TW202317580A - Deuterated compounds useful as kras g12d inhibitors - Google Patents

Deuterated compounds useful as kras g12d inhibitors Download PDF

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TW202317580A
TW202317580A TW111122693A TW111122693A TW202317580A TW 202317580 A TW202317580 A TW 202317580A TW 111122693 A TW111122693 A TW 111122693A TW 111122693 A TW111122693 A TW 111122693A TW 202317580 A TW202317580 A TW 202317580A
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methoxy
diazabicyclo
pyrimidin
octane
pyrido
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海權 方
劉曉雷
楊惠
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大陸商南京燧坤智能科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

Provided are deuterated compounds of Formula (I), or Formula (I'), or a salt thereof, wherein at least one of R 1 to R 6 is D (Deuterium atom), and X 0, Y, and R is defined herein. Also provided are methods of using such compounds to modulate or inhibit the activity of KRAS G12D mutant protein, and pharmaceutical compositions comprising such compounds. These compounds are useful in the treatment of various diseases or conditions, such as cancer.

Description

用作KRAS　G12D抑制劑的氘代化合物Deuterated compounds useful as KRAS G12D inhibitors

本發明涉及作為KRAS G12D抑制劑的式(I)的氘代化合物(deuterated compound)或式(I’)的氘代化合物、或其鹽，其中R 1至R 6，它們中的至少一個是D(氘原子)，並且X 0、Y和R在本文中被定義。在本文中，式(I)的化合物或式(I’)的化合物以及包含此類化合物的藥物組合物用於治療多種紊亂(disorder)例如癌症。還描述了抑制KRAS G12D活性的方法，以及用其用於治療KRAS G12D相關的紊亂的方法，以及用於製備式(I)化合物或式(I’)化合物的方法。 The present invention relates to a deuterated compound of formula (I) or a deuterated compound of formula (I′), or a salt thereof, as a KRAS G12D inhibitor, 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, compounds of formula (I) or compounds of formula (I') and pharmaceutical compositions comprising such compounds are useful in the treatment of various disorders such as cancer. Also described are methods of inhibiting the activity of KRAS G12D, and methods of using the same for treating KRAS G12D-associated disorders, and methods of preparing compounds of formula (I) or compounds of formula (I').

Kirsten大鼠肉瘤2型病毒基因同源物(Kirsten rat sarcoma 2 viral oncogene homolog, KRAS)基因是被稱為KRAS的原癌基因(proto-oncogene)，所述原癌基因編碼小GTPase轉運蛋白(small GTPase transductor protein)。KRAS蛋白在分別經由結合至鳥苷三磷酸(GTP)和鳥苷二磷酸(GDP)的無活性形式與活性形式之間轉換(Alamgeer等人，Current Opin Pharmcol, 2013年；第13期：第394-401頁)。GTPase活化蛋白(GTPase activating proteins，GAPs)有助於通過KRAS使GTP水解，同時鳥嘌呤核苷酸交換因數(guanine nucleotide exchange factors, GAPs)催化GDP解離(Vetter等人，Science 2001年，第94期：第1299-1304頁)(K. Scheffzek等人，Science, 1997年，第277期：第333-338頁)。在生理條件下，KRAS主要是GDP結合的。在通過諸如表皮生長因數(epidermal growth factor，EGF)受體的受體酪氨酸激酶活化之後，GEFs被募集至KRAS並且引發GDP與GTP的交換。活化的KRAS與效應蛋白(effector protein)相互作用並且活化下游細胞信號轉導通路，所述下游細胞信號轉導通路包括RAF-MEK-ERK通路、PI3K-AKT-MTOR通路以及RalGDS通路，調節許多重要的細胞過程，所述細胞過程包括細胞分化、細胞生長以及細胞增殖(Rajalingam，等人，Biochim. Biophys. Acta, Mol. Cell Res.第1773期，第1177−1195頁)(McCormick等人，Curr. Opin. Biotechnol，1996年，第7期，第449–456頁)。  在受調節的KRAS迴圈中，信號傳導在GTP水解後關閉。最通常在密碼子12、密碼子13和密碼子61處使KRAS中的突變活化，損害其本身的功能或GAP介導的GTPase功能，這導致KRAS-GTP的累積，KRAS-GTP是組成型活性的(constitutively active)，並且KRAS-GTP的累積從而造成不受控制的細胞生長/增殖，不受控制的細胞生長/增殖導致腫瘤形成(tumorigenesis)和腫瘤發育(tumor development)(Cox AD等人，Small GTPases，2010年，第(1)期：第2–27頁)(Prior IA等人，Cancer Res, 2012年，第72期第(10)卷：第2457–2467頁)。所有人類腫瘤的約15%包含(harbor)突變的KRAS。在它們中，KRAS中的G12D突變最頻繁地發生並且在~45%的胰腺導管腺癌患者、13%的結腸直腸癌患者、10%的直腸癌患者、4%的非小細胞肺癌患者以及1.7%的所有小細胞肺癌患者中被發現(A. G. Stephen等人，Cancer Cell, 2014年，第25期：第272–281頁)。The Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) gene is a proto-oncogene called KRAS, which encodes a small GTPase transporter (small GTPase transducer protein). The KRAS protein switches between an inactive form and an active form via binding to guanosine triphosphate (GTP) and guanosine diphosphate (GDP), respectively (Alamgeer et al., Current Opin Pharmacol, 2013; Issue 13: Issue 394 -401 pages). GTPase activating proteins (GAPs) contribute to the hydrolysis of GTP by KRAS, while guanine nucleotide exchange factors (GAPs) catalyze the dissociation of GDP (Vetter et al., Science 2001, No. 94 : pp. 1299-1304) (K. Scheffzek et al., Science, 1997, No. 277: pp. 333-338). Under physiological conditions, KRAS is predominantly GDP-bound. Following activation by receptor tyrosine kinases such as epidermal growth factor (EGF) receptors, GEFs are recruited to KRAS and initiate the exchange of GDP for GTP. Activated KRAS interacts with effector proteins and activates downstream cell signal transduction pathways, which include RAF-MEK-ERK pathway, PI3K-AKT-MTOR pathway and RalGDS pathway, which regulate many important Cellular processes of , including cell differentiation, cell growth, and cell proliferation (Rajalingam, et al., Biochim. Biophys. Acta, Mol. Cell Res. Issue 1773, pp. 1177−1195) (McCormick et al., Curr . Opin. Biotechnol, 1996, No. 7, pp. 449–456). In the regulated KRAS loop, signaling is switched off following GTP hydrolysis. Most commonly activating mutations in KRAS at codon 12, codon 13, and codon 61, impairing its own function or GAP-mediated GTPase function, which leads to the accumulation of KRAS-GTP, which is constitutively active (constitutively active), and the accumulation of KRAS-GTP thereby causing uncontrolled cell growth/proliferation, which leads to tumorigenesis (tumorigenesis) and tumor development (tumor development) (Cox AD et al., Small GTPases, 2010, Vol. (1): pp. 2–27) (Prior IA et al., Cancer Res, 2012, Vol. 72, Vol. (10): pp. 2457–2467). About 15% of all human tumors contain (harbor) mutated KRAS. Among them, the G12D mutation in KRAS occurred most frequently and was 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 It is found in % of all small cell lung cancer patients (A. G. Stephen et al., Cancer Cell, 2014, No. 25: pp. 272–281).

儘管靶向KRAS G12C突變存在某些突破，例如Amgene的AMG 510(Sotorasib)、Mirati的MRTX 849，並且近些年更多在研發中(D-1553、JAB-21822、GH35,、GFH925、BPI-421286)，然而抑制KRAS活性的化合物仍然是高度合意的。高頻率的KRAS G12D突變使得其為理想的藥物靶標，但是靶向KRAS G12D突變型KRAS的有效藥物仍然未進入臨床試驗。Although there have been some breakthroughs targeting the KRAS G12C mutation, such as Amgene's AMG 510 (Sotorasib), Mirati's MRTX 849, and more in development in recent years (D-1553, JAB-21822, GH35, GFH925, BPI- 421286), however compounds that inhibit KRAS activity are still highly desirable. The high frequency of KRAS G12D mutation makes it an ideal drug target, but effective drugs targeting KRAS G12D mutant KRAS have not yet entered clinical trials.

