroaryl; and each of the 6-to 10-membered aryl or 5-to 10-membered heteroaryl is independently optionally unsubstituted or independently optionally substituted with one or more R 2x Substitution;
R 2x each of which is independently selected from halogen, -OH, -NH 2 、-CN、C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Deuterated alkynyl, cyano, (C) 1-6 Alkoxy) C 1-6 Alkyl, (C) 1-6 Alkoxy) C 1-6 Alkoxy, (C) 1-6 Hydroxyalkoxy) C 1-6 Alkoxy, 3-to 7-membered cycloalkyl or 3-to 7-membered heterocycloalkyl; and each of which is independently optionally unsubstituted or independently optionally substituted with one or more-NH' s 2 Halogen, deuterium, -CN, -OH, -C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
X 3 independently selected from H, halogen, C 1-6 Alkyl or C 1-6 An alkoxy group;
Figure BDA0004093773770000151
is a single bond or a double bond;
5 x is N or CR 7 Wherein
i) When (when) 5 X is N or 5 X is CR 7 In the time-course of which the first and second contact surfaces,
Figure BDA0004093773770000152
is a double bond;
ii) when 5 X is C (R) 7 ) 2 Or (b) 5 X is NR 7 In the time-course of which the first and second contact surfaces,
Figure BDA0004093773770000153
is a single bond.
R 7 Independently H, halogen, -C 1-6 Alkyl or substituted by one or more halogens, deuterium, -OH or NH 2 substituted-C 1-6 An alkyl group; or (b)
Two R 7 Along with two R 7 The C atoms to which both are attached form oxo (=o), where oxo is with X 2 To which the N atom is attached to form a lactam, or
R 7 And R is 7 Together with the C atom to which they are each attached form a 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycle; or (b)
W is O or NR w And R is w Is H, deuterium or C 1-3 An alkyl group.
In certain embodiments of formula (I'), wherein X 0 Is H, deuterium, F, cl, OH, NH 2 、CN、-C 1-3 Alkyl NHC (O) NHC 1-3 Alkyl, -C 1-3 Alkyl NHC (O) N (C) 1-3 Alkyl group 2 、-OH、-C 1-3 Alkyl OH, -C 1-3 Alkyl OC (O) NHC 1-3 Alkyl, -C 1-3 Alkyl OC (O) N (C) 1-3 Alkyl group 2 、
Figure BDA0004093773770000154
C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or C 1-3 Alkoxy, and each of which may independently be optionally unsubstituted or independently optionally substituted with a 3-to 7-membered heterocyclic ring having one or more heteroatoms independently selected from N, O or S and at least one of which is N, the heteroatoms being directly attached to C 1-3 Alkyl or C 1-3 One of the C atoms of the hydroxyalkyl group; the 3-to 7-membered heterocycle is additionally optionally unsubstituted or additionally optionally substituted by-CH 3 or-N (CH) 3 ) 2 And (3) substitution.
In certain embodiments of formula (I'), X 0 Is H, deuterium, F, cl, OH, NH 2 、CN、-NHC(O)NHMe、-NHC(O)N(Me) 2 、-OH、-MeOH、-OC(O)NHMe、-OC(O)N(Me) 2 、
Figure BDA0004093773770000155
Methyl or methoxy.
In certain embodiments of formula (I'), wherein X 0 Is H.
In certain embodiments of formula (I'), R 1 And R is 2 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
In certain embodiments of formula (I'), R 1 And R is 2 Each of which is independently selected from H, deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy, and each of which is independently optionally unsubstituted or independently optionally deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy substitution.
In certain embodiments of formula (I'), R 1 And R is 2 Independently selected from H or deuterium.
In certain embodiments of formula (I'), R 3 And R is 4 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
In certain embodiments of formula (I'), R 3 And R is 4 Each of which is independently selected from H, deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy, and each of which is independently optionally unsubstituted or independently optionally deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy substitution.
In certain embodiments of formula (I'), R 3 And R is 4 Independently selected from H or deuterium.
In certain embodiments of formula (I'), R 5 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
In certain embodiments of formula (I'), R 5 Each of which is independently selected from H, deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy, and each of which is independently optionally unsubstituted or independently optionally deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy substitution.
In certain embodiments of formula (I'), R 5 Independently selected from H, deuterium, or F.
In certain embodiments of formula (I'), R 1 、R 2 、R 3 、R 4 And R is 5 At least one of which is deuterium; and R is 5 Is deuterium.
In certain embodiments of formula (I'), R 1 、R 2 、R 3 、R 4 And R is 5 At least two of which are deuterium; r is R 1 And R is 2 Both are deuterium.
In certain embodiments of formula (I'), R 1 、R 2 、R 3 、R 4 And R is 5 At least two of which are deuterium; r is R 3 And R is 4 Both are deuterium.
In certain embodiments of formula (I'), R 1 、R 2 、R 3 、R 4 And R is 5 At least three of (a) are deuterium; r is R 1 And R is 2 Both are deuterium, and R 5 Is deuterium.
In certain embodiments of formula (I'), R 1 、R 2 、R 3 、R 4 And R is 5 At least three of (a) are deuterium; r is R 3 And R is 4 Is deuterium, and R 5 Is deuterium.
In certain embodiments of formula (I'), R 1 、R 2 、R 3 、R 4 And R is 5 At least four of (a) are deuterium, R 1 And R is 2 Both of which are deuterium and which are both a noble metal,and R is 3 And R is 4 Both are deuterium.
In certain embodiments of formula (I'), R 1 、R 2 、R 3 、R 4 And R is 5 All of which are deuterium.
In certain embodiments of formula (I'), R is independently:
Figure BDA0004093773770000171
In certain embodiments of formula (I'), R is independently:
Figure BDA0004093773770000172
in certain embodiments of formula (I'), R is independently:
Figure BDA0004093773770000173
in certain embodiments of formula (I'), R is independently:
Figure BDA0004093773770000174
in certain embodiments of formula (I'), n is 2.
In certain embodiments of formula (I'), X 1 Is H, -CH 2 CN、C 1-3 Alkyl or C 1-3 An alkoxy group.
In certain embodiments of formula (I'), X 1 Is H, -CH 2 CN, methyl or methoxy.
In certain embodiments of formula (I'), X 1 Is H.
In certain embodiments of formula (I'), X 2 Is phenyl, naphthyl or 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl; and each of phenyl, naphthyl or 5-to 10-membered heteroaryl is independently optionally unsubstituted or independently optionally substituted with 1R 2x 2R 2x Or 3R 2x And (3) substitution.
In some casesIn an embodiment of (I'), X 2 Is phenyl, naphthyl or 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl or 8-membered heteroaryl; and each of phenyl, naphthyl, or 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, or 8-membered heteroaryl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
In certain embodiments of formula (I'), X 2 Is phenyl or naphthyl, and each of the phenyl or naphthyl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
In certain embodiments of formula (I'), X 2 Is phenyl, and phenyl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
In certain embodiments of formula (I'), X 2 Is naphthyl, and naphthyl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
In certain embodiments of formula (I'), R 2x Each of which is independently selected from F, cl, -OH, -NH 2 、-CN、C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Deuterated alkynyl, cyano, (C) 1-3 Alkoxy) C 1-3 Alkyl, (C) 1-3 Alkoxy) C 1-3 Alkoxy, (C) 1-3 Hydroxyalkoxy) C 1-3 Alkoxy, 3-or 4-membered cycloalkyl, or 3-or 4-membered heterocycloalkyl; and each of which is independently optionally unsubstituted or independently optionally substituted with 1, 2 or 3-NH 2 F, cl, deuterium, -CN, -OH, -C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
In certain embodiments of formula (I'), R 2x Each of which is independently selected from F, cl, -OH, -NH 2 -CN, methyl, ethyl, methoxy, cyclopropyl, methyl substituted with 3F, methyl substituted with 3 Cl, ethyl substituted with 3F, vinyl, ethynyl substituted with deuteriumA group, or cyano; and each of which is independently optionally unsubstituted or independently optionally substituted with 1, 2 or 3-NH 2 F, cl, deuterium, -CN, -OH, methyl or methoxy substitution.
In certain embodiments of formula (I'), R 2x Independently selected from F, cl, -OH, methyl substituted with 3F, vinyl, ethynyl, or cyclopropyl; and each of which is independently optionally unsubstituted or independently optionally substituted with 3F, 3 deuterium or methyl groups.
In certain embodiments of formula (I'), X 3 Independently selected from H, F, cl, C 1-3 Alkyl or C 1-3 An alkoxy group.
In certain embodiments of formula (I'), X 3 Independently selected from H, F, cl, methyl or methoxy.
In certain embodiments of formula (I'), X 3 Independently selected from F.
In certain embodiments of formula (I'),
Figure BDA0004093773770000181
is a single bond.
In certain embodiments of formula (I'),
Figure BDA0004093773770000182
is a double bond.
In certain embodiments of formula (I'), 5 x is N, and the number of the X is N,
Figure BDA0004093773770000183
Is a double bond; or (b) 5 X is C (R) 7 ) 2 ，
Figure BDA0004093773770000184
Is a single bond.
In certain embodiments of formula (I'), 5 x is CR 7 ，R 7 H, F, cl, -C independently 1-3 Alkyl or substituted by 1, 2 or 3F, cl, deuterium, -OH or NH 2 substituted-C 1-3 Alkyl group。
In certain embodiments of formula (I'), 5 x is CR 7 ，R 7 Is independently H, F, cl, methyl or is substituted with 1, 2 or 3F, cl, deuterium, -OH or NH 2 Substituted methyl.
In certain embodiments of formula (I'), R 7 And R is 7 Together with the C atom to which they are each attached form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl or 6-membered cycloalkyl, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle or 6-membered heterocycle.
In certain embodiments of formula (I'), R 7 And R is 7 Together with the C atom to which they are each attached form a 5-or 6-membered cycloalkyl, or a 5-or 6-membered heterocycle.
In certain embodiments of formula (I '), two R' s 7 Along with two R 7 The C atoms to which both are attached form oxo (=o), where oxo together with X 2 The N atom attached to forms a 4-, 5-, or 6-membered lactam with one or two N.
In certain embodiments of formula (I'), 5 x is N, and
Figure BDA0004093773770000191
is a double bond.
In certain embodiments of formula (I'), W is NR w And R is w Is H, deuterium or C 1-3 An alkyl group.
In certain embodiments of formula (I'), W is NR w And R is w Is H, deuterium, methyl or ethyl.
In certain embodiments of formula (I'), W is NR w And R is w Is H.
In certain embodiments of formula (I'), W is O.
In certain embodiments of formula (I'), R N Each of (a) is independently H, deuterium, F, cl, -NH 2 、-CN、-OH、-CH 2 NHC(O)NHC 1-3 Alkyl, -CH 2 NHC(O)N(C 1-3 Alkyl group 2 、-CH 2 OH、-CH 2 OC(O)NHC 1-3 Alkyl, -CH 2 OC(O)N(C 1-3 Alkyl group 2 、
Figure BDA0004093773770000192
-C 1-3 Alkyl, -C 1-3 Alkoxy or +.>
Figure BDA0004093773770000193
In certain embodiments of formula (I'), R N Each of (a) is independently H, deuterium, F, cl, -NH 2 、-CH 2 NHC(O)NHMe、-CH 2 NHC(O)N(Me) 2 、-CH 2 OH、-CH 2 OC(O)NHMe、-CH 2 OC (O) NMe, methyl, methoxy or
Figure BDA0004093773770000194
In certain embodiments of formula (I'), R N Each of which is independently H, deuterium, F or
Figure BDA0004093773770000195
In certain embodiments of formula (I'), one R N Is H, deuterium, or F; other R N Is that
Figure BDA0004093773770000196
And Y is C (R) N ) 2 。
In certain embodiments of formula (I'), R N Is that
Figure BDA0004093773770000197
And Y is NR N 。
Furthermore, exemplary compounds (exemplary compounds) of the present disclosure are listed below:
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine) -7a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4-(4-((1R，5S) -3, 8-diazabicyclo [3.2.1]Octane-3-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4-mono (4- ((1 r, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((S) -1- (methyl-d 3) pyrrolidin-2-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) -pyrrolidin-2-yl) methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4-1- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4，3-d]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido-s[4，3-d]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -8-oxa-3-azabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (3, 6-diazabicyclo [ 3.2.1)]Heptane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1-methylpyrrole)Alk-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2) ]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [2.2 ]).2]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d ] pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((1- (pioglyc)Pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro)-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoro) Methyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1 r, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d 3) pyrrolidin-2-yl) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d ]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine)-7a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -6- (trifluoromethyl) pyridineAnd [3,4-d ]]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d ]Pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetralinhydrogen-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidine-8 (7H)A ketone;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo[3.2.1]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d ]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidine-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-7 (8H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ] ]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4-(4-((1R，5S)-3, 8-diazabicyclo [3.2.1]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ] ]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ] ]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ] ]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo)[3.2.1]Octane-3-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy-d 2) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy-d 2) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1 r, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d ]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalene-1-Radical) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d ]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methyl)Oxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetray-l)hydrogen-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7-mono (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2) ]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidine-8(7H) -a ketone;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4-mono (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -6- (trifluoromethyl) pyrido[3，4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d 3) pyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4-mono (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d 3) pyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d ]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d ]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7,8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrido[3，4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4-mono (2, 5-diazabicyclo [ 2.2.2) ]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- ((dimethylamino)Group) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2) ]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((tetrayhydrogen-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-7 (8H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H)-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1- (methyl-d 3) pyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -58-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d ]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2) ]Octane-2-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diaza)Bicyclo [2.2.2]Octane-2-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo-parallel[2.2.2]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxyNaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2-mono (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy-d 2) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2) ]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2-)(trifluoromethyl) phenyl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- ((. About.)R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinyl) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) -d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
3- (4- (1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
3- (4- (1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -4-cyclopropyl-5-fluorophenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol; or (b)
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -4-cyclopropyl-5-fluorophenol.
Furthermore, the present invention discloses a pharmaceutical composition comprising a therapeutically effective amount of at least one compound as defined above or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers thereof, and pharmaceutically acceptable excipients.
In certain embodiments of the pharmaceutical compositions, the pharmaceutical compositions comprise a therapeutically effective amount of at least one compound as defined above for formula (I), pharmaceutically acceptable salts, prodrugs, hydrates, tautomers and isomers thereof, and pharmaceutically acceptable excipients.
In certain embodiments of the pharmaceutical compositions, the pharmaceutical compositions comprise a therapeutically effective amount of at least one compound as defined by formula (I'), pharmaceutically acceptable salts, prodrugs, hydrates, tautomers and isomers thereof as defined above, and pharmaceutically acceptable excipients.
In certain embodiments of the pharmaceutical compositions, the pharmaceutical compositions comprise a therapeutically effective amount of at least one compound as defined for the exemplary compounds, or pharmaceutically acceptable salts, prodrugs, hydrates, tautomers and isomers thereof as defined above, and pharmaceutically acceptable excipients.
Furthermore, the present invention discloses a method of inhibiting KRAS G12D activity in a cell, comprising contacting a cell wherein inhibition of KRAS G12D activity is desired with a therapeutically effective amount of at least one compound as defined above or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer and isomer thereof.
In certain embodiments of the methods, the method for inhibiting KRAS G12D activity in a cell comprises contacting a cell in which inhibition of KRAS G12D activity is desired with a therapeutically effective amount of at least one compound as defined in formula (I), pharmaceutically acceptable salts, prodrugs, hydrates, tautomers and isomers thereof as defined above.
In certain embodiments of the methods, the method for inhibiting KRAS G12D activity in a cell comprises contacting a cell in which it is desired to inhibit KRAS G12D activity with a therapeutically effective amount of at least one compound as defined in formula (I'), pharmaceutically acceptable salts, prodrugs, hydrates, tautomers and isomers thereof as defined above.
In certain embodiments of the methods, the method for inhibiting KRAS G12D activity in a cell comprises contacting a cell in which inhibition of KRAS G12D activity is desired with a therapeutically effective amount of at least one compound as defined for the exemplary compounds, pharmaceutically acceptable salts, prodrugs, hydrates, tautomers and isomers thereof as defined above.
Furthermore, the present invention discloses a method for treating KRAS G12D-related cancer, comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound as defined above or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer and isomer thereof.
In certain embodiments of the methods, the method for treating KRAS G12D-related cancer comprises administering to a patient in need thereof a therapeutically effective amount of at least one compound as defined in formula (I), pharmaceutically acceptable salts, prodrugs, hydrates, tautomers and isomers thereof as defined above.
In certain embodiments of the methods, the method for treating KRAS G12D-related cancer comprises administering to a patient in need thereof a therapeutically effective amount of at least one compound as defined by formula (I'), pharmaceutically acceptable salts, prodrugs, hydrates, tautomers and isomers thereof as defined above.
In certain embodiments of the methods, the methods for treating KRAS G12D-related cancer comprise administering to a patient in need thereof a therapeutically effective amount of at least one compound as defined as an exemplary compound, pharmaceutically acceptable salts, prodrugs, hydrates, tautomers, and isomers thereof as defined above.
In certain method embodiments, as in the methods defined above, the therapeutically effective amount of the compound is between about 0.01 mg/kg/day and 100 mg/kg/day.
In certain method embodiments, as in the methods defined above, the therapeutically effective amount of the compound is between about 0.1 mg/kg/day and 50 mg/kg/day.
In embodiments of certain methods, the KRAS G12D-related cancer is selected from the group consisting of: and (3) heart: sarcomas (angiosarcoma), fibrosarcoma, rhabdomyosarcoma (rhabdomyosarcoma), liposarcoma (liposarcoma), myxoma (myxoma), rhabdomyoma (rhabdomyoma), fibromas, lipomas, and teratomas (teratoms); lung: bronchogenic carcinoma (bronchogenic carcinoma) (squamous cell), undifferentiated small cell, undifferentiated large cell, adenocarcinoma (adenoma)), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, lung chomatoid hamartoma (chondromatous hamartoma), mesothelioma (mesothelioma); intestines and stomach: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenoma (ductal adenocarcinoma), insulinoma (insulinoma), glucagon tumor (glucagonoma), gastrinoma (gastrinoma), carcinoid tumor (carcinoid tumor), vasoactive intestinal peptide tumor (vipoma)), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyosarcoma); urogenital tract: kidney (adenocarcinoma, wilm's tumor), lymphoma, leukemia, bladder and urinary tract (squamous cell carcinoma, transitional cell carcinoma (transitional cell carcinoma), adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma), teratoma (terato), embryonal carcinoma (embryonal carcinoma), teratocarcinoma (terato), choriocarcinoma (choriocarcinoma), sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma (fibroadenoma), adenomatoid tumors (adenomatoid tumors), lymphoma; hepatoma (hepatocellular carcinoma), cholangioma (hepatoma), hepatoblastoma (hemangiosarcoma), angiosarcoma, hepatocellular adenoma, hemangioma (hemangioma); bile duct: gall bladder cancer, ampulla cancer (ampullary carcinoma), bile duct cancer; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulocytosoma (reticulum cell sarcoma)), multiple myeloma, malignant giant cell tumor (malignant giant cell tumor), chordoma (chordoma), osteochondral tumor (osteochondral exotosoma (osteocartilaginous exostoses)), benign chondrioma (benign chondroma), chondroblastoma (chondrobaston), chondromyomatoid fibroma (chondromicxofangma), osteoid osteoma (osteoid osteoma) and giant cell tumor (giant cell tumors); the nervous system: skull (bone tumor, hemangioma, granuloma (granuloma), yellow tumor (xanthoma), osteoarthritis of deformity (osteitis deformans)), meninges (meningioma), meningioma (meningioma), glioma (retinosarcoma), glioma (gliomatosis), brain (astrocytoma, medulloblastoma), glioma (glioma), ependymoma, germ cell tumor (germinoma) (pineal tumor (pinealoma)), glioblastoma multiforme (glioblastoma multiform), oligodendroglioma (oligomeroglma), schwannoma (schwannoma), retinoblastoma (retinobastoma), congenital tumor (congenital tumors)), spinal neurofibroma (spinal cord neurofibroma), meningioma, glioma, sarcoma; gynaecology: uterus (endometrial carcinoma, (serous cyst adenocarcinoma (serous cystadenocarcinoma), mucinous cyst adenocarcinoma (mucinous cystadenocarcinoma), unclassified carcinoma), granulosa sheath cell tumors (granulosa-thecal cell tumors), sertoli-Leydig cell tumors (Sertoli-Leydig cell tumors), asexual cell tumors (dysgerminoma), malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma (intraepithelial carcinoma), adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma (clear cell carcinoma), squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma (embryonal rhabdomyosarcoma)), fallopian tubes (carcinoma)); blood: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia (acute lymphoblastic leukemia), chronic lymphoblastic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome (myelodysplastic syndrome)), hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, nevi, dysplastic nevi (moles dysplastic nevi), lymphomas, hemangiomas, cutaneous fibromas (dermotofibrimas), keloids (keloids), psoriasis; adrenal gland: neuroblastoma.
In certain method embodiments, the cancer is non-small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer, as defined above.
Furthermore, the present invention discloses methods for treating cancer in a patient in need thereof, the methods comprising (a) determining that the cancer is associated with a KRAS G12D mutation (e.g., KRAS G12D-associated cancer); and (b) administering to the patient a therapeutically effective amount of at least one compound as defined above.
In certain embodiments of the methods for treating cancer in a patient in need thereof, the methods comprise (a) determining that the cancer is associated with a KRAS G12D mutation (e.g., KRAS G12D-associated cancer); and (b) administering to the patient a therapeutically effective amount of at least one compound as defined above.
In certain embodiments of the methods for treating cancer in a patient in need thereof, the methods comprise (a) determining that the cancer is associated with a KRAS G12D mutation (e.g., KRAS G12D-associated cancer); and (b) administering to the patient a therapeutically effective amount of at least one compound as defined by formula I, formula I', or exemplary compounds.
In certain embodiments of the methods for treating cancer in a patient in need thereof, the methods comprise (a) determining that the cancer is associated with a KRAS G12D mutation (e.g., KRAS G12D-associated cancer); and (b) administering to the patient a therapeutically effective amount of a pharmaceutical composition as defined above.
In certain embodiments of the methods for treating cancer in a patient in need thereof, wherein the administering is via a route selected from the group consisting of: parenteral administration, intraperitoneal administration, transdermal administration, intracardiac administration, intraventricular administration, intracranial administration, intraventricular administration (intracerebrospinal administration), intrasynovial administration, intrathecal administration, intramuscular injection, intravitreal injection (intravitreous injection), intravenous injection, intraarterial injection, oral administration, intranasal administration, buccal administration (buccal), sublingual administration (sublingual administration), transdermal administration, topical administration, intratracheal administration, intrarectal administration, subcutaneous administration, and topical administration.
In certain embodiments of the methods for treating cancer in a patient in need thereof, administration is via intravenous injection.
In certain embodiments of the methods for treating cancer in a patient in need thereof, administration is via intramuscular injection.
In certain embodiments of the methods for treating cancer in a patient in need thereof, administration is via intramuscular injection.
In certain embodiments of the methods for treating cancer in a patient in need thereof, administering comprises employing a delivery device.
In certain embodiments of the methods for treating cancer in a patient in need thereof, administration is via a hospital setting (hospital setting).
It will be understood that the invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present invention encompasses all combinations of aspects and/or embodiments of the invention mentioned herein. It is also to be understood that each individual element of an embodiment is intended to be combined with any element from any embodiment and all other elements to describe additional embodiments.
Definition of the definition
The following description is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. For convenience, headings used in this disclosure are provided and are not to be construed as limiting the claims in any way. The embodiments shown under any heading may be combined with any other of the illustrated heading embodiments.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It should be noted that, as used in this disclosure, the singular forms "a," and "the" include plural referents unless the context clearly dictates otherwise. Thus, "the compound" includes a plurality of such compounds and "assay" includes one or more assays, and the like.
As used in this disclosure, the following words (words), expressions (phrases) and symbols are generally intended to have the same meaning as the words, expressions and symbols listed below, except to the extent that they are otherwise described in the context in which they are used.
For convenience, a short line (dash) "-" is used at the front or end of the chemical group to indicate the attachment point (point of attachment) of the substituent. For example, -OH is attached through a carbon atom; chemical groups may be described with or without one or more short lines without losing their usual meaning. Wavy lines (wavy lines) drawn through lines in the structure indicate the attachment points of the groups. Unless chemically or structurally required, directionality is not indicated or implied by the order in which chemical groups are written or named. Solid lines (solid lines) from the center of the ring indicate that the attachment point of the substituents on the ring can be at any ring atom. For example, X in the following structure 1 May be attached to any of the carbon ring atoms, including the bridging carbon atoms:
Figure BDA0004093773770000611
prefix "C m-n "indicates that the following groups have from m to n carbon atoms. For example, "C 1-8 Alkyl "indicates that the alkyl group has from 1 to 8 carbon atoms. In a similar manner, the term "m-n membered" ring, where m and n are a range of values, e.g. "3-12 membered heterocyclyl", refers to rings containing 3-12 atoms, up to 80% of which may be heteroatoms, e.g. N, O, S, P, and the remaining atoms are carbon.
In addition, some commonly used alternative chemical names may or may not be used. For example, a divalent group such as a divalent "alkyl" group, a divalent "aryl" group, or the like may also be referred to as an "alkylene" group or an "alkenylene" group or an alkynylene group, an "arylene (arylene)" group or an "arylene (arylene)" group, respectively.
"Compound provided herein" or "compound described herein" or "compound disclosed herein" or "compound of the present disclosure" refers to a compound of formula (I), a compound of formula (I'), a compound of formula (II-a), a compound of formula (II-b), a compound of formula (III-a), a compound of formula (III-b), a compound of formula (IV-a), a compound of formula (IV-b), a compound of formula (V-a) and a compound of formula (V-b), which are also used in the specific compounds of examples 1 to 37 or the exemplary compounds mentioned above.
In certain embodiments, the term "about" with respect to a value or parameter itself includes the indicated amount ± 10%, ± 5% or ± 1%. In addition, the term "about X" includes descriptions of "X".
As used herein, "adjoining atoms" refers to atoms in close proximity to each other. For example, in "C1-C2-C3-C4", atom C1 is adjacent to atom C2, atom C2 is adjacent to atom C1 and atom C3, and so on.
The term "alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl groups have 1 to 6 carbon atoms (i.e., C 1-6 Alkyl) or 1 to 10 carbon atoms (i.e., C 1-10 Alkyl). Alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl group having a specified number of carbons is named by chemical name or is identified by molecular formula, all positional isomers having that number of carbons may be included (positional isomers), thus, as an example, "butyl" includes n-butyl (i.e., - (CH) 2 ) 3 CH 3 ) Sec-butyl (i.e., -CH (CH) 3 )CH 2 CH 3 ) Isobutyl (i.e., -CH) 2 CH(CH 3 ) 2 ) Tert-butyl (i.e., -C (CH) 3 ) 3 ) And "propyl" includes n-propyl (i.e., - (CH) 2 ) 2 CH 3 ) And isopropyl (i.e，-CH(CH 3 ) 2 )。
The term "alkenyl" refers to a compound containing at least one carbon-carbon double bond (c=c) and having from 2 to 15 carbon atoms (i.e., C 2-15 Alkenyl) or from 2 to 4 carbon atoms (i.e., C 2-4 Alkenyl) aliphatic groups. Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1, 2-butadienyl and 1, 3-butadienyl).
The term "alkynyl" refers to a compound containing at least one carbon-carbon triple bond (c≡c) and having from 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl) or from 2 to 4 carbon atoms (i.e., C 2-4 Alkynyl), and the like. The term "alkynyl" also includes those groups having one triple bond and one double bond.
The term "alkoxy" refers to the group "-O-alkyl", such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1, 2-dimethylbutoxy. The term "haloalkoxy" refers to an alkoxy group as indicated above wherein one or more hydrogen atoms are replaced with halogen.
The term "acyl" refers to the group-C (=o) R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, and each of which may be optionally substituted, as defined herein. Examples of the acyl group include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and the like.
The term "amide group (amido)" refers to both a "C-amide" group, which refers to the group-C (=o) NR, and an "N-amide" group a R b The term "N-amido" group refers to the group-NR a C(＝O)R b Wherein R is a And R is b Independently selected from the group consisting of: hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, and heterocyclyl; and each of which may be optionally substituted.
"amino" refers to the group-NR a R b This isR at a And R is b Independently selected from the group consisting of: hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; and each of which may be optionally substituted.
The term "aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, an aryl group has 6 to 20 ring carbon atoms (i.e., C 6-20 Aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 Aryl), and the like. Some examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracyl. Herein, aryl does not in any way encompass and does not in any way overlap with heteroaryl as defined below. If one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is heteroaryl.
The term "cyano" group or "nitrile" group is represented by-CN.
The term "cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group (cyclic alkyl group) having a single ring or multiple rings, including fused ring systems, bridged ring systems, and spiro ring systems. The term "cycloalkyl" also includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl groups have from 3 to 20 ring carbon atoms (i.e., C 3-20 Cycloalkyl), from 3 to 8 ring carbon atoms (i.e., C 3-8 Cycloalkyl) or from 3 to 5 ring carbon atoms (i.e., C 3-5 Cycloalkyl), and the like. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "bridged" refers to ring fusion where non-adjacent atoms on the ring are connected by a divalent substituent, such as an alkenyl group, an alkenyl group containing one or two heteroatoms, or a single heteroatom. Examples of bridged ring systems include quinuclidinyl (quinuclidinyl) and adamantyl (admantanyl).
The term "fused" refers to a ring that binds to an adjacent ring.
The term "spiro" (spiro) refers to a ring substituent attached at the same carbon atom through two bonds. Some examples of spiro groups include 1, 1-diethylcyclopentane, dimethyldioxane, and 4-benzyl-4-methylpiperidine, wherein cyclopentane and piperidine are each spiro substituents.
"halogen (halogen)" or "halogen (halo)" includes fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). "haloalkyl" includes unbranched or branched alkyl groups as defined above wherein one or more hydrogen atoms are replaced by halogen. If a residue is substituted with more than one halogen, it may be referred to as by using a prefix (prefix) corresponding to the number of attached halogen moieties. Dihaloalkyl (dihaloalkyl) and trihaloalkyl (trihaloalkyl) refer to alkyl groups substituted with two (two) halogen groups or three (three) halogen groups, which may, but need not, be the same halogen. Some examples of haloalkyl groups include difluoromethyl (-CHF) 2 ) And trifluoromethyl (-CF) 3 )。
The term "heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, the aromatic group having one or more ring heteroatoms independently selected from N, O and S. As used herein, examples include heteroaryl groups including 1 to 20 carbon ring atoms (i.e., C 1-20 Heteroaryl), 3 to 12 carbon ring atoms (i.e., C 3-20 Heteroaryl), and the like, as well as the number of ring heteroatoms, as used therein, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. The term "heteroaryl" does not encompass and overlap with an "aryl" as defined above.
"hydroxyl" or "hydroxyl" refers to the group-OH.
"oxo" refers to the group (=o) or (O).
Unless otherwise indicated, where all groups terminate with a single bonded nitrogen atom, the group represents an-NH group. Similarly, unless otherwise stated, in view of the knowledge of those skilled in the art, (imary) hydrogen atoms are necessarily contained and are considered to be present if necessary to complete the valence (valency) or to provide stability.
"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. In addition, the term "optionally substituted" means that any one or more hydrogen atoms on the indicated atom or group may or may not be substituted with a moiety other than hydrogen.