因此，對於開發用於KRAS G12D介導的癌症中具有充分的效力和安全概況(safety profile)的靶向KRAS G12D的新的治療劑存在需求。本發明涉及一類新的氘代化合物，所述氘代化合物直接結合至KRAS G12D並且阻斷其活性。提供這些氘代化合物以用作具有對其成藥性(drugability)重要的合意的穩定性、生物利用度、治療指數(therapeutic index)和毒性值(toxicity values)的藥物。Therefore, there is a need for the development of new therapeutic agents targeting KRAS G12D with sufficient potency and safety profile for use in KRAS G12D-mediated cancers. The present invention relates to a new class of deuterated compounds that directly bind to KRAS G12D and block its activity. These deuterated compounds are provided for use as drugs with desirable stability, bioavailability, therapeutic index and toxicity values important for their drugability.

動力學同位素效應(Kinetic isotope effect，KIE)使得C-D鍵比C-H鍵強6-10倍(Chemical Science, 2012年，第3期，第3231-3236頁；J. Med. Chem., 2014年，第57期，第3595-3611頁)。氘代化合物的不含D的化合物包含被一個或更多個C-D鍵取代的一個或更多個C-H鍵作為薄弱代謝位點(soft metabolite spot)，氘代化合物將增加其對代謝的抗性(resistance)並且因此改進DMPK(藥物代謝和藥代動力學)性質並且用於增加化合物的半衰期，所述DMPK性質涉及吸收、分佈、代謝和分泌(ADME)，所述化合物被施用至哺乳動物，特別地人類(Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 第5期，第12卷：第524-527頁(1984年))。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, No. 3, pp. 3231-3236; J. Med. Chem., 2014, p. 57, pp. 3595-3611). The D-free compound of the deuterated compound contains one or more C-H bonds replaced by one or more C-D bonds as a weak metabolic site (soft metabolite spot), and the deuterated compound will increase its resistance to metabolism ( resistance) and thus improve the DMPK (Drug Metabolism and Pharmacokinetics) properties involved in absorption, distribution, metabolism and secretion (ADME) and are used to increase the half-life of compounds administered to mammals, especially (Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. No. 5, Vol. 12: pp. 524-527 (1984)).

發明概述Summary of the invention

本公開內容涉及式(I)的氘代化合物或式(I’)的氘代化合物、包含式(I)的部分或式(I’)的部分的PROTAC化合物、或其鹽，其中R 1至R 6，它們中的至少一個是D(氘原子)，所述式(I)的氘代化合物或式(I’)的氘代化合物用作KRAS G12D活性的調節劑。 The present disclosure relates to a deuterated compound of formula (I) or a deuterated compound of formula (I′), a PROTAC compound comprising a moiety of formula (I) or a moiety of formula (I′), or a salt thereof, wherein R to R 6 , at least one of which is D (deuterium atom), the deuterated compound of formula (I) or the deuterated compound of formula (I′) is used as a modulator of KRAS G12D activity.

本公開內容還涉及藥物組合物，所述藥物組合物包含前面提及的式(I)氘代化合物或式(I’)的氘代化合物、包含式(I)的部分或式(I’)的部分的PROTAC化合物、和/其藥學上可接受的鹽；以及藥學上可接受的載體(carrier)。The present disclosure also relates to pharmaceutical compositions comprising the aforementioned deuterated compounds of formula (I) or deuterated compounds of formula (I'), moieties comprising formula (I) or formula (I') Part of the PROTAC compound, and/or its pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier (carrier).

本公開內容還涉及治療與KRAS G12D的活性相關的疾病或紊亂的方法，該方法包括：確定受試者是否具有KRAS G12D突變；以及如果受試者被確定為具有KRAS G12D突變，然後向受試者施用治療有效量的式(I)的化合物或式(I’)的化合物、包含式(I)的部分或式(I’)的部分的PROTAC化合物、和/或其藥學上可接受的鹽，或其藥物組合物。The present disclosure also relates to a method of treating a disease or disorder associated with KRAS G12D activity, the method comprising: determining whether a subject has a KRAS G12D mutation; The patient is administered a therapeutically effective amount of a compound of formula (I) or a compound of formula (I′), a PROTAC compound comprising a part of formula (I) or a part of formula (I′), and/or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof.

本公開內容還涉及用於製備式(I)的化合物或式(I’)的化合物和/或其鹽的工藝和中間體。The present disclosure also relates to processes and intermediates for the preparation of compounds of formula (I) or compounds of formula (I') and/or salts thereof.

本公開內容還涉及用於治療的式(I)的化合物或式(I’)的化合物、包含式(I)的部分或式(I’)的部分的PROTAC化合物、和/或其藥學上可接受的鹽。The present disclosure also relates to 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 its pharmaceutically acceptable Accepted salt.

本公開內容還涉及式(I)的化合物或式(I’)的化合物、和/或其藥學上可接受的鹽在製造用於治療或預防諸如癌症的KRAS G12D相關紊亂的藥物中的用途。作為單獨的劑(agent)或與其他活性成分組合。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 sole agent or in combination with other active ingredients.

當前公開的治療性化合物，其R 1基團至R 6基團中的至少一個，式(I)的化合物或式(I’)的化合物中的取代基，是D。 In the presently disclosed therapeutic compounds, at least one of the R1 to R6 groups, a substituent in a compound of formula (I) or a compound of formula (I′), is D.

本公開內容涉及至少一種式(I)的化合物或式(I’)的化合物：

Figure 02_image005
或
Figure 02_image007
The present disclosure relates to at least one compound of formula (I) or compound of formula (I′):
Figure 02_image005
or
Figure 02_image007

其中：in:

m選自1至4的整數；m is an integer selected from 1 to 4;

X 0是H、D、鹵素、C 1-4烷基、C 1-4羥基烷基；其中的每個可以被3元至7元雜環取代，所述3元至7元雜環具有一個或更多個獨立地選自N、O或S的雜原子，並且雜原子中的至少一個是N，所述雜原子被直接連接至C 1-4烷基或C 1-4羥基烷基的C原子中的一個；3元至7元雜環另外任選地被-CH 3或-N(CH 3) 2取代； X is H, D, halogen, C 1-4 alkyl, C 1-4 hydroxyalkyl; each of which may be substituted by a 3- to 7-membered heterocycle having one or more heteroatoms independently selected from N, O or S, and at least one of the heteroatoms is N, said heteroatoms are directly attached to C 1-4 alkyl or C 1-4 hydroxyalkyl One of the C atoms; 3-7 membered heterocycles are additionally optionally substituted by -CH 3 or -N(CH 3 ) 2 ;

Y是C或N；Y is C or N;

R 1、R 2獨立地選自H、D、-CH 3；並且R 1、R 2和R 1和R 2被附接至的C原子可以形成3元至5元環烷基、3元至5元雜環烷基； R 1 , R 2 are independently selected from H, D, -CH 3 ; and R 1 , R 2 and the C atom to which R 1 and R 2 are attached may form a 3- to 5-membered cycloalkyl group, a 3- to 5-membered cycloalkyl group, a 3-membered to 5-membered heterocycloalkyl;

R 3是H、D、C 1-3烷基、C 1-3羥基烷基；其中的每個可以被3元至7元雜環取代，所述3元至7元雜環具有一個或更多個獨立地選自N、O或S的雜原子，並且雜原子中的至少一個是N，所述雜原子被直接連接至C 1-4烷基或C 1-4羥基烷基的C原子中的一個；3元至7元雜環另外任選地被-CH 3或-N(CH 3) 2取代； R 3 is H, D, C 1-3 alkyl, C 1-3 hydroxyalkyl; each of which may be substituted by a 3- to 7-membered heterocycle having one or more A plurality of heteroatoms independently selected from N, O or S, and at least one of the heteroatoms is N, said heteroatoms are directly attached to the C atom of C 1-4 alkyl or C 1-4 hydroxyalkyl One of; 3-membered to 7-membered heterocycle is additionally optionally substituted by -CH 3 or -N(CH 3 ) 2 ;

R 1至R 6，它們中的至少一個，是D； R 1 to R 6 , at least one of them, is D;

R 4至R 6選自選自H、-OH、-NH 2，D和F； R 4 to R 6 are selected from H, -OH, -NH 2 , D and F;

R獨立地是：

Figure 02_image009
、
Figure 02_image011
、
Figure 02_image013
或
Figure 02_image015
R independently is:
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
or
Figure 02_image015

其中：in:

n是0、1或2；n is 0, 1 or 2;

q是0至3的整數；q is an integer from 0 to 3;

X 1是H、-CH 2CN、C 1-3烷基、C 1-3烷氧基； X 1 is H, -CH 2 CN, C 1-3 alkyl, C 1-3 alkoxy;

X 2是6元至10元芳基或5元至10元雜芳基，所述6元至10元芳基選自苯基或萘基，其中苯基或萘基任選地被一個或更多個R 2x取代；所述5元至10元雜芳基任選地被一個或更多個R 2x取代； X is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, the 6- to 10-membered aryl group is selected from phenyl or naphthyl, wherein phenyl or naphthyl is optionally replaced by one or more A plurality of R 2x is substituted; the 5-10 membered heteroaryl is optionally substituted by one or more R 2x ;

R 2x獨立地選自F、Cl、-OH、-NH 2、C 1-3烷基、C 1-3羥基烷基、C 1-3烷氧基、C 1-3鹵代烷基、C 2-4烯基、C 2-4炔基、C 2-4氘代炔基、氰基、(C 1-3烷氧基)C 1-3烷基、(C 1-3烷氧基)C 1-3烷氧基、(C 1-3羥基烷氧基)C 1-3烷氧基； R 2x is 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 alkoxy;

X 3獨立地選自F、Cl、C 1-3烷基或C 1-3烷氧基； X 3 is independently selected from F, Cl, C 1-3 alkyl or C 1-3 alkoxy;

“

Figure 02_image017
”是單鍵或雙鍵； "
Figure 02_image017
” is a single or double bond;

5X是N或CR 7，其中 5 X is N or CR 7 where

當 5X是N時，“

Figure 02_image017
”是雙鍵； When 5 X is N, "
Figure 02_image017
" is a double bond;

當 5X是CR 7時，“

Figure 02_image017
”是單鍵或雙鍵； When 5 X is CR 7 ,"
Figure 02_image017
” is a single or double bond;

R 7是H、鹵素、-CH 3或-CF 3；其中兩個R 7連同兩個R 7被附接至的C原子可以形成氧代(=O)，兩個R 7連同環上的N原子形成內醯胺；3元至6元環烷基、3元至6元雜環； R 7 is H, halogen, -CH 3 or -CF 3 ; wherein two R 7 together with the C atom to which the two R 7 are attached may form oxo (=O), and the two R 7 together with the N on the ring Atoms form lactamides; 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycles;

W是O或NR w，其中R w是H、C 1-3烷基。 W is O or NR w , wherein R w is H, C 1-3 alkyl.

在一種實施方案中，提供了式(I)的氘代化合物或其鹽，所述氘代化合物具有式(II-a)的結構，其中n、W、X 0至X 3、R 1至R 6在第一方面中被定義：

Figure 02_image019
。 In one embodiment, there is provided a deuterated compound of formula (I) or a salt thereof, said deuterated compound having a structure of formula (II-a), wherein n, W, X 0 to X 3 , R 1 to R 6 is defined in the first aspect:
Figure 02_image019
.

在一種實施方案中，提供了式(I)的氘代化合物或其鹽，所述氘代化合物具有式(II-b)的結構，其中W、X 0至X 3、R 1至R 6在第一方面中被定義：

Figure 02_image021
。 In one embodiment, there is provided a deuterated compound of formula (I) or a salt thereof, said deuterated compound having a structure of formula (II-b), wherein W, X 0 to X 3 , R 1 to R 6 are in The first aspect is defined as:
Figure 02_image021
.

在另一種實施方案中，提供了式(I)的氘代化合物或其鹽，所述氘代化合物具有式(III-a)的結構，其中m、n、W、X 0至X 3、Y、R 1至R 5在第一方面中被定義：

Figure 02_image023
。 In another embodiment, there is provided a deuterated compound of formula (I) or a salt thereof, said deuterated compound having the structure of formula (III-a), wherein m, n, W, X 0 to X 3 , Y , R 1 to R 5 are defined in the first aspect:
Figure 02_image023
.

在另一種實施方案中，提供了式(I)的氘代化合物或其鹽，所述氘代化合物具有式(III-b)的結構，其中m、W、X 0至X 3、R 1至R 5在第一方面中被定義：

Figure 02_image025
。 In another embodiment, there is provided a deuterated compound of formula (I) or a salt thereof, said deuterated compound having a structure of formula (III-b), wherein m, W, X 0 to X 3 , R 1 to R 5 is defined in the first aspect:
Figure 02_image025
.

在另一種實施方案中，提供了式(I)的氘代化合物或其鹽，所述氘代化合物具有式(IV-a)的結構，其中n、q、“

Figure 02_image017
”、W、X 0至X 2、 5X、R 1至R 7在第一方面中被定義：
Figure 02_image027
。 In another embodiment, there is provided a deuterated compound of formula (I) or a salt thereof, said deuterated compound having a structure of formula (IV-a), wherein n, q, "
Figure 02_image017
”, W, X 0 to X 2 , 5 X, R 1 to R 7 are defined in the first aspect:
Figure 02_image027
.

在另一種實施方案中，提供了式(I)的氘代化合物或其鹽，所述氘代化合物具有式(IV-b)的結構，其中q、“

Figure 02_image017
”、W、X 0至X 2、 5X和R 1至R 7在第一方面中被定義：
Figure 02_image029
。 In another embodiment, there is provided a deuterated compound of formula (I) or a salt thereof, said deuterated compound having a structure of formula (IV-b), wherein q, "
Figure 02_image017
”, W, X 0 to X 2 , 5 X and R 1 to R 7 are defined in the first aspect:
Figure 02_image029
.

在另一種實施方案中，提供了式(I)的氘代化合物或其鹽，所述氘代化合物具有式(V-a)的結構，其中m、n、q、“

Figure 02_image017
”、W、X 0至X 2、 5X、R 1至R 5在第一方面中被定義：
Figure 02_image031
In another embodiment, there is provided a deuterated compound of formula (I), or a salt thereof, said deuterated compound having a structure of formula (Va), wherein m, n, q, "
Figure 02_image017
”, W, X 0 to X 2 , 5 X, R 1 to R 5 are defined in the first aspect:
Figure 02_image031

在另一種實施方案中，提供了式(I)的氘代化合物或其鹽，所述氘代化合物具有式(V-b)的結構，其中m、q、“

Figure 02_image017
”、W、X 0至X 2、 5X、R 1至R 5在第一方面中被定義：
Figure 02_image033
。 In another embodiment, there is provided a deuterated compound of formula (I), or a salt thereof, said deuterated compound having a structure of formula (Vb), wherein m, q, "
Figure 02_image017
”, W, X 0 to X 2 , 5 X, R 1 to R 5 are defined in the first aspect:
Figure 02_image033
.

詳細描述A detailed description

在一個方面中，本發明涉及至少一種式(I)的化合物，以及包含式(I)的部分的PROTAC化合物

Figure 02_image005
In one aspect, the invention relates to at least one compound of formula (I), and PROTAC compounds comprising moieties of formula (I)
Figure 02_image005

或其藥學上可接受的鹽、前驅藥、溶劑化物、水合物、互變異構體和異構體，or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers thereof,

其中：in:

X 0是H、氘、鹵素、OH、NH 2、CN、C 1-6烷基、C 1-6羥基烷基或C 1-6烷氧基；並且其中的每個可以獨立地任選地是未被取代的或獨立地任選地被3元至7元雜環取代，所述3元至7元雜環具有一個或更多個獨立地選自N、O或S的雜原子，並且雜原子中的至少一個是N，所述雜原子被直接連接至C 1-6烷基或C 1-6羥基烷基的C原子中的一個；3元至7元雜環另外任選地被-CH 3或-N(CH 3) 2取代； X O is H, deuterium, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 alkoxy; and each of which can be independently optionally is unsubstituted or independently optionally substituted with a 3- to 7-membered heterocycle having one or more heteroatoms independently selected from N, O, or S, and At least one of the heteroatoms is N which is directly attached to one of the C atoms of a C1-6 alkyl or C1-6 hydroxyalkyl; a 3- to 7-membered heterocycle is additionally optionally -CH 3 or -N(CH 3 ) 2 substitution;

R 1和R 2中的每個獨立地選自H、氘、鹵素、-NH 2、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、鹵素、-NH 2、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基取代； Each of R 1 and R 2 is independently selected from H, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkyl or -C 1-6 alkoxy, and each of them are independently optionally unsubstituted or independently optionally substituted by deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkyl or -C 1-6 alkoxy;