"substituted" means that one or more hydrogen atoms on a given atom or group are replaced with one or more substituents other than hydrogen under conditions that do not exceed the normal valence of the given atom. Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino (amidino), aryl, azido, carbamoyl (carbamoyl), carbonyl ester, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl (alkylsulfinyl), sulfonic acid, alkylsulfonyl, thiocyanate (thiocyanite), thiol, thione (thio), or combinations thereof. Similar ambiguities obtained by defining substituents with additional substituents attached to infinity are not intended herein (e.g., substituted aryl groups with substituted alkyl groups themselves substituted with substituted aryl groups, which are additionally substituted with substituted heteroalkyl groups, etc.). Unless otherwise mentioned, the maximum number of consecutive substitutions (serial substitutions) in the compounds described herein is three. For example, sequential substitution of a substituted aryl group having two other substituted aryl groups is limited to ((substituted aryl) substituted aryl. Similarly, the above definition is not intended to include impossible substitution types (e.g., methyl substituted with 5 fluorine or heteroaryl groups having two adjacent oxygen ring atoms). Such impossible substitution types are well known to those skilled in the art. In all cases where chemical groups are modified, "substituted" may describe other chemical groups as defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl. Unless explicitly stated otherwise, if a group is described as optionally substituted, any substituents of that group are themselves unsubstituted.
In certain instances, "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxy, halogen, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other instances, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxy; by "substituted heterocyclyl", it is meant a heterocyclyl group having one or more substituents including alkyl, amino, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxy; the term "substituted aryl" refers to aryl groups having one or more substituents including halogen, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; the term "substituted heteroaryl" refers to aryl groups having one or more substituents including halogen, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; the term "substituted heteroaryl" refers to heteroaryl groups having one or more substituents including halogen, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, and cyano; and the term "substituted sulfonyl" refers to the group-S (O) 2 R, where R is one or moreSubstituted with substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other cases, one or more substituents may be additionally substituted with: halogen, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other cases, the substituents may be additionally substituted with: halogen, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
In certain embodiments, substituted cycloalkyl, substituted heterocyclyl, substituted aryl, and/or substituted heteroaryl includes cycloalkyl, heterocyclyl, aryl, and/or heteroaryl groups having substituents on the ring atoms, the ring atoms of the cycloalkyl, heterocyclyl, aryl, and/or heteroaryl groups being attached to the remainder of the compound (rest). For example, in the following moieties, the benzene ring is substituted with a meta-chloro group:
Figure BDA0004093773770000651
herein, a disclosed compound or pharmaceutically acceptable salt thereof may include one or more asymmetric centers and thereby produce tautomers, diastereomers and other stereoisomeric forms, which may be defined as (R) -or (S) -or as (D) -or (L) -for amino acids, depending on absolute stereochemistry. The present disclosure includes all such possible isomers, as well as racemic or optically pure forms thereof. Optically active (+) and (-) isomers, (R) -and (S) -or (D) -and (L) -isomers may be prepared using chiral synthons or chiral reagents or resolved by conventional techniques such as chromatography and fractional crystallization (Qian actional crystallization). Traditional techniques for the preparation, isolation of individual tautomers include chiral synthesis from suitable optically pure precursors (procursors) or resolution of racemates (racemates of salts or derivatives) using, for example, chiral High Performance Liquid Chromatography (HPLC). When the compounds disclosed herein contain olefinic double bonds or other centers of geometric asymmetry, and unless explicitly specified otherwise, these compounds include both the E geometric isomer and the z geometric isomer. Likewise, all tautomeric forms are also intended to be encompassed. Where a compound is represented in its chiral form, it is understood that embodiments include, but are not limited to, specific diastereomerically or tautomerically enriched forms. Where chirality is not explicitly specified but is present, it is understood that embodiments are intended to include specific diastereoisomerically or tautomerically enriched forms; or a racemic or non-racemic (scalemic) mixture of such compounds. "non-racemic mixture" is a stereoisomer to the exclusion of 1:1, and a mixture of ratios other than 1.
The term "stereoisomer" refers to a non-tautomeric compound that contains the same atoms, but has different three-dimensional structures, the same atoms being bonded through the same bonds. The present disclosure encompasses a variety of stereoisomers and mixtures thereof, and includes "tautomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.
The term "tautomer" represents a pair of stereoisomers that are non-superimposable mirror images of each other. The 1:1 mixture of a pair of tautomers is a "racemic" mixture. Mixtures of tautomers in ratios other than 1:1 are "non-racemic" mixtures.
The term "diastereoisomer" represents a stereoisomer having at least two asymmetric atoms, but not mirror images of each other.
The term "PROTAC" stands for proteolytically targeted chimera (proteolysis-targeting chimeras).
The interaction of the solvent and the compound forms a "solvate". Solvates herein also include solvates of salts of the disclosed compounds and hydrates of the compounds provided herein.
The present disclosure includes compounds of formula (I), compounds of formula (I'), compounds of formula (II-a), compounds of formula (II-b), compounds of formula (III-a), compounds of formula (III-b), compounds of formula (IV-a), compounds of formula (IV-b), compounds of formula (V-a) and compounds of formula (V-b), wherein R attached to a carbon atom in the molecule 1 To R 6 At least one of them is a deuterium atom (D). Such compounds have enhanced resistance to metabolism and are therefore useful for increasing the half-life of any compound of formula (I), any compound of formula (I'), any compound of formula (II-a), any compound of formula (II-b), any compound of formula (III-a), any compound of formula (III-b), any compound of formula (IV-a), any compound of formula (IV-b), any compound of formula (V-a) and any compound of formula (V-b) administered to a mammal, particularly a human (Foster "," Deuterium Isotope Effects in Studies of Drug Metabolism "," Trends Pharmacol.Sci.5 (12): 524-527 (1984)). The synthesis of such compounds is accomplished by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced with deuterium.
Deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties involving absorption, distribution, metabolism and excretion (ADME). Improvements in certain therapeutic advantages resulting from stronger metabolic stability, such as increased in vivo half-life, reduced dosage requirements (dosage requirement), and/or therapeutic index (therapeutic index) may be achieved by substitution with heavier isotopes such as deuterium. It should be clarified that in this context deuterium is considered to be R 1 Radicals to R 6 At least one of the radicals being D, R 1 Radicals to R 6 The group is a substituent in the compound of formula (I), the compound of formula (I'), the compound of formula (II-a), the compound of formula (II-b), the compound of formula (III-a), the compound of formula (III-b), the compound of formula (IV-a), the compound of formula (IV-b), the compound of formula (V-a) and the compound of formula (V-b).
The isotopically enriched factor (isotopic enrichment factor) can be used to define the concentration of such heavier isotopes, in particular deuterium. It is understood that in the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. If a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its natural isotopically enriched composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.
In many cases, the compounds of the present disclosure are capable of forming acid salts by virtue of the presence of amino groups or groups similar thereto.
The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. Where the compounds of the present invention are acidic, their corresponding salts may be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases. Where the compounds of the present invention are basic, their corresponding salts may be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of formula (I), formula (I'), formula (II-a), formula (II-b), formula (III-a), formula (III-b), formula (IV-a), formula (IV-b), formula (V-a) and formula (V-b) are intended for pharmaceutical use they are preferably provided in a substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% on a weight to weight basis).
The pharmaceutical composition of the present invention comprises, as an active ingredient, a compound represented by formula (I), formula (I'), formula (II-a), formula (II-b), formula (III-a), formula (III-b), formula (IV-a), formula (IV-b), formula (V-a) and formula (V-b) (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants (adjuvant). Although in any given case, the most suitable route will depend on the particular host (host) and the nature and severity of the condition in which the active ingredient is being administered, compositions include those suitable for oral administration, rectal administration, topical administration and parenteral (including subcutaneous, intramuscular and intravenous) administration. The pharmaceutical compositions may be provided conventionally in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts.
In practice, the compounds represented by formula (I), formula (I'), formula (II-a), formula (II-b), formula (III-a), formula (III-b), formula (IV-a), formula (IV-b), formula (V-a) and formula (V-b) or prodrugs thereof or metabolites thereof or pharmaceutically acceptable salts thereof according to conventional drug mixing techniques (conventional pharmaceutical compounding technique) of the present invention may be combined as an active ingredient with a drug carrier in a close admixture (intimate admixture). The carrier may take a variety of forms depending on the form of formulation (preparation) desired for administration, such as oral administration or parenteral administration (including intravenous administration). Thus, the pharmaceutical composition of the invention may be provided as discrete units (discrete units) suitable for oral administration, such as capsules, cachets (cachets) or tablets, each containing a predetermined amount of the active ingredient. In addition, the composition may be provided as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the usual dosage forms set out above, the compounds represented by formula I or formula I' or pharmaceutically acceptable salts thereof may also be administered by controlled release means (controlled release mean) and/or delivery devices. The composition may be prepared by any of the methods of pharmacy. Typically, such methods include the step of bringing into association the active ingredient with a carrier which is composed of one or more essential ingredients. Typically, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided (fine divided) solid carriers or both. The product is then conventionally shaped into the desired presentation form.
Accordingly, the pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier and a compound of formula I or formula I' or a pharmaceutically acceptable salt thereof. The compound of formula I or formula I', or a pharmaceutically acceptable salt thereof, may also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier used may be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba (terra alba), sucrose, talc (tac), gelatin, agar, pectin, acacia (acacia), magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, and water. Examples of the gas carrier include carbon dioxide and nitrogen. In preparing the composition for oral dosage form, any conventional pharmaceutical vehicle (media) may be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations (oral liquid preparation), such as suspensions, elixirs and solutions; and carriers such as starches, sugars, microcrystalline cellulose (microcrystalline cellulose), diluents, granulating agents (granulating agent), lubricants, binders, disintegrating agents and the like may be used to form oral solid preparations (oral solid preparation), such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are preferred oral dosage forms, thereby employing solid pharmaceutical carriers. Optionally, the tablets may be coated by standard aqueous or non-aqueous techniques.
Tablets comprising the composition of the invention may be prepared by compression (compression) or moulding (molding), optionally with one or more accessory ingredients (accessory ingredient) or adjuvants. Compressed tablets may be prepared by: the active ingredient in free-flowing form, for example a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant, is compressed in a suitable apparatus. Molded tablets may be prepared by molding in a suitable apparatus a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient, and each elixir or capsule preferably contains from about 0.05mg to about 5g of the active ingredient. For example, a formulation intended for oral administration to humans may contain from about 0.5mg to about 5g of the active ingredient, mixed with a suitable and convenient amount of carrier material (component), which may vary from about 0.05% to about 95% of the total composition. The unit dosage form will generally comprise between about 0.01mg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg.
The pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. Suitable surfactants may be included such as, for example, hydroxypropyl cellulose. Dispersing agents (dispersions) may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. In addition, preservatives may be included to prevent the growth of harmful microorganisms.
The pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or sterile dispersions. Furthermore, the composition may be in the form of a sterile powder for in situ preparation of such sterile injectable solutions or dispersions (extemporaneous preparation). In all cases, the final injectable form must be sterile and must be virtually fluid for easy injectability (syringability). The pharmaceutical composition must be stable under the conditions of manufacture and storage; thus, it should preferably be protected from contaminating action by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion vehicle comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycols), vegetable oils, and suitable mixtures thereof.
The pharmaceutical composition of the present invention may be in a form suitable for topical use, such as, for example, aerosol (aerosol), cream (stream), ointment (cream), lotion (formulation), dusting powder (delivery powder), or the like. In addition, the composition may be in a form suitable for use in a percutaneous device (transdermal devices). These formulations can be prepared by conventional processing methods using the compounds represented by the formula (I), formula (I'), formula (II-a), formula (II-b), formula (III-a), formula (III-b), formula (IV-a), formula (IV-b), formula (V-a) and formula (V-b) of the present invention or pharmaceutically acceptable salts thereof. As an example, a cream or ointment is prepared by blending a hydrophilic material and water together with about 0.05wt% to about 10wt% of a compound to produce a cream or ointment having a desired viscosity
The pharmaceutical composition of the invention may be in a form suitable for rectal administration wherein the carrier is a solid. It is preferred that the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories may be formed conventionally by first blending the composition with a softened or melted carrier and then by freezing or shaping in a mold.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may also contain one or more additional carrier ingredients as desired, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like. In addition, other adjuvants may be included to render the formulation isotonic with the blood of the intended subject (recipient). Compositions comprising a compound described by formula I or formula I' or a pharmaceutically acceptable salt thereof may also be prepared in the form of a powder or liquid concentrate.
Typically, dosage levels on the order of from about 0.001mg/kg body weight/day to about 150mg/kg body weight/day, or alternatively, about 0.05 mg/patient/day to about 7 g/patient/day, are used to treat the conditions indicated above. For example, cancer may be effectively treated by administering from about 0.001mg compound/kg body weight/day to 50mg compound/kg body weight/day, alternatively from about 0.05 mg/patient/day to about 3.5 g/patient/day.
However, it will be appreciated that the specific dosage level for any particular patient will depend on a variety of factors including age, body weight, health (general health), sex, diet, time of administration, route of administration, rate of excretion (rate of excretion), drug combination and the severity of the particular disease undergoing therapy.
The term "KRAS G12D" mutant refers to a mutant form of a mammalian KRAS protein comprising an amino acid substitution of glycine with aspartic acid at amino acid position 12. The positioning of amino acid codons and amino acid residues of human KRAS (positioning) is based on the amino acid residues expressed by UniProtKB/Swiss-Prot P01116: amino acid sequence determined by Variant p.Gly12Asp.
The term "inhibition" refers to a decrease in the baseline activity (baseline activity) of a biological activity or biological process. The "inhibition of KRAS G12D activity" refers to a decrease in KRAS G12D activity compared to the activity of the enzyme in the absence of a compound of the present disclosure.
Compounds of the present disclosure may bind to KRAS G12D and then inhibit or negatively modulate KRAS G12D activity through a variety of molecular mechanisms, non-limiting examples include those shown: (a) a decrease in GTPase activity of KRAS; (b) A decrease in GTP binding affinity or an increase in GDP binding affinity; (c) K of GTP Dissociation of (K off ) Is reduced or K of GDP Dissociation of Is reduced; (d) Reduced binding of guanylate conversion factors (GEFs, guanine nucleotide exchange factors), including but not limited to SOS1; (e) Reduced binding of effectors or downstream signaling molecules including, but not limited to Raf.
By negatively modulating KRAS G12D activity, the subject matter disclosed herein may be used to inhibit undesired cell proliferation and/or support independent cell growth (ankara-independent cell growth).
The deuterated compounds of formula (I)/formula (I') of the present disclosure, or salts thereof, exhibit excellent selectivity of KRAS G12D over wild-type KRAS, which allows such deuterated compounds, or salts thereof, to selectively access KRAS G12D-mediated cancer cells, bypassing (sparing) KRAS wild-type cells. Thus, the deuterated compounds of the invention, or pharmaceutically acceptable salts thereof, prodrugs, metabolites, or derivatives thereof, may be used as therapeutic agents (therapeutic) against KRAS G12D-mediated tumors with an improved safety profile.
The term "KRAS G12D-related disease or disorder" refers to a disease or disorder associated with a KRAS G12D mutation or mediated by a KRAS G12D mutation or having a KRAS G12D mutation. Examples include, but are not limited to, KRAS G12D-associated cancers.
The terms "subject," "individual," or "patient" are used interchangeably and refer to any mammal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In certain embodiments, the patient is a human. In certain embodiments, the subject has been considered or has been diagnosed as having a KRAS G12D mutation-positive cancer (e.g., the cancer is determined by a measurement method approved by a regulatory agency, such as the united states Food and Drug Administration (FDA)). In certain embodiments, the subject is suspected of having a KRAS G12D gene-associated cancer.
The term "disease" refers to any disease, disorder, condition, symptom or indication, and may be interchangeable with the term "disorder" or "condition.
The term "cancer" encompasses all forms of cancer, including but not limited to all forms of cancer (carpinomas), melanoma, blastoma (blastmas), sarcoma, lymphoma, and leukemia. Examples include, but are not limited to, breast cancer, bladder cancer (bladder carcinoma), urinary tract cancer, brain tumor, cervical cancer, colorectal cancer, esophageal cancer (esophageal cancer), endometrial cancer, liver cancer (including HCC), laryngeal cancer, lung cancer, osteosarcoma (osteoarcoma), ovarian cancer, pancreatic cancer, prostate cancer, renal cancer (renal cancer), renal cancer (kidney cancer) (including RCC), thyroid cancer, acute lymphoblastic leukemia, acute myelogenous leukemia, ependymoma, ewing's sarcoma, gliobaoma (gliobaastoma), medulloblastoma (medullobalastoma), neuroblastoma, osteosarcoma, rhabdomyosarcoma (rhabdomyosarcoma), rhabdomyoid cancer (rhabdaor), renal cell carcinoma (wilms's tumor).
In certain such embodiments, the presently disclosed subject matter can be used to inhibit, block, reduce or reduce KRAS G12D activation, for reducing tumor growth and/or tumor metastasis (tumor metastasis), wherein the method comprises administering to the subject an effective amount of a compound of formula I or formula I' or a pharmaceutical composition described herein.
In certain such embodiments, the compounds detailed herein, or pharmaceutically acceptable salts, prodrugs, metabolites, or derivatives thereof, may also be used in combination with additional therapies. The additional therapies may optionally include one or more therapeutic agents, radiation therapy, surgery (e.g., lumpectomy (lumpectomy) and mastectomy (mastectomy)), chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy (nanotherapy), monoclonal antibody therapy, or a combination of the foregoing.
Preparation method
The compounds of the present invention may be synthesized by a variety of methods by those skilled in the art of organic chemistry, and general synthetic schemes for preparing the compounds of the present invention are described herein. These schemes are exemplary and are not meant to limit the possible methods of preparing the compounds disclosed herein to those skilled in the art. Different methods of preparing the compounds of the present disclosure will be apparent to those skilled in the art. General schemes for preparing the compounds of the present invention are given in the examples section listed below. The preparation of the prochiral examples can be achieved by techniques known to those skilled in the art. For example, prochiral compounds can be prepared by separating the racemic product or diastereoisomer from chiral phase preparation HPLC (chiral phase preparative HPLC). Alternatively, the example compounds may be prepared by methods known to give tautomerically or diastereomerically enriched products.
The reactions and techniques disclosed hereinafter in this section are carried out in solvents appropriate for the reagents and materials employed, and for the transformations to be effected. In addition, it should be understood that all the presented reaction conditions are selected as conditions for this reaction standard, including the choice of solvent, the reaction atmosphere (reaction atmosphere), the reaction temperature, the duration of the experiment, and the post-treatment procedure (work up procedure), which should be easily accomplished by one skilled in the art. Those skilled in the art of organic synthesis will also appreciate that the functional groups present on various parts (portions) of the molecule must be compatible with the reagents and reactions chosen. The limitations of substituents compatible with the reaction conditions will be apparent to those skilled in the art in the presence of the required alternatives which may be incompatible with the substituents. Sometimes, it is necessary to modify the order of the synthesis steps or the judgment of selecting one particular route with respect to another in order to obtain the desired compound of the invention. It will also be appreciated that any synthetic route planning in the art will cover the judicial selection of protecting groups for protecting reactive functional groups present in the compounds described in the present invention (Wuts and Greene, greene's Protective Groups in Organic Synthesis, fourths Edition, wiley and Sons (2007)).
Reaction scheme and examples
The disclosed compounds of the present invention can be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those skilled in the art. For example, the compounds of the present invention may be prepared using general schemes I-VIII, which may be followed by a deprotection step to deprotect protecting groups to obtain the disclosed compounds.
General reaction scheme
Compounds of formula (II-a) wherein n, W, X 0 To X 3 、R 1 To R 6 As defined above, can be prepared according to scheme I:
scheme I
Figure BDA0004093773770000721
Figure BDA0004093773770000731
At elevated temperature, e.g. 100 ℃, in POCl 3 Treatment of compound (1) in the presence of a base such as DIEA provides the trichloride (2). At 0℃in an amine (3), a base such as DIEA and a solvent such asThe selective substitution of trichloride (2) in the presence of DCM yields compound (4). The selective nucleophilic substitution of dichloride (4) in the presence of alcohol (5) in the presence of a base such as DIEA in a solvent such as 1, 4-dioxane provides compound (6). Subsequently, a Suzuki coupling of chloride (6) with a heteroaromatic boronic acid pinacol ester (aromatic pinacoborate) (7) under Suzuki coupling conditions provides a compound of formula (II-a).
A compound of formula (II-b) wherein W, X 0 To X 3 、R 1 To R 6 As defined above, can be prepared according to a procedure analogous to the synthesis of the compounds applicable to formula (II-a) as outlined in scheme I and/or by substituting amine (a) for amine (3) with the necessary modifications:
Figure BDA0004093773770000732
a compound of formula (III-a) wherein m, n, W, X 0 To X 3 、Y、R 1 To R 5 As defined above, can be prepared according to the procedure outlined in scheme II:
scheme II
Figure BDA0004093773770000733
The selective nucleophilic substitution of dichloride (4) in the presence of alcohol (8) in the presence of a base such as DIEA in a solvent such as 1, 4-dioxane provides compound (9). Subsequently, a Suzuki coupling of chloride (9) with a heteroaromatic pinacol borate or a heteroaromatic pinacol borate (7) under Suzuki coupling conditions provides a compound of formula (III-a).
Except that amine (A) is used in place of amine (3), a compound of formula (III-b) wherein m, W, X 0 To X 3 、R 1 To R 5 As defined above, can be prepared according to a procedure analogous to the synthesis of the compounds of formula (III-a) applicable in scheme II and/or with suitable modifications:
Figure BDA0004093773770000741
a compound of formula (IV-a-1) wherein n, W, X 0 To X 3 And R is 1 To R 7 As defined above, can be prepared according to the procedure as outlined in scheme III:
Scheme III
Figure BDA0004093773770000742
N-acylation of amine (10) with acid chloride (a) in the presence of a base such as TEA and a solvent such as DCM provides compound (11). Coupling of intermediate (11) with a commercially available reagent (b), such as (E) -4-ethoxy-1, 1-trifluorobut-3-en-2-one, in the presence of an organic base, such as DBU, and a solvent, such as THF, provides compound (12). Reflux of intermediate (12) in the presence of p-TsOH and toluene yields intermediate (13). Hydrolysis of intermediate (13) in the presence of a base, e.g., 1N aqueous NaOH, and a solvent such as THF provides compound (14). Subsequent treatment of intermediate (14) (kertts rearrangement (Curtius Rearangement)) in the presence of TEA, t-BuOH as solvent and a reagent such as diphenyl azide phosphate (diphenyl azidophosphate) gives amine (15). Bromination of (15) in the presence of NBS yields bromide (16). The bromide (16) reacts with CuCN in a suitable solvent such as NMP at elevated temperature to give cyanide intermediate (17). Under acidic conditions, e.g. aqueous H, at elevated temperature 2 SO 4 Hydrolysis of cyanide (17) provides compound (18) at (1M). Cyclization (cyclization) of intermediate (18) in the presence of reagents such as CDI provides compound (19). Subsequently, at elevated temperature, at POCl 3 In the presence of an intermediate (19) to provide a chloride (20). The selective substitution of the chloride in the presence of amine (20), base, e.g., TEA, and solvent, e.g., DCM, yields intermediate (21). Subsequent treatment of compound (21) in the presence of alcohol (5), an organic base such as DIEA and a solvent such as 1, 4-dioxane at elevated temperature provides a compound of formula (IV-a-1).
Except that amine (3) is replaced by amine (A), a compound of formula (IV-b-1), wherein W, X 0 To X 2 And R is 1 To R 7 As defined above, can be prepared according to similar procedures as outlined in scheme III and/or if necessary with suitable modifications.
Figure BDA0004093773770000751
A compound of formula (V-a-1) wherein m, n, W, X 0 To X 2 、Y、R 1 To R 5 And R is 7 As defined above, can be prepared according to the procedure as outlined in scheme IV:
scheme IV
Figure BDA0004093773770000752
The treatment of compound (21) in the presence of alcohol (8), an organic base such as DIEA and a solvent such as 1, 4-dioxane at elevated temperature provides (V-a-1).
Except that the base (3) is replaced by a base (A), a compound of formula (V-b-1) wherein m, W, X 0 To X 2 、R 1 To R 5 And R is 7 As defined above, can be prepared according to a similar procedure as outlined in scheme IV.
Figure BDA0004093773770000761
A compound of formula (IV-a-2) wherein n, q, W, X 0 To X 2 And R is 1 To R 7 As defined above, can be prepared according to the procedure as outlined in scheme IV.
Scheme IV
Figure BDA0004093773770000762
Selective nucleophilic substitution of dichloride (22) in the presence of amine (3), a base such as DIEA, and a solvent such as DMSO at elevated temperature provides intermediate (23). Subsequently, at elevated temperature, in alcohol (5), t-Buona, BINAP, catalyst such as Pd (OAc) 2 And a solvent such as toluene, to produce intermediate (24). Deprotection of a protecting group P, e.g., -Cbz or Boc, provides intermediate (25) under appropriate conditions, e.g., pd/C, H 2 Wherein P is Cbz; or TFA/DCM, wherein P is Boc-. Subsequently, at elevated temperature, under aryl or heteroaryl bromide (d), buchwald coupling conditions such as RuPhos, pd 2 (dba) 3 Buchwald coupling of intermediate (25) in the presence of t-BuOna, and a solvent such as toluene provides a compound of formula (IV-a-2).
Except that base (3) is replaced by base (A), a compound of formula (IV-b-2) wherein q, W, X 0 To X 2 And R is 1 To R 7 As defined above, can be prepared according to a similar procedure as outlined in scheme IV:
Figure BDA0004093773770000771
a compound of formula (V-a-2) wherein m, n, q, W, X 0 To X 2 、R 1 To R 5 And R is 7 As defined above, can be prepared according to similar procedures as outlined in scheme IV and/or if necessary with suitable modifications.
Figure BDA0004093773770000772
Except that amine (3) is replaced by amine (A), a compound of formula (IV-b-2), wherein n, q, W, X 0 To X 2 And R is 1 To R 7 As defined above, can be prepared according to similar procedures as outlined in scheme IV and/or if necessary with suitable modifications.
Figure BDA0004093773770000773
A compound of formula (IV-a-3) wherein n, W, X 0 To X 2 And R is 1 To R 6 As defined above, can be prepared according to the procedure as outlined in scheme V.
Figure BDA0004093773770000774
Scheme V
Treatment of aldehyde (26) in the presence of hydrazine (27), a base such as DIEA and a solvent such as DMF provides the isodiazene (28). The reaction of isodiazene (28) in the presence of amine (3), a base such as TEA and a solvent such as DMF provides compound (29). At elevated temperature in a CO (gas) atmosphere, a base such as TEA, pd (dppf) Cl 2 And solvents such as MeOH, the work-up of intermediate (29) affords methyl ester (30). Cyclization of intermediate (30) provides compound (31) under acidic conditions, such as glacial acetic acid, at elevated temperatures. The oxidation of thioether (31) in the presence of an oxidizing agent, e.g., m-CPBA, in a solvent such as DCM provides sulfoxide (32). Substitution of sulfoxide (32) in the presence of alcohol (5) yields a compound of formula (IV-a-3).
Except that base (3) is replaced by base (A), a compound of formula (IV-b-3), wherein W, X 0 To X 2 And R is 1 To R 6 As defined above, can be prepared according to a similar procedure as outlined in scheme V:
Figure BDA0004093773770000781
a compound of formula (V-a-3) wherein m, n, W, X 0 To X 2 、R 1 To R 5 And Y is as defined above, can be prepared according to the procedure as outlined in scheme VI:
scheme VI
Figure BDA0004093773770000782
Substitution of sulfoxide (32) in the presence of alcohol (8) yields a compound of formula (V-a-3).
Except that the base (3) is replaced by a base (A), a compound of formula (V-b-3) wherein m, W, X 0 To X 2 And R is 1 To R 5 As defined above, can be prepared according to a similar procedure as outlined in scheme VI:
Figure BDA0004093773770000783
examples
The examples provided herein describe the synthesis of the compounds disclosed herein and intermediates useful in the preparation of the compounds. It is to be understood that the individual steps described herein may be combined. It is also understood that individual batches of compounds may be combined and then carried out in the next synthetic step.
In the following description of the examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the disclosure. Other embodiments may be utilized and logical changes and other changes may be made without departing from the scope of the present disclosure. The following description is, therefore, not intended to limit the scope of the disclosure, which is defined solely by the appended claims.
Table 1 shows some abbreviations of the invention Table 1
Figure BDA0004093773770000791
Figure BDA0004093773770000801
Figure BDA0004093773770000811
Intermediate preparation
Intermediate 1 and intermediate 2
2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methanol (diastereomer-A) and 2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methanol (diastereomer-B)
Figure BDA0004093773770000812
Step 1: 2-hydroxytetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid ethyl ester-2-d
At 0 ℃ at N 2 Next, naBD was added in portions to a solution of ethyl 2, 5-dioxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (19.0 g,89.9mmol,1 eq.) in dry EtOH (100.0 mL) 4 (1.13 g,26.9mmol,0.3 eq.). At 0 ℃ at N 2 The reaction mixture was stirred for 10min. Based on LCMS, the conversion was complete. At 0℃aqueous NH for reaction 4 Cl (4 mL) was carefully quenched and stirred at this temperature for 30min. The mixture was then poured into a separatory funnel and partitioned between brine and EtOAc. After separation, the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried and concentrated on a rotary evaporator to give a residue. The resulting oil was purified by column chromatography (eluting with DCM/meoh=2% -5%) to give the expected ethyl 2-hydroxy-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate-2-d (15.0 g,70% yield) as a colourless oil. LC-MS [ M+H ] ] + ＝201.1。
Step 2: 2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid ethyl ester-2-d
At-70 ℃ at N 2 DAST (16.9 g,105.0mol,1.5 eq) was added dropwise to a solution of 2-hydroxy-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid ethyl ester-2-d (15.0 g,70.0mol,1.0 eq) in DCM (80 mL) over 5 min. The reaction mixture was gradually warmed to rt and stirred for 16h. Based on LCMS, the conversion was complete. The reaction mixture was cooled in an ice-water bath with the addition of MeOH (4 mL) dropwiseQuench and use H 2 O (156 mL) dilution. The reaction mixture was poured into a separatory funnel and extracted with DCM (200 ml×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (eluting with PE/etoac=2/1) to give a mixture of diastereomers 2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid ethyl ester-2-d (4.90 g,29% yield) as a pale oil (light oil).
LC-MS[M+H] + ＝217.1。
Step 3: chiral SFC
Mixtures of diastereomers (4.90 g,22.6 mmol) were prepared by chiral SFC (Daicel Chiralpak IB SFC 4.6.6 mm. Times.250 mm. Times.5 μm; 0.1% NH in MeOH) 4 OH；CO 2 Percent: 70%,10 min). Fractions corresponding to the two peaks were collected, combined and concentrated under reduced pressure to provide two components.
Diastereoisomer-a: peak 1, rt=4.1 min,1.8g,36% yield as colorless oil; LC-MS [ M+H ]] + ＝217.1。 1 H NMR(400MHz，CDCl 3 )δ4.22-4.13(m，3H)，3.21-3.09(m，1H)，2.82-2.70(m，2H)，2.63(dd，J＝32.8，15.2Hz，1H)，2.44-2.37(m，1H)，2.26-2.15(m，1H)，2.14-2.06(m，1H)，1.27(t，J＝7.2Hz，3H)。
Diastereoisomer-b: peak 2, rt=5.9 min,1.8g,35% yield as colorless oil. LC-MS [ M+H ]] + ＝217.1。 1 H NMR(400MHz，CDCl 3 )δ4.23-4.14(m，3H)，3.21-3.10(m，1H)，2.83-2.70(m，2H)，2.64(dd，J＝32.8，15.2Hz，1H)，2.45-2.38(m，1H)，2.27-2.16(m，1H)，2.13-2.07(m，1H)，1.28(t，J＝7.2Hz，3H)。
Step 4: (2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methanol (intermediate 1, diastereomer-A) and (2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methanol (intermediate 2, diastereomer-B)
Two diastereomers a and B were synthesized in parallel.
At 20 ℃ at N 2 In the presence of an atmosphere,to a solution of 2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid ethyl ester-2-d (peak 1, 500mg,2.3mmol,1.0 eq.) in THF (5.5 mL) was added LiAlH4 (131 mg,3.46mmol,1.5 eq.) in one portion. In the case of a condenser, the reaction mixture was gradually warmed to reflux and stirred for 2h. Based on LCMS, the conversion was complete. The reaction mixture was cooled to 0 ℃ and carefully quenched with dropwise addition of aqueous NaOH (0.3 ml,1 n). The mixture being saturated with aqueous NH 4 Partition between Cl and DCM. After separation, the aqueous layer was extracted with DCM (2×). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (with DCM/meoh=30/1 (containing 1% nh) 3 ·H 2 O) elution) to provide (2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methanol (diastereomer a,200mg,52% yield) as a pale oil. LC-MS [ M+H ]] + ＝161.1。 1 H NMR(400MHz，CD 3 OD)δ 3.35(d，J＝10.4Hz，1H)，3.31-3.29(m，1H)，3.27(d，J＝10.4Hz，1H)，3.16-3.10(m，2H)，3.08—2.99(m，1H)，2.96-2.90(m，1H)，2.17-2.06(m，1H)，2.04-2.00(m，1H)，1.98-1.88(m，2H)，1.85-1.72(m，2H)。
diastereomer-B (peak 2, 500mg,2.31 mmol) was converted to (2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methanol as a pale oil (diastereomer B:176mg,43% yield). LC-MS [ M+H ]] + ＝161.1。 1 H NMR(400MHz，CD 3 OD)δ3.35(d，J＝10.4Hz，1H)，3.31-3.29(m，1H)，3.27(d，J＝10.4Hz，1H)，3.15-3.12(m，2H)，3.07-2.99(m，1H)，2.96-2.90(m，1H)，2.17-1.98(m，2H)，1.97-1.88(m，2H)，1.86-1.72(m，2H)。
Intermediate 3
(2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methyl-d 2-ol
Figure BDA0004093773770000831
At 0 ℃ at N 2 Down to 2-fluoro-5-oxotetrahydro-1H-A solution of pyrrolizine-7 a (5H) -carboxylic acid ethyl ester-2-d (1.0 g,4.6 mmol) in anhydrous EtOH (10.0 mL) was added NaBD in portions 4 (0.21 g,5.1 mmol). The mixture was warmed to rt and taken up in N 2 Stirring was continued for 20min. Based on LCMS, the conversion was complete. The reaction was cooled in an ice bath and the aqueous NH was added dropwise with stirring 4 Cl (1 mL) to quench. After 30min stirring, the mixture was partitioned between water and DCM. After separation, the aqueous phase was extracted with DCM (2×). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, collected by filtration and concentrated on a rotary evaporator to give a residue. The resulting oil was purified by column chromatography (eluting with DCM/MeOH (30/1)) to provide the title compound 6-fluoro-7 a- (hydroxymethyl-d) as a yellow oil 2 ) hexahydro-3H-pyrrolizin-3-one-6-d (720 mg, yield: 80.4%). LC-MS [ M+H ]] + ＝177.2。
Step 2: fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methyl-d 2 -alcohols
At rt at N 2 Down to 6-fluoro-7 a- (hydroxymethyl-d) 2 ) A solution of hexahydro-3H-pyrrolizin-3-one-6-d (720 mg,4.09 mmol) in anhydrous THF (7 ml) was added LiAlH4 (233 mg,6.13 mmol) in portions. The reaction mixture was warmed to reflux with a condenser and stirred for 2h. Based on LC-MS, the transformation was complete. The reaction mixture was cooled to 0 ℃ and carefully quenched with dropwise addition of aqueous NaOH (0.2 ml,1 m). The mixture was partitioned between water and DCM. After separation, the aqueous layer was extracted with DCM (2×). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (with DCM/(NH in MeOH) 3 ) (30/1) elution) to afford the title compound (2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) -2-d) methyl-d 2-ol as a colourless oil (449.04 mg, yield: 58.53%). LC-MS [ M+H ]] + ＝163.1。 1 H NMR(400MHz，CDCl 3 )δ3.22-2.88(m，4H)，2.15-2.04(m，2H)，1.98-1.71(m，4H)。
Intermediate 4
(2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5.5-d 2) methanol
Figure BDA0004093773770000841
Step 1: 2-Hydroxytetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid ethyl ester
At 0 ℃ at N 2 NaBH was added in portions to a solution of ethyl 2, 5-dioxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (19.0 g,89.9mmol,1 eq.) in dry EtOH (100.0 mL) over 1min 4 (1.13 g,26.9mmol,0.3 eq.). At 0 ℃ at N 2 The reaction mixture was stirred for 10min. Based on LCMS, the conversion was complete. At 0℃aqueous NH for reaction 4 Cl (4 mL) was carefully quenched and stirring was continued at this temperature for 30min. The mixture was then poured into a separatory funnel and partitioned between brine and EtOAc. After separation, the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried and concentrated on a rotary evaporator to give a residue. The resulting oil was purified by column chromatography (eluting with DCM/meoh=2% -5%) to provide the expected title compound as a colourless oil (15.0 g,70% yield). LC-MS [ M+H ]] + ＝200.1。
Step 2: 2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid ethyl ester
At-70 ℃ at N 2 DAST (16.9 g,105.0mol,1.5 eq.) was added dropwise to a solution of ethyl 2-hydroxytetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (15.0 g,70.0mol,1.0 eq.) in DCM (80 mL) over 5 min. The reaction mixture was gradually warmed to rt and stirred for 16h. Based on LCMS, the conversion was complete. The reaction mixture was cooled in an ice-water bath, quenched with dropwise addition of MeOH (4 mL), and quenched with H 2 O (156 mL) dilution. The reaction mixture was poured into a separatory funnel and extracted with DCM (200 ml×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (eluting with PE/etoac=2/1) to provide diastereomer 2-fluoro-5-oxotetrahydro-1H-Pyrrolizine-7 a (5H) -carboxylic acid ethyl ester (5.40 g,32.0% yield). LC-MS [ M+H ]] + ＝216.1。
Step 3: chiral SFC separation
A mixture of the diastereomers 2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid ethyl ester (132 g,612 mmol) was separated by chiral SFC (column: CHIRALPAKAY-3 (AY 30CD-TJ 004) 4.6 mm. Times.150 mm. Times.0.2 μm; mobile phase: etOH; flow rate: 0.5ml/min;10 min). Fractions corresponding to the two peaks were combined separately and concentrated under reduced pressure to provide two components.
Diastereoisomer-a: peak 1, compound 9, rt=5.7 min,60.8g,46% yield as colorless oil;
diastereoisomer-b: peak 2, compound 10, rt=7.5 min,58.8g,45% yield as yellow oil;
step 4: 6-fluoro-7 a- (hydroxymethyl) hexahydro-3H-pyrrolizin-3-one
At 0 ℃ at N 2 To a solution of ethyl 2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (compound 10, diastereomer-b, 1g,4.6 mmol) in anhydrous EtOH (10.0 mL) was added NaBH in portions 4 (0.19 g,5.1 mmol). The reaction mixture was gradually warmed to rt and taken up in N 2 Stirring was continued for 20min. Based on LCMS, the conversion was complete. At 0 ℃, the reaction is carried out by adding aqueous NH dropwise 4 Cl (1 mL) was carefully quenched and stirring continued for 30min. The mixture was then partitioned between water and DCM. After separation, the aqueous layer was extracted with DCM (2×). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, collected by filtration and concentrated on a rotary evaporator to give a residue. The resulting oil was purified by column chromatography (eluting with DCM/MeOH (30/1)) to give the title compound 6-fluoro-7 a- (hydroxymethyl) hexahydro-3H-pyrrolizin-3-one as a yellow oil (680 mg, yield: 76.1%). LC-MS [ M+H ]] + ＝174.2。
Step 5: 2-Fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl-5.5-d 2 ) Methanol
At rt at N 2 Next, 6-fluoro-7 a- (hydroxymethyl) hexahydro-3H-pyrrolizin-3-one (680 mg,3.88 m)mol) solution in Me-THF (7 ml) LiAlD was added in portions 4 (349mg, 8.15 mmol). The reaction mixture was warmed to 90 ℃ with a condenser and stirred for 2h. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to 0 ℃ and carefully quenched with dropwise addition of aqueous NaOH (7 ml,1 mol/L). The mixture was partitioned between water and DCM. After separation, the aqueous layer was extracted with DCM (2×). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (with DCM/(NH in MeOH) 3 ) (30/1) elution) to afford the title compound as a colourless oil (418 mg, yield: 60%). LC-MS [ M+H ]] + ＝162.2。 1 H NMR(400MHz，CDCl 3 )δ5.23(m，1H)，3.27(s，2H)，3.16-3.13(m，1H)，3.10-3.00(m，1H)，2.16-2.02(m，2H)，1.93-1.73(m，4H)。
Intermediate 5
(2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methyl-d 2-ol
Figure BDA0004093773770000861
Step 1: 6-fluoro-7 a- (hydroxymethyl-d) 2 ) hexahydro-3H-pyrrolizin-3-one
At 0 ℃ at N 2 To a solution of ethyl 2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (compound 10,1g,4.6 mmol) in anhydrous EtOH (10.0 mL) was added NaBD in portions 4 (0.21 g,5.1 mmol). The reaction mixture was warmed to rt and taken up in N 2 Stirring was continued for 20min. The reaction was monitored by LCMS. After the conversion is complete, the reaction is cooled in an ice-water bath and saturated aqueous NH is added dropwise 4 Cl (0.2 mL) was carefully quenched. After stirring for 30min, the mixture was partitioned between water and DCM. After separation, the aqueous layer was extracted with DCM (2×). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 Dried and collected by filtration. The filtrate was concentrated on a rotary evaporator to give a residue.The resulting oil was purified by column chromatography (eluting with DCM/MeOH (30/1)) to give the title compound as a yellow oil (700 mg, yield: 78%). LC-MS [ M+H ] ] + ＝176.1。
Step 2: (2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methyl-d 2 -alcohols
At rt at N 2 Down to 6-fluoro-7 a- (hydroxymethyl-d) 2 ) A solution of hexahydro-3H-pyrrolizin-3-one (300 mg,1.71 mmol) in anhydrous THF (7 ml) was added LiAlH in portions 4 (97.5 mg,2.57 mmol). The reaction mixture was warmed to reflux with a condenser and stirred for 2h. Based on LCMS, the conversion was complete. The reaction mixture was cooled to 0 ℃ and carefully quenched with dropwise addition of aqueous NaOH (0.2 ml,1 mol/L). The reaction mixture was partitioned between water and DCM. After separation, the aqueous layer was extracted with DCM (2×). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried and collected by filtration. The filtrate was concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (with DCM/(NH in MeOH) 3 ) (30/1) elution) to afford the title compound (199 mg, yield) as a colourless oil: 64%). LC-MS [ M+H ]] + ＝162.1。 1 H NMR(400MHz，CDCl 3 )δ5.27-5.11(m，1H)，3.36(s，1H)，3.21-3.11(m，2H)，3.10-2.88(m，2H)，2.16-2.01(m，2H)，1.91-1.81(m，2H)，1.80-1.71(m，2H)。
Intermediate 6
(2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5.5-d 2) methyl-d 2-ol
Figure BDA0004093773770000871
At rt at N 2 Next, liAlH4 (210 mg,5.02 mmol) was added in portions to a solution of 6-fluoro-7 a- (hydroxymethyl-d 2) hexahydro-3H-pyrrolizin-3-one (compound 11, 400mg,2.28 mmol) in anhydrous Me-THF (8 ml). The reaction mixture was warmed to 90 ℃ with a condenser and stirred for 2h. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to 0 ℃ and aqueous NaOH (0.2 ml,1 m) was added dropwise ol/L) was carefully quenched. The mixture was partitioned between water and DCM. After separation, the aqueous layer was extracted with DCM (2×). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried and collected by filtration. The filtrate was concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (with DCM/(NH in MeOH) 3 ) (30/1) elution) to afford the title compound as a colourless oil (185 mg, yield: 45%). LC-MS [ M+H ]] + ＝164.1。 1 H NMR(400MHz，CDCl 3 )δ5.27-5.11(m，1H)，3.39(s，1H)，3.17-2.98(m，2H)，2.16-2.01(m，2H)，1.94-1.81(m，2H)，1.79-1.72(m，2H)。
Intermediate 7
(tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methyl-d 2-ol
Figure BDA0004093773770000872
At 0 ℃ at N 2 To a solution of tetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid ethyl ester 12 (5.0 g,27.3 mmol) in anhydrous THF (30 mL) was added NaBD in portions over 2min 4 (1.25 g,30.0 mmol). The resulting mixture was slowly warmed to rt and stirred for 30min. Based on LC/MS, the transformation was complete. The reaction mixture was cooled in an ice-water bath, carefully quenched with dropwise addition of MeOH, and quenched with saturated aqueous NH 4 Cl (30 mL) and DCM (50 mL). After separation, the aqueous layer was extracted with DCM (2×). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 Dried, collected by filtration and concentrated on a rotary evaporator to afford the expected crude compound (3.64 g,93% yield, 25.4 mmol) as a colourless oil, which was sufficiently pure for use in the next step. LC-MS [ M+H ] ] + ＝144。
Intermediate 8
((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methanol
Figure BDA0004093773770000881
Step 1: (6R, 7 aS) -6-fluoro-7 a- (hydroxymethyl) hexahydro-3H-pyrrolizin-3-one-6-d
At 0 ℃ at N 2 Next, naBH was slowly added in portions to a solution of (2R, 7 aS) -2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid ethyl ester-2-d (2 g,9.25 mmol) in anhydrous EtOH (20.0 mL) 4 (426 mg,11.1 mmol). At rt at N 2 The mixture was stirred under stirring for 10min. The reaction was monitored by LC/MS. After the conversion is complete, at 5℃the reaction is carried out with NH 4 Cl (1 mL) was carefully quenched and stirred at this temperature for 30min. The mixture was then concentrated on a rotary evaporator to give a residue. The resulting oil was purified by column chromatography (eluting with DCM/MeOH (20/1)) to give the title compound as a yellow oil (1.6 g, yield: 90%). LC-MS [ M+H ]] + ＝175.2。
Step 2: ((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methanol
At rt at N 2 LiAlD was carefully added in portions to a solution of (6R, 7 aS) -6-fluoro-7 a- (hydroxymethyl) hexahydro-3H-pyrrolizin-3-one-6-d (900 mg,5.1 mmol) in Me-THF (10 ml) 4 (450.3 mg,10.7 mmol). The reaction mixture was warmed to 90 ℃ and stirred for 2h. The reaction was monitored by LCMS. After the conversion was complete, the reaction mixture was cooled to 0 ℃ and carefully quenched with the addition of aqueous NaOH (0.9 ml,1 n), filtered and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (eluting with DCM/MeOH (30/1)) to give the title compound as a yellow oil (540 mg, yield: 65%). LC-MS [ M+H ] ] + ＝163.1。 1 H NMR(400MHz，CDCl 3 )δ3.43(s，1H)，3.27(s，2H)，3.20—2.99(m，2H)，2.17—1.97(m，2H)，1.95-1.71(m，4H)。
Intermediate 9
((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methyl-d 2-ol
Figure BDA0004093773770000882
Step 1: (6R, 7 aS) -6-fluoro-7 a- (hydroxymethyl-d) 2 ) hexahydro-3H-pyrrolizine-3-one-6-d
At 0 ℃ at N 2 Next, naBD was slowly added in portions to a solution of (2R, 7 aS) -2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid ethyl ester-2-d (1 g,4.6 mmol) in absolute EtOH (10.0 mL) 4 (0.21 g,5.1 mmol). At rt at N 2 The mixture was stirred under stirring for 20min. The reaction was monitored by LCMS. After the conversion is complete, the reaction is carried out with saturated aqueous NH at 5 DEG C 4 Cl (1 mL) was carefully quenched and stirring was continued at this temperature for 30min. The mixture was then concentrated on a rotary evaporator to give a residue. The resulting oil was purified by column chromatography (eluting with DCM/MeOH (30/1)) to give the title compound as a yellow oil (720 mg, yield: 80%). LC-MS [ M+H ]] + ＝177.2。
Step 2: ((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Nail-d 2 -alcohols
At rt at N 2 Next, (6R, 7 aS) -6-fluoro-7 a- (hydroxymethyl-d) 2 ) LiAlD was carefully added as a solution of hexahydro-3H-pyrrolizin-3-one-6-d (650 mg,3.7 mmol) in Me-THF (10 mL) 4 (328 mg,7.8 mmol). The reaction mixture was warmed to 90 ℃ and stirred for 2h. The reaction was monitored by LCMS. After the conversion was complete, the reaction mixture was cooled to 0 ℃ and carefully quenched with aqueous NaOH (0.9 ml,1 n), filtered and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (eluting with DCM/MeOH (30/1)) to give the title compound as a yellow oil (360 mg, yield: 59%). LC-MS [ M+H ] ] + ＝165.0。 1 H NMR(400MHz，CDCl 3 )δ3.54(s，1H)，3.26-2.97(m，2H)，2.17-1.96(m，2H)，1.95-1.69(m，4H)。
Intermediate 10
((2S, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methanol
Figure BDA0004093773770000891
Step 1: (6S, 7 aR) -6-fluoro-7 a- (hydroxymethyl) hexahydro-3H-pyrrolizin-3-one-6-d
At 0 ℃ at N 2 Next, naBH was slowly added in portions to a solution of (2S, 7 aR) -2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid ethyl ester-2-d (2 g,9.3 mmol) in absolute EtOH (20.0 mL) 4 (426 mg,11.1 mmol). At rt at N 2 The mixture was stirred under stirring for 10min. The reaction was monitored by LCMS. After the conversion is complete, the reaction is carried out with saturated aqueous NH at 5 DEG C 4 Cl (1 mL) was carefully quenched and stirring was continued at this temperature for 30min. The mixture was then concentrated on a rotary evaporator to give a residue. The resulting oil was purified by column chromatography (eluting with DCM/MeOH (30/1)) to give the title compound as a yellow oil (1.6 g, yield: 89%). LC-MS [ M+H ]] + ＝175.2
Step 2: (6S, 7 aR) -6-fluoro-7 a- (hydroxymethyl) hexahydro-3H-pyrrolizin-3-one-6-d
At 0 ℃ at N 2 LiAlH was carefully added in portions to a solution of (6S, 7 aR) -6-fluoro-7 a- (hydroxymethyl) hexahydro-3H-pyrrolizin-3-one-6-d (700 mg,4.01 mmol) in THF (10 ml) 4 (226 mg,5.96 mmol). The reaction mixture was warmed to 70 ℃ and stirred for 2h. The reaction was monitored by LCMS. After the conversion was complete, the reaction mixture was cooled to 0 ℃ and carefully quenched with aqueous NaOH (0.9 ml,1 n), filtered and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (with DCM/(NH in MeOH) 3 ) (30/1) elution) to afford the title compound as a colourless oil (450 mg, yield: 70%). LC-MS [ M+H ]] + ＝161.1。 1 H NMR(400MHz，CDCl 3 )δ3.53(s，1H)，3.27(s，2H)，3.23-3.16(m，1H)，3.16-3.11(m，1H)，3.10-2.99(m，1H)，2.96-2.88(m，1H)，2.18-1.96(m，2H)，1.96-1.71(m，4H)。
Intermediate 11
((2S, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methanol
Figure BDA0004093773770000901
At 0 ℃ at N 2 LiAlD was carefully added to a solution of (6S, 7 aR) -6-fluoro-7 a- (hydroxymethyl) hexahydro-3H-pyrrolizin-3-one-6-d (900 mg,5.11 mmol) in Me-THF (10 m 1) 4 (450 mg,10.73 mmol). The reaction mixture was warmed to 90 ℃ and stirred for 2h. The reaction was monitored by LC/MS. After the conversion was complete, the reaction mixture was cooled to 0 ℃ and carefully quenched with aqueous NaOH (0.9 ml,1 n), filtered and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (with DCM/(NH in MeOH) 3 ) (30/1) elution) to afford the title compound (540 mg, yield) as a colourless oil: 65%). LC-MS [ M+H ]] + ＝163.1。 1 H NMR(400MHz，CDCl 3 )δ3.43(s，1H)，3.27(s，2H)，3.20-2.98(m，2H)，2.17-1.97(m，2H)，1.95-1.69(m，4H)。
Intermediate 12
((2S, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methyl-d 2-ol
Figure BDA0004093773770000902
Step 1: (6S, 7 aR) -6-fluoro-7 a- (hydroxymethyl-d 2) hexahydro-3H-pyrrolizin-3-one-6-d
At 0 ℃ at N 2 Next, naBD was added slowly in portions to a solution of ethyl (2S, 7 aR) -2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid ethyl ester-2-d (2.0 g,9.25 mmol) in absolute EtOH (20.0 mL) 4 (430 mg,10.2 mmol). At rt at N 2 The mixture was stirred under stirring for 10min. The reaction was monitored by LCMS. After the conversion is complete, the reaction is carried out with saturated aqueous NH at 5 DEG C 4 Cl (1 mL) was carefully quenched and stirring was continued at this temperature for 30min. The mixture was then concentrated on a rotary evaporator to give a residue. The resulting oil was purified by column chromatography (eluting with DCM/MeOH (20/1)) to give the title compound as a yellow oil (1.30 g, yield: 71%). LC-MS [ M+H ]] + ＝177.1
Step 2: ((2S)7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Nail-d 2 -alcohols
At 0 ℃ at N 2 Next, (6S, 7 aR) -6-fluoro-7 a- (hydroxymethyl-d) 2 ) LiAlD was carefully added as a solution of hexahydro-3H-pyrrolizin-3-one-6-d (650 mg,3.7 mmol) in Me-THF (10 ml) 4 (420 mg,10 mmol). The reaction mixture was warmed to 90 ℃ and stirred for 2h. The reaction was monitored by LCMS. After the conversion was complete, the reaction mixture was cooled to 0 ℃ and carefully quenched with aqueous NaOH (0.9 ml,1 n), filtered and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (with DCM/(NH in MeOH) 3 ) (30/1) elution) to afford the title compound as a colourless oil (360 mg, yield: 60%). LC-MS [ M+H ] ] + ＝165.0。 1 H NMR(400MHz，CDCl 3 )δ3.54(s，1H)，3.19-2.98(m，2H)，2.17-1.96(m，2H)，1.95-1.68(m，4H)。
Intermediate 13
((2S, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methyl-d 2-ol
Figure BDA0004093773770000911
At 0 ℃ at N 2 Next, (6S, 7 aR) -6-fluoro-7 a- (hydroxymethyl-d) 2 ) LiAlH was carefully added as a solution of hexahydro-3H-pyrrolizin-3-one-6-d (650 mg,3.7 mmol) in THF (10 ml) 4 (213 mg,5.6 mmol). The reaction mixture was warmed to 70 ℃ and stirred for 2h. The reaction was monitored by LC/MS. After the conversion was complete, the reaction mixture was cooled to 0 ℃ and carefully quenched with aqueous NaOH (0.5 ml,1 n), filtered and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (with DCM/(NH in MeOH) 3 ) (30/1) elution) to afford the title compound as a yellow oil (340 mg, yield: 56%). LC-MS [ M+H ]] + ＝163.1。 1 H NMR(400MHz，CDCl 3 )δ3.34(s，1H)，3.23-3.11(m，2H)，3.10-2.87(m，2H)，2.17-2.00(m，2H)，1.98-1.71(m，4H)。
Intermediate 14
((2S, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methyl-d 2-ol
Figure BDA0004093773770000921
Step 1: (6S, 7 aR) -6-fluoro-7 a- (hydroxymethyl-d) 2 ) hexahydro-3H-pyrrolizin-3-one
At 0 ℃ at N 2 To a solution of ethyl (2S, 7 aR) -2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (2.0 g,9.3 mmol) in anhydrous EtOH (20.0 mL) was added NaBD slowly in portions 4 (430 mg,10.2 mmol). At rt at N 2 The mixture was stirred under stirring for 10min. The reaction was monitored by LC/MS. After the conversion is complete, the reaction is carried out with saturated aqueous NH at 5 DEG C 4 Cl (1 mL) was carefully quenched and stirring was continued at this temperature for 30min. The mixture was then concentrated on a rotary evaporator to give a residue. The resulting oil was purified by column chromatography (eluting with DCM/MeOH (20/1)) to give the title compound as a yellow oil (1.6 g, yield: 88%). LC-MS [ M+H ]] + ＝176.1
Step 2: ((2S, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methyl-d 2 -alcohols
At 0 ℃ at N 2 LiAlH was carefully added to a solution of (6S, 7 aR) -6-fluoro-7 a- (hydroxymethyl-d 2) hexahydro-3H-pyrrolizin-3-one (800 mg,4.6 mmol) in THF (10 ml) 4 (263 mg,6.9 mmol). The reaction mixture was stirred at 70 ℃ for 2h. The reaction was monitored by LCMS. After the conversion was complete, the reaction mixture was cooled to 0 ℃ and carefully quenched with aqueous NaOH (0.5 ml,1 n), filtered and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (with DCM/(NH in MeOH) 3 ) (30/1) elution) to afford the title compound as a colourless oil (480 mg, yield: 65%). LC-MS [ M+H ]] + ＝162.1。 1 H NMR(400MHz，CDCl 3 )δ5.29-5.10(m，1H)，3.22-3.09(m，2H)，3.05-2.87(m，2H)，2.17-2.00(m，2H)，1.99-1.71(m，4H)。
Intermediate 15
((2S, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2) methyl-d 2-ol
Figure BDA0004093773770000922
At 0 ℃ at N 2 LiAlD was added to a solution of (6S, 7 aR) -6-fluoro-7 a- (hydroxymethyl-d 2) hexahydro-3H-pyrrolizin-3-one-d (800 mg,4.6 mmol) in Me-THF (10 ml) 4 (407 mg,9.7 mmol). The reaction mixture was stirred at 90 ℃ for 2h. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to 0 ℃ and quenched with NaOH (0.9 ml,1 mol/L), filtered and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (with DCM/(NH in MeOH) 3 ) (30/1) elution) to afford the title compound, ((2 s,7 ar) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) -5,5-d 2) methyl-d 2-ol as a colorless oil (480 mg, yield: 64%). LC-MS [ M+H ]] + ＝164.1。 1 H NMR(400MHz，CDCl3)δ5.28-5.11(m，1H)，3.28(s，1H)，3.15-2.98(m，2H)，2.17-2.00(m，2H)，1.95-1.70(m，4H)。
Intermediate 16
((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol,
Figure BDA0004093773770000931
step 1: (6S, 7 aR) -6-fluoro-7 a- (hydroxymethyl) hexahydro-3H-pyrrolizin-3-one
At 0 ℃ at N 2 To a solution of ethyl (2S, 7 aR) -2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (2.0 g,9.3 mmol) in anhydrous EtOH (20 mL) was slowly added NaBH 4 (426 mg,11.1 mmol). At room temperature at N 2 The mixture was stirred under stirring for 10min. The reaction was monitored by LCMS. After completion, at 5 ℃, the reaction was performed with NH 4 Cl (1 mL) was diluted and stirred at this temperature for 30min. The mixture was then concentrated on a rotary evaporator to give a residue. The resulting oil was purified by column chromatography (with DCM/MeOH (30/1) ) Elution) to afford the title compound as a yellow oil (1.6 g, yield: 89%). LC-MS [ M+H ]] + ＝174.1。
Step 2: ((2S, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol
At 20 ℃ at N 2 Next, liAlH was added to a solution of (6S, 7 aR) -6-fluoro-7 a- (hydroxymethyl) hexahydro-3H-pyrrolizin-3-one-d (800 mg,4.62 mmol) in THF (7 ml) 4 (263 mg,6.93 mmol). The reaction mixture was stirred at 70 ℃ for 2h. The reaction was monitored by LCMS. After the conversion was complete, the reaction mixture was cooled to 0 ℃ and carefully quenched with aqueous NaOH (0.5 ml,1 n), filtered and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (with DCM/(NH in MeOH) 3 ) (30/1) elution) to afford the title compound (460 mg, yield) as a colourless oil: 56%). LC-MS [ M+H ]] + ＝160.1。
1 H NMR(400MHz，CDCl 3 )δ5.29-5.10(m，1H)，3.27(s，2H)，3.24—3.17(m，1H)，3.17-3.12(m，1H)，3.11-3.00(m，1H)，2.96-2.88(m，1H)，2.17-2.01(m，2H)，1.97-1.71(m，4H)。
Intermediate 17
((2S, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2) methanol
Figure BDA0004093773770000932
Figure BDA0004093773770000941
At 20 ℃ at N 2 LiAlD was carefully added to a solution of (6S, 7 aR) -6-fluoro-7 a- (hydroxymethyl) hexahydro-3H-pyrrolizin-3-one (800 mg,4.62 mmol) in Me-THF (7 ml) 4 (407 mg,9.70 mmol). The reaction mixture was warmed to 90 ℃ and stirred for 2h. The reaction was monitored by LCMS. After the conversion was complete, the reaction mixture was cooled to 0 ℃ and carefully quenched with aqueous NaOH (0.5 ml,1 n), filtered and concentrated on a rotary evaporator Concentrating. The resulting oil was purified by column chromatography (with DCM/(NH in MeOH) 3 ) (30/1) elution) to afford the title compound as a colourless oil (470 mg, yield: 57%). LC-MS [ M+H ]] + ＝162.1。 1 H NMR(400MHz，CDCl 3 )δ5.28-5.11(m，1H)，3.26(s，2H)，3.19—3.12(m，1H)，3.11-2.99(m，1H)，2.17-2.01(m，2H)，1.95-1.71(m，4H)。
Intermediate 18
2,4, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidine
Figure BDA0004093773770000942
At rt, 7-chloro-8-fluoropyrido [4,3-d ]]Pyrimidine-2, 4-diol (4.61 g,21.4 mmol) in POCl 3 A solution in (76.0 g,496 mmol) was slowly added DIEA (14.0 g,108 mmol). The mixture was heated at 110 ℃ for 3 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under vacuum to afford 2,4, 7-trichloro-8-fluoropyrido [4,3-d ]]Pyrimidine (4 g, crude), 2,4, 7-trichloro-8-fluoropyrido [4,3-d ]]The pyrimidine was used directly in the next step without further purification. LC-MS [ M+H ]] + ＝354.2。
Example 1
4- (4- (3, 6-diazabicyclo [ 3.2.1)]Heptane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Figure BDA0004093773770000943
Step 1: 7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalene-1, 3-diol
At N 2 Next, ruthenium dichloride and 1-isopropyl-4-methylbenzene were added to a mixture of 7-fluoronaphthalene-1, 3-diol (12 g,67.3mmol,1 equivalent), 2-bromoethynyl (triisopropyl) monosilane (18.5 g,70.7mmol,1.05 equivalent), and KOAc (13.2 g,134mmol,2.0 equivalent) in 1, 4-dioxane (80 mL) Dimer (4.13 g,6.74mmol,0.1 eq.). The resulting mixture was warmed to 110 ℃ and under N 2 The stirring was continued for 2h. Based on LC/MS, the transformation was complete. The reaction mixture was cooled to rt and partitioned between brine and EtOAc. After separation, the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried and collected by filtration. The filtrate was concentrated to give a residue, which was purified by column chromatography (SiO 2 PE/etoac=i/0 to 5/1) to give the title compound (15.6 g,65% yield) as a black oil. LC-MS [ M-H ]] - ＝357.2。
Step 2: 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalene-1-ol
At 0 ℃ at N 2 To a mixture of 7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalene-l, 3-diol (37 g,103.2 mmol) and DIEA (40 g,309.6mmol,3 eq.) in DCM (370 mL) was added MOMCl (10.8 g,134 mmol). The mixture was warmed to rt and stirred for 0.5h. Based on LC/MS, the reaction transformation was completed. The reaction mixture was diluted with ice-water (200 mL) and extracted with EtOAc (100 ml×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 PE/etoac=1/0 to 50/1) to give the title compound (29 g,70% yield) as a yellow oil. LCMS [ M+H] + ＝403.2。
Step 3: 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl triflate
At-40 ℃ at N 2 To a solution of 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalene-1-ol (29.0 g,72 mmol) and DIEA (27.9 g,10.4mL,129 mmol) in DCM (200 mL) was added Tf 2 O (30.5 g,108.0mmol,17.9mL,1.5 eq.). At N 2 The reaction mixture was stirred under stirring for 0.5h. Based on LC/MS, the transformation was complete. The reaction mixture was diluted with ice-water (200 mL) and extracted with DCM (400 mL). The organic phase was washed with brine, dried over anhydrous Na 2 SO 4 Drying and passing throughAnd (5) filtering and collecting. The filtrate was concentrated on a rotary evaporator. The residue was purified by column chromatography (SiO 2 PE/etoac=1/0 to 60/1) to afford the title compound (38.0 g,99% yield) as a yellow oil. LCMS [ M+H] + ＝535.1。
Step 4: ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane
To a mixture of 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate (8 g,15.0mmol,1 eq.), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (16.0 g,63.0mmol,4.2 eq.) and KOAc (4.80 g,48.9mmol,3.26 eq.) in degassed toluene (200 mL) was added Pd (dppf) Cl 2 (1.20 g,1.64mmol,0.11 eq.). The mixture was evacuated using N 2 Filled and fitted with a condenser and N 2 A balloon. The resulting mixture was heated in an oil bath at 130 ℃ and under N 2 The stirring was continued for 12h. Based on LC/MS, the transformation was complete. The reaction mixture was cooled to rt and partitioned between water and EtOAc. After separation, the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 Dried and collected by filtration. The filtrate was concentrated on a rotary evaporator. The residue was purified by column chromatography (SiO 2, PE/etoac=100/1 to 50/1) to give the title compound (1.0 g,17% yield) as a pale yellow oil. LCMS [ M+H] + ＝513。 1 H NMR(400MHz，CDCl 3 )δ7.68(dd，J＝9.0，5.8Hz，1H)，7.52(d，J＝2.6Hz，1H)，7.39(d，J＝2.6Hz，1H)，7.24(t，J＝8.8Hz，1H)，5.29(s，2H)，3.52(s，3H)，1.45(s，12H)，1.18(d，J＝2.4Hz，21H)。
Step 5:3- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester
At rt, to 2,4, 7-trichloro-8-fluoropyrido [4,3-d ]]A solution of pyrimidine (intermediate 18,3.4g,13.55mmol,1 eq.) in dry DCM (40.0 mL) was added DIEA (13.4 mL,81.30 m)mol,6 equivalents). The mixture was then cooled to-40℃at N 2 Dropwise addition of 3, 6-diazabicyclo [3.1.1] within 10min]A solution of tert-butyl heptane-6-carboxylate (2.68 g,13.55mmol,1 eq.) and stirring was continued for 0.5h. Based on LC/MS, the transformation was complete. The reaction was quenched with water (30.0 mL). The resulting reaction mixture was extracted with EtOAc (30.0 mL. Times.3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (nash chromatography) on a silica gel column (silica gel column) (PE/etoac=40/1 to 20/1) to afford 3- (2, 7 dichloro-8-fluoropyrido [4, 3-d) as a white solid]Pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid tert-butyl ester (1.9 g,34% yield, 4.6 mmol). LC-MS [ M+H ]] + ＝414.1。
Step 6:3- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d ] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester
At N 2 Down to 3- (2, 7-dichloro-8-fluoropyrido [4, 3-d)]Pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1]A solution of tert-butyl heptane-6-carboxylate (500 mg,1.21mol,1 eq.) in dry 1, 4-dioxane (4 mL) was added (tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methyl-d 2-ol (intermediate 7, 348 mg,2.4 mmol) and DIEA (0.6 mL,3.63mmol,3 eq.). The reaction was warmed to 80 ℃ and stirred overnight. Based on LC/MS, the transformation was complete. The reaction mixture was cooled to rt, diluted with water (50.0 mL) and EtOAc (50.0 mL) was then added. The two layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on a silica gel column (DCM/meoh=20/1) to provide the expected 3- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid tert-butyl ester (530 mg,84% yield, 1.0 mmol). LC-MS [ M+H ]] + ＝521.2。