R 3和R 4中的每個獨立地選自H、氘、鹵素、-NH 2、-CN、-OH、-C 1-4烷基或-C 1-4烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、鹵素、-NH 2、-NHC(O)NHC 1-6烷基、-NHC(O)N(C 1-6烷基) 2、-OH、-OC(O)NHC 1-6烷基、-OC(O)N(C 1-6烷基) 2、

Figure 02_image036
、-C 1-6烷基或-C 1-6烷氧基取代； Each of R 3 and R 4 is independently selected from H, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-4 alkyl or -C 1-4 alkoxy, and each of them independently optionally unsubstituted or independently optionally replaced by deuterium, halogen, -NH 2 , -NHC(O)NHC 1-6 alkyl, -NHC(O)N(C 1-6 alkane base) 2 , -OH, -OC(O)NHC 1-6 alkyl, -OC(O)N(C 1-6 alkyl) 2 ,
Figure 02_image036
, -C 1-6 alkyl or -C 1-6 alkoxy;

R 5和R 6中的每個獨立地選自H、氘、鹵素、-NH 2、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、鹵素、-NH 2、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基取代； Each of R 5 and R 6 is independently selected from H, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkyl or -C 1-6 alkoxy, and each of them are independently optionally unsubstituted or independently optionally substituted by deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkyl or -C 1-6 alkoxy;

並且R 1、R 2、R 3、R 4、R 5和R 6中的至少一個是氘； and at least one of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is deuterium;

R獨立地是：

Figure 02_image009
、
Figure 02_image011
、
Figure 02_image040
或
Figure 02_image015
R independently is:
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image040
or
Figure 02_image015

其中：in:

n是0、1、2或3；n is 0, 1, 2 or 3;

q是0、1、2或3；q is 0, 1, 2 or 3;

X 1是H、-CH 2CN、C 1-6 烷基或C 1-6烷氧基； X 1 is H, -CH 2 CN, C 1-6 alkyl or C 1-6 alkoxy;

X 2是6元至10元芳基或5元至10元雜芳基；並且6元至10元芳基或5元至10元雜芳基中的每個獨立地任選地是未被取代的或獨立地任選地被一個或更多個R 2x取代； X is 6-10 membered aryl or 5-10-membered heteroaryl; and each of the 6-10-membered aryl or 5-10-membered heteroaryl is independently optionally unsubstituted or independently optionally substituted with one or more R 2x ;

R 2x中的每個獨立地選自鹵素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6羥基烷基、C 1-6烷氧基、C 1-6鹵代烷基、C 2-6烯基、C 2-6炔基、C 2-6氘代炔基、氰基、(C 1-6烷氧基)C 1-6烷基、(C 1-6烷氧基)C 1-6烷氧基、(C 1-6羥基烷氧基)C 1-6烷氧基、3元至7元環烷基或3元至7元雜環烷基；並且其中的每個獨立地任選地是未被取代的或獨立地任選地被一個或更多個-NH 2、鹵素、氘、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基取代； Each of R 2x is independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkane Base, 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 alkane Oxygen) C 1-6 alkoxy, (C 1-6 hydroxyalkoxy) C 1-6 alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; and wherein Each of is independently optionally unsubstituted or independently optionally replaced by one or more -NH 2 , halogen, deuterium, -CN, -OH, -C 1-6 alkyl or -C 1 -6 alkoxy substitution;

X 3獨立地選自H、鹵素、C 1-6烷基或C 1-6烷氧基； X is independently selected from H, halogen, C 1-6 alkyl or C 1-6 alkoxy;

“

Figure 02_image017
”是單鍵或雙鍵； "
Figure 02_image017
” is a single or double bond;

5X是N或CR 7，其中 5 X is N or CR 7 where

當 5X是N或 5X是CR 7時，“

Figure 02_image017
”是雙鍵； When 5 X is N or 5 X is CR 7 ,"
Figure 02_image017
" is a double bond;

當 5X是C(R 7) 2或 5X是NR 7時，“

Figure 02_image017
”是單鍵； When 5 X is C(R 7 ) 2 or 5 X is NR 7 , "
Figure 02_image017
" is a single key;

R 7獨立地是H、鹵素、-C 1-6烷基或被一個或更多個鹵素、氘、-OH或NH 2取代的-C 1-6烷基；或 R is independently H, halogen, -C 1-6 alkyl, or -C 1-6 alkyl substituted by one or more halogen, deuterium, -OH or NH 2 ; or

兩個R 7連同兩個R 7兩者均被附接至的C原子形成氧代(=O)，此處氧代連同X 2被附接至的N原子形成內醯胺，或 two R 's together with the C atom to which both R's are attached form oxo (=0), where oxo together with the N atom to which X 's are attached form a lactam, or

R 7和R 7連同它們各自被附接至的C原子形成3元至6元環烷基、3元至6元雜環；或 R7 and R7 , together with the C atom to which they are each attached, form a 3-6 membered cycloalkyl, 3-6 membered heterocycle; or

W是O或NR w，並且R w是H、氘或C 1-6烷基。 W is O or NRw , and Rw is H, deuterium or C1-6 alkyl.

在某些式(I)的實施方案中，X 0是H、氘、F、Cl、OH、NH 2、CN、C 1-3烷基、C 1-3羥基烷基或C 1-3烷氧基，並且其中的每個可以獨立地任選地是未被取代的或獨立地任選地被3元至7元雜環取代，所述3元至7元雜環具有一個或更多個獨立地選自N、O或S的雜原子，並且雜原子中的至少一個是N，所述雜原子被直接連接至C 1-3烷基或C 1-3羥基烷基的C原子中的一個；3元至7元雜環另外任選地被-CH 3或-N(CH 3) 2取代。 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 alkane Oxy, and each of which may be independently optionally unsubstituted or independently optionally substituted with a 3- to 7-membered heterocycle having one or more A heteroatom independently selected from N, O or S, and at least one of the heteroatoms is N, said heteroatom being directly attached to one of the C atoms of a C 1-3 alkyl or C 1-3 hydroxyalkyl a; 3- to 7-membered heterocycle is additionally optionally substituted with -CH3 or -N( CH3 ) 2 .

在某些式(I)的實施方案中, X 0是H、氘、F、Cl、OH、NH 2、CN、甲基或甲氧基。 In certain embodiments of formula (I), X 0 is H, deuterium, F, Cl, OH, NH 2 , CN, methyl or methoxy.

在某些式(I)的實施方案中，其中X 0是H。 In certain embodiments of formula (I), wherein X 0 is H.

在某些式(I)的實施方案中，R 1和R 2中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基取代。 In certain embodiments of formula (I), each of R and R 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 replaced by deuterium, F, Cl, -NH 2 , -CN, -OH, -C 1-3 alkyl or -C 1-3 alkoxy substituted.

在某些式(I)的實施方案中，R 1和R 2中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基取代。 In certain embodiments of formula (I), each of R and R is independently selected from H, deuterium, F, Cl, -NH2 , -CN, -OH, methyl or methoxy, and each of which is independently optionally unsubstituted or independently optionally substituted with deuterium, F, Cl, -NH2 , -CN, -OH, methyl or methoxy.

在某些式(I)的實施方案中，R 1和R 2中的每個獨立地選自H或氘。 In certain embodiments of formula (I), each of R and R is independently selected from H or deuterium.

在某些式(I)的實施方案中，R 3和R 4中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、-NHC(O)NHC 1-3烷基、-NHC(O)N(C 1-3烷基) 2、-OC(O)NHC 1-3烷基、-CH 2OC(O)N(C 1-3烷基) 2、

Figure 02_image036
、-C 1-3烷基或-C 1-3烷氧基取代。 In certain embodiments of formula (I), each of R and R 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 replaced by deuterium, F, Cl, -NH 2 , -CN, -OH, -NHC (O)NHC 1-3 alkyl, -NHC(O)N(C 1-3 alkyl) 2 , -OC(O)NHC 1-3 alkyl, -CH 2 OC(O)N(C 1- 3 alkyl) 2 ,
Figure 02_image036
, -C 1-3 alkyl or -C 1-3 alkoxy.