Step 7:3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d ] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester
To 3- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid tert-butyl ester (530 mg,1.02 mmol) in dioxane (3.0 mL) and H 2 A solution of ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (787.9 mg,2.05mmol,2 eq.) Cs was added to a degassed mixed solvent of O (1.0 mL) 2 CO 3 (668 mg,2.05 mmol) and Pd (dppf) Cl 2 (150 mg,0.20 mmol). The mixture was evacuated using N 2 Filling, and this procedure was repeated three times. The reaction vessel was sealed. The resulting mixture was warmed to 110 and stirred for 1h. Based on LC/MS, the transformation was complete. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 ml×3). The combined organic layers were purified by Na 2 SO 4 Dried and collected by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on a silica gel column (DCM/meoh=10/1) to give the title compound (217 mg,26% yield, 0.25 mmol). LC-MS [ M+H ]] + ＝871.4。
Step 8:3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid tert-butyl ester
At rt, 3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1]A solution of tert-butyl heptane-6-carboxylate (217 mg,0.25 mmol) in DMF (2.0 mL) was added CsF (190 mg,1.25 mmol). The resulting mixture was stirred for 1h, diluted with water (20.0 mL) and extracted with EtOAc (20.0 ml×3). Combined organic layers Anhydrous Na 2 SO 4 Dried, collected by filtration and concentrated under reduced pressure to give the expected title compound (300 mg, crude) as a yellow oil, which was used directly without additional purification. LC-MS [ M+H ]] + ＝715.3。
Step 10:4- (4- (3, 6-diazabicyclo [ 3.2.1)]Heptane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
At rt, 3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1]A solution of tert-butyl heptane-6-carboxylate (300 mg,0.42 mmol) in MeCN (2.0 mL) was added 4N HCl/MeOH (2.0 mL). The reaction mixture was stirred for 1h with saturated NaHCO 3 Adjusted to pH-7, diluted with water (20 mL) and extracted with EtOAc (20 ml×3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Prep-HPLC) (mobile phase A:0.1% FA; mobile phase B: meCN; gradient: 30% -70% B over 55 min; flow rate: 70 mL/min) to give the title compound (8 mg,0.14mmol,3% yield) as a white solid. LC-MS [ M+H ] ] + ＝571.2。
Example 2
3- (4- (8-oxa-3-azabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-fluoro-4- (trifluoromethyl) phenol
Figure BDA0004093773770000981
Step 1:2- (3-bromo-5-chloro-4- (trifluoromethyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane
At N 2 Next, 1-bromo-3-chloro-2- (trifluoromethyl) benzene (5.0 g,19.3 mmol) and 4, 5-tetramethyl-1, 3, 2-dioxaboronA solution of alkane (4.93 g,38.5 mmol) in THF (60.0 mL) was added dtbbpy (6271 mg,2.31 mmol) and (Ir (OMe) (cod)) 2 (1.28 g,1.93mmol,0.1 eq.). The resulting mixture was treated with N 2 For 1min, sealed, warmed to 60 ℃ and for 2 hours. Based on TLC, the conversion was complete. The reaction mixture was cooled to rt and partitioned between brine and DCM. After separation, the organic phase was concentrated in vacuo to give the title intermediate (12.0 g, crude) as a black oil, which was used directly in the next step without further purification. LCMS [ M+H] + ＝385.0。
Step 2: 3-bromo-5-chloro-4- (trifluoromethyl) phenol
To 5-chloro-4- (trifluoromethyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (12.0 g,31.1 mmol) in THF (100.0 mL) and H 2 AcOH (74.8 g,1.25 mol) was added to a solution of O (50.0 mL). Then, at 0 ℃, H 2 O 2 (70.6 g,623mmol, 30%) was added dropwise to the mixture for 20min. The mixture was stirred at 0 ℃ for 1h. Based on TLC, the reaction conversion was complete. Water (200 mL) and EtOAc (200 mL) were added. The two phases were separated. Na for organic phase 2 SO 3 Solution (200.0 mL. Times.2), brine (100 mL. Times.2), washed with anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated on a rotary evaporator. The residue was purified on a silica gel column (PE/etoac=40:1 to 5:1) to give 3-bromo-5-chloro-4- (trifluoromethyl) phenol (5.2 g, 83% yield over two steps) as a pale brown oil. LC-MS [ M+H ]] + ＝275。
Step 3:5- (benzyloxy) -1-bromo-3-chloro-2- (trifluoromethyl) benzene
To 3-bromo-5-chloro-4- (trifluoromethyl) phenol (5 g,18.15mmol,1.0 eq.) in CH 3 A solution in CN (125 mL) was added benzyl bromide (3.73 g,21.78mmol,1.2 eq.) and K 2 CO 3 (7.53 g,54.46mmol,3.0 eq.). The resulting mixture was stirred for 2h. Based on LC/MS, the transformation was complete. The reaction mixture was filtered through celite (celite) and taken up in CH 3 CN (100 mL) was washed. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (PE/etoac=1:0), followed by reverse phase Preparative HPLC (mobile A:0.1% FA; mobile B: ACN; gradient: 60% -90% B over 55 min; flow rate: 70 mL/min) gave 5- (benzyloxy) -1-bromo-3-chloro-2- (trifluoromethyl) benzene (4.5 g,68% yield) as a pale yellow liquid. LC-MS [ M+H ]] + ＝366。 1 H NMR(60MHz，CDCl 3 )：δ7.67-6.84(m，7H)，5.15(s，2H)。
Step 4:2- (5- (benzyloxy) -3-chloro-2- (trifluoromethyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane
At N 2 Pd (dppf) Cl was added to a mixture of 5- (benzyloxy) -1-bromo-3-chloro-2- (trifluoromethyl) benzene (2.01 g,5.47 mmol), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (4.17 g,16.4 mmol) and KOAc (1.62 g,16.4 mmol) in degassed 1, 4-dioxahexacyclic ring (80.0 mL) 2 (0.90 g,1.10mmol,0.2 eq.). N for mixtures 2 Flushing (purge) for 10 seconds, equipped with condenser and N 2 A balloon. The resulting reaction mixture was stirred in an oil bath at 110 ℃ for 12h. Based on LC/MS, the transformation was complete. The reaction mixture was cooled to rt, filtered and the filtrate concentrated to give a residue, which was diluted with EtOAc (100 mL) and water (80 mL). After separation, the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/etoac=100/1 to 20/1) to give the title intermediate 2- (5- (benzyloxy) -3-chloro-2- (trifluoromethyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (1.2 g,53% yield) as a white solid. LC-MS [ M+H ]] + ＝413。 1 H NMR(60MHz，CDCl 3 )：δ7.49-7.46(m，5H)，7.15-7.03(m，2H)，5.17(s，2H)1.45(s，12H)。
Step 5:3- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -8-oxa-3-azabicyclo [3.2.1] octane
At rt, to 2,4, 7-trichloro-8-fluoropyrido [4,3-d ]]A solution of pyrimidine (intermediate 18,2g,7.9 mmol) in DCM (30 mL) was added DIEA (5.8 mL,35.5 mmol). MixingN for the composition 2 The gas stream was flushed for 10 seconds, then cooled to-40 ℃ followed by N 2 Adding 8-oxa-3-azabicyclo [3.2.1]Octane (intermediate 7,0.81g,7.1mmol,1.0 eq.). The resulting reaction mixture was stirred for 1h. Based on LC/MS, the transformation was complete. The reaction mixture was diluted with DCM (50 mL) and poured into water (20 mL). After separation, the organic layer was washed with brine, dried over Na 2 SO 4 Dried, collected by filtration, and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography (PE/etoac=3:1) to give the title compound (1.4 g,54% yield) as a yellow solid. LC-MS [ M+H ] ] + ＝329.0。
Step 6:3- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -8-oxa-3-azabicyclo [3.2.1]Octane (octane)
To 3- {2, 7-dichloro-8-fluoropyrido [4,3-d ]]Pyrimidin-4-yl } -8-oxa-3-azabicyclo [3.1.1]A solution of octane (1.4 g,4.2 mmol) in 1, 4-dioxane (20 mL) was added sequentially (tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methyl-d 2 Alcohol (0.90 g,6.4 mmol) and DIEA (2.1 mL,12.7 mmol). The reaction mixture was warmed to 80 ℃ and under N 2 The stirring was continued for 12h. The reaction mixture was cooled to rt, taken up with EtOAc (100 mL) and H 2 O (50 mL) dilution. After separation, the organic layer was washed with brine, dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE/etoac=1:1 to DCM/meoh=10:1 (containing 0.1% et) 3 N)) to give the title compound as a yellow solid (1.40 g,76% yield). LC-MS [ M+H ]] + ＝436.2。
Step 7:3- (7- (5- (benzyloxy) -3-chloro-2- (trifluoromethyl) phenyl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -8-oxa-3-azabicyclo [3.2.1]Octane (octane)
To 3- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -8-oxa-3-azabicyclo [3.2.1]Octane (200 mg of the crude oil,0.46 mmol) in degassed 1, 4-dioxane (9.0 mL) and H 2 Cs addition to suspension in O (3.0 mL) 2 CO 3 (300mg，0.92mmol)、Pd(dppf)Cl 2 (33.7 mg,0.0461 mmol) and 2- [5- (benzyloxy) -3-chloro-2- (trifluoromethyl) phenyl)]-4, 5-tetramethyl-1, 3, 2-dioxaborane (190 mg,0.460 mmol). The mixture was evacuated using N 2 Filled and fitted with a condenser and N 2 A balloon. The resulting reaction mixture was warmed to 110 ℃ and stirred for 2h. Based on LC/MS, the reaction transformation was completed. The reaction mixture was cooled to rt and quenched with EtOAc (100 mL) and H 2 O (50 mL) dilution. The two layers were separated. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/etoac=1:1 to EtOAc (containing 0.1% et) 3 N)) to give the title compound as a yellow solid (110 mg,35% yield). LC-MS [ M+H ]] + ＝686.2。
Step 8:3- (4- (8-oxa-3-azabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol
To 3- (7- (5- (benzyloxy) -3-chloro-2- (trifluoromethyl) phenyl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -8-oxa-3-azabicyclo [3.2.1]Octane (110 mg,0.16 mmol) in CH 3 Pd/C (11.0 mg,10% wt) was added to a solution in OH (5 mL). The mixture was degassed in vacuo and purified by H 2 Filling, and this sequence is repeated three times. The mixture is put in H 2 Stirring under an atmospheric balloon was continued for 1h. Based on LC/MS, the reaction transformation was completed. The resulting reaction mixture was filtered through a thin layer of celite (a thin pad of celite) with EtOAc (30 mL). The filtrate was concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (mobile phase A:0.1% FA; mobile phase B: ACN; gradient: 30% -80% B in 55 min; flow rate: 70 mL/min) and lyophilized to give the title compound 3- (4- (-8-oxa-3-azabicyclo [ 3.2.1) as a white solid]Octane-3-yl) -8-fluoro-2- ((tetrahydro)-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol (14.3 mg, 5% yield over two steps). LC-MS [ M+H ]] + ＝596.2。 1 H NMR(400MHz，CD 3 OD)δ9.09(s，1H)，8.55(s，1H)，7.10(d，J＝2.4Hz，1H)，6.71(d，J＝2.4Hz，1H)，4.56-4.52(m，6H)，3.60-3.53(m，2H)，3.21-3.16(m，2H)，2.32-2.25(m，2H)，2.21-1.97(m，8H)，1.87-1.84(m，2H)。
Example 3
4- (4- (3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Figure BDA0004093773770001011
Step 1:3- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
At-40 ℃ at N 2 Down to 2,4, 7-trichloro-8-fluoropyrido [4-d ]]A solution of pyrimidine (intermediate 18,5.6g,22.18mmol,1 eq.) in DCM (30.0 mL) was added DIEA (18.3 mL,110.91mmol,5 eq.) and 3, 8-diazabicyclo [ 3.2.1)]Octane-8-carboxylic acid tert-butyl ester (4.24 g,20.0 mmol). The reaction mixture was stirred at-40 ℃ for 1h. The reaction mixture was poured into DCM (100 mL) and water (100 mL). The two layers were separated. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with (PE: etoac=5:1 to 3:1) to give 3- (2, 7-dichloro-8-fluoropyrido [4, 3-d) as a yellow solid]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (5.2 g,55% yield, 12.1 mmol). LC-MS [ M+H ]] + ＝428.1。
Step 2:3- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acidAcid tert-butyl ester
To 3- (2, 7-dichloro-8-fluoropyrido [4, 3-d) ]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (1.00 g,2.33 mmol) in 1, 4-dioxane (15.0 mL) was added (tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methyl-d 2 Alcohol (intermediate 7, 659mg,4.67 mmol) and DIEA (1.2 ml,7 mmol). The reaction mixture was warmed to 80 ℃ and stirred for 6h. Based on LC/MS, the reaction was complete. The reaction mixture was cooled to rt and diluted with EtOAc (50 mL) and water (50 mL). The organic layer was separated, washed with brine, dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/etoac=1:1 to DCM/meoh=10:1 (containing 0.1% et) 3 N)) to give the title compound as a yellow solid (960 mg,77% yield, 1.80 mmol). LC-MS [ M+H ]] + ＝535.2。
Step 3:3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester
To 3- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1 ]octane-8-Carboxylic acid tert-butyl ester (481mg, 0.909 mmol) in degassed 1, 4-dioxane (15.0 mL) and H 2 Cs was added to a solution in O (5.0 mL) 2 CO 3 (611mg，1.87mmol)、Pd(dppf)Cl 2 (68.6 mg,0.0909mmol,0.1 eq) and ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) naphthalen-1-yl) ethynyl) triisopropylmonosilane (from example 1, step 4, 424mg,0.826 mmol). The mixture was evacuated using N 2 Filling, and this sequence is repeated three times. The resulting reaction vessel was equipped with a condenser and N 2 Balloon and stirred at 110 ℃ for 5h. Based on LC/MS, the reaction was complete. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated, washed with brine (20 mL), and dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/etoac=5:1 to DCM/meoh=10:1) to give the title compound (677 mg,82% yield, 0.76 mmol) as a black solid. LC-MS [ M+H ]] + ＝885.4。
Step 4:3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1 ]Octane-8-carboxylic acid tert-butyl ester
At rt, 3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (1.95 g,2.21 mmol) in DMF (25 mL) was added CsF (1.68 g,11.0 mmol). The reaction was stirred for 1h. Based on LC/MS, the reaction was complete. The reaction mixture was poured into EtOAc (20 mL) and brine (20 mL). After separation, the organic layer was subjected to anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated in vacuo to give the title compound (2.3 g, crude) as a brown solid. LC-MS [ M+H ]] + ＝729.3。
Step 5:4- (4- (3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
To 3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (2.3 g,3.16mmol,1 eq.) in acetonitrile (2.0 mL) was added 1N HCl (40 mL) in 1, 4-dioxane. The reaction was stirred at room temperature for 1h. Based on LC/MS, the reaction was complete. After careful addition of saturated aqueous NaHCO 3 In the case of (2), the reaction mixture is adjusted to a pH of 7. The mixture was poured into water and DCM. After separation, the organic phase was washed with brine, dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated in vacuo. The residue was purified by preparative HPLC (mobile phase A:0.1% FA; mobile phase B: ACN; gradient: 30% -80% B in 55 min; flow rate: 70 mL/min). The solution was lyophilized to give the expected compound as a white solid (100 mg,0.17mmol, 8% yield over two steps). LC-MS [ M+H ]] + ＝585.3。 1 H NMR(400MHz，CD 3 OD-d 6 )δ9.08(s，1H)，8.51(s，1H)，7.88(dd，J＝8.0Hz，4.0Hz 1H)，7.36-7.21(m，2H)，4.71-4.58(m，4H)，3.83-3.62(m，4H)，3.36(s，1H)，3.28-3.21(m，2H)，2.35-2.27(m，2H)，2.24-2.06(m，6H)，1.99-1.80(m，4H)。
Example 4
4- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Figure BDA0004093773770001031
Step 1:3- (7-chloro-8-fluoro-2- ((2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
To 3- (2, 7-dichloro-8-fluoropyrido [4, 3-d)]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (762 mg,1.78 mmol) in 1, 4-dioxane (15.0 mL) was added (2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methanol (intermediate 1, 190mg,1.19 mmol) and DIEA (460.00 mg,3.56mmol,3 eq.). The reaction mixture was stirred at 80 ℃ for 6h. Based on LC/MS, the reaction was complete. The reaction mixture was cooled to rt and diluted with EtOAc (20.0 mL) and water (20.0 mL). After separation, the organic layer was washed with brine, dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/etoac=1:1 to DCM/meoh=10:1 (containing 0.1% et) 3 N)) to give the title compound as a yellow solid (230 mg,35% yield，0.41mmol)。LC-MS[M+H] + ＝552.2。
Step 2:3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
To 3- (7-chloro-8-fluoro-2- ((2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]octane-8-Carboxylic acid tert-butyl ester (180 mg,0.33 mmol) in degassed 1, 4-dioxane (9.0 mL) and H 2 A solution of ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (from example 1, step 4, 334mg,0.65 mmol), cs 2 CO 3 (212 mg,0.65 mmol) and Pd (dppf) Cl 2 (23.9 mg,0.0301 mmol). The mixture was evacuated using N 2 Filling, and this sequence is repeated three times. Will be equipped with a condenser and N 2 The resulting mixture of balloons was stirred at 110℃overnight. Based on LC/MS, the reaction was complete. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL) and water (30 mL). After separation, the organic layer was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 Dried, collected by filtration, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/etoac=5:1 to DCM/meoh=10:1) to give the title compound (200 mg,68% yield, 0.22 mmol) as a black solid. LC-MS [ M+H ]] + ＝902.4。
Step 3:3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ((2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate to 3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (260 mg,0.29 mmol) in DMF (2 mL) was added CsF (219 mg,1.44 mm)And (3) an ol). The reaction mixture was stirred at rt for 1h. Based on LC/MS, the reaction was complete. The reaction mixture was diluted with EtOAc (10.0 mL) and water (10.0 mL). After isolation, the organic layer was concentrated in vacuo to give the title intermediate (215 mg, crude). LC-MS [ M+H ] ] + ＝746.3。
Step 4:4- (4- (3, 8-diazabicyclo [3.2.1] oct-2-yl) -8-fluoro-2- ((2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
To (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ((2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (215 mg,0.29 mmol) in MeCN (7.0 mL) was added HCl (7.0 mL, 4M) in 1, 4-dioxane. The reaction mixture was stirred at rt for 1h. Based on LC/MS, the reaction was complete. The solvent was removed in vacuo. The residue was purified by preparative HPLC (mobile phase A:0.1% FA; mobile phase B: ACN; gradient: 30% -70% B in 55 min; flow rate: 70 mL/min) and lyophilized to give the expected title compound (8.1 mg,0.013mmol, 5% yield over two steps). LC-MS [ M+H ]] + ＝602.3。 1 H NMR(400MHz，CD 3 OD)δ9.08(s，1H)，8.51(s，1H)，7.89(dd，J＝9.2，5.6Hz，1H)，7.38-7.33(m，2H)，7.23(d，J＝2.6Hz，1H)，4.78-4.71(m，2H)，4.53-4.43(m，2H)，3.87-3.83(m，2H)，3.68-3.47(m，3H)，3.37(d，J＝4.4Hz，1H)，3.26-3.21(m，1H)，2.55-1.94(m，10H)。
Example 5
4- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (diastereomer of example 4)
Figure BDA0004093773770001051
Synthesis of the Compound of example 5 in parallel with example 4, non-para-example 4An enantiomer. LC-MS [ M+H ]] + ＝602.3。 1 H NMR(400MHz，CD 3 OD)δ9.08(s，1H)，8.51(s，1H)，7.89(dd，J＝8.0，4.0Hz，1H)，7.39-7.33(m，2H)，7.23(d，J＝2.6Hz，1H)，4.74(s，2H)，4.54-4.44(m，2H)，3.91(d，J＝44Hz，2H)，3.68—3.52(m，3H)，3.37(d，J＝4.0Hz，1H)，3.28—3.20(m，1H)，2.56—1.89(m，10H)。
Example 6/example 7
3- (4- (3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) -5, 8-dihydro-pyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol and 3- (4- (3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -4- (trifluoromethyl) phenol
Figure BDA0004093773770001052
Step 1:2, 4-dichloro-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine
To 2, 4-dichloro-5, 8-dihydropyridine [3,4-d ]]A solution of pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (2.0 g,6.6 mmol) in DCM (20.0 mL) was added TFA (7.0 mL) and the reaction stirred at rt for 3H. The reaction was concentrated under reduced pressure to give 2, 4-dichloro-5, 6,7, 8-tetrahydropyrido [3,4-d ] as a yellow oil]Pyrimidine (3.5 g, crude), 2, 4-dichloro-5, 6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine was used directly in the next step. LC-MS [ M+H ]] + ＝204.0。
Step 2:2, 4-dichloro-5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid benzyl ester
To 2, 4-dichloro-5, 6,7, 8-tetrahydropyrido [3,4-d ] at 0 DEG C ]A solution of pyrimidine (3.50 g,17.2mmol,1 eq.) in THF (50.0 mL) was added DIEA (4.45 g,34.5 mmol) and CbzCl (2.93 g,17.24 mmol). The reaction was stirred at rt for 1h. The mixture was concentrated in vacuo. The residue was taken up in EtOAc (100 mL) and H 2 O (100 mL) between partitions. After separation, the organic isThe layers were concentrated in vacuo. The residue was purified by column chromatography (PE/etoac=5/1 to 3/1) to give the title intermediate (2.10 g,6.23mmol, 94% yield over two steps) as a yellow oil. LC-MS [ M+H ]] + ＝338.0。
Step 3:4- (8- (tert-Butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid benzyl ester
To 2, 4-dichloro-5, 8-dihydropyrido [3,4-d ]]A solution of pyrimidine-7 (6H) -carboxylic acid benzyl ester (2.10 g,6.23 mmol) in DMSO (30.0 mL) was added DIEA (2.01 g,15.6 mmol) and 3, 8-diazabicyclo [ 3.2.1)]Tert-butyl octane-8-carboxylate (1.32 g,6.23mmol,1 eq.) and the reaction was stirred at 55℃for 12 hours. The reaction was cooled to rt, taken up with EtOAc (100 mL) and H 2 O (50 mL) dilution. After separation, the organic layer was washed with brine, dried over Na 2 SO 4 Dried, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE/etoac=5/1 to 3/1) to give 4- (8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [ 3.2.1) as a yellow solid ]Octane-3-yl) -2-chloro-5, 8-dihydropyrido [3,4-d]Pyrimidine-7 (6H) -carboxylic acid benzyl ester (2.10 g,65% yield, 4.09 mmol). LC-MS [ M+H ]] + ＝514.3。
Step 4:4- (8- (tert-Butoxycarbonyl) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidine-7 (6H) -carboxylic acid benzyl ester
To 4- (8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2-chloro-5, 8-dihydropyrido [3,4-d]A solution of pyrimidine-7 (6H) -carboxylic acid benzyl ester (1.40 g,2.73 mmol) in degassed toluene (80 mL) was added (tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methyl-d 2 -alcohol (intermediate 7, 770mg,5.4 mmol), t-Buona (650 mg,6.83 mmole 6), pa 2 (dba) 3 (2476 mg,0.27 mmole 6) and BINAP (3426 mg,0.55 mmole 6). N for mixtures 2 Degassing 6 was continued for 1min. Will be equipped with a condenser and N 2 The mixture of balloons was stirred at 110℃for 3h. The reaction mixture was cooled to rt, taken up with EtOAc and H 2 O dilution. After separation, the organic layerAnhydrous Na 2 SO 4 Dried, filtered, and concentrated. The residue was purified by preparative HPLC (mobile phase A:0.1% FA; mobile phase B: ACN; gradient: 50% -90% B in 55 min; flow: 70 mL/min) to give 4- (8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [ 3.2.1) as a yellow solid ]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) -5, 8-dihydropyrido [3,4-d ]]Pyrimidine-7 (6H) -carboxylic acid benzyl ester (0.62 g,36% yield, 1.0 mmol). LC-MS [ M+H ]] + ＝621.3。
Step 5:3- (2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d) 2 ) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester
To 4- (8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]A solution of pyrimidine-7 (6H) -carboxylic acid benzyl ester (0.62 g,1.0mmol,1 eq.) in MeOH (20.0 mL) was added NH 3 MeOH solution (20 mL) and Pd/C (0.20 g). The mixture was evacuated and treated with H 2 Filling. The mixture was taken up at rt at H 2 Stirring was continued for 4h under an atmosphere. TLC showed complete consumption of starting material and the reaction was filtered. The filtrate was concentrated in vacuo to afford the title compound as a yellow solid (470 mg,60% yield, 0.6 mmol). LC-MS [ M+H ]] + ＝487.3。
Step 6:3- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1 ]Octane-8-carboxylic acid tert-butyl ester
At rt at N 2 Next, 3- (2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d) 2 ) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (230 mg,0.48 mmol) in degassed toluene (8.0 mL) was added RuPhos (46.6 mg,0.10 mmol), cs 2 CO 3 (469 mg,1.44 mmol), 1-bromo-3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) benzene (from example 2, step 3,154mg,0.48 mmol) and Pd 2 (dba) 3 (45.8 mg,0.050 mmol). The mixture was degassed in vacuo and purified with N 2 Filling. Will be equipped with a condenser and N 2 The mixture of balloons was stirred at 110℃for 8 hours. LCMS showed complete consumption of starting material, cooling the reaction to rt, diluting with EtOAc (30.0 mL) and water (30.0 mL). After separation, the organic layer was washed with brine (20.0 mL), dried over anhydrous Na 2 SO 4 Dried, filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM/meoh=3/1 to 1/1) to give the title intermediate as a brown solid (340 mg,71% yield). LC-MS [ M+H ]] + =725. Deuterated compound, 3- (7- (5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] ]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester. LC-MS [ M+H ]] + ＝689。
Step 7:3- (4- (3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydro-pyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol and 3- (4- (3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -4- (trifluoromethyl) phenol
To a solution of 3- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy-d 2) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (340 mg,0.47 mmol) in MeOH (25.0 mL) was added 4N HCl (25.0 mL) in pressure tube (pressure tube). The reaction was stirred at 70 ℃ for 8 hours. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by preparative HPLC (mobile phase a:0.1% fa; mobile phase B: ACN; gradient: 30% -80% B over 55 min; flow rate: 70 mL/min) to afford:
example 6, P1: 3- (4- (3, 8-diazabicyclo [ 3.2.1) as a white solid ]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) -5, 8-dihydroPyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol (16.0 mg, 6% yield over two steps). LC-MS [ M+H ]] + ＝581.3。 1 H NMR(400MHz，CD 3 OD)δ6.78(d，J＝4.0Hz，1H)，6.73(d，J＝4.0Hz，1H)，4.49(s，2H)，4.23-4.13(m，2H)，4.07(s，2H)，3.71—3.62(m，2H)，3.49-3.40(m，2H)，3.31-3.24(m，2H)，3.22—3.14(m，2H)，2.85(s，2H)，2.31-2.26(m，2H).2.23-2.15(m，4H).2.12-2.04(m，6H)；
Example 7, P2: 3- (4- (3, 8-diazabicyclo [ 3.2.1) as a white solid]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -4- (trifluoromethyl) phenol (8.0 mg, 3% yield over two steps). LC-MS [ M+H ]] + ＝547.3. 1 H NMR(400MHz，CD 3 OD)δ7.61(d，J＝8.8Hz，1H)，6.90(d，J＝2.4Hz，1H)，6.44(dd，J＝8.8Hz，2.4Hz，1H)，4.49(s，2H)，4.19-4.14(m，2H)，4.00(s，2H)，3.69-3.62(m，2H)，3.43-3.40(m，2H)，3.30—3.24(m，2H)，3.16(q，d，J＝5.6Hz，2H)，3.16(q，d，J＝5.6Hz，2H)，2.85(q，d，J＝5.2Hz，2H)，2.33-2.25(m，2H).2.23-2.14(m，4H).2.10-2.03(m，6H)。
The compounds in table 2 below were synthesized using similar procedures as described in example 4:
TABLE 2
Figure BDA0004093773770001081
Example 10
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Figure BDA0004093773770001082
Figure BDA0004093773770001091
Step 1: (1R, 5S) -3- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
At-40 ℃ at N 2 Next, 2,4, 7-trichloro-8-fluoropyrido [4,3-d ]]A solution of pyrimidine (intermediate 18,5.01g,19.8 mmol) in DCM (30 mL) was added DIEA (18.3 mL,111 mmol) and (1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-8-carboxylic acid tert-butyl ester (4.24 g,20.0 mmol). The reaction mixture was stirred at-40 ℃ for 1h. The reaction mixture was poured into DCM (100 mL) and water (100 mL). The two layers were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, collected by filtration, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with (PE/etoac=5:1 to 3:1) to give the title compound as a yellow solid (5.21 g,61% yield). LC-MS [ M+H ]]+＝428.1。
Step 2: (1R, 5S) -3- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -3.8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester
(1R, 5S) -3- (2, 7-dichloro-8-fluoropyrido [4, 3-d)]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (180 mg,0.420 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methanol (intermediate 8, 74.8mg, 0.463mmol) and Cs 2 CO 3 (410 mg,1.26 mmol) in 1, 4-dioxane (10 mL) was warmed to 95℃and under N 2 Stirring was continued for 12h under an atmosphere. The reaction was monitored by LCMS. After completion, the mixture was allowed to cool down to rt and concentrated under reduced pressure. The residue was purified by reaction with [ MeOH: DCM (DCM) ](1:100-1:20) to afford the title intermediate as a yellow solid (100 mg, 43% yield). LC-MS [ M+H ]] + ＝554.3
Step 3: (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethyl)Alkynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -3.8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester
(1R, 5S) -3- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy) pyrido [4, 3-d)]Pyrimidin-4-yl) -3.8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (350 mg, 0.630 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (from example 1, step 4, 640 mg,1.26 mmol) and K 2 CO 3 (261 mg,1.89 mmol) in 1, 4-dioxane (4.0 mL) and H 2 The mixture in O (0.8 mL) was evacuated using N 2 Backfilling (backfill), and this sequence is repeated three times. At N 2 To the resulting mixture was added RuPhos Pd G3 (52.7 mg,0.0630 mmol). The mixture was sealed, warmed to 90 ℃ and heated to N 2 Stirring was continued for 2h under an atmosphere. The reaction was monitored by LCMS. After completion, the mixture was allowed to cool down to rt and concentrated under reduced pressure. The residue was purified by using MeOH: DCM](1:100-1:20) to afford the title intermediate as a brown solid (300 mg, 53% yield). LC-MS [ M+H ]] + ＝904.5
Step 4:4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol
At 0 ℃ at N 2 To (1 r,5 s) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) under an atmosphere 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -3.8-diazabicyclo [3.2.1]A stirred mixture of tert-butyl octane-8-carboxylate (300 mg,0.332 mmol) in MeCN (5.0 mL) was added HCl (4N in dioxane) (1.0 mL) in one portion. The reaction mixture was stirred at rt for 1h. Reverse-rotationShould be monitored by LCMS. After completion, the residue was concentrated under reduced pressure to give the title compound (300 mg crude), which was used in the next step without additional purification. LC-MS [ M+H ] ] + ＝760.4
Step 5:4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
At N 2 In the atmosphere, 4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]A mixture of pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol (300 mg, crude) in DMF (4 mL) was added CsF (200 mg,1.32 mmol) in one portion. The mixture was stirred at rt overnight. The reaction was monitored by LC/MS. After completion, the mixture was purified by preparative-HPLC (column: gemini 5um C18 150*21.2mm, mobile phase: water (0.05% nh 3 -H 2 O) -ACN; b%:20% -95%,20 min) to afford the title compound as a yellow solid (55.1 mg, 28% yield (two steps)). LC-MS [ M+H ]] + ＝604.3。 1 H NMR(400MHz，DMSO-d6)δ10.20(s，1H)，9.03(s，1H)，7.97(dd，J＝9.2，6.0Hz，1H)，7.46(t，J＝9.2Hz，1H)，7.38(d，J＝2.4Hz，1H)，7.17(d，J＝2.0Hz，1H)，4.46(d，J＝12.0Hz，1H)，4.31(d，J＝12.0Hz，1H)，4.10(dd，J＝10.4，3.2Hz，1H)，4.00(dd，J＝10.4，2.4Hz，1H)，3.93(s，1H)，3.68—3.49(m，4H)，3.08(q，J＝13.6Hz，1H)，3.00(s，1H)，2.60(s，1H)，2.16-1.96(m，3H)，1.85-1.73(m，3H)，1.65(s，4H)。
Example 11
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (2-ethyl-5- (prop-1-en-2-yl) phenyl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d ] pyrimidine
Figure BDA0004093773770001111
Step 1: (1R, 5S) -3- (7- (2-ethyl-5- (2-hydroxy-propan-2-yl) phenyl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester
2- [ 4-ethyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl]Propan-2-ol (from EX.37, step 4, 162mg,0.560 mmol), (1R, 5S) -3- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d) 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (from EX.3, step 4, 200mg,0.373 mmol) and K 2 CO 3 (155 mg,1.12 mmol) in 1, 4-dioxane/H2O (V/v=5:1, 5 mL). Then RuPhos Pd G3 (31.2 mg,0.0373 mmol) was added. The mixture was evacuated, backfilled with N2, and the sequence was repeated three times. The resulting mixture was warmed to 90 ℃ and under N 2 Stirring was continued for 4h under an atmosphere. The reaction was monitored by LCMS. After completion, the mixture was allowed to cool down to rt and concentrated under reduced pressure. The residue was purified by using MeOH: DCM](1:100-1:20) to afford a yellow solid (100 mg,43% yield). LC-MS [ M+H ] ] + ＝663.4。
Step 2:4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (2-ethyl-5- (prop-1-en-2-yl) phenyl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidine
At rt, (1R, 5S) -3- (7- (2-ethyl-5- (2-hydroxy-prop-2-yl) phenyl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A mixture of tert-butyl octane-8-carboxylate (44.0 mg,0.0663 mmol) and TMSI (26.5 mg,0.133 mmol) in MeCN (5.0 mL) was stirred for 1h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give a residue, which was purified by column chromatography on silica gel (eluting with DCM/MeOH,0 to 15%),to afford the expected product, which was additionally purified by preparative-HPLC (5% meoh in DCM) to afford the title compound as a yellow solid (15.0 mg,41% yield). LC-MS [ M+H ]] + ＝545.3。
1 H NMR(400MHz，DMSO-d6)δ9.10(s，1H)，7.58(dd，J＝8.0，1.6Hz，1H)，7.44-7.36(m，2H)，5.44(s，1H)，5.10(s，1H)，4.46-4.33(m，3H)，3.62-3.54(m，4H)，3.00-2.94(m，2H)，2.63-2.52(m，4H)，2.11(s，3H)，1.92-1.86(m，2H)，1.84-1.74(m，4H)，1.65-1.57(m，6H)，1.04(t，J＝7.6Hz，3H)。
Example 12-example 21 in table 3 were synthesized following a similar procedure to example 10 except that their corresponding deuterated butterfly alcohols (butterfly alcohol) were used.
TABLE 3 Table 3
Figure BDA0004093773770001121
Figure BDA0004093773770001131
Example 22
7a- (((4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4,3-d]Pyrimidin-2-yl) oxy) methyl-d 2 ) Hexahydropyrrolizine 4 (1H) -oxide
Figure BDA0004093773770001132
Step 1:2- [ 8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl ] -4, 5-tetramethyl-1, 3, 2-dioxaborane
At rt, {2- [ 2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) naphthalen-1-yl]A mixture of ethynyl } triisopropylsilane (from example 1, step 4, 200mg,0.39 mmol) in DMF (5 mL) was added CsF (593 mg,3.9 mmol)). The reaction mixture was stirred at rt for 12h. The reaction was monitored by LC-MS. After completion, the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (10 ml×3). The combined organic layers were washed with brine (20 mL), and dried over Na 2 SO 4 Dried, filtered, and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography (eluting with MeOH/DCM,1% to 5%) to provide the title compound as a pale yellow oil (120 mg,77% yield). LC-MS [ M+H ]] + ＝356.9
Step 2:2- [ 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl ] -4, 5-tetramethyl-1, 3, 2-dioxaborane
At rt at N 2 Under the flow of gas, 2- [ 8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl ]Pd/C (120 mg, 10%) was added to a mixture of-4, 5-tetramethyl-1, 3, 2-dioxaborane (120 mg,0.337 mmol) in EtOAc (10 mL) and at H 2 Stirring was continued for 1.5h under (1 atm) atmosphere. The reaction was monitored by LC-MS. After completion, the resulting mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EtOAc/PE,1% to 10) to give the title compound as a pale yellow oil (110 mg,81% yield). LC-MS [ M+H ]] + ＝361.2
Step 3:7a- (((4- ((1R, 5S) -8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoropyrido [4,3-d ] pyrimidin-2-yl) oxy) methyl-d 2) hexahydro-pyrrolizine 4 (1H) -oxide
{3- [ 7-chloro-8-fluoro-2- (hexahydropyrrolizin-7 a-ylmethoxy) pyrido [4,3-d ]]Pyrimidin-4-yl]-3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-yl } carboxylate (from step 2, 100mg,0.187mmol, example 3), 2- [ 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl]-4, 5-tetramethyl-1, 3, 2-dioxaborane (101 mg,0.279 mmol), K 2 CO 3 (77.3 mg,0.559 mmol) and RuPhos Pd G3 (15.6 mg,0.0186 mmol) in 1, 4-dioxane (5 mL) and H 2 The mixture in O (1 mL) was N at 90 degrees Celsius 2 Stirring was continued for 3h under an atmosphere. The reaction was monitored by LC-MS.After completion, the mixture was allowed to cool down to rt and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with MeOH/DCM,1% to 10) to give the title compound as a yellow solid (80 mg,51% yield). LC-MS [ M+H ]] + ＝749.4
Step 4:7a- (((4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4,3-d]Pyrimidin-2-yl) oxy) methyl-d 2 ) Hexahydropyrrolizine 4 (1H) -oxide
At rt, 7a- [ ({ 4- [8- (tert-butyl- $1 {3} -oxy) -3, 8-diazabicyclo [3.2.1 ]]Octane-3-yl]-7- [ 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl]-8-fluoropyrido [4,3-d ]]Pyrimidin-2-yl } oxy) methyl]A mixture of hexahydropyrrolizine-4-ium-oxide (oleate) (80 mg,0.107 mmol) in MeCN (2.5 mL) was added to HCl in 1, 4-dioxane (0.5 mL, 4N) and stirring continued for 1h. The reaction was monitored by LC-MS. After completion, the mixture was concentrated under reduced pressure. The mixture was purified by prep-HPLC to afford 7a- { [ (4- {3, 8-diazabicyclo [ 3.2.1) as a yellow solid ]Octane-3-yl } -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4,3-d ]]Pyrimidin-2-yl) oxy]Methyl } -hexahydropyrrolizine-4-ium-4-oxide (10.9 mg,16% yield (two steps)). LC-MS [ M+H ]] + ＝605.2。 1 H NMR(400MHz，DMSO-d6)δ9.06(s，1H)，7.70(dd，J＝8.8，6.0Hz，1H)，7.42-7.14(m，2H)，6.94(d，J＝2.4Hz，1H)，4.38(t，J＝11.6Hz，2H)，3.77—3.66(m，2H)，3.58-3.43(m，6H)，2.37-2.28(m，1H)，2.24-2.04(m，5H)，2.01-1.87(m，4H)，1.64-1.50(m，4H)，0.70(t，J＝7.2Hz，3H)。
Example 23
4- (4- ((1R, 5S) -3, 8-Di-azabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol
Figure BDA0004093773770001151
Step 1:5, 6-difluoro-1, 4-dihydro-1, 4-epoxynaphthalene
At-15 ℃ at N 2 n-BuLi (1.6M, 7.10L) was added dropwise to a mixture of 1-bromo-2, 3, 4-trifluorobenzene (2000 g,9.48 mol) and furan (1286 g,19.0 mol) in toluene (10L) over 2h under an atmosphere. The mixture was stirred at-15 ℃ for 30 minutes, then warmed to rt and stirred for 17 hours. Subsequently, the reaction mixture was quenched with water (3L). The two layers were separated. The aqueous layer was extracted with EtOAc (2X 2L). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (PE/ea=50/1) to give the product as a brown oil (750 g,4.17mol,44% yield). LC-MS [ M-H ]]-＝179。
Step 2:7, 8-difluoronaphthalen-1-ol
To a solution of 5, 6-difluoro-1, 4-dihydro-1, 4-epoxynaphthalene (750 g,4.17 mol) in EtOH (7.5L) was added aqueous HCl (4.9L, 12M) over 1h at rt. The mixture was gradually warmed to reflux and stirred for 2 hours. The mixture was cooled to rt and concentrated under vacuum. The residue was purified by silica gel (PE/ea=100:1). The resulting solid was washed with PE (200 mL) to afford 7, 8-difluoronaphthalene-1-ol (420 g,56% yield) as a white solid. LCMS (ESI-179).
Step 3:1, 2-difluoro-8- (methoxymethoxy) naphthalene
DIPEA (849 g,1.14L,6.57 mol) and then MOMBr (543 g,355mL,4.38 mol) were added dropwise to a stirred solution of 7, 8-difluoronaphthalene-1-ol (3995 g,2.19 mol) in DCM (4L) in an ice-H2O bath. The mixture was stirred at 0 ℃ for 0.5h, allowed to warm to ambient temperature (ambient temperature), and stirred for 1.5h. The reaction mixture was poured over saturated aqueous Na 2 CO 3 In (2L) extracted with DCM, passed through Na 2 SO 4 Dried, filtered and concentrated to a yellow oil. The crude residue was purified by silica gel chromatography eluting with 5% etoac in PE to provide the title compound as a yellow solid (450 g,92% yield). LC/MS [ M+H ]] + ＝225.1。 1 H-NMR(400MHz，CDCl 3 )7.55-7.51(m，1H)，7.46-7.43(m，1H)，7.36-7.28(m，2H)，7.15(d，J＝7.6Hz，1H)，5.35(s，2H)，3.57(s，3H)。
Step 4:2- (5.6-difluoro-4- (methoxymethoxy) naphthalen-2-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane
To a solution of 1, 2-difluoro-8- (methoxymethoxy) naphthalene (450 g,2.01 mol) in dry toluene (4.5L) was added [ Ir (OMe) (cod) ] 2 ] 2 (43.9 g,66.2 mmol), 4 '-di-tert-butyl-2, 2' -bipyridine (64.5 g,239 mmol) and HBpin (641 g,5.01 mol). The mixture was evacuated using N 2 Backfilling and the sequence is repeated three times. The resulting mixture was warmed to 70 ℃ and stirred for 2h to give complete conversion based on LC/MS. The reaction mixture was cooled to rt and passed through a thin layer of celite. The filtrate was concentrated to give the crude product as a dark brown oil (530 g,75% yield). [ M+H ] ] + ＝351.2
Step 5:5, 6-difluoro-4- (methoxymethoxy) naphthalen-2-ol
In ice-H 2 HOAc (362 g,6.04 mol) was added to a stirred solution of 2- (5, 6-difluoro-4- (methoxymethoxy) naphthalen-2-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (530 g,1.51 mol) in THF (2.0L) in an O bath followed by 35% H dropwise over 1h 2 O 2 (1.99 kg,20.5 mol). The mixture was stirred at 0 ℃ for a further 0.5h, allowed to warm to ambient temperature, and stirred for another 1.5h. Saturated NaHSO for reaction 3 Quench (aqueous) and extract with EtOAc (1 l×2). The combined organic layers were purified by Na 2 SO 4 Dried, filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 5% etoac in PE to give the title compound (185 g,51% yield). LCMS (ESI-239).
Step 6:5, 6-difluoro-4- (methoxymethoxy) naphthalen-2-ylacetic acid ester
To a solution of 5, 6-difluoro-4- (methoxymethoxy) naphthalene-2-ol (185 g,1 eq, 770 mmol) in DCM (1.8L) was added Et 3 N (156 g,1.54 mol) and DMAP (30 mg,0.245 mmol). Then acetyl chloride is added dropwise at 0 DEG C(121 g,1.54 mol). The mixture was warmed to rt and stirred for 0.5 hours. After completion, the reaction mixture was diluted with water (1000 mL) and extracted with DCM (2×1L). The combined organic layers were purified by Na 2 SO 4 Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (PE/ea=100/1 to 20/1) to give the title compound (125 g,58% yield) as a yellow oil. LC/MS [ M+H ]] + ＝283.2。
Step 7:5, 6-difluoro-4-hydroxynaphthalen-2-ylacetic acid ester
HC1 (4M, 1300 mL) in EA was added to a solution of 5, 6-difluoro-4- (methoxymethoxy) naphthalen-2-ylacetate (125 g, 447 mmol) in EA (600 mL) at-40℃and stirring continued for 0.5 h, then stirring continued for another 0.5 h at 0 ℃. After completion, the reaction mixture was diluted with water (300 mL) and extracted with EA (2×300 mL). The combined organic layers were purified by Na 2 SO 4 Dried, filtered, and concentrated in vacuo, which provided the title compound as a yellow crude oil (91 g, crude) which was purified by silica gel chromatography (PE/ea=20/1) to provide the title compound as a white solid (68 g,64% yield).
Step 8:5, 6-difluoro-4- (((trifluoromethyl) sulfonyl) oxy) naphthalen-2-yl acetate
at-78deg.C at N 2 Tf2O (96.5 g,342 mmol) was added dropwise to a solution of 5, 6-difluoro-4-hydroxynaphthalen-2-ylacetate (68 g, 284 mol) and DIPEA (110 g, 850 mmol) in DCM (660 mL) under an atmosphere over 30min and stirring continued for 0.5 h. After completion, the reaction mixture was diluted with water (200 mL), warmed to rt and extracted with DCM (2×200 mL). The combined organic layers were purified by Na 2 SO 4 Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (PE/ea=1/10 to 20/1) to give the title compound (40.1 g,38% yield) as a white solid.
Step 9:7, 8-difluoro-3-hydroxynaphthalen-1-yl triflate
To 5, 6-difluoro-4- (((trifluoromethyl) sulfonyl) oxy) naphthalen-2-ylacetate (40.1 g,108 mmol) in THF (420 mL) and H at 0deg.C 2 LiOH.H was added to a solution in O (84 mL) 2 O (5.30 g,130 mmol). The mixture was stirred at 0 ℃ for 0.5 hours. After completion, the reaction mixture was pH adjusted to about 6 with AcOH. The mixture was diluted with water (400 mL) and extracted with EA (2×400 mL). The combined organic layers were purified by Na 2 SO 4 Dried, filtered, and concentrated in vacuo, which provided the title compound (39 g, crude) as a brown oil. LC/MS [ M ]]+＝329.1
Step 9:7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl triflate
To a solution of 7, 8-difluoro-3-hydroxynaphthalen-1-yl triflate (39.0 g,120 mmol) in DCM (400 mL) was added DIPEA (46.4 g,360 mmol) at 0deg.C, and then MOMBr (18.0 g,144 mmol) was added dropwise. The mixture was stirred at 0 ℃ for 1 hour. After completion, the reaction mixture was diluted with water (400 mL) and extracted with DCM (2×400 mL). The combined organic layers were purified by Na 2 SO 4 Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (PE/ea=1/0 to 10/1) and followed by prep-HPLC to provide the title compound (8.01 g,18% yield). LC/MS [ M+H ]]+＝373.1。 1 H-NMR(400MHz，CDCl 3 )：7.53-7.52(m，1H)，7.44-7.38(m，2H)，7.28-7.26(m，1H)，5.28(s，2H)，3.52(s，3H)。
Step 10:2- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane
To a solution of 7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl triflate (8.01 g,21.5 mmol) and 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (6.55 g,25.8 mmol) in DMF (60 mL) was added Pd (dppf) Cl 2 DCM (227 mg, 0.640 mmol) and KOAc (64.5 mmol). The mixture was evacuated, backfilled with N2, and the sequence was repeated three times. The resulting mixture was warmed to 80 ℃ and under N 2 Stirring was continued for 16 hours under an atmosphere. After completion, the reaction mixture was cooled to rt, diluted with water (100 mL) and extracted with EA (2×500 mL). The combined organic layers were washed with brine (100 mL), and dried over Na 2 SO 4 Dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (PE/ea=20/1) to give the title compound (3.20 g,43% yield) as a white solid. LC/MS [ M+H ] ]+＝351.1。 1 H-NMR(400MHz，CDCl 3 )：7.45-7.43(m，1H)，7.43-7.38(m，2H)，7.29-7.26(m，1H)，5.26(s，2H)，3.50(s，3H)，1.44(s，12H)。
Step 11: (1R, 5S) -3- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
(1R, 5S) -3- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (from EX.3, step 2, 100mg,0.186 mmol), 2- [7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl]-4, 5-tetramethyl-1, 3, 2-dioxaborane (97.9 mg,0.279 mmol), K 2 CO 3 (77.3 mg,0.556 mmol), ruPhos Pd G3 (15.6 mg,0.0186 mmol) in dioxane (5 mL) and H 2 The mixture in O (1 mL) was N at 90 degrees Celsius 2 Stirring was continued for 4h under an atmosphere. The reaction was monitored by LC-MS. After completion, the mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with MeOH/DCM,1% to 10%) to provide (3- {7- [7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) as a yellow solid]-8-fluoro-2- (hexahydropyrrolizin-7 a-ylmethoxy) pyrido [4,3-d]Pyrimidin-4-yl } -3, 8-diazabicyclo [3.2.1 ]Tert-butyl octan-8-yl formate (70 mg,46% yield). LC-MS [ M+H ]] + ＝723.2
Step 12:4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol
At rt, (1R, 5S) -3- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A stirred solution of tert-butyl octane-8-carboxylate (80.0 mg,0.111 mmol) in ACN (5 ml) was added HCl (4N, 1 mL) in 1, 4-dioxane. The reaction mixture was then stirred at rt for 1h. The resulting mixture was concentrated under vacuum. The crude product was purified by prep-HPLC (0.05% nh 3 -H 2 O) -ACN; b%:20% -95%,20 min) to afford the title compound as a white solid (15.4 mg,23% yield). LC-MS [ M+H ]] + ＝759.3。 1 H NMR(400MHz，DMSO-d6)δ9.10(s，1H)，7.80—7.67(m，1H)，7.57(dd，J＝17.2，9.2Hz，1H)，7.39(s，1H)，7.24(s，1H)，4.42(t，J＝11.2Hz，2H)，3.68-3.49(m，6H)，3.02-2.85(m，3H)，1.97-1.50(m，12H)。
EX.24 through EX.27 in Table 4 were synthesized following a similar procedure as EX.23.
TABLE 4 Table 4
Figure BDA0004093773770001191
Example 28
3- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol
Figure BDA0004093773770001192
Step 1: 1-bromo-3-chloro-2-cyclopropylbenzene
To 1-bromo-3-chloro-2-iodobenzene (10.0 g,31.5 mmol), K 3 PO 4 (24.7 g,11.3 mmol) and Pd (dppf) Cl 2 (2.30 g,3.14 mmol) in 1, 4-dioxane (180 mL) and H 2 A mixture of O (6 mL) was added cyclopropylboronic acid (3.52 g,40.9 mmol). The mixture was evacuated, backfilled with N2, and the sequence was repeated three times. The resulting mixture was warmed to 100 ℃ and under N 2 The stirring was continued for 18 hours. The mixture was allowed to cool down to rt. Water (50 ml) was added to the mixture. The resulting mixtureThe compound was extracted with EA (3X 200 ml). The combined organic layers were dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (100/1) to give the title compound (4.70 g,58% yield) as a colourless oil. LC/MS [ M+H ]]+＝232.4。 1 H NMR(400MHz，CDCl 3 )δ7.46(dd，J＝8.0，1.2Hz，1H)，7.30(dd，J＝8.0，0.8Hz，1H)，6.99(t，J＝8.0Hz，1H)，1.81-1.72(m，1H)，1.21-1.15(m，2H)，0.80-0.74(m，2H)。
Step 2:2- (3-bromo-5-chloro-4-cyclopropylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane
1-bromo-3-chloro-2-cyclopropylbenzene (4.70 g,20.3 mmol), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (25.8 g,102 mmol), [ Ir (OMe) (1, 5-cod)] 2 (340 mg, 0.313 mmol) and 4,4 '-di-tert-butyl-2, 2' -bipyridine (330 mg,1.23 mmol) in hexane (100 mL) and degassed with N 2 Washing 3 times. The mixture was heated to 60℃under N 2 Stirring was continued for 4 hours under an atmosphere. The reaction was monitored by TLC. After the conversion is complete, the resulting mixture is cooled down to rt and concentrated under reduced pressure. The crude product was used directly in the next step without further purification.