在某些式(I)的實施方案中，R 3和R 4中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、-CH 2NHC(O)NHMe 、-CH 2NHC(O)N(Me) 2、-OH、-CH 2OH、-CH 2OC(O)NHMe、-CH 2OC(O)N(Me) 2、

Figure 02_image044
、甲基或甲氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、NHC(O)NHMe、-NHC(O)N(Me) 2、-OH、-OC(O)NHMe、-OC(O)N(Me)2、
Figure 02_image036
、甲基或甲氧基取代。 In certain embodiments of formula (I), each of R and R is independently selected from H, deuterium, F, Cl, -NH2 , -CN, -OH, -CH2NHC (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 02_image044
, methyl or methoxy, and each of which is independently optionally unsubstituted or independently optionally replaced by deuterium, F, Cl, -NH 2 , NHC(O)NHMe, -NHC(O )N(Me) 2 , -OH, -OC(O)NHMe, -OC(O)N(Me)2,
Figure 02_image036
, methyl or methoxy substitution.

在某些式(I)的實施方案中，R 3和R 4中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、-CH 2NHC(O)NHMe 、-CH 2NHC(O)N(Me) 2、-OH、-CH 2OH、-CH 2OC(O)NHMe、-CH 2OC(O)N(Me) 2、

Figure 02_image044
、甲基或甲氧基。 In certain embodiments of formula (I), each of R and R is independently selected from H, deuterium, F, Cl, -NH2 , -CN, -OH, -CH2NHC (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 02_image044
, methyl or methoxy.

在某些式(I)的實施方案中，R 3和R 4中的每個獨立地選自H或氘。 In certain embodiments of formula (I), each of R and R is independently selected from H or deuterium.

在某些式(I)的實施方案中，R 5和R 6中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基取代。 In certain embodiments of formula (I), each of R and R 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 replaced by deuterium, F, Cl, -NH 2 , -CN, -OH, -C 1-3 alkyl or -C 1-3 alkoxy substituted.

在某些式(I)的實施方案中，R 5和R 6中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基取代。 In certain embodiments of formula (I), each of R and R 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 substituted with deuterium, F, Cl, -NH2 , -CN, -OH, methyl or methoxy.

在某些式(I)的實施方案中，R 5和R 6中的每個獨立地選自H、氘、OH或F。 In certain embodiments of formula (I), each of R and R is independently selected from H, deuterium, OH or F.

在某些式(I)的實施方案中，R 1、R 2、R 3、R 4、R 5和R 6中的至少一個是氘；並且R 5是氘。 In certain embodiments of formula (I), at least one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is deuterium; and R 5 is deuterium.

在某些式(I)的實施方案中，R 1、R 2、R 3、R 4、R 5和R 6中的至少一個是氘；並且R 6是氘。 In certain embodiments of formula (I), at least one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is deuterium; and R 6 is deuterium.

在某些式(I)的實施方案中，R 1、R 2、R 3、R 4、R 5和R 6中的至少兩個是氘；並且R 1和R 2兩者均是氘。 In certain embodiments of formula (I), at least two of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are deuterium; and both R 1 and R 2 are deuterium.

在某些式(I)的實施方案中，R 1、R 2、R 3、R 4、R 5和R 6中的至少兩個是氘；並且R 3和R 4兩者均是氘。 In certain embodiments of formula (I), at least two of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are deuterium; and both R 3 and R 4 are deuterium.

在某些式(I)的實施方案中，R 1、R 2、R 3、R 4、R 5和R 6中的至少三個是氘；並且R 1和R 2兩者均是氘，並且R 5是氘或R 6是氘。 In certain embodiments of formula (I), at least three of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are deuterium; and both R 1 and R 2 are deuterium, and R5 is deuterium or R6 is deuterium.

在某些式(I)的實施方案中，R 1、R 2、R 3、R 4、R 5和R 6中的至少三個是氘；並且R 3和R 4是氘，並且R 5是氘或R 6是氘。 In certain embodiments of formula (I), at least three of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are deuterium; and R 3 and R 4 are deuterium, and R 5 is Deuterium or R 6 is deuterium.

在某些式(I)的實施方案中，R 1、R 2、R 3、R 4、R 5和R 6中的至少四個是氘；並且R 1和R 2兩者均是氘，並且R 3和R 4兩者均是氘。 In certain embodiments of formula (I), at least four of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are deuterium; and R 1 and R 2 are both deuterium, and Both R3 and R4 are deuterium.

在某些式(I)的實施方案中，R 1、R 2、R 3、R 4、R 5和R 6中的至少五個是氘；並且R 1和R 2兩者均是氘，並且R 3和R 4兩者均是氘，並且R 5是氘或R 6是氘。 In certain embodiments of formula (I), at least five of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are deuterium; and both R 1 and R 2 are deuterium, and Both R3 and R4 are deuterium, and either R5 is deuterium or R6 is deuterium.

在某些式(I)的實施方案中，R獨立地是：

Figure 02_image009
。 In certain embodiments of formula (I), R is independently:
Figure 02_image009
.

在某些式(I)的實施方案中，R獨立地是：

Figure 02_image011
。 In certain embodiments of formula (I), R is independently:
Figure 02_image011
.

在某些式(I)的實施方案中，R獨立地是：

Figure 02_image040
。 In certain embodiments of formula (I), R is independently:
Figure 02_image040
.

在某些式(I)的實施方案中，R獨立地是：

Figure 02_image015
。 In certain embodiments of formula (I), R is independently:
Figure 02_image015
.

在某些式(I)的實施方案中，n是2。 In certain embodiments of formula (I), n is 2.

在某些式(I)的實施方案中，X 1是H、-CH 2CN、C 1-3烷基或C 1-3烷氧基。 In certain embodiments of formula (I), X 1 is H, —CH 2 CN, C 1-3 alkyl, or C 1-3 alkoxy.

在某些式(I)的實施方案中，X 1是H、-CH 2CN、甲基或甲氧基。 In certain embodiments of formula (I), X1 is H, -CH2CN , methyl or methoxy.

在某些式(I)的實施方案中，X 1是H。 In certain embodiments of formula (I), X is H.

在某些式(I)的實施方案中，X 2是苯基、萘基或5元雜芳基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基或10元雜芳基；並且苯基、萘基或5元至10元雜芳基中的每個獨立地任選地是未被取代的或獨立地任選地被1個R 2x、2個R 2x或3個R 2x取代。 In certain embodiments of formula (I), X 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 replaced by 1 R 2x , 2 R 2x or 3 R 2x substitutions.

在某些式(I)的實施方案中，X 2是苯基、萘基或5元雜芳基、6元雜芳基、7元雜芳基或8元雜芳基；並且苯基、萘基或5元雜芳基、6元雜芳基、7元雜芳基或8元雜芳基中的每個獨立地任選地是未被取代的或獨立地任選地被3個R 2x取代。 In certain embodiments of formula (I), X is phenyl, naphthyl, or 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, or 8-membered heteroaryl; and phenyl, naphthalene or each of the 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, or 8-membered heteroaryl is independently optionally unsubstituted or independently optionally replaced by 3 R 2x replace.

在某些式(I)的實施方案中，X 2是苯基或萘基，並且苯基或萘基中的每個獨立地任選地是未被取代的或獨立地任選地被3個R 2x取代。 In certain embodiments of formula (I), X is phenyl or naphthyl, and each of phenyl or naphthyl is independently optionally unsubstituted or independently optionally replaced by 3 R 2x substituted.

在某些式(I)的實施方案中，X 2是苯基，並且苯基獨立地任選地是未被取代的或獨立地任選地被3個R 2x取代。 In certain embodiments of formula (I), X is phenyl, and phenyl is independently optionally unsubstituted or independently optionally substituted with 3 R 2x .

在某些式(I)的實施方案中，X 2是萘基，並且萘基獨立地任選地是未被取代的或獨立地任選地被3個R 2x取代。 In certain embodiments of formula (I), X is naphthyl, and naphthyl is independently optionally unsubstituted or independently optionally substituted with 3 R 2x .

在某些式(I)的實施方案中，R 2x中的每個獨立地選自F、Cl、-OH、-NH 2、-CN、C 1-3烷基、C 1-3羥基烷基、C 1-3烷氧基、C 1-3鹵代烷基、C 2-4烯基、C 2-4炔基、C 2-4氘代炔基、氰基、(C 1-3烷氧基)C 1-3烷基、(C 1-3烷氧基)C 1-3烷氧基、(C 1-3羥基烷氧基)C 1-3烷氧基、3元或4元環烷基、或3元或4元雜環烷基；並且其中的每個獨立地任選地是未被取代的或獨立地任選地被1個、2個或3個-NH 2、F、Cl、氘、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基取代。 In certain embodiments of formula (I), each of R 2x 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 cycloalkane or 3- or 4-membered heterocycloalkyl; and each of which is independently optionally unsubstituted or independently optionally replaced by 1, 2 or 3 -NH 2 , F, Cl , deuterium, -CN, -OH, -C 1-3 alkyl or -C 1-3 alkoxy substitution.