The residue was taken up in THF (60 mL) and H 2 O (30 mL) was dissolved. AcOH (43.2 g,719 mmol) and H were added to the above mixture at 0deg.C 2 O 2 (24.3 g,214 mmol). The resulting mixture was stirred at 0 ℃ for an additional 1h. The reaction was monitored by LCMS. After the conversion was complete, water (50 ml) was added to the mixture. The resulting mixture was extracted with EtOAc (3X 150 ml). The combined organic layers were dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, 0.1% FA in ACN-water, gradient 10% to 50% over 10 min; detector, UV214 nm) to afford the title compound as a yellow oil (3.31 g,66% yield). LC-MS [ M-H ]] - ＝247.1
Step 3: 1-bromo-3-chloro-2-cyclopropyl-5- (methoxymethoxy) benzene
At 0 ℃ at N 2 To a mixture of 3-bromo-5-chloro-4-cyclopropylphenol (11.2 g,45.2 mmol) in THF (200 mL) was added NaH (60%, 5.42g,136mmol in mineral oil) in portions under a stream of gas. The mixture was warmed to rt and stirred for 0.5 hours. Then, 1-1-bromo-1-methoxymethane (11.3 g,90.4 mmol) was added dropwise to the mixture over 5min, and stirring was continued at rt for 1h. The reaction was monitored by TLC. After completion, the reaction was carried out by adding saturated aqueous NH at 0 ℃ 4 Cl (100 ml) was used for quenching. The resulting mixture was extracted with EA (3X 200 ml). The combined organic layers were dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: ea=100:1-30:1) to provide the title compound (10.8 g,74% yield). LC/MS [ M+H ]] + ＝292.4。 1 H NMR(400MHz，CDCl3)δ7.19(d，J＝2.4Hz，1H)，7.03(d，J＝2.4Hz，1H)，5.11(s，2H)，3.45(s，3H)，1.73—1.64(m，1H)，1.16-1.08(m，2H)，0.75—0.68(m，2H)。
Step 4:2- [ 3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl ] -4, 5-tetramethyl-1, 3, 2-dioxaborane
To 1-bromo-3-chloro-2-cyclopropyl-5- (methoxymethoxy) benzene (10.8 g,37.7 mmol), K 2 CO 3 (22.2 g,226 mmol) and 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (38.3 g,151 mmol) in 1, 4-dioxane (100 mL) were added Pd (dppf) Cl 2 (2.76 g,3.7 mmol). The mixture was evacuated using N 2 Backfilling and the sequence is repeated three times. The resulting mixture was warmed to 100 ℃ and under N 2 Stirring was continued for 4 hours under an atmosphere. The reaction was monitored by TLC. After completion, the reaction mixture was cooled to rt, water (50 mL) was added and extracted with EtOAc (3×300 mL). The organic layer is treated by Na 2 SO 4 Dried, filtered, and concentrated. The residue was purified by reverse phase flash chromatography (C18 column; ACN-NH in water) 3 .H 2 O, 0% to 100% gradient over 20 min; inspection and detectionThe tester, UV 254 nm) to afford the title compound as a brown oil (6.50 g,52% yield). LC/MS [ M+H ]] + ＝339.7。 1 H NMR(400MHz，CDCl 3 )δ7.19(s，1H)，7.02(s，1H)，5.06(s，2H)，3.38(s，3H)，1.93-1.86(m，1H)，1.30(s，12H)，0.92-0.88(m，2H)，0.48-0.41(m，2H)。
Step 5:5- (2, 7-difluoro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester
At-40 ℃ at N 2 In the atmosphere, to 2,4, 7-trichloro-8-fluoropyrido [4,3-d ]]A solution of pyrimidine (crude intermediate 18,4.02g,15.9 mmol) and DIEA (12.0 g,93.0 mmol) in DCM (100 mL) was added dropwise 2, 5-diazabicyclo [ 2.2.2.2)]Tert-butyl octane-2-carboxylate (3.41 g,16.1 mmol) and stirring was continued for 30min. The reaction was monitored by LCMS. After completion, the reaction mixture was purified by adding H 2 O (50 mL) to quench. The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with DCM (50 mL. Times.3). The combined organic layers were washed with brine (50 mL), and dried over Na 2 SO 4 Dried, filtered, and concentrated on a rotary evaporator. The resulting oil was purified by flash column chromatography (DCM/meoh=50/1) to afford the title compound as a yellow solid (4.12 g,61% yield). LC-MS [ M+H ]] + ＝428.2。
Step 6:5- (7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -2.5-diazabicyclo [2.2.2]Octane-2-carboxylic acid tert-butyl ester
5- (2, 7-dichloro-8-fluoropyrido [4, 3-d)]Pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylic acid tert-butyl ester (1.51 g,3.53 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methanol (intermediate 8, 680mg,4.19 mmol) and Cs 2 CO 3 (3.40 g,10.4 mmol) in 1, 4-dioxane (30 mL) at 95℃under N 2 Stirring was continued for 12h under an atmosphere. The reaction was monitored by LCMS. After completion, the mixture was allowed to cool down to rt and concentrated under reduced pressure. The residue is passed through siliconColumn chromatography (DCM/MeOH, 1% to 5%) was purified to give the title compound as a yellow solid (1.5 g,68% yield). LC-MS [ M+H ]] + ＝554.4
Step 7:5- (7- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -2.5-diazabicyclo [2.2.2]Octane-2-carboxylic acid tert-butyl ester
5- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy) pyrido [4, 3-d)]Pyrimidin-4-yl) -2.5-diazabicyclo [2.2.2 ]Tert-butyl octane-2-carboxylate (1.05 g,1.90 mmol), 2- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (from step 4, 910mg,2.69 mmol), K 3 PO 4 (1.20G, 5.65 mmol) and RuPhos Pd G3 (150 mg, 0.178 mmol) in 1, 4-dioxane (20 mL) and H 2 The mixture in O (4 mL) was evacuated using N 2 Backfilling and the sequence is repeated three times. The resulting mixture was warmed to 60 ℃ and under N 2 Stirring was continued for 2h under an atmosphere. The reaction was monitored by LCMS. After completion, the mixture was allowed to cool down to rte and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH,1% to 5%) to provide the title compound as a yellow solid (650 mg,45% yield). LC-MS [ M+H ]] + ＝730.7
Step 8:3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-chloro-4-cyclopropylphenols
At rt, 5- (7- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d ]Pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.2]A stirred mixture of tert-butyl octane-2-carboxylate (650 mg, 0.89mmol) in MeCN (10 mL) was added dropwise to HCl (4N, 2 mL) in 1, 4-dioxane and stirring continued for 1h. The reaction was monitored by LCMS. After the completion of this process,the reaction mixture was concentrated to give a residue that was purified by silica gel column chromatography (eluting with DCM/MeOH,0 to 3%) to provide the title compound as a white solid (333 mg,60% yield). LC-MS [ M+H ]] + ＝586.4。 1 H NMR(400MHz，DMSO-d6)δ9.98(s，1H)，9.21(s，1H)，6.95(d，J＝2.4Hz，1H)，6.76(d，J＝2.4Hz，1H)，4.86(s，1H)，4.25—4.05(m，3H)，4.02(dd，J＝10.4，2.4Hz，1H)，3.31-3.25(m，1H)，3.15-3.04(m，3H)，3.00(s，1H)，2.12-1.75(m，11H)，0.60(d，J＝6.0Hz，2H)，-0.02(d，J＝5.6Hz，2H)。
Example 29
3- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 s,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol
Figure BDA0004093773770001231
Example 29 (16.9 mg) was synthesized using a similar procedure as outlined in example 28, except intermediate 11 was used instead of intermediate 8. LC-MS [ M+H ]] + ＝586.5。 1 H NMR(400MHz，DMSO-d6)δ9.98(s，1H)，9.21(s，1H)，6.95(d，J＝2.4Hz，1H)，6.76(d，J＝2.4Hz，1H)，4.86(s，1H)，4.29-3.95(m，4H)，3.31-3.23(m，2H)，3.13—2.98(m，4H)，2.12-1.74(m，11H)，0.67-0.53(m，2H)，0--0.07(m，2H)。
Example 30
3- (4- (1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol
Figure BDA0004093773770001232
Except (1R, 5S) -3, 8-diazabicyclo [3.2.1]Octane substituted 2, 5-diazabicyclo [2.2.2 ]Octane, makeExample 30 (425 mg) was synthesized using a similar procedure as outlined in example 28. LC-MS [ M+H ]] + ＝586.5。 1 H NMR(400MHz，DMSO-d6)δ10.00(s，1H)，9.08(s，1H)，6.95(d，J＝2.4Hz，1H)，6.77(d，J＝2.4Hz，1H)，4.40(d，J＝12.4Hz，2H)，4.11(d，J＝10.4Hz，1H)，4.01(d，J＝10.4Hz，1H)，3.63-3.48(m，4H)，3.13—2.96(m，2H)，2.15—1.96(m，3H)，1.86—1.71(m，4H)，1.68-1.53(m，4H)，0.58(d，J＝6.8Hz，2H)，-0.00--0.08(m，2H)。
Example 31
4- (4- ((2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Figure BDA0004093773770001241
Step 1:5- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -2.5-diazabicyclo [2.2.2]Octane-2-carboxylic acid tert-butyl ester
5- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy) pyrido [4, 3-d)]Pyrimidin-4-yl) -2.5-diazabicyclo [2.2.2]Tert-butyl octane-2-carboxylate (step 6 from EX.28, 900mg,1.62 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (step 4 from EX.1, 1.03g,2.01 mmol), K 2 CO 3 (67 mg,4.87 mmol) and RuPhos Pd G3 (135 mg,0.161 mmol) in 1, 4-dioxane (20 mL) and H 2 The mixture in O (4 mL) was evacuated using N 2 Backfilling and the sequence is repeated three times. The resulting mixture was warmed to 90 ℃ and under N 2 Stirring was continued for 2h under an atmosphere. The reaction was monitored by LCMS. After completion, the mixture was allowed to cool down to rt and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (C18 column, with 10% to 100% nh containing 0.1% 3 -H 2 MeCN/H of O 2 O elution) to afford the title compound as a yellow solid (900 mg,61% yield). LC-MS [ M+H ]] + ＝905.0
Step 2:4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol
At rt, 5- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.2]A stirred mixture of tert-butyl octane-2-carboxylate (900 mg,0.995 mmol) in MeCN (20 mL) was added HCl in 1, 4-dioxane (4N, 10 mL) and stirring continued for 1h. The reaction was monitored by LCMS. The resulting mixture was neutralized to pH 7-8 with ammonium hydroxide solution. The mixture obtained is purified by reverse phase flash chromatography (C18 column, with 10% to 80% containing 0.1% NH 3 -H 2 MeCN/H of O 2 O elution) to afford the title compound as an off-white solid (500 mg,66% yield). LC-MS [ M+H ]] + ＝760.8。
Step 3:4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
At N 2 In the atmosphere, 4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]A mixture of pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol (500 mg, 0.618 mmol) in DMF (10 mL) was added CsF (1.00 g,6.58 mmpl) at one time. The mixture was warmed to 50 ℃ and stirred for 1h. The reaction was monitored by LCMS. After completion, the mixture was purified by prep-HPLC (C18 column, with 0%Up to 50% contains 0.1% NH 3 -H 2 MeCN/H of O 2 O elution) to afford the title compound as a yellow solid (300 mg, yield: 76%).
LC-MS[M+H] + ＝604.6。 1 H NMR(400MHz，DMSO—d6)δ9.14(s，1H)，7.97(dd，J＝9.2，6.0Hz，1H)，7.47(t，J＝8.8Hz，1H)，7.40(d，J＝2.8Hz，1H)，7.17(s，1H)，4.83(s，1H)，4.36—3.90(m，5H)，3.28(d，J＝10.8Hz，1H)，3.16—2.97(m，4H)，2.18-1.97(m，4H)，1.96—1.69(m，6H)。
Example 32
3- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -4-cyclopropyl-5-fluorophenol
Figure BDA0004093773770001251
Step 1: 1-bromo-2-cyclopropyl-3-fluorobenzene
1-bromo-3-fluoro-2-iodobenzene (5.50 g,18.3 mmol), pd (dppf) Cl 2 (1.34 g,1.83 mmol), cyclopropylboronic acid (1.94 g,22.5 mmol) and K 3 PO 4 (13.6 g,64.1 mmol) in 1, 4-dioxane (80 mL) and H 2 The mixture in O (4 mL) was evacuated using N 2 Backfilling and the sequence is repeated three times. The resulting mixture was warmed to 100 ℃ and stirred for 18 hours. The reaction was monitored by LCMS. The reaction mixture was cooled to rt, diluted with water (100 mL) and extracted with EtOAc (150 ml×3). The combined organic layers were purified by Na 2 SO 4 Dried, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography with PE to afford the title compound as a yellow solid (3.01 g,46% yield). LC-MS [ M+H ]] + ＝302.1。 1 H NMR(400MHz，DMSO-d6)δ7.46-7.44(m，1H)，7.27-7.09(m，2H)，1.85-1.78(m，1H)，1.08-1.00(m，2H)，0.82-0.75(m，2H)。
Step 2: 3-bromo-4-cyclopropyl-5-fluorophenol
1-bromo-2-cyclopropyl-3-fluorobenzene (3.30 g,15.3 mmol), 4', 5',5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (11.6 g,45.9 mmol), [ Ir (OMe) (1, 5-cod)] 2 (0.510 g,0.769 mmol) and 4,4 '-di-tert-butyl-2, 2' -bipyridine (0.250 g,0.933 mmol) in (100 mL) were evacuated with N 2 Backfilling and the sequence is repeated three times. The resulting reaction mixture was warmed to 60 ℃ and under N 2 Stirring was continued for 18h under an atmosphere. The reaction was monitored by TLC. The reaction mixture was concentrated in vacuo to afford the title compound (5.31 g, crude) as a yellow oil, which was dissolved in THF (40 mL) and H 2 O (20 mL), cooled to 0deg.C, and AcOH (60.1 g,1.00 mol) and H were added 2 O 2 (10.1 g,298 mmol). The resulting mixture was stirred at 0 ℃ for 1h. The reaction was monitored by LCMS, diluted with water (100 mL) and extracted with EtOAc (150 ml×3). The combined organic layers were purified by Na 2 SO 4 Dried, filtered, and concentrated under vacuum. The residue obtained was purified by flash chromatography (eluting with PE/EtOAc,0 to 20%) to provide the title compound (1.31 g,18% yield) as a yellow oil. LC-MS [ M-H ]]-＝231.0。
Step 3: 1-bromo-2-cyclopropyl-3-fluoro-5- (methoxymethoxy) benzene
At 0 ℃ at N 2 Sodium hydride (60%, 0.670g,16.8mmol in mineral oil) was added slowly in portions to a solution of 3-bromo-4-cyclopropyl-5-fluorophenol (1.31 g,5.65 mmol) in THF (50 mL) under an atmosphere, and stirring continued for 30 minutes. Bromomethane (1.41 g,11.2 mmol) was then added dropwise at 0 ℃. The resulting mixture was slowly warmed to rt and stirred for 30 min. The reaction was monitored by TLC. The reaction mixture was concentrated to give a residue, which was purified by flash chromatography (eluting with PE/EtOAc,0 to 5%) to afford the title compound as a colourless oil (1.65 g,75% yield). LC-MS [ M-H ] ]-＝273.2。 1 H NMR(400MHz，CDCl 3 )δ7.07(t，J＝2Hz 1H)，6.68(dd，J＝12，2.4Hz，1H)，5.11(s，2H)，3.45(s，3H)，1.73-1.66(m，1H)，1.02-0.97(m，2H)，0.79-0.75(m，2H)。
Step 4:2- (2-cyclopropyl-3-fluoro-5- (methoxymethoxy) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane
(1-bromo-2-cyclopropyl-3-fluoro-5- (methoxymethoxy) benzene (600 mg,2.18 mmol), acOK (640 mg,6.54 mmol), 4 '; 4',5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (1.11 g,4.36 mmol) and Pd (dppf) Cl 2 (159 g,0.22 mmol) in 1, 4-dioxane (10 mL) was evacuated using N 2 Backfilling and the sequence is repeated three times. The resulting mixture was warmed to 100 ℃ and under N 2 Stirring was continued for 12 hours under an atmosphere. The reaction was monitored by TLC. After completion, the reaction mixture was cooled to rt, diluted with water (10 mL) and extracted with EtOAc (50 ml×3). The combined organic layers were purified by Na 2 S0 4 Dried, filtered, and concentrated under vacuum. The obtained residue was purified by reverse phase flash chromatography to provide the title compound (3836 mg,38% yield) as a yellow solid. LC-MS [ M-H ]]-＝321.3。 1 H NMR(400MHz，CD 3 OD)δ6.94(d，J＝2.4Hz，1H)，6.65(dd，J＝10.4，2.4Hz，1H)，5.04(s，2H)，3.34(s，3H)，1.962-1.906(m，1H)，1.27(s，12H)，0.80-0.74(m，2H)，0.56-0.52(m，2H)。
Step 5:5- (7- (2-cyclopropyl-3-fluoro-5-hydroxyphenyl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -2.5-diazabicyclo [2.2.2 ]Octane-2-carboxylic acid tert-butyl ester
5- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy) pyrido [4, 3-d)]Pyrimidin-4-yl) -2.5-diazabicyclo [2.2.2]Tert-butyl octane-2-carboxylate (step 6 from EX.28, 100mg,0.180 mmol), 2- (2-cyclopropyl-3-fluoro-5- (methoxymethoxy) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (145 mg,0.450 mmol), K 3 PO 4 (115 mg, 0.540 mmol) and RuPhos Pd G3 (15.1 mg,0.018 mmol) in THF (2 mL) and H 2 The mixture in O (4 mL) was evacuated using N 2 Backfilling and the sequence is heavyRepeating the process three times. The resulting mixture was warmed to 40 ℃ and under N 2 Stirring was continued for 2 hours under an atmosphere. The reaction was monitored by LCMS. The reaction mixture was diluted with water (3 mL) and extracted with EtOAc (10 mL). The combined organic layers were purified by Na 2 SO 4 Dried, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluting with DCM/MeOH,0% to 20%) to provide the title compound as a white solid (105 mg,57% yield). LC-MS [ M+H ]] + ＝714.4。
Step 6:3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -4-cyclopropyl-5-fluorophenol
At rt, 5- (7- (2-cyclopropyl-3-fluoro-5-hydroxyphenyl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.2]A solution of tert-butyl octane-2-carboxylate (100 mg,0.140 mmol) in ACN (1 mL) was added HCl in 1, 4-dioxane (4N, 0.2 mL). The mixture was stirred at rt for 1 hour. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give a residue, which was purified by prep-HPLC to afford the title compound as a white solid (15.5 mg,12% yield). LC-MS [ M+H ]] + ＝570.4。 1 H NMR(400MHz，DMSO-d6)δ9.96(s，1H)，9.21(s，1H)，6.68-6.60(m，2H)，4.86(s，1H)，4.30-4.07(m，3H)，4.01(dd，J＝10.4，2.4Hz，1H)，3.30-3.22(m，1H)，3.15-3.03(m，3H)，3.00(s，1H)，2.12-1.64(m，11H)，0.53(d，J＝8.8Hz，2H)，0.15(d，J＝4.4Hz，2H)。
Example 33/example 34
4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (EX.33, diastereomer 1) and 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (EX.34, diastereomer 2)
Figure BDA0004093773770001281
EX.33 (diastereomer 1) and EX.34 (diastereomer 2)
Step 1: 1-benzyl 2-methyl 2- (but-3-en-1-yl) pyrrolidine-1, 2-dicarboxylic acid ester
at-78deg.C at N 2 LHMDS (1.0M in THF, 0.458L, 0.458 mol) was added dropwise to a solution of 1-benzyl 2-methyl (S) -pyrrolidine-1, 2-dicarboxylic acid ester (100 g,0.380 mol) in dry THF (200 mL) under atmosphere and stirring was continued for 1h. 4-Bromobut-1-ene (51.3 g,0.380 mol) was then added dropwise to the reaction mixture at-78 ℃. The reaction mixture was warmed to rt and stirred for 12h. The reaction was monitored by LCMS. After completion, the reaction is completed by adding saturated aqueous NH 4 Cl (200 mL) was quenched, poured into a separatory funnel and separated. The aqueous layer was extracted twice with EtOAc (500 mL). The combined organic layers were washed with brine (200 mL), and dried over Na 2 SO 4 Dried and collected by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (PE/etoac=10:1) to give the desired compound as a yellow oil (80.0 g,66% yield). LC-MS [ M+H ]] + ＝318.1
Step 2: 1-benzyl 2-methyl 2- (2- (oxiran-2-yl) ethyl) pyrrolidine-1, 2-dicarboxylic acid ester
To a solution of 1-benzyl 2-methyl 2- (but-3-en-1-yl) pyrrolidine-1, 2-dicarboxylic acid ester (20.0 g,63.0 mmol) in DCM (200 mL) was added m-CPBA (27.3 g,158 mmol) in portions and the resulting mixture stirred at ambient temperature for 5h. The reaction was monitored by LCMS. After completion of the reaction, the reaction was quenched with saturated aqueous sodium sulfite and extracted with EtOAc (500 ml×3). The combined organic phases were washed with brine and dried over Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/etoac=4:1),to give the title compound as a colourless oil (19.0 g,90% yield). LC-MS [ M+H ]] + ＝334.1
Step 3:3- (hydroxymethyl) tetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl esters (diastereoisomer 1) and (diastereoisomer 2)
To a solution of 1-benzyl 2-methyl 2- (2- (oxiran-2-yl) ethyl) pyrrolidine) -1, 2-dicarboxylic acid ester (18.0 g,54.0 mmol) in MeOH (200 mL) was added Pd/C (10%, on charcoal, 1.8 g). The mixture was evacuated, backfilled with hydrogen, and the sequence was repeated three times. The resulting mixture was then taken up at rt at H 2 Stirring was continued for 16 hours with (1 atm). The reaction was monitored by LCMS. After completion, the mixture was carefully filtered through a thin layer of celite. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0 to 10% meoh/DCM) to provide the two diastereomers (two isomers) of methyl 3- (hydroxymethyl) tetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate:
diastereoisomer 1:4.00g,37% yield, yellow oil, LC-MS [ M+H ]] + =200.1; and
diastereoisomer 2:4.90g,46% yield as yellow oil. LC-MS [ M+H ] ] + ＝200.1
Step 4:3- (((tert-Butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester (diastereomer 1) and 3- (((tert-Butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester (diastereomer 2)
TBSCl (8.50 g,56.4 mmol) was added to a solution of methyl 3- (hydroxymethyl) tetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (diastereomer 1,7.49g,37.6 mmol) and 1H-imidazole (7.68 g,113 mmol) in DCM (100 mL) at room temperature. The mixture was stirred at rt for 2h. The reaction was monitored by LCMS. After completion, the reaction was quenched by the addition of water (100 mL). The reaction mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (100 mL. Times.3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 Drying after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatographyPurification by method (DCM/meoh=40:1) afforded the desired product 3- (((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester (diastereomer 1,8.20g,70% yield) as a yellow oil. LC-MS [ M+H ]] + ＝314.1。 1 H NMR(400MHz，DMSO-d 6 )δ3.61(s，3H)，3.54(dd，J＝10.0，6.0Hz，1H)，3.43(dd，J＝10.0，6.4Hz，1H)，2.98-2.90(m，1H)，2.82-2.72(m，2H)，2.35-2.27(m，1H)，2.13-2.04(m，1H)，1.97-1.89(m，1H)，1.83-1.74(m，2H)，1.74-1.64(m，1H)，1.63-1.48(m，2H)，0.90(s，9H)，0.07(s，6H)。
Similar procedure is applicable for the synthesis of methyl 3- (((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (diastereomer 2):
Methyl 3- (hydroxymethyl) tetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (diastereomer 2, 10.0g,50.2 mmol) and 1H-imidazole (10.3 g,151 mmol) are converted to the desired product 3- (((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (diastereomer 2,9.50g,60% yield) as a yellow oil. LC-MS [ M+H ]] + ＝314.1。 1 H NMR(400MHz，DMSO-d 6 )δ3.77(dd，J＝10.4，5.6Hz，1H)，3.69(dd，J＝10.4，5.6Hz，1H)，3.58(s，3H)，3.20-3.08(m，1H)，2.84-2.68(m，2H)，2.37-2.26(m，1H)，2.14-2.00(m，1H)，1.83-1.44(m，6H)，0.87(s，9H)，0.05(s，6H)。
Step 5: (3- (((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methyl-d 2 Alcohols (diastereoisomer 1)
At 0 ℃ at N 2 To 3- { [ (tert-butyldimethylsilyl) oxy group under an atmosphere]A stirred solution of methyl } -hexahydropyrrolizine-7 a-carboxylic acid methyl ester (diastereomer 1,1.01g,3.22 mmol) in THF (20 ml) was added NaBD 4 (200 mg,4.78 mmol) and ZnCl 2 (650 mg,4.77 mmol). The reaction was then stirred at rt overnight. The reaction was carried out by adding saturated aqueous NH at 0 ℃ 4 Cl (20 ml) was used for quenching. The resulting mixture was extracted with EA (3X 50 ml). Concentrating the combined organic layers under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH (10:1)) to give the title compound as a white solid (440 mg,47% yield). LC-MS [ M+H ]] + ＝288.0
Step 6: (1R, 5S) -3- (2, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
At-40 ℃ at N 2 Next, 2,4, 7-trichloro-8-fluoropyrido [4,3-d ]]A solution of pyrimidine (intermediate 18,5.01g,19.8 mmol) in DCM (30 mL) was added DIEA (18.3 mL,111 mmol) and (1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-8-carboxylic acid tert-butyl ester (4.24 g,20.0 mmol). The reaction mixture was stirred at-40 ℃ for 1h. The reaction mixture was poured into DCM (100 mL) and water (100 mL). The two layers were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, collected by filtration, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with (PE/etoac=5:1 to 3:1) to give the title compound as a yellow solid (5.21 g,61% yield). LC-MS [ M+H ]]+＝428.1。
Step 7: (1R, 5S) -3- (2- ((3- (((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d) 2 ) -7-chloro-8-fluoropyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester) (diastereomer 1)
At 0 ℃ at N 2 To a stirred solution of (3- (((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methyl-d 2-ol (diastereomer 1, 200mg,0.696 mmol) in THF (4 mL) was slowly added NaH (166.9 mg,6.9 mmol). After addition, the resulting mixture was slowly warmed to rt and stirred for 30 min. Adding (1R, 5S) -3- (2, 7-dichloro-8-fluoropyrido [4, 3-d) to the above mixture ]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (298 mg,0.696 mmol). The resulting mixture was stirred at rt for an additional 16h. The reaction was monitored by LCMS. After the conversion is complete, the reaction is carried out by saturation of aqueous NH at 0 ℃ 4 Cl. The resulting mixture was extracted with EA (3X 100 ml). Combined organic layersAnhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA/PE (6:10) to give the title compound (140 mg,27% yield) as an off-white solid.
LC-MS[M+H] + ＝680.4。
Step 8: (1R, 5S) -3- (2- ((3- (((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d) 2 ) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) naphthalen-1-yl) pyrido [4, 3-d)]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester) (diastereomer 1)
(3- {2- [ (3- { [ (tert-butyldimethylsilyl) oxy]Methyl } -hexahydropyrrolizine-7 a-yl) methoxy]-7-chloro-8-fluoropyrido [4,3-d ]]Pyrimidin-4-yl } -3, 8-diazabicyclo [3.2.1]Tert-butyl octan-8-yl) formate (120 mg,0.176 mmol), {2- [ 2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) naphthalen-1-yl ]Ethynyl triisopropylsilane (90.4 mg,0.176 mmol), K 2 CO 3 (73.1 mg,0.530 mmol) in 1, 4-dioxane (3 mL) and H 2 The mixture in O (0.6 mL) was degassed. RuPhos Pd G3 (14.8 mg,0.0177 mmol) was then added. The mixture was evacuated using N 2 Backfilling and the sequence is repeated three times. The resulting mixture was warmed to 90 ℃ and under N 2 Stirring was continued for 2h under an atmosphere. The reaction was monitored by LCMS. After completion, the mixture was allowed to cool down to rt and concentrated under reduced pressure. The residue was purified by reverse phase flash (reversephase flash) (NH 3 H 2 O: ACN 20-95%,20 min) to afford the title compound as a yellow solid (100 mg,50% yield). LC-MS [ M+H ]] + ＝1030.6。
Step 9: (1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ((3- (hydroxymethyl) tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (diastereomer 1)
At rt at N 2 Under an atmosphere, (1R, 5S) -3- (2- ((3- (((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d) 2 ) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) naphthalen-1-yl) pyrido [4, 3-d) ]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (600 mg,0.583 mmol) in DMF (6 mL) was added CsF (442 mg,2.91 mmol) and stirred overnight. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3X 50 ml). The combined organic layers were dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash to afford the title compound as a yellow solid (150 mg,31% yield). LC-MS [ M+H ]] + ＝759.4。 1 H NMR(400MHz，DMSO-d6)δ9.08(s，1H)，8.10(dd，J＝9.2，6.0Hz，1H)，7.75(d，J＝2.4Hz，1H)，7.55(t，J＝8.8Hz，1H)，7.38(s，1H)，5.38(s，2H)，4.55(d，J＝12.8Hz，1H)，4.39(d，J＝11.2Hz，1H)，4.31(s，2H)，3.99(s，1H)，3.64(t，J＝14.0Hz，2H)，3.44(d，J＝5.7Hz，3H)，3.28-3.20(m，2H)，2.94-2.86(m，1H)，2.74-2.63(m，2H)，2.04-1.97(m，1H)，1.95-1.72(m，8H)，1.66-1.49(m，4H)，1.47(s，9H)。
Step 10:4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((3- (hydroxymethyl) tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (diastereomer 1)
At rt, (1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ((3- (hydroxymethyl) tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A stirred solution of tert-butyl octane-8-carboxylate (100 mg,0.132 mmol) in ACN (5 mL) was added 4M HCl (1 mL) in 1, 4-dioxane and stirring continued for 1h. The reaction was monitored by LCMS. After conversion was complete, the resulting mixture was concentrated in vacuo and the residue was purified by prep-HPLC (0.05% nh 3 -H 2 O) -ACN; b%:20% -95%,20 min) to afford the title compound 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [ 3.2.1) as an off-white solid]Octane-3-yl) -8-fluoro-2- ((3- (hydroxymethyl) tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (diastereomer 1, 15.4mg,23% yield). LC-MS [ M+H ]] + ＝615.3。 1 H NMR(400MHz，DMSO-d6)δ10.15(s，1H)，9.04(s，1H)，7.98(dd，J＝9.2，6.0Hz，1H)，7.46(t，J＝9.2Hz，1H)，7.39(d，J＝2.4Hz，1H)，7.17(d，J＝2.4Hz，1H)，4.50(d，J＝13.2Hz，1H)，4.45-4.27(m，2H)，3.93(s，1H)，3.78-3.51(m，4H)，2.90(s，1H)，2.71(s，1H)，2.03-1.57(m，12H)。
Following a similar procedure from steps 7 to 10 as outlined in ex.33 (diastereomer 1), using (3- (((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methyl-d 2-ol (diastereomer 2) in place of (3- (((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methyl-d 2 Alcohol (diastereomer 1), compound (diastereomer 2) of ex.34 was synthesized. Ex.34 as off-white solid (diastereomer 2, 12.6mg,15% yield). LC-MS [ M+H ]] + ＝615.2。 1 H NMR(400MHz，DMSO-d6)δ10.15(s，1H)，9.03(s，1H)，7.97(dd，J＝9.2，6.0Hz，1H)，7.46(t，J＝9.2Hz，1H)，7.39(d，J＝2.4Hz，1H)，7.17(d，J＝2.4Hz，1H)，4.59(s，1H)，4.47(d，J＝11.6Hz，1H)，4.31(d，J＝12.4Hz，1H)，3.94(s，1H)，3.68-3.47(m，6H)，3.08(s，1H)，2.81-2.65(m，2H)，2.06-2.01(m，1H)，1.77-1.44(m，11H)。
Example 35
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (5- (difluoromethyl) -2-ethylphenyl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidine
Figure BDA0004093773770001321
Step 1: 4-ethyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde
Figure BDA0004093773770001322
To 3-bromo-4-ethylbenzaldehyde (500 mg,2.13 mmol), B at room temperature 2 Pin 2 A solution of (640 mg,2.55 mmol) and KOAc (626 mg,6.38 mmol) in 1, 4-dioxane (5 mL) was added Pd (dppf) Cl in one portion 2 (109 mg,0.151 mmol). The mixture was evacuated using N 2 Backfilling and the sequence is repeated three times. The resulting mixture was warmed to 100 ℃ and under N 2 Stirring was continued for 4h under an atmosphere. The reaction was monitored by LCMS. After completion, the mixture was cooled down to rt and concentrated under reduced pressure. The residue was purified by reaction with [ PE: EA (EA)](1:100-60:1) to afford the title compound (250 mg, yield: 45%) as a yellow oil. LC-MS [ M+H ]]+＝261.1
Step 2: (1R, 5S) -3- (7- (2-ethyl-5-formylphenyl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester
4-Ethyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzaldehyde (50.0 mg,0.192 mmol), (1R, 5S) -3- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1 ]Tert-butyl octane-8-carboxylate (from step 2, 124mg,0.232mmol, from example 3) and K 2 CO 3 (79.7 mg,0.578 mmol) in 1, 4-dioxane (2 mL) and H20 (0.5 mL) and backfilled three times with nitrogen. RuPhos Pd G3 (16.1 mg,0.0192 mmol) was then added. The mixture was warmed to 90 ℃ and under N 2 Stirring was continued for 4h under an atmosphere. The reaction was monitored by LCMS. After completion, the mixture was cooled down to rt and concentrated under reduced pressure. The residue was purified by using MeOH: DCM](1:100-1:30) elution by silica gel column chromatographyPurification by the method provided the title compound as a yellow solid (60 mg, 49% yield). LC-MS [ M+H ]] + ＝633.4
Step 3: (1R, 5S) -3- (7- (5- (difluoromethyl) -2-ethylphenyl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8.diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
At 0 ℃ at N 2 In the atmosphere {3- [7- (2-ethyl-5-formylphenyl) -8-fluoro-2- (hexahydropyrrolizine-7 a-ylmethoxy) pyrido [4,3-d ]]Pyrimidin-4-yl]-3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-yl } carboxylate (50.1 mg,0.0792 mmol) in DCM (3 mL) was added BAST (175 mg,0.795 mmol) in one portion. The reaction mixture was slowly warmed to rt and stirred for 16h. The reaction was monitored by LCMS. After completion, the residue was concentrated under reduced pressure to give the title crude compound (50 mg crude), which was used in the next step without additional purification. LC-MS [ M+H ] ] + ＝655.3
Step 4:4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (5- (difluoromethyl) -2-ethylphenyl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d ] pyrimidine
At N 2 To (1R, 5S) -3- (7- (5- (difluoromethyl) -2-ethylphenyl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d ] under an atmosphere]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A mixture of tert-butyl octane-8-carboxylate (50 mg crude) in 1, 4-dioxane (2 mL) was added HCl (4N, 1mL in dioxane) in one portion. The mixture was stirred at rt for 1h. The reaction was monitored by LCMS. After completion, the mixture was concentrated and the residue was purified by preparative-HPLC (column: gemini5um C18 x 21.2mm, mobile phase: water (0.05% nh 3-H2O) -ACN; B%:20% -95%,20 min) to afford the title compound as a yellow solid (11 mg,25% yield). LC-MS [ M+H ]] + ＝555.4。 1 H NMR(400MHz，DMSO-d6)δ9.13(s，1H)，7.66(d，J＝8.4Hz，1H)，7.59(d，J＝8.0Hz，1H)，7.53(s，1H)，7.08(t，J＝56.0Hz，1H)，4.49(d，J＝12.0Hz，2H)，3.74-3.66(m，4H)，3.16-3.08(m，2H)，2.79—2.70(m，2H)，2.61(q，J＝7.2Hz，2H)，2.01-1.81(m，6H)，1.79-1.63(m，6H)，1.07(t，J＝7.6Hz，3H)。
Example 36
3- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d ] pyrimidin-7-yl) -4-ethylphenol
Figure BDA0004093773770001341
Step 1: 3-chloro-4-ethylphenol
At rt, methyl 4-bromo-3-chlorophenol (1.00 g,4.82 mmol) and Pd (t-BmP) 2 A solution of (247 mg, 0.480 mmol) in THF (20.0 mL) was added dropwise diethyl zinc (24.0 mL,24.0mmol,1M in hexanes). The reaction mixture was evacuated with N 2 Backfilling and the sequence is repeated three times. The resulting mixture was warmed to 50 ℃ and under N 2 Stirring was continued for 18h under an atmosphere. The reaction was monitored by TLC. After completion, the reaction mixture was taken up with H 2 O (50.0 mL) quench. The mixture was then poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (30 mL. Times.3). The combined organic layers were washed with brine (30.0 mL), and dried over Na 2 SO 4 Dried, filtered, and concentrated on a rotary evaporator. The crude oil produced was purified by silica gel chromatography (PE/etoac=100:1-2:1) to afford the title compound (700 mg,92% yield) as a yellow oil. LC-MS [ M+H ]]+＝157.4。 1 H NMR(400MHz，CDCl 3 )δ7.06(d，J＝8.0Hz，1H)，6.86(d，J＝2.4Hz，1H)，6.69(dd，J＝8.4，2.4Hz，1H)，4.06(s，1H)，2.67(q，J＝7.6Hz，2H)，1.19(t，J＝7.6Hz，3H)。
Step 2: 4-ethyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenol
3-chloro-4-ethylphenol (500 mg,3.19 mmol), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane(1.21g，4.78mmol)、Cy 3 P (107 mg,0.382 mmol), KOAc (626 mg,6.38 mmol) and Pd2 (dba) 3 (87.7 mg,0.0957 mmol) in DME (7.0 mL) was evacuated with N 2 Backfilling and the sequence is repeated three times. The resulting mixture was then heated to 150℃under N 2 The treatment in the microwave reactor was continued for 2 hours under an atmosphere. The reaction was monitored by TLC. After completion, the reaction mixture was quenched by addition of water (20.0 mL) and extracted with EtOAc (10 ml×3). The combined organic layers were washed with brine (20 mL), and dried over Na 2 SO 4 Dried, filtered, and concentrated on a rotary evaporator. The crude oil produced was purified by silica gel chromatography (PE/etoac=100:1-2:1) to afford the title compound (40.0 mg,5% yield) as a yellow oil. LC-MS [ M+H ]]+＝249.0。 1 H NMR(400MHz，CDCl 3 )δ7.21(d，J＝2.8Hz，1H)，7.06(d，J＝8Hz，1H)，6.85(dd，J＝8.4，3.2Hz，1H)，2.83(q，J＝7.2Hz，2H)，1.27(d，J＝5.6Hz，12H)，1.15(t，J＝7.6Hz，3H)。
Step 3: (1R, 5S) -3- (7- (2-ethyl-5-hydroxyphenyl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester
4-Ethyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenol (90.0 mg,0.362 mmol), (1R, 5S) -3- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]octane-8-Carboxylic acid tert-butyl ester (from step 2, 96.8mg,0.181mmol, from example 3), cs 2 CO 3 (354 mg,1.08 mmol) and Pd (dppf) Cl 2 (13.2 mg,0.0181 mmol) in 1, 4-dioxane/H 2 The mixture in O (4:1, 2.0 mL) was evacuated using N 2 Backfilling and the sequence is repeated three times. The resulting mixture was warmed to 90 ℃ and under N 2 Stirring was continued for 2h under an atmosphere. The reaction was monitored by LC-MS. After completion, the mixture was cooled to rt and volatiles (volatile) were removed on a rotary evaporator. The residue was purified by silica gel chromatography (DCM/meoh=100:1 to 10:1) to affordThe title compound (70.0 mg,62% yield) was a yellow solid. LC-MS [ M+H ]] + ＝621.3
Step 4:3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4-ethylphenol
At rt, to (1R, 5S) -3- (7- (2-ethyl-5-hydroxyphenyl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (70.0 mg,0.113 mmol) in ACN (2.0 mL) was added HCl in 1, 4-dioxane (0.4 mL, 4M) and stirring continued for 1h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give a residue which was purified by reverse flash chromatography (column, C18 silica gel, mobile phase: ACN-H 2 O(0.1％NH 4 OH); gradient: 55-65%) was purified directly to afford as a white solid (10.1 mg,17% yield).
LC-MS[M+H] + ＝521.3。 1 H NMR(400MHz，CD 3 CN)δ9.07(s，1H)，7.26(d，J＝8.4Hz，1H)，6.91(dd，J＝8.4，2.4Hz，1H)，6.80(d，J＝2.7Hz，1H)，5.38(t，J＝4.8Hz，2H)，4.51(d，J＝10.8Hz，2H)，3.60(d，J＝10.8Hz，5H)，3.17(s，2H)，2.79(s，3H)，2.50(dd，J＝14.8，7.6Hz，3H)，2.07-2.03(m，6H)，1.91—1.84(m，2H)，1.81-1.76(m，2H)，1.58-1.53(m，2H)，1.04(t，J＝7.6Hz，3H)。
Example 37
2- (3- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d ] pyrimidin-7-yl) -4-ethylphenyl) propan-2-ol
Figure BDA0004093773770001361
Step 1: 3-bromo-4-ethylbenzoic acid
To 4-ethylbenzoic acid (5.00 g,33.3 mmol), nitric acid (65% over 1h at rtAgNO was added dropwise from a solution of 22 mL), water (20 mL), acetic acid (120 mL) and bromine (5.85 g,36.6 mmol) 3 (5.66 g,33.3 mmol) in water (20 mL). The resulting mixture was stirred at rt for 3h. The reaction was monitored by LCMS. After completion, the reaction mixture was poured into ice-water, and the precipitate was collected by filtration. Saturated aqueous Na for solids 2 CO 3 (100 ml) treatment and stirring for 10min. The remaining solids were removed by filtration. The solution was adjusted to pH 2-3 with 12N HCl. The mixture was extracted with EtOAc (200 mL. Times.2). The combined organic layers were purified by Na 2 SO 4 Dried, filtered, and concentrated on a rotary evaporator. The residue obtained was purified by flash chromatography (eluting with MeOH/DCM,0 to 50%) to provide the title compound as a white solid (7.50 g,98% yield). LC-MS [ M+H ] ]-＝229.1。
Step 2: 3-bromo-4-ethylbenzoic acid methyl ester
To a solution of 3-bromo-4-ethylbenzoic acid (7.30 g,31.9 mmol) in MeOH (73.0 mL) was added dropwise concentrated H 2 SO 4 (0.73 mL). The mixture was heated to reflux and stirred overnight. The reaction was monitored by LCMS. Most of the solvent was removed under reduced pressure. The residue was taken up in EtOAc and saturated NaHCO 3 The aqueous solutions are partitioned and separated. The aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue obtained was purified by flash chromatography (eluting with PE/EtOAc,0 to 20%) to provide the title compound (6.10 g,79% yield) as a colourless oil. LC-MS [ M+H ]] + ＝242.2。
Step 3:2- (3-bromo-4-ethylphenyl) propan-2-ol
At 0 ℃ at N 2 To a stirred solution of methyl 3-bromo-4-ethylbenzoate (3.00 g,12.3 mmol) in THF (15.0 mL) was added MeMgBr (1.0M in diethyl ether, 24.6 mL) dropwise under an atmosphere. The mixture was then allowed to warm to ambient temperature and stirring continued for 3.5h. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to 0 ℃ and quenched by dropwise addition of aqueous 10% hcl (30 mL). The resulting mixture was extracted with EtOAc (50 mL. Times.3). Merging The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash chromatography (eluting with PE/EtOAc,0 to 20%) to provide the title compound (2.40 g,80% yield) as a colourless oil. LC-MS [ M- (OH) - )] + ＝227.2。
Step 4:2- [ 4-ethyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl ] propan-2-ol
2- (3-bromo-4-ethylphenyl) propan-2-ol (500 mg,2.06 mmol), B 2 Pin 2 (574.4 mg,2.26 mmol), acOK (605 mg, 6.17 mmol) and Pd (dppf) Cl 2 (99.3 mg,0.136 mmol) in dioxane was evacuated with N 2 Backfilling and the sequence is repeated three times. The resulting mixture was warmed to 90 ℃ and under N 2 Stir overnight under an atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to rt. The reaction mixture was concentrated to give a residue, which was purified by flash chromatography (eluting with PE/EtOAc,0 to 10%) to afford the title compound as a white solid (560 mg,93% yield). LC-MS [ M- (OH) - )] + ＝273.3。
Step 5:4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidine
At rt, to (1R, 5S) -3- (7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (from step 2, 92.0mg,0.172mmol of example 3) in ACN (2.0 mL) was added HCl (0.4 mL, 4M) in 1, 4-dioxane and stirring continued for 1h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give a residue (72 mg), which was used directly in the next step. LC-MS [ M+H ]]+＝436.01。
Step 5:2- (3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d]Pyrimidin-7-yl) -4-ethylphenyl-propan-2-ol
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2) pyrido [4,3-d]Pyrimidine (75.0 mg,0.172 mmol), 2- [ 4-ethyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl]A mixture of propan-2-ol (75.1 mg, 0.299 mmol), ruPhos Pd G3 (14.4 mg,0.0172 mmol) and potassium carbonate (109.8 mg, 0.517mmol) in 1, 4-dioxane/H2O (v/v=5:1) was evacuated with N 2 Backfilling and the sequence is repeated three times. The resulting mixture was warmed to 90 ℃ and under N 2 Stirring was continued for 4h under an atmosphere. The reaction was monitored by LCMS. After completion, the mixture was allowed to cool down to rt. The reaction mixture was concentrated to give a residue that was purified by preparative-TLC (10% meoh/DCM) to provide the title compound as a white solid (9.88 mg,10% yield, two steps). LC-MS [ M+H ]] + ＝563.4。 1 H NMR(400MHz，DMSO-d6)δ9.09(s，1H)，7.50(dd，J＝8.0，2.0Hz，1H)，7.40(s，1H)，7.33(d，J＝8.0Hz，1H)，5.03(s，1H)，4.40(d，J＝11.6Hz，2H)，3.62—3.49(m，4H)，2.97-2.87(m，2H)，2.56—2.50(m，4H)，1.91-1.71(m，6H)，1.65-1.51(m，6H)，1.43(s，6H)，1.03(t，J＝7.6Hz，3H)。
Similar procedures as in the examples above were used to synthesize other compounds as shown herein and the exemplary compounds mentioned previously.
Biochemical activity and cellular activity
EXAMPLE I KRAS G12D-SOS1 interaction assay
SOS1 is a key guanine exchange factor (guanine exchange factor, GEF) contributing to the active form of KRAS. The ability of test compounds to bind to KRAS G12D and impair KRAS G12D-SOS1 interaction was measured by HTRF assay using the Cisbio KRAS/SOS1 binding kit (cat No. 63ADK000CB21 PEH). The interaction between Tag1-KRAS G12D and Tag2-SOS1 was detected by energy transfer from Terbium cryptate (HTRF donor) labeled on anti-Tag 2 and XL665 (HTRF acceptor) labeled on anti-Tag 1. A decrease in HTRF signal indicates a compromised KRAS G12D-SOS1 interaction.
The procedure was performed according to the manufacturer's instructions, tag1-KRAS G12D, tag-SOS 1 mixed with diluted compound and incubated at 25℃for 15min. anti-Tag 1-Tb and anti-Tag 2-XL665 were then added to the assay plate and the mixture incubated for an additional 3h. In Envision TM The fluorescent signal was read on a Plate Reader. IC50 was determined from the nonlinear regression equation by Graphpad Prism 8. The results of the exemplary compounds of formula (I) are shown in table 5. The KRAS G12D-SOS1 HTRF assay ranges are: a=ic 50 is less than or equal to 50nM; b=ic 50 > 50nM to 250nM; c=ic 50 > 250nM to 1 μm; and d=ic 50 > 1 μm.
TABLE 5 inhibition of KRAS G12D-SOS1 interaction
Numbering of compounds IC 50 (nM) Numbering of compounds IC 50 (nM)
MRTX1133 A EX.19 A
EX.1 C EX.20 A
EX.2 C EX.21 A
EX.3 A EX.22 A
EX.4 A EX.23 A
EX.5 A EX.24 A
EX.6 B EX.25 A
EX.7 C EX.26 A
EX.8 A EX.27 A
EX.9 A EX.28 A
EX.10 A EX.29 A
EX.11 D EX.30 A
EX.12 A EX.31 A
EX.13 A EX.32 A
EX.14 A EX.33 A
EX.15 A EX.34 A
EX.16 A EX.35 D
EX.17 A EX.36 B
EX.18 A EX.37 D
Example II measurement of cell Signal transduction Activity (Cellular signaling activity assay)
The compounds of the invention inhibit KRAS G12D activity and thus inhibit the production of the downstream effector pERK (phospho-ERK).
GP2D cells (CBP 60010) were cultured in DMEM medium containing 10% fetal bovine serum and penicillin/streptomycin, seeded in 384 well cell culture plates and allowed to adhere (attach) for 12h-14h. Dilute compounds were added to the cell culture plates and incubated for 3h. 4.0% formaldehyde was added to fix cells and plates were washed with PBS and infiltrated with 100% methanol (permeablize). Plates were blocked for 1h at room temperature using non-specific antibodies.
Antibodies specific for phosphorylated forms of ERK were used to determine the amount of pERK and compared to the amount of GAPDH. Primary antibodies phosphoERK (CST, 4370S) and GADPH (CST, 97166S) were added to the plates and incubated overnight at 4 ℃. Plates were washed with PBST. The secondary antibodies IRDye 800CW goat anti-rabbit IgG (LI-COR, 926-32211) and IRDye 680RD goat anti-mouse IgG (LI-COR, 926-68070) were added to the plates and incubated at room temperature for 1 hour. Plates were washed with PBST and read on an Odyssey CLx microplate reader.
For each well, pERK signal was normalized to GAPDH signal and DMSO control well values were calculated. IC (integrated circuit) 50 Values are generated from a nonlinear regression equation: y=bottom+ (top-bottom)/(1+10 ++logic 50 -X) Hill slope).
The results of the exemplary compounds are shown in table 6. The range of cell signaling activity assays is: a=ic 50 ≤50nM；B＝IC 50 > 50nM to 250nM; c=ic 50 > 250nM to 1. Mu.M; d=ic 50 ＞1μM.
TABLE 6 KRAS G12D mediated inhibition of ERK in GP2D
Numbering of compounds IC 50 (nM) Numbering of compounds IC 50 (nM)
MRTX1133 A EX.19 A
EX.1 C EX.20 A
EX.2 D EX.21 A
EX.3 B EX.22 A
EX.4 A EX.23 A
EX.5 A EX.24 A
EX.6 B EX.25 A
EX.7 C EX.26 A
EX.8 A EX.27 A
EX.9 A EX.28 A
EX.10 A EX.29 B
EX.11 D EX.30 A
EX.12 A EX.31 A
EX.13 A EX.32 C
EX.14 A EX.33 A
EX.15 A EX.34 A
EX.16 A EX.35 D
EX.17 A EX.36 D
EX.18 A EX.37 D
Example III KRAS-CRAF interaction assay: inhibition of KRAS G12D mutants binding to CRAF relative to wild-type (WT) KRAS
CRAF is a well-studied KRAS effector protein, and KRAS-CRAF interactions are known to contribute to MAPK signaling. The compounds of the invention bind to KRAS and block interactions between KRAS and CRAF. To determine the selectivity of compounds between KRASG12D and wild-type (WT) KRAS, inhibition of KRAS G12D-CRAF and KRAS WT-CRAF was measured by HTRF assay. The interaction between Tag1-CRAF (in house) purified GST-CRAF) and Tag2-KRAS G12D/KRAS WT was detected by energy transfer from terbium cryptates (HTRF donors) labeled on anti-Tag 1 and XL665 (HTRF acceptors) labeled on anti-Tag 2 (Cisbo, 63ADK000CB21 PEH). A decrease in HTRF signal indicates a compromised KRAS G12D/KRAS WT-CRAF interaction.
The procedure was followed according to the manufacturer's instructions, with Tag1-KRAS G12D/KRAS WT, tag2-CRAF mixed with diluted compound, and incubated at 25℃for 15min. anti-Tag 1-Tb and anti-Tag 2-XL665 were then added to the assay plate and the mixture incubated at 4℃for 3h. In Envision TM And reading fluorescent signals on an enzyme label instrument. IC (integrated circuit) 50 Determined from a nonlinear regression equation by Graphpad Prism 8. The results of the exemplary compounds of formula (I) are shown in table 7.
TABLE 7 Selective inhibition of KRAS G12D over KRAS WT
Figure BDA0004093773770001401
The results demonstrate that exemplary compounds of the invention have higher selectivity between KRAS G12D and wild-type (WT) KRAS relative to reference compound MRTX1133, which reference compound MRTX1133 is described in patent WO 2021/04671, WO2022/015375 or in "Identiffcation of MRTX1133, a Noncovient, patent, and Selective KRAS G12D Inhibitor ", J.Med. Chem.2022, 65, 3123-3133, doi: 10.1021/acs.jmedchem.1c01688.
Figure BDA0004093773770001402
EXAMPLE IV liver microsomal Metabolic stability
The metabolic stability disclosed herein is assessed using a liver microsomal stability assay. Human liver microsomes, rat liver microsomes, mouse liver microsomes, canine liver microsomes, monkey liver microsomes (from Corning) were evaluated. Test compounds and liver microsomes were added to 0.1M potassium phosphate buffer, 1.0mM EDTA,pH 7.4, to concentrations of 6 μm and 0.75mg/mL, respectively. The 30uL of the mixture transferred to the assay plate was preheated in a 37 ℃ water bath for 5min. mu.L of 6mM NADPH solution was added to each plate to start the reaction, and microsomal reactions were terminated at 5-min, 15-min, 30-min and 45-min by adding 135. Mu.L of acetonitrile. For the 0-min plate, NADPH solution and acetonitrile were added simultaneously. The plates were centrifuged at 5594g for 15min at 20 ℃. The supernatant was collected and quantified by HPLC. T (T) 1/2 (minutes) and Clint (mL/min/kg) were calculated as follows:
T 1 / 2 =0.693/K (K is ln [ concentration ]]Rate constant of (c) with respect to incubation time
Clint＝(0.693/T 1/2 ) X (1/(microsomal protein concentration (0.5 mg/mL))). Times.scaling factor
Figure BDA0004093773770001411
a Scale factor = (microsomal protein/g liver) × (liver weight/kg body weight)
As shown in tables 8 and 9, the compounds of the present invention exhibited higher metabolic stability of liver microsomes than the reference compound MRTX 1133.
TABLE 8 metabolism stability of liver microsomes
Figure BDA0004093773770001412
TABLE 9 metabolism stability of liver microsomes
Figure BDA0004093773770001413
Figure BDA0004093773770001421
Example V-1. Pharmacokinetics of deuterated Compounds of the invention in SD rats relative to non-deuterated Compounds
The purpose of this study was to determine the Pharmacokinetics (PK) of the deuterated compounds of the invention relative to non-deuterated compounds after a single Intravenous (IV) administration in male SD rats using LC-MS/MS.
Animal information: SD rats, SPF, 6-8 week old, male, weighing 300-315 g, purchased from Hunan Slaike Jinda Experimental Animal Co., LTD.
The formula comprises the following components: 5% DMSO+5% polyoxyethylated castor oil EL+90% saline. It was used immediately after preparation.
And (3) application: intravenous administration;
dosage is as follows: 1mg/kg;
drug administration concentration: 0.5mg/mL;
dosage of: 2mL;
time point of plasma collection: after administration, 2min, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h.
Sample collection (plasma): 0.2mL of blood was collected and placed in a labeled EDTA-2K anticoagulant tube. Immediately after the anticoagulant (EDTA-2K) was gently mixed upside down with the blood, the blood was placed in wet ice and the plasma was centrifuged within 1 hour after blood collection. The centrifugation conditions were set at 4℃for 6800g and 6 minutes.
Sample storage: after centrifugation, the separated plasma was placed in a labeled EP tube and stored in an ultra-low temperature refrigerator as quickly as possible until sample analysis.
Instrument: LC-MS/MS (API 5000) (LC-MS-005);
mobile phase: mobile phase a:0.3% FA-10mM ammonium acetate water: mobile phase B:70% MeOH-30% ACN.
Flow rate: 0.800mL/min
Column: nano chrom core C18 (4.6X530 mm,3.0 μm).
Data analysis and calculation:
the concentration of the test compounds of the invention in rat plasma at various time points after administration was achieved by LC-MS/MS. The data were processed and pharmacokinetic parameters of the post-administration rats were calculated by non-compartmental model using Phoenix winnonlin 7.0 software (pharsight, USA). Peak time T Maximum value And peak concentration C Maximum value Is a measurement;
AUC 0-t calculating the value of the area under the curve by a trapezoid method;
AUC 0-infinity ＝AUC 0-t +C t /k e ，C t Is the concentration of the detectable compound, k, in the plasma at the last measurable time point e Is the erasure rate constant;
elimination half-life t 1/2 ＝0.693/k e ；
Average retention time, mrt=aumc/AU;
clearance, cl=d/AUC 0-infinity (D is the dose);
apparent distribution volume at steady state, V SS ＝CL x MRT。
Pharmacokinetic results (Table 10)
TABLE 10 PK in SD rats
Figure BDA0004093773770001431
Example V-2 pharmacokinetics of deuterated Compounds of the invention relative to non-deuterated Compounds in ICR mice
The purpose of this study was to determine the Pharmacokinetics (PK) of the deuterated compounds of the invention relative to non-deuterated compounds after a single Intravenous (IV) administration in ICR mice using LC-MS/MS.
Animal information: ICR mice, SPF, male, purchased from Hunan Slaike Jingda Experimental Animal co., ltd., accession number 430727221100520536.
The formula comprises the following components: 5% DMSO+5% polyoxyethylated castor oil EL+90% saline. It was used immediately after preparation.
And (3) application: intravenous administration;
dosage is as follows: 1mg/kg;
drug administration concentration: 0.2mg/mL;
dosage of: 5mL/kg;
time point of plasma collection: after administration, 5min, 15min, 30min, 1h, 2h, 4h, 8h, 24h.
Sample collection (plasma): 0.2mL of blood was collected and placed in a labeled EDTA-2K anticoagulant tube. Immediately after the anticoagulant (EDTA-2K) was gently mixed upside down with the blood, the blood was placed in wet ice and the plasma was centrifuged within 1 hour after blood collection. The centrifugation conditions were set at 4℃for 6800g and 6 minutes.
Sample storage: after centrifugation, the separated plasma was placed in a labeled EP tube and stored as quickly as possible in a-20 ℃ refrigerator until sample analysis.
Instrument: LC-MS/MS (API 5000) (LC-MS-005);
mobile phase: mobile phase a:0.3FA-10mM ammonium acetate water; mobile phase B:70% MeOH-30% ACN.
Flow rate: 0.800mL/min
Column Nano chrom core C (4.6X530 mm,3.0 μm).
Data analysis and calculation:
the concentration of the test compounds of the invention in rat plasma at various time points after administration was achieved by LC-MS/MS. The data were processed and pharmacokinetic parameters of the post-administration rats were calculated by non-compartmental model using Phoenix winnonlin 7.0 software (pharsight, USA). Peak time T Maximum value And peak concentration C Maximum value Is a measurement;
AUC o-t calculating the value of the area under the curve by a trapezoid method;
AUC 0-infinity ＝AUC 0-t +C t /k e ，C t Is the concentration of the detectable compound, k, in the plasma at the last measurable time point e Is the erasure rate constant;
elimination half-life t 1/2 ＝0.693/k e ；
Average retention time, mrt=aumc/AU;
clearance, cl=d/AUC o-infinity (D is the dose);
apparent distribution volume at steady state, V SS ＝CL x MRT
Pharmacokinetic results (Table 11)
TABLE 11 PK in ICR mice
Figure BDA0004093773770001441

Claims (140)

1. A compound comprising a moiety of formula (I) or a PROTAC compound comprising a moiety of formula (I),
Figure FDA0004093773760000011
or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers thereof,
wherein:
X 0 is H, deuterium, halogen, OH, NH 2 、CN、C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C1-6 alkoxy; and each of which can independently be optionally unsubstituted or independently optionally substituted with a 3-to 7-membered heterocyclic ring having one or more heteroatoms independently selected from N, O or S, and at least one of which is N, the heteroatoms being directly attached to the C 1-6 Alkyl or C 1-6 One of the C atoms of the hydroxyalkyl group; the 3-to 7-membered heterocyclic ring is additionally optionally substituted with-CH 3 or-N (CH) 3 ) 2 Substitution;
R 1 and R is 2 Each of which is independently selected from H, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy groups, and each of which is independently optionallyUnsubstituted or independently optionally substituted with deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
R 3 and R is 4 Each of which is independently selected from H, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-4 Alkyl or-C 1-4 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, halogen, -NH 2 、-CN、-OH、-NHC(O)NHC 1-6 Alkyl, -NHC (O) N (C) 1-6 Alkyl group 2 、-OH、-OC(O)NHC 1-6 Alkyl, -OC (O) N (C) 1-6 Alkyl group 2 、
Figure FDA0004093773760000012
-C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
R 5 and R is 6 Each of which is independently selected from H, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
and R is 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least one of which is deuterium;
r is independently:
Figure FDA0004093773760000021
wherein:
n is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
X 1 is H, -CH 2 CN、C 1-6 Alkyl or C 1-6 An alkoxy group;
X 2 is a 6-to 10-membered aryl or a 5-to 10-membered heteroaryl; and the 6-to 10-membered aryl or the 5-to 10-membered heteroarylEach of the radicals is independently optionally unsubstituted or independently optionally substituted with one or more R 2x Substitution;
R 2x each of which is independently selected from halogen, -OH, -NH 2 、-CN、C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Deuterated alkynyl, cyano, (C) 1-6 Alkoxy) C 1-6 Alkyl, (C) 1-6 Alkoxy) C 1-6 Alkoxy, (C) 1-6 Hydroxyalkoxy) C 1-6 Alkoxy, 3-to 7-membered cycloalkyl or 3-to 7-membered heterocycloalkyl; and each of which is independently optionally unsubstituted or independently optionally substituted with one or more-NH' s 2 Halogen, deuterium, -CN, -OH, -C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
X 3 independently selected from H, halogen, C 1-6 Alkyl or C 1-6 An alkoxy group;
Figure FDA0004093773760000022
is a single bond or a double bond;
5 x is N or CR 7 Wherein
i) When (when) 5 X is N or 5 X is CR 7 In the time-course of which the first and second contact surfaces,
Figure FDA0004093773760000023
is a double bond;
ii) when 5 X is C (R) 7 ) 2 Or (b) 5 X is NR 7 In the time-course of which the first and second contact surfaces,
Figure FDA0004093773760000024
is a single bond;
R 7 each of which is independently H, halogen, -C 1-6 Alkyl or substituted by one or more halogens, deuterium, -OH or NH 2 substituted-C 1-6 An alkyl group; or (b)
Two R 7 Along with two R 7 The C atoms to which both are attached form oxo (=o), and the oxo together with the X 2 To which the N atom is attached to form a lactam, or
R 7 And R is 7 Together with the C atom to which they are each attached form a 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycle; or (b)
W is O or NR w And R is w Is H, deuterium or C 1-6 An alkyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X 0 Is H, deuterium, F, cl, OH, NH 2 、CN、C 1-3 Alkyl, C 1-3 Hydroxyalkyl or C 1-3 An alkoxy group; and each of which can independently be optionally unsubstituted or independently optionally substituted with a 3-to 7-membered heterocyclic ring having one or more heteroatoms independently selected from N, O or S, and at least one of which is N, the heteroatoms being directly attached to the C 1-3 Alkyl or C 1-3 One of the C atoms of the hydroxyalkyl group; the 3-to 7-membered heterocyclic ring is additionally optionally substituted with-CH 3 or-N (CH) 3 ) 2 And (3) substitution.
3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein X 0 Is H, deuterium, F, cl, OH, NH 2 CN, methyl or methoxy.
4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X 0 Is H.
5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy groups, and each of which is independentlyOptionally unsubstituted or independently optionally substituted with deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Each of which is independently selected from H, deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy, and each of which is independently optionally unsubstituted or independently optionally deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy substitution.
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Independently selected from H or deuterium.
8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 3 And R is 4 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, F, cl, -NH 2 、-CN、-OH、-NHC(O)NHC 1-3 Alkyl, -NHC (O) N (C) 1-3 Alkyl group 2 、-OC(O)NHC 1-3 Alkyl, -OC (O) N (C) 1-3 Alkyl group 2 、
Figure FDA0004093773760000041
-C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3 And R is 4 Each of which is independently selected from H, deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy, and each of themIndependently optionally unsubstituted or independently optionally substituted with deuterium, F, cl, -NH 2 、-CN、-OH、NHC(O)NHMe、-NHC(O)N(Me) 2 、-OH、-OC(O)NHMe、-OC(O)N(Me) 2 、
Figure FDA0004093773760000042
Methyl or methoxy substituted, or R 3 And R is 4 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-CH 2 NHC(O)NHMe、-CH 2 NHC(O)N(Me) 2 、-CH 2 OH、-CH 2 OC(O)NHMe、-CH 2 OC(O)N(Me) 2 、
Figure FDA0004093773760000043
Methyl or methoxy.
10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 3 And R is 4 Independently selected from H or deuterium.
11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 5 And R is 6 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 5 And R is 6 Each of which is independently selected from H, deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy, and each of which is independently optionally unsubstituted or independently optionally deuterium, F, cl, -NH 2 -CN, -OH methyl or methoxy groupAnd (3) replacing.
13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 5 And R is 6 Independently selected from H, deuterium, -OH, or F.
14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least one of which is deuterium; and R is 5 Is deuterium.
15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least one of which is deuterium; and R is 6 Is deuterium.
16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least two of which are deuterium; and R is 1 And R is 2 Both are deuterium.
17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least two of which are deuterium; and R is 3 And R is 4 Both are deuterium.
18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least three of (a) are deuterium; and R is 1 And R is 2 Both are deuterium, and R 5 Is deuterium or R 6 Is deuterium.
19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least three of (a) are deuterium; and R is 3 And R is 4 Is deuterium, and R 5 Is deuterium or R 6 Is deuterium.
20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 At least four of which are deuterium; and R is 1 And R is 2 Both are deuterium, and R 3 And R is 4 Both are deuterium.
21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 Is deuterium; and R is 1 And R is 2 Both are deuterium, and R 3 And R is 4 Both are deuterium, and R 5 Is deuterium or R 6 Is deuterium.
22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R is independently:
Figure FDA0004093773760000051
23. the compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R is independently:
Figure FDA0004093773760000052
24. the compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R is independently:
Figure FDA0004093773760000061
25. the compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R is independently:
Figure FDA0004093773760000062
26. the compound of any one of claims 1 to 22 or claim 24, or a pharmaceutically acceptable salt thereof, wherein n is 2.
27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein X 1 Is H, -CH 2 CN、C 1-3 Alkyl or C 1-3 An alkoxy group.