在某些式(I)的實施方案中，R 2x中的每個獨立地選自F、Cl、-OH、-NH 2、-CN、甲基、乙基、甲氧基、被3個F取代的甲基、被3個Cl取代的甲基、被3個F取代的乙基、乙烯基、乙炔基、被氘取代的乙炔基、或氰基、3元環烷基、或3元雜環烷基；並且其中的每個獨立地任選地是未被取代的或獨立地任選地被1個、2個或3個-NH 2、F、Cl、氘、-CN、-OH、甲基或甲氧基取代。 In certain embodiments of formula (I), each of R 2x is independently selected from F, Cl, -OH, -NH 2 , -CN, methyl, ethyl, methoxy, 3 F Substituted methyl, methyl substituted by 3 Cl, ethyl substituted by 3 F, vinyl, ethynyl, ethynyl substituted by deuterium, or cyano, 3-membered cycloalkyl, or 3-membered hetero Cycloalkyl; and each of which is independently optionally unsubstituted or independently optionally replaced by 1, 2 or 3 -NH 2 , F, Cl, deuterium, -CN, -OH, Methyl or methoxy substitution.

在某些式(I)的實施方案中，R 2x中的每個獨立地選自F、Cl、-OH、甲基、被3個F取代的甲基、乙烯基、乙炔基或環丙基；並且其中的每個獨立地任選地是未被取代的或獨立地任選地被3個F、3個氘或甲基取代。 In certain embodiments of formula (I), each of R is independently selected from F, Cl, -OH, methyl, methyl substituted with 3 F, vinyl, ethynyl, or cyclopropyl and each of which is independently optionally unsubstituted or independently optionally substituted with 3 F, 3 deuterium or methyl.

在某些式(I)的實施方案中，X 3獨立地選自H、F、Cl、C 1-3烷基或C 1-3烷氧基。 In certain embodiments of formula (I), X 3 is independently selected from H, F, Cl, C 1-3 alkyl or C 1-3 alkoxy.

在某些式(I)的實施方案中，X 3獨立地選自H、F、Cl、甲基或甲氧基。 In certain embodiments of formula (I), X is independently selected from H, F, Cl, methyl or methoxy.

在某些式(I)的實施方案中，X 3獨立地選自F。 In certain embodiments of formula (I), X3 is independently selected from F.

在某些式(I)的實施方案中，“

Figure 02_image017
”是單鍵。 In certain embodiments of formula (I), "
Figure 02_image017
" is a single key.

在某些式(I)的實施方案中，“

Figure 02_image017
”是雙鍵。 In certain embodiments of formula (I), "
Figure 02_image017
" is a double bond.

在某些式(I)的實施方案中， 5X是N，“

Figure 02_image017
”是雙鍵；或 5X是C(R 7) 2，“
Figure 02_image017
”是單鍵。 In certain embodiments of formula (I), 5X is N,"
Figure 02_image017
" is a double bond; or 5 X is C(R 7 ) 2 , "
Figure 02_image017
" is a single key.

在某些式(I)的實施方案中， 5X是CR 7，R 7獨立地是H、F、Cl、-C 1-3烷基或被1個、2個或3個F、Cl、氘、-OH或NH 2取代的-C 1-3烷基。 In some embodiments of formula (I), 5 X is CR 7 , R 7 is independently H, F, Cl, -C 1-3 alkyl or replaced by 1, 2 or 3 F, Cl, -C 1-3 alkyl substituted by deuterium, -OH or NH 2 .

在某些式(I)的實施方案中， 5X是CR 7，R 7獨立地是H、F、Cl、甲基或被1個、2個或3個取代F、Cl、氘、-OH或NH 2的甲基。 In certain embodiments of formula (I), 5 X is CR 7 , and R 7 is independently H, F, Cl, methyl or substituted by 1, 2 or 3 F, Cl, deuterium, -OH or NH2 for methyl.

在某些式(I)的實施方案中，R 7和R 7連同它們各自被附接至的C原子形成3元環烷基、4元環烷基、5元環烷基或6元環烷基、3元雜環、4元雜環、5元雜環或6元雜環。 In certain embodiments of formula (I), R and R , 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 cycloalkane group, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle or 6-membered heterocycle.

在某些式(I)的實施方案中，R 7和R 7連同它們各自被附接至的C原子形成5元環烷基或6元環烷基或5元雜環或6元雜環。 In certain embodiments of formula (I), R7 and R7 , together with the C atom to which they are each attached, form a 5-membered cycloalkyl or 6-membered cycloalkyl or a 5-membered heterocycle or a 6-membered heterocycle.

在某些式(I)的實施方案中，兩個R 7連同兩個R 7兩者均被附接至的C原子形成氧代(=O)，此處氧代連同X 2被附接至的N原子與一個N或兩個N形成4元、5元或6元內醯胺。 In certain embodiments of formula (I), two R 7 along with the C atom to which both R 7 are attached form oxo (=O), where oxo together with X 2 are attached to The N atom of N and one N or two N form 4-membered, 5-membered or 6-membered lactamides.

在某些式(I)的實施方案中， 5X是N，並且“

Figure 02_image017
”是雙鍵。 In certain embodiments of formula (I), 5X is N, and "
Figure 02_image017
" is a double bond.

在某些式(I)的實施方案中，W是NR w，並且R w是H、氘或C 1-3烷基。 In certain embodiments of formula (I), W is NRw , and Rw is H, deuterium, or C1-3 alkyl.

在某些式(I)的實施方案中，W是NR w，並且R w是H、氘、甲基或乙基。 In certain embodiments of formula (I), W is NRw , and Rw is H, deuterium, methyl or ethyl.

在某些式(I)的實施方案中，W是NR w，並且R w是H。 In certain embodiments of formula (I), W is NRw , and Rw is H.

在某些式(I)的實施方案中，W是O。In certain embodiments of formula (I), W is O.

在另一個方面中，本發明涉及至少一種式(I′)的化合物、或包含式(I′)的部分的PROTAC化合物

Figure 02_image007
In another aspect, the present invention relates to at least one compound of formula (I'), or a PROTAC compound comprising a moiety of formula (I')
Figure 02_image007

或其藥學上可接受的鹽、前驅藥、溶劑化物、水合物、互變異構體和異構體，or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers thereof,

其中：in:

m選自1、2、3或4。m is selected from 1, 2, 3 or 4.

X 0是H、氘、鹵素、OH、NH 2、CN、-NHC(O)NHC 1-6烷基、-NHC(O)N(C 1-6烷基) 2、-OH、-OC(O)NHC 1-6烷基、-OC(O)N(C 1-6烷基) 2、

Figure 02_image036
、-C 1-6烷基NHC(O)NHC 1-6烷基、-C 1-6烷基NHC(O)N(C 1-6烷基l) 2、-OH、-CH 2OH、-CH 2OC(O)NHC 1-6烷基、-CH 2OC(O)N(C 1-6烷基) 2、
Figure 02_image044
、C 1-6烷氧基、C 1-6羥基烷基、或C 1-6烷氧基；並且其中的每個可以獨立地任選地是未被取代的或獨立地任選地被3元至7元雜環取代，所述3元至7元雜環具有一個或更多個獨立地選自N、O或S的雜原子，並且雜原子中的至少一個是N，所述雜原子直接被連接至C 1-6烷基或C 1-6羥基烷基的C原子中的一個；3元至7元雜環另外任選地被-CH 3或-N(CH 3) 2取代； X 0 is H, deuterium, halogen, OH, NH 2 , CN, -NHC(O)NHC 1-6 alkyl, -NHC(O)N(C 1-6 alkyl) 2 , -OH, -OC( O)NHC 1-6 alkyl, -OC(O)N(C 1-6 alkyl) 2 ,
Figure 02_image036
, -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) 2 ,
Figure 02_image044
, C 1-6 alkoxy, C 1-6 hydroxyalkyl, or C 1-6 alkoxy; and each of which may be independently optionally unsubstituted or independently optionally replaced by 3 Member to 7-membered heterocyclic ring substitution, the 3-membered to 7-membered heterocyclic ring has one or more heteroatoms independently selected from N, O or S, and at least one of the heteroatoms is N, and the heteroatoms directly attached to one of the C atoms of C 1-6 alkyl or C 1-6 hydroxyalkyl; 3-7 membered heterocycles are additionally optionally substituted by -CH 3 or -N(CH 3 ) 2 ;

Y是C(R N) 2或NR N；R N中的每個獨立地是H、氘、鹵素、-NH 2、-CN、-OH、-NHC(O)NHC 1-6烷基、 -NHC(O)N(C 1-6烷基) 2、-OH、-OC(O)NHC 1-6烷基、-OC(O)N(C 1-6烷基) 2、

Figure 02_image036
、C 1-6烷基NHC(O)NHC 1-6烷基、-C 1-6烷基NHC(O)N(C 1-6烷基) 2、-OH、-C 1-6烷基OH、-C 1-6烷基OC(O)NHC 1-6烷基、-C 1-6烷基OC(O)N(C 1-6烷基) 2、
Figure 02_image044
、-C 1-6烷基、-C 1-6烷氧基或
Figure 02_image052
； Y is C(R N ) 2 or NR N ; each of R N is independently H, deuterium, halogen, -NH 2 , -CN, -OH, -NHC(O)NHC 1-6 alkyl, - NHC(O)N(C 1-6 alkyl) 2 , -OH, -OC(O)NHC 1-6 alkyl, -OC(O)N(C 1-6 alkyl) 2 ,
Figure 02_image036
, C 1-6 alkyl NHC (O) NHC 1-6 alkyl, -C 1-6 alkyl NHC (O) N (C 1-6 alkyl) 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) 2 ,
Figure 02_image044
, -C 1-6 alkyl, -C 1-6 alkoxy or
Figure 02_image052
;

R 1和R 2中的每個獨立地選自H、氘、鹵素、-NH 2、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、鹵素、-NH 2、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基取代； Each of R 1 and R 2 is independently selected from H, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkyl or -C 1-6 alkoxy, and each of them are independently optionally unsubstituted or independently optionally substituted by deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkyl or -C 1-6 alkoxy;

R 3和R 4中的每個獨立地選自H、氘、鹵素、-NH 2、-CN、-OH、-C 1-4烷基或-C 1-4烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、鹵素、-NH 2、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基取代； Each of R 3 and R 4 is independently selected from H, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-4 alkyl or -C 1-4 alkoxy, and each of them are independently optionally unsubstituted or independently optionally substituted by deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkyl or -C 1-6 alkoxy;

R 5中的每個獨立地選自H、鹵素、氘、-NH 2、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、鹵素、-NH 2、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基取代； Each of R 5 is independently selected from H, halogen, deuterium, -NH 2 , -CN, -OH, -C 1-6 alkyl or -C 1-6 alkoxy, and each of them is independently optionally unsubstituted or independently optionally substituted with deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkyl or -C 1-6 alkoxy;

並且R 1、R 2、R 3、R 4和R 5中的至少一個是氘； and at least one of R 1 , R 2 , R 3 , R 4 and R 5 is deuterium;

R獨立地是：

Figure 02_image009
、
Figure 02_image011
、
Figure 02_image040
或
Figure 02_image015
R independently is:
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image040
or
Figure 02_image015

其中：in:

n是0、1、2或3；n is 0, 1, 2 or 3;

q是0、1、2或3；q is 0, 1, 2 or 3;

X 1是H、-CH 2CN、C 1-6烷基或C 1-6烷氧基； X 1 is H, -CH 2 CN, C 1-6 alkyl or C 1-6 alkoxy;

X 2是6元至10元芳基或5元至10元雜芳基；並且6元至10元芳基或5元至10元雜芳基中的每個獨立地任選地是未被取代的或獨立地任選地被一個或更多個R 2x取代； X is 6-10 membered aryl or 5-10-membered heteroaryl; and each of the 6-10-membered aryl or 5-10-membered heteroaryl is independently optionally unsubstituted or independently optionally substituted with one or more R 2x ;

R 2x中的每個獨立地選自鹵素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6羥基烷基、C 1-6烷氧基、C 1-6鹵代烷基、C 2-6烯基、C 2-6炔基、C 2-6氘代炔基、氰基、(C 1-6烷氧基)C 1-6烷基、(C 1-6烷氧基)C 1-6烷氧基、(C 1-6羥基烷氧基)C 1-6烷氧基、3元至7元環烷基或3元至7元雜環烷基；並且其中的每個獨立地任選地是未被取代的或獨立地任選地被一個或更多個-NH 2、鹵素、氘、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基取代； Each of R 2x is independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkane Base, 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 alkane Oxygen) C 1-6 alkoxy, (C 1-6 hydroxyalkoxy) C 1-6 alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; and wherein Each of is independently optionally unsubstituted or independently optionally replaced by one or more -NH 2 , halogen, deuterium, -CN, -OH, -C 1-6 alkyl or -C 1 -6 alkoxy substitution;

X 3獨立地選自H、鹵素、C 1-6烷基或C 1-6烷氧基； X is independently selected from H, halogen, C 1-6 alkyl or C 1-6 alkoxy;

“

Figure 02_image017
”是單鍵或雙鍵； "
Figure 02_image017
” is a single or double bond;

5X是N或CR 7，其中 5 X is N or CR 7 where

當 5X是N或 5X是CR 7時，“

Figure 02_image017
”是雙鍵； When 5 X is N or 5 X is CR 7 ,"
Figure 02_image017
" is a double bond;

當 5X是C(R 7) 2或 5X是NR 7時，“

Figure 02_image017
”是單鍵。 When 5 X is C(R 7 ) 2 or 5 X is NR 7 , "
Figure 02_image017
" is a single key.

R 7獨立地是H、鹵素、-C 1-6烷基或被一個或更多個鹵素、氘、-OH或NH 2取代的-C 1-6烷基；或 R is independently H, halogen, -C 1-6 alkyl, or -C 1-6 alkyl substituted by one or more halogen, deuterium, -OH or NH 2 ; or

兩個R 7連同兩個R 7兩者均被附接至的C原子形成氧代(=O)，此處氧代與X 2被附接至的N原子形成內醯胺，或 two R 7 together with the C atom to which both R 7 are attached form oxo (=0), where oxo and the N atom to which X 2 are attached form a lactam, or

R 7和R 7連同它們各自被附接至的C原子形成3元至6元環烷基、3元至6元雜環；或 R7 and R7 , together with the C atom to which they are each attached, form a 3-6 membered cycloalkyl, 3-6 membered heterocycle; or

W是O或NR w，並且R w是H、氘或C 1-3烷基。 W is O or NRw , and Rw is H, deuterium or C1-3 alkyl.

在某些式(I′)的實施方案中，X 0是H、氘、F、Cl、OH、NH 2、CN、-C 1-3烷基NHC(O)NHC 1-3烷基、-C 1-3烷基NHC(O)N(C 1-3烷基) 2、-OH、-C 1-3烷基OH、-C 1-3烷基OC(O)NHC 1-3烷基、-C 1-3烷基OC(O)N(C 1-3烷基) 2、

Figure 02_image044
、C 1-3烷氧基、C 1-3羥基烷基或C 1-3烷氧基，並且其中的每個可以獨立地任選地是未被取代的或獨立地任選地被3元至7元雜環取代，所述3元至7元雜環具有一個或更多個獨立地選自N、O或S的雜原子並且雜原子中的至少一個是N，所述N直接地被連接至C 1-3烷基或C 1-3羥基烷基的C原子中的一個；3元至7元雜環另外任選地是未被取代的或另外任選地被-CH 3或-N(CH 3) 2取代。 In certain embodiments of formula (I′), X 0 is H, deuterium, F, Cl, OH, NH 2 , CN, —C 1-3 alkylNHC(O)NHC 1-3 alkyl, — C 1-3 alkylNHC(O)N(C 1-3 alkyl) 2 , -OH, -C 1-3 alkylOH, -C 1-3 alkylOC(O)NHC 1-3 alkyl , -C 1-3 alkyl OC(O)N(C 1-3 alkyl) 2 ,
Figure 02_image044
, C 1-3 alkoxy, C 1-3 hydroxyalkyl or C 1-3 alkoxy, and each of which may be independently optionally unsubstituted or independently optionally 3-membered Substituted to a 7-membered heterocyclic ring, the 3-membered to 7-membered heterocyclic ring has one or more heteroatoms independently selected from N, O or S and at least one of the heteroatoms is N, and the N is directly replaced by One of the C atoms attached to C 1-3 alkyl or C 1-3 hydroxyalkyl; 3- to 7-membered heterocycle is additionally optionally unsubstituted or additionally optionally replaced by -CH or - N(CH 3 ) 2 substitution.