28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein X 1 Is H, -CH 2 CN, methyl or methoxy.
29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein X 1 Is H.
30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein X 2 Is phenyl, naphthyl or a 5-, 6-, 7-, 8-, 9-or 10-membered heteroaryl group; and each phenyl, naphthyl, or the 5-to 10-membered heteroaryl is independently optionally unsubstituted or independentOptionally by 1R 2x 2R 2x Or 3R 2x And (3) substitution.
31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein X 2 Is phenyl, naphthyl or a 5-, 6-, 7-or 8-membered heteroaryl group; and each phenyl, naphthyl, or the 5-, 6-, 7-, or 8-membered heteroaryl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein X 2 Is phenyl or naphthyl, and each of the phenyl or naphthyl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein X 2 Is phenyl, and the phenyl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein X 2 Is naphthyl, and the naphthyl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R 2x Each of which is independently selected from F, cl, -OH, -NH 2 、-CN、C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Deuterated alkynyl, cyano, (C) 1-3 Alkoxy) C 1-3 Alkyl, (C) 1-3 Alkoxy) C 1-3 Alkoxy, (C) 1-3 Hydroxyalkoxy) C 1-3 Alkoxy, 3-or 4-membered cycloalkyl, or 3-or 4-membered heterocycloalkyl; and each of which is independently optionally unsubstituted or independently optionally substituted with 1, 2 or 3-NH 2 F, cl, deuterium, -CN, -OH, -C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R 2x Each of which is independently selected from F, cl, -OH, -NH 2 -CN, methyl, ethyl, methoxy, methyl substituted with 3F, methyl substituted with 3 Cl, ethyl substituted with 3F, vinyl, ethynyl substituted with deuterium, 3 membered cycloalkyl, 3 membered heterocycloalkyl or cyano; and each of which is independently optionally unsubstituted or independently optionally substituted with 1, 2 or 3-NH 2 F, cl, deuterium, -CN, -OH, methyl or methoxy substitution.
37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R 2x Independently selected from F, cl, -OH, methyl substituted with 3F, vinyl, ethynyl, or cyclopropyl; and each of which is independently optionally unsubstituted or independently optionally substituted with 3F, 3 deuterium or methyl groups.
38. The compound of any one of claims 1 to 23, or claim 26 to 37, or a pharmaceutically acceptable salt thereof, wherein X 3 Independently selected from H, F, cl, C 1-3 Alkyl or C 1-3 An alkoxy group.
39. The compound of any one of claims 1 to 23, or claim 26 to 38, or a pharmaceutically acceptable salt thereof, wherein X 3 Independently selected from H, F, cl, methyl or methoxy.
40. The compound of any one of claims 1 to 23, or claim 26 to 39, or a pharmaceutically acceptable salt thereof, wherein X 3 Independently selected from F.
41. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein
Figure FDA0004093773760000081
Is a single bond.
42. The compound according to any one of claim 1 to claim 41, or a pharmaceutically acceptable salt thereof, wherein
Figure FDA0004093773760000082
Is a double bond.
43. The compound of any one of claims 1 to 21, or 24 to 37, or a pharmaceutically acceptable salt thereof, wherein 5 X is N, and the number of the X is N,
Figure FDA0004093773760000083
is a double bond; or (b) 5 X is C (R) 7 ) 2 ，
Figure FDA0004093773760000084
Is a single bond.
44. A compound according to any one of claims 1 to 21, or 24 to 37, or 43, or a pharmaceutically acceptable salt thereof, wherein 5 X is CR 7 ，R 7 H, F, cl, -C independently 1-3 Alkyl or substituted by 1, 2 or 3F, cl, deuterium, -OH or NH 2 substituted-C 1-3 An alkyl group.
45. The compound of any one of claims 1 to 21, or 24 to 37, or 43 to 44, or a pharmaceutically acceptable salt thereof, wherein 5 X is CR 7 ，R 7 Is independently H, F, cl, methyl or is substituted with 1, 2 or 3F, cl, deuterium, -OH or NH 2 Substituted methyl.
46. The compound of any one of claims 1 to 21, or 24 to 37, or 43 to 45, or a pharmaceutically acceptable salt thereof, wherein R 7 And R is 7 Together with the C atom to which they are each attached form a 3-, 4-, 5-or 6-membered cycloalkyl, 3-, 4-, 5-or 6-membered heterocycle.
47. The compound of any one of claims 1 to 21, or 24 to 37, or 43 to 46, or a pharmaceutically acceptable salt thereof, wherein R 7 And R is 7 Together with the C atom to which they are each attached form a 5-or 6-membered cycloalkyl, or a 5-or 6-membered heterocycle.
48. The compound of any one of claims 1 to 21, or 24 to 37, or 43 to 47, or a pharmaceutically acceptable salt thereof, wherein two R 7 Along with two R 7 The C atoms to which both are attached form oxo (=o), and the oxo together with the X 2 The N atoms attached to form a 4-, 5-, or 6-membered lactam having one or two N.
49. A compound according to any one of claims 1 to 21, or 24 to 37, or 43 to 48, or a pharmaceutically acceptable salt thereof, wherein 5 X is N, and
Figure FDA0004093773760000091
is a double bond.
50. The compound of any one of claim 1 to claim 49, or a pharmaceutically acceptable salt thereof, wherein W is NR w And R is w Is H, deuterium or C 1-3 An alkyl group.
51. The compound of any one of claim 1 to claim 50, or a pharmaceutically acceptable salt thereof, wherein W is NR w And R is w Is H, deuterium, methyl or methoxy.
52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein W is NR w And R is w Is H.
53. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein W is O.
54. A compound comprising a moiety of formula (I ') or a PROTAC compound comprising a moiety of formula (I'),
Figure FDA0004093773760000092
or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers thereof,
wherein:
m is selected from 1, 2, 3 or 4;
X 0 is H, deuterium, halogen, OH, NH 2 、CN、-NHC(O)NHC 1-6 Alkyl, -NHC (O) N (C) 1-6 Alkyl group 2 、-OH、-OC(O)NHC 1-6 Alkyl, -OC (O) N (C) 1-6 Alkyl group 2 、
Figure FDA0004093773760000093
-C 1-6 Alkyl NHC (O) NHC 1-6 Alkyl, -C 1-6 Alkyl NHC (O) N (C) 1-6 Alkyl l) 2 、-OH、-CH 2 OH、-CH 2 OC(O)NHC 1-6 Alkyl, -CH 2 OC(O)N(C 1-6 Alkyl group 2 、
Figure FDA0004093773760000094
C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or C 1-6 An alkoxy group; and each of which can independently be optionally unsubstituted or independently optionally substituted with a 3-to 7-membered heterocyclic ring having one or more heteroatoms independently selected from N, O or S, and at least one of the heteroatoms is N, the heteroatoms being directly attached to C 1-6 Alkyl or C 1-6 One of the C atoms of the hydroxyalkyl group; the 3-to 7-membered heterocyclic ring is additionally optionally unsubstituted or optionally-CH 3 or-N (CH) 3 ) 2 Substitution;
y is C (R) N ) 2 Or NR (NR) N ；R N Each of which is independently H, deuterium, halogen, -NH 2 、-CN、-OH、-NHC(O)NHC 1-6 Alkyl, -NHC (O) N (C) 1-6 Alkyl group 2 、-OH、-OC(O)NHC 1-6 Alkyl, -OC (O) N (C) 1-6 Alkyl group 2 、
Figure FDA0004093773760000101
C 1-6 Alkyl NHC (O) NHC 1-6 Alkyl, -C 1-6 Alkyl NHC (O) N (C) 1-6 Alkyl group 2 、-OH、-C 1-6 Alkyl OH, -C 1-6 Alkyl OC (O) NHC 1-6 Alkyl, -C 1-6 Alkyl OC (O) N (C) 1-6 Alkyl group 2 、
Figure FDA0004093773760000102
-C 1-6 Alkyl, -C 1-6 Alkoxy or +.>
Figure FDA0004093773760000103
R 1 And R is 2 Each of which is independently selected from H, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
R 3 And R is 4 Each of which is independently selected from H, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-4 Alkyl or-C 1-4 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
R 5 each of which is independently selected from H, halogen, deuterium, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
and R is 1 、R 2 、R 3 、R 4 And R is 5 At least one of which is deuterium;
r is independently:
Figure FDA0004093773760000104
wherein:
n is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
X 1 is H, -CH 2 CN、C 1-6 Alkyl or C 1-6 An alkoxy group;
X 2 is a 6-to 10-membered aryl or a 5-to 10-membered heteroaryl; and each of the 6-to 10-membered aryl or the 5-to 10-membered heteroaryl is independently optionally unsubstituted or independently anyOptionally by one or more R 2x Substitution;
R 2x each of which is independently selected from halogen, -OH, -NH 2 、-CN、C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Deuterated alkynyl, cyano, (C) 1-6 Alkoxy) C 1-6 Alkyl, (C) 1-6 Alkoxy) C 1-6 Alkoxy, (C) 1-6 Hydroxyalkoxy) C 1-6 Alkoxy, 3-to 7-membered cycloalkyl or 3-to 7-membered heterocycloalkyl; and each of which is independently optionally unsubstituted or independently optionally substituted with one or more-NH' s 2 Halogen, deuterium, -CN, -OH, -C 1-6 Alkyl or-C 1-6 Alkoxy substitution;
X 3 independently selected from H, halogen, C 1-6 Alkyl or C 1-6 An alkoxy group;
Figure FDA0004093773760000111
is a single bond or a double bond;
5 x is N or CR 7 Wherein
i) When (when) 5 X is N or 5 X is CR 7 In the time-course of which the first and second contact surfaces,
Figure FDA0004093773760000112
is a double bond;
ii) when 5 X is C (R) 7 ) 2 Or (b) 5 X is NR 7 In the time-course of which the first and second contact surfaces,
Figure FDA0004093773760000113
is a single bond;
R 7 independently H, halogen, -C 1-6 Alkyl or substituted by one or more halogens, deuterium, -OH or NH 2 substituted-C 1-6 An alkyl group; or (b)
Two R 7 Along with the two R' s 7 The C atoms to which both are attached form oxo(=o), and the oxo is identical to the X 2 To which the N atom is attached to form a lactam, or
R 7 And R is 7 Together with the C atom to which they are each attached form a 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycle; or (b)
W is O or NR w And R is w Is H, deuterium or C 1-3 An alkyl group.
55. The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein X 0 Is H, deuterium, F, cl, OH, NH 2 、CN、C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or C 1-3 An alkoxy group; and each of which can independently be optionally unsubstituted or independently optionally substituted with a 3-to 7-membered heterocyclic ring having one or more heteroatoms independently selected from N, O or S, and at least one of which is N, the heteroatoms being directly attached to the C 1-3 Alkyl or C 1-3 One of the C atoms of the hydroxyalkyl group; the 3-to 7-membered heterocyclic ring is additionally optionally substituted with-CH 3 or-N (CH) 3 ) 2 And (3) substitution.
56. The compound of claim 54 or claim 55, or a pharmaceutically acceptable salt thereof, wherein X 0 Is H, deuterium, F, cl, OH, NH 2 CN, methyl or methoxy.
57. The compound of any one of claim 54 to claim 56, or a pharmaceutically acceptable salt thereof, wherein X 0 Is H.
58. The compound of any one of claims 54 to 57, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, F,Cl、-NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
59. The compound of any one of claims 54 to 58, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Each of which is independently selected from H, deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy, and each of which is independently optionally unsubstituted or independently optionally deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy substitution.
60. The compound of any one of claims 54 to 59, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Independently selected from H or deuterium.
61. The compound of any one of claims 54 to 60, or a pharmaceutically acceptable salt thereof, wherein R 3 And R is 4 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
62. The compound of any one of claim 54 to claim 61, or a pharmaceutically acceptable salt thereof, wherein R 3 And R is 4 Each of which is independently selected from H, deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy, and each of which is independently optionally unsubstituted or independently optionally deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy substitution.
63. The compound of any one of claims 54 to 62, or a pharmaceutically acceptable salt thereof, wherein R 3 And R is 4 Independently selected from H, or deuterium.
64. The compound of any one of claims 54 to 63, or a pharmaceutically acceptable salt thereof, wherein R 5 Each of which is independently selected from H, deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, F, cl, -NH 2 、-CN、-OH、-C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
65. The compound of any one of claims 54 to 64, or a pharmaceutically acceptable salt thereof, wherein R 5 Each of which is independently selected from H, deuterium, F, cl, -NH 2 -CN, -OH, methyl or methoxy, and each of which is independently optionally unsubstituted or independently optionally deuterium, F, cl, -NH 2 -CN, -OH methyl or methoxy substitution.
66. The compound of any one of claims 54 to 65, or a pharmaceutically acceptable salt thereof, wherein R 5 Independently selected from H, deuterium, or F.
67. The compound of any one of claims 54 to 66, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 And R is 5 At least one of which is deuterium, and R 5 Is deuterium.
68. The compound of any one of claims 54 to 67, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 And R is 5 At least two of which are deuterium, and R 1 And R is 2 Both are deuterium.
69. As claimed in claim 54 to claim 68 or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 And R is 5 At least two of which are deuterium, and R 3 And R is 4 Both are deuterium.
70. The compound of any one of claims 54 to 69, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 And R is 5 At least three of (a) are deuterium, and R 1 And R is 2 Both are deuterium, and R 5 Is deuterium.
71. The compound of any one of claims 54 to 70, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 And R is 5 At least three of (a) are deuterium, R 3 And R is 4 Both are deuterium, and R 5 Is deuterium.
72. The compound of any one of claims 54 to 71, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 And R is 5 At least four of (a) are deuterium, R 1 And R is 2 Both are deuterium, and R 3 And R is 4 Both are deuterium.
73. The compound of any one of claims 54 to 70, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 And R is 5 All of which are deuterium.
74. The compound of any one of claims 54 to 73, or a pharmaceutically acceptable salt thereof, wherein R is independently:
Figure FDA0004093773760000131
75. the compound of any one of claims 54 to 73, or a pharmaceutically acceptable salt thereof, wherein R is independently:
Figure FDA0004093773760000141
76. The compound of any one of claims 54 to 73, or a pharmaceutically acceptable salt thereof, wherein R is independently:
Figure FDA0004093773760000142
77. the compound of any one of claims 54 to 73, or a pharmaceutically acceptable salt thereof, wherein R is independently:
Figure FDA0004093773760000143
78. the compound of any one of claims 54 to 74 or claim 76, or a pharmaceutically acceptable salt thereof, wherein n is 2.
79. The compound of any one of claims 54 to 78, or a pharmaceutically acceptable salt thereof, wherein X 1 Is H, -CH 2 CN、C 1-3 Alkyl or C 1-3 An alkoxy group.
80. The compound of any one of claims 54 to 79, or a pharmaceutically acceptable salt thereof, wherein X 1 Is H, -CH 2 CN, methyl or methoxy.
81. The compound of any one of claims 54 to 80, or a pharmaceutically acceptable salt thereof, wherein X 1 Is H.
82. The compound of any one of claims 54 to 81, or a pharmaceutically acceptable salt thereof, wherein X 2 Is phenyl, naphthyl or a 5-, 6-, 7-, 8-, 9-or 10-membered heteroaryl group; and each phenyl, naphthyl, or the 5-to 10-membered heteroaryl is independently optionally unsubstituted or independently optionally substituted with 1R 2x 2R 2x Or 3R 2x And (3) substitution.
83. The compound of any one of claims 54 to 82, or a pharmaceutically acceptable salt thereof, wherein X 2 Is phenyl, naphthyl or a 5-, 6-, 7-or 8-membered heteroaryl group; and each phenyl, naphthyl, or the 5-, 6-, 7-, or 8-membered heteroaryl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
84. The compound of any one of claims 54 to 83, or a pharmaceutically acceptable salt thereof, wherein X 2 Is phenyl or naphthyl, and each of the phenyl or naphthyl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
85. The compound of any one of claims 54 to 84, or a pharmaceutically acceptable salt thereof, wherein X 2 Is phenyl, and the phenyl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
86. The compound of any one of claims 54 to 85, or a pharmaceutically acceptable salt thereof, wherein X 2 Is naphthyl, and the naphthyl is independently optionally unsubstituted or independently optionally substituted with 3R 2x And (3) substitution.
87. The compound of any one of claims 54 to 86, or a pharmaceutically acceptable salt thereof, wherein R 2x Each of (3)Each independently selected from F, cl, -OH, -NH 2 、-CN、C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Deuterated alkynyl, cyano, (C) 1-3 Alkoxy) C 1-3 Alkyl, (C) 1-3 Alkoxy) C 1-3 Alkoxy, (C) 1-3 Hydroxyalkoxy) C 1-3 Alkoxy, 3-or 4-membered cycloalkyl, or 3-or 4-membered heterocycloalkyl; and each of which is independently optionally unsubstituted or independently optionally substituted with 1, 2 or 3-NH 2 F, cl, deuterium, -CN, -OH, -C 1-3 Alkyl or-C 1-3 Alkoxy substitution.
88. The compound of any one of claims 54 to 87, or a pharmaceutically acceptable salt thereof, wherein R 2x Each of which is independently selected from F, cl, -OH, -NH 2 -CN, methyl, ethyl, methoxy, cyclopropyl, methyl substituted with 3F, methyl substituted with 3 Cl, ethyl substituted with 3F, vinyl, ethynyl substituted with deuterium, or cyano; and each of which is independently optionally unsubstituted or independently optionally substituted with 1, 2 or 3-NH 2 F, cl, deuterium, -CN, -OH, methyl or methoxy substitution.
89. The compound of any one of claims 54 to 88, or a pharmaceutically acceptable salt thereof, wherein R 2x Independently selected from F, cl, -OH, methyl substituted with 3F, vinyl, ethynyl, or cyclopropyl; and each of which is independently optionally unsubstituted or independently optionally substituted with 3F, 3 deuterium or methyl groups.
90. The compound of any one of claims 54 to 73, or 76 to 89, or a pharmaceutically acceptable salt thereof, wherein X 3 Independently selected from H, F, cl, C 1-3 Alkyl or C 1-3 An alkoxy group.
91. The compound of any one of claims 54 to 73, or 76 to 90, or a pharmaceutically acceptable salt thereof, wherein X 3 Independently selected from H, F, cl, methyl or methoxy.
92. The compound of any one of claims 54 to 73, or 76 to 91, or a pharmaceutically acceptable salt thereof, wherein X 3 Independently selected from F.
93. The compound of any one of claims 54 to 92, or a pharmaceutically acceptable salt thereof, wherein
Figure FDA0004093773760000161
Is a single bond.
94. The compound of any one of claims 54 to 93, or a pharmaceutically acceptable salt thereof, wherein
Figure FDA0004093773760000162
Is a double bond.
95. The compound of any one of claims 54 to 73, or 24 to 89, or a pharmaceutically acceptable salt thereof, wherein 5 X is N, and the number of the X is N,
Figure FDA0004093773760000163
is a double bond; or (b) 5 X is C (R) 7 ) 2 ，
Figure FDA0004093773760000164
Is a single bond.
96. As in claim 54 to claim 73, claim 76 to claim 89, or claim 95The compound of any one of claims, or a pharmaceutically acceptable salt thereof, wherein 5 X is CR 7 ，R 7 H, F, cl, -C independently 1-3 Alkyl or substituted by 1, 2 or 3F, cl, deuterium, -OH or NH 2 substituted-C 1-3 An alkyl group.
97. The compound of any one of claims 54 to 73, 76 to 89, or 95 to 96, or a pharmaceutically acceptable salt thereof, wherein 5 X is CR 7 ，R 7 Is independently H, F, cl, methyl or is substituted with 1, 2 or 3F, cl, deuterium, -OH or NH 2 Substituted methyl.
98. The compound of any one of claims 54 to 73, 76 to 89, or 95 to 97, or a pharmaceutically acceptable salt thereof, wherein R 7 And R is 7 Together with the C atom to which they are each attached form a 3-, 4-, 5-or 6-membered cycloalkyl, 3-, 4-, 5-or 6-membered heterocycle.
99. The compound of any one of claims 54 to 73, 76 to 89, or 95 to 98, or a pharmaceutically acceptable salt thereof, wherein R 7 And R is 7 Together with the C atom to which they are each attached form a 5-or 6-membered cycloalkyl, or a 5-or 6-membered heterocycle.
100. The compound of any one of claims 54 to 73, 76 to 89, or 95 to 99, or a pharmaceutically acceptable salt thereof, wherein two R 7 Along with the two R' s 7 The C atoms to which both are attached form oxo (=o), and the oxo together with the X 2 The N atoms attached to form a 4-, 5-, or 6-membered lactam having one or two N.
101. The compound of any one of claims 54 to 73, 76 to 89, or 95 to 100, or a pharmaceutically acceptable salt thereof, wherein 5 X is N, and
Figure FDA0004093773760000171
is a double bond.
102. The compound of any one of claims 54 to 101, or a pharmaceutically acceptable salt thereof, wherein W is NR w And R is w Is H, deuterium or C 1-3 An alkyl group.
103. The compound of any one of claims 54 to 102, or a pharmaceutically acceptable salt thereof, wherein W is NR w And R is w Is H, deuterium, methyl or ethyl.
104. The compound of any one of claims 54 to 103, or a pharmaceutically acceptable salt thereof, wherein W is NR w And R is w Is H.
105. The compound of any one of claims 54 to 104, or a pharmaceutically acceptable salt thereof, wherein W is O.
106. The compound of any one of claims 54 to 105, or a pharmaceutically acceptable salt thereof, wherein R N Each of (a) is independently H, deuterium, F, cl, -NH 2 、-CN、-OH、-NHC(O)NHC 1-3 Alkyl, -NHC (O) N (C) 1-3 Alkyl group 2 、-OH、-OC(O)NHC 1-3 Alkyl, -OC (O) N (C) 1-3 Alkyl group 2 、
Figure FDA0004093773760000172
C 1-3 Alkyl NHC (O) NHC 1-3 Alkyl, -C 1-3 Alkyl NHC (O) N (C) 1-3 Alkyl group 2 、-OH、/>
Figure FDA0004093773760000173
107. The compound of any one of claims 54 to 106, or a pharmaceutically acceptable salt thereof, wherein R N Each of (a) is independently H, deuterium, F, cl, -NH 2 、NHC(O)NHMe、-NHC(O)N(Me) 2 、-OH、-OC(O)NHMe、-OC(O)N(Me) 2 、
Figure FDA0004093773760000177
-CH 2 NHC(O)NHMe、-CH 2 NHC(O)N(Me) 2 、-OH、-CH 2 OH、-CH 2 OC(O)NHMe、-CH 2 OC(O)N(-CH 2 ) 2 、
Figure FDA0004093773760000174
Methyl, methoxy or->
Figure FDA0004093773760000175
108. The compound of any one of claims 54 to 107, or a pharmaceutically acceptable salt thereof, wherein R N Each of which is independently H, deuterium, F or
Figure FDA0004093773760000176
109. The compound of any one of claims 54 to 108, or a pharmaceutically acceptable salt thereof, wherein one R N Is H, deuterium, or F; other R N Is that
Figure FDA0004093773760000181
And Y is C (R) N ) 2 。
110. The compound of any one of claims 54 to 108, or a pharmaceutically acceptable salt thereof, wherein R N Is that
Figure FDA0004093773760000182
And Y is NR N 。
111. The compound or pharmaceutically acceptable salt thereof is selected from the group consisting of: 3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo)[3.2.1]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) -pyrrolidin-2-yl) methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H)-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) A pyrido group [4 ] having a structure represented by formula,3-d]pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3-(4-((1R,5S) -8-oxa-3-azabicyclo [3.2.1]Octane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (3, 6-diazabicyclo [ 3.2.1)]Heptane-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ] ]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2) ]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1- (methyl) bolo)d 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoroNaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ] ]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyriPyrido [4,3-d]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [4,3-d]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ] ]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -8-fluoropyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d ]Pyrimidin-7-yl) -8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-7-yl) -8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl)2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-7-yl) -8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl)) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (. About.(S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-py-ridine)Alloxazin-7 a (5H) -yl-5, 5-d 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyri-dinePyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy (methoxy)Base-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d ]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- ((dimethylamino)Group) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-7 (8H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ] ]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalen-2-ol；
3- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4-(4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluormethyl)Radical) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d ]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-acetylene1-hydroxy-7-fluoro-1-naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1) ]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl-7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d ]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methylsOxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2) ]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2) ]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxy groupNaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2 ] o.2.2]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -6-Trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -6- (trifluoromethyl) pyrido [3,4-d ] pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-Di)Azabicyclo [2.2.2]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d ]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [3,4-d ]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido[3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2) ]Octane-2-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoroNaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrido [3,4-d]Pyrimidin-7 (8H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2) ]Octane-2-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2) ]Octane-2-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane (octane)-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ] ]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2) ]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-di)Azabicyclo [2.2.2]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d ]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalene-2-ol;
3- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -5-ethynyl-6-fluoronaphthalene-2-ol;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-Hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) AzoxystrobinPyrido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2-d) methoxy) pyrimido [4,5-d ] pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((S) -1- (methyl-d) 3 ) Pyrrolidin-2-yl) methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo)And [2.2.2]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d) 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrimido [4,5-d]pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-5, 5-d) 2 ) Methoxy) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- (2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy-d 2 ) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4,5-d]Pyridazin-8 (7H) -one;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ] ]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (morpholinomethyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diaza)Bicyclo [3.2.1]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -8-fluoro-2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl-d) 2 ) Cyclopropyl) methoxy-d 2 ) Pyrido [4,3-d ]]Pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d ]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (morpholinomethyl)) Cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) -6- (trifluoromethyl) pyrido [3,4-d]Pyrimidin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (((R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ((1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- (. Sub.1- (morpholinomethyl) cyclopropyl) methoxy-d 2 ) Pyrimido [4,5-d]Pyridazin-8 (7H) -one;
3- (4- (1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol;
3- (4- (1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -4-cyclopropyl-5-fluorophenol;
3- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol; or (b)
3- (4- (2, 5-diazabicyclo [2.2.2] oct-2-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl-2, 5-d 3) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -4-cyclopropyl-5-fluorophenol.
112. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
113. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1 to 53 or 111, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
114. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 54, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
115. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 54-111, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
116. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 111, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
117. A method of inhibiting KRAS G12D activity in a cell, the method comprising contacting the cell in which inhibition of KRAS G12D activity is desired with a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof.
118. A method of inhibiting KRAS G12D activity in a cell, the method comprising contacting the cell wherein inhibition of KRAS G12D activity is desired with a therapeutically effective amount of at least one compound according to any one of claims 1 to 53 or claim 111, or a pharmaceutically acceptable salt thereof.
119. A method of inhibiting KRAS G12D activity in a cell, the method comprising contacting the cell in which inhibition of KRAS G12D activity is desired with a therapeutically effective amount of at least one compound according to any one of claims 54 to 111, or a pharmaceutically acceptable salt thereof.
120. A method of inhibiting KRAS G12D activity in a cell, the method comprising contacting the cell wherein inhibition of KRAS G12D activity is desired with a therapeutically effective amount of at least one compound of claim 111 or a pharmaceutically acceptable salt thereof.
121. A method of inhibiting KRAS G12D activity in a cell, the method comprising contacting the cell wherein inhibition of KRAS G12D activity is desired with the pharmaceutical composition of any one of claims 117-111.
122. A method of treating KRAS G12D-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof.
123. A method of treating KRAS G12D-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound according to any one of claims 1 to 53 or claim 111, or a pharmaceutically acceptable salt thereof.
124. A method of treating KRAS G12D-related cancer comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound according to any one of claims 54 to 111, or a pharmaceutically acceptable salt thereof.
125. A method of treating KRAS G12D-related cancer, comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of claim 111, or a pharmaceutically acceptable salt thereof.
126. A method of treating KRAS G12D-related cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of at least one pharmaceutical composition of any one of claims 112-116, or a pharmaceutically acceptable salt thereof.
127. The method of any one of claims 117-126, wherein the therapeutically effective amount of the compound is between about 0.01 mg/kg/day and 100 mg/kg/day.
128. The method of any one of claims 117-127, wherein the therapeutically effective amount of the compound is between about 0.1 mg/kg/day and 50 mg/kg/day.
129. The method of any one of claims 122 to 128, wherein the KRAS G12D-related cancer is selected from the group consisting of: and (3) heart: sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, fibromatous hamartoma, mesothelioma; intestines and stomach: esophageal carcinoma (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric carcinoma (carcinoma, lymphoma, leiomyosarcoma), pancreatic carcinoma (ductal adenoma, insulinoma, glucagon tumor, gastrinoid tumor, angio-active intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyosarcoma); urogenital tract: kidney (adenocarcinoma, wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lymphomas); hepatoma (hepatocellular carcinoma), cholangioma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gall bladder cancer, ampulla cancer, bile duct cancer; bone: osteogenic sarcomas (osteosarcoma), fibrosarcomas, malignant fibrous histiocytomas, chondrosarcomas, ewing's sarcoma, malignant lymphomas (reticulosarcoma), multiple myeloma, malignant giant cell tumors, chordoma, osteochondral tumors (osteochondral exotoses), benign chondrias, chondroblastomas, chondromyomatoid fibromas, osteoid osteomas, and giant cell tumors; the nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, malformed osteomyelitis), meninges (meningioma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma; gynaecology: uterus (endometrial carcinoma, (serous cystic adenocarcinoma, mucinous cystic adenocarcinoma, unclassified carcinoma), granulosa sheath cell tumors, sertoli-Leydig cell tumors, asexual cell tumors, malignant teratomas), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, grape-like sarcoma, (embryonic rhabdomyosarcoma), fallopian tubes (carcinoma)); blood: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, nevi, dysplastic nevi, lymphomas, hemangiomas, cutaneous fibromas, keloids, psoriasis; adrenal gland: neuroblastoma.
130. The method of claim 129, wherein the cancer is non-small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.
131. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS G12D mutation (e.g., KRAS G12D-associated cancer); and (b) administering to the patient a therapeutically effective amount of at least one compound according to claim 1 or claim 54.
132. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS G12D mutation (e.g., KRAS G12D-associated cancer); and (b) administering to the patient a therapeutically effective amount of at least one compound according to claim 111.
133. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS G12D mutation (e.g., KRAS G12D-associated cancer); and (b) administering to the patient a therapeutically effective amount of at least one compound according to any one of claims 1 to 111.
134. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS G12D mutation (e.g., KRAS G12D-associated cancer); and (b) administering to the patient a therapeutically effective amount of at least one pharmaceutical composition according to any one of claims 112-116.
135. The method of any one of claims 131 to 134, wherein the administering is via a route selected from the group consisting of: parenteral administration, intraperitoneal administration, transdermal administration, intracardiac administration, intraventricular administration, intracranial administration, intracardiac administration, intrasynovial administration, intrathecal administration, intramuscular injection, intravitreal injection, intravenous injection, intraarterial injection, oral administration, intranasal administration, buccal administration, sublingual administration, transdermal administration, topical administration, intratracheal administration, intrarectal administration, subcutaneous administration, and topical administration.
136. The method of claim 135, wherein the administering is via intravenous injection.
137. The method of claim 135, wherein the administering is via intramuscular injection.
138. The method of claim 135, wherein the administering is via oral.
139. The method of claim 135, wherein the administering comprises utilizing a delivery device.
140. The method of claim 135, wherein the administering is via a hospital facility.
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张寅生: "氘代药物研发的过去、现在与未来", 药学进展, vol. 41, no. 12, pages 902 - 918 *

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