在某些式(I′)的實施方案中，X 0是H、氘、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 02_image044
、甲基或甲氧基。 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 02_image044
, methyl or methoxy.

在某些式(I′)的實施方案中，其中X 0是H。 In certain embodiments of formula (I'), wherein X 0 is H.

在某些式(I′)的實施方案中，R 1和R 2中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基取代。 In certain embodiments of formula (I′), each of R and R is independently selected from H, deuterium, F, Cl, —NH 2 , —CN, —OH, —C 1-3 alkane or -C 1-3 alkoxy, and each of which is independently optionally unsubstituted or independently optionally replaced by deuterium, F, Cl, -NH 2 , -CN, -OH, - C 1-3 alkyl or -C 1-3 alkoxy substituted.

在某些式(I′)的實施方案中，R 1和R 2中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基取代。 In certain embodiments of formula (I′), each of R and R 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 substituted with deuterium, F, Cl, —NH 2 , —CN, —OH, methyl, or methoxy.

在某些式(I′)的實施方案中，R 1和R 2中的每個獨立地選自H或氘。 In certain embodiments of formula (I'), each of R and R is independently selected from H or deuterium.

在某些式(I′)的實施方案中，R 3和R 4中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基取代。 In certain embodiments of formula (I′), each of R and R is independently selected from H, deuterium, F, Cl, —NH 2 , —CN, —OH, —C 1-3 alkane or -C 1-3 alkoxy, and each of which is independently optionally unsubstituted or independently optionally replaced by deuterium, F, Cl, -NH 2 , -CN, -OH, - C 1-3 alkyl or -C 1-3 alkoxy substituted.

在某些式(I′)的實施方案中，R 3和R 4中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基取代。 In certain embodiments of formula (I′), each of R and R 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 substituted with deuterium, F, Cl, —NH 2 , —CN, —OH, methyl, or methoxy.

在某些式(I′)的實施方案中，R 3和R 4中的每個獨立地選自H或氘。 In certain embodiments of formula (I'), each of R and R is independently selected from H or deuterium .

在某些式(I′)的實施方案中，R 5中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基取代。 In certain embodiments of formula (I′), each of R 5 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 replaced by deuterium, F, Cl, -NH 2 , -CN, -OH, -C 1- 3 alkyl or -C 1-3 alkoxy substituted.

在某些式(I′)的實施方案中，R 5中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基取代。 In certain embodiments of formula (I′), each of R is independently selected from H, deuterium, F, Cl, —NH 2 , —CN, —OH, methyl, or methoxy, and wherein Each of is independently optionally unsubstituted or independently optionally substituted with deuterium, F, Cl, -NH2 , -CN, -OH, methyl or methoxy.

在某些式(I′)的實施方案中，R 5中的每個獨立地選自H、氘或F。 In certain embodiments of formula (I′), each of R 5 is independently selected from H, deuterium or F.

在某些式(I′)的實施方案中，R 1、R 2、R 3、R 4和R 5中的至少一個是氘；並且R 5是氘。 In certain embodiments of formula (I'), at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is deuterium; and R 5 is deuterium.

在某些式(I′)的實施方案中，R 1、R 2、R 3、R 4和R 5中的至少兩個是氘；並且R 1和R 2兩者均是氘。 In certain embodiments of formula (I'), at least two of R 1 , R 2 , R 3 , R 4 , and R 5 are deuterium; and both R 1 and R 2 are deuterium.

在某些式(I′)的實施方案中，R 1、R 2、R 3、R 4和R 5中的至少兩個是氘；並且R 3和R 4兩者均是氘。 In certain embodiments of formula (I'), at least two of R 1 , R 2 , R 3 , R 4 , and R 5 are deuterium; and both R 3 and R 4 are deuterium.

在某些式(I′)的實施方案中，R 1、R 2、R 3、R 4和R 5中的至少三個是氘；並且R 1和R 2兩者均是氘，並且R 5是氘。 In certain embodiments of formula (I′), at least three of R 1 , R 2 , R 3 , R 4 , and R 5 are deuterium; and both R 1 and R 2 are deuterium, and R 5 is deuterium.

在某些式(I′)的實施方案中，R 1、R 2、R 3、R 4和R 5中的至少三個是氘；並且R 3和R 4是氘，並且R 5是氘。 In certain embodiments of formula (I'), at least three of R 1 , R 2 , R 3 , R 4 , and R 5 are deuterium; and R 3 and R 4 are deuterium, and R 5 is deuterium.

在某些式(I′)的實施方案中，R 1、R 2、R 3、R 4和R 5中的至少四個是氘，並且R 1和R 2兩者均是氘，並且R 3和R 4兩者均是氘。 In certain embodiments of formula (I′), at least four of R 1 , R 2 , R 3 , R 4 , and R 5 are deuterium, and both R 1 and R 2 are deuterium, and R 3 and R are both deuterium.

在某些式(I′)的實施方案中，R 1、R 2、R 3、R 4和R 5中的全部都是氘。 In certain embodiments of formula (I'), all of R 1 , R 2 , R 3 , R 4 and R 5 are deuterium.

在某些式(I′)的實施方案中，R獨立地是：

Figure 02_image009
。 In certain embodiments of formula (I'), R is independently:
Figure 02_image009
.

在某些式(I′)的實施方案中，R獨立地是：

Figure 02_image011
。 In certain embodiments of formula (I'), R is independently:
Figure 02_image011
.

在某些式(I′)的實施方案中，R獨立地是：

Figure 02_image040
。 In certain embodiments of formula (I'), R is independently:
Figure 02_image040
.

在某些式(I′)的實施方案中，R獨立地是：

Figure 02_image015
。 In certain embodiments of formula (I'), R is independently:
Figure 02_image015
.

在某些式(I′)的實施方案中，n是2。In certain embodiments of formula (I'), n is 2.

在某些式(I′)的實施方案中，X 1是H、-CH 2CN、C 1-3烷基或C 1-3烷氧基。 In certain embodiments of formula (I'), X 1 is H, -CH 2 CN, C 1-3 alkyl or C 1-3 alkoxy.

在某些式(I′)的實施方案中，X 1是H、-CH 2CN、甲基或甲氧基。 In certain embodiments of formula (I'), X1 is H, -CH2CN , methyl or methoxy.

在某些式(I′)的實施方案中，X 1是H。 In certain embodiments of formula (I'), X is H.

在某些式(I′)的實施方案中，X 2是苯基、萘基或5元雜芳基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基或10元雜芳基；並且苯基、萘基或5元至10元雜芳基中的每個獨立地任選地是未被取代的或獨立地任選地被1個R 2x、2個R 2x或3個R 2x取代。 In certain embodiments of formula (I'), X 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 replaced by 1 R 2x , 2 R 2x or 3 R 2x substitutions.

在某些式(I′)的實施方案中，X 2是苯基、萘基或5元雜芳基、6元雜芳基、7元雜芳基或8元雜芳基；並且苯基、萘基或5元雜芳基、6元雜芳基、7元雜芳基或8元雜芳基中的每個獨立地任選地是未被取代的或獨立地任選地被3個R 2x取代。 In certain embodiments of formula (I'), X is phenyl, naphthyl, or 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, or 8-membered heteroaryl; and phenyl, Each of naphthyl or 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, or 8-membered heteroaryl is independently optionally unsubstituted or independently optionally replaced by 3 R 2x replaced.

在某些式(I′)的實施方案中，X 2是苯基或萘基，並且苯基或萘基中的每個獨立地任選地是未被取代的或獨立地任選地被3個R 2x取代。 In certain embodiments of formula (I′), X is phenyl or naphthyl, and each of phenyl or naphthyl is independently optionally unsubstituted or independently optionally replaced by 3 R 2x substitution.

在某些式(I′)的實施方案中，X 2是苯基，並且苯基獨立地任選地是未被取代的或獨立地任選地被3個R 2x取代。 In certain embodiments of formula (I'), X 2 is phenyl, and phenyl is independently optionally unsubstituted or independently optionally substituted with 3 R 2x .

在某些式(I′)的實施方案中，X 2是萘基，並且萘基獨立地任選地是未被取代的或獨立地任選地被3個R 2x取代。 In certain embodiments of formula (I′), X 2 is naphthyl, and naphthyl is independently optionally unsubstituted or independently optionally substituted with 3 R 2x .

在某些式(I′)的實施方案中，R 2x中的每個獨立地選自F、Cl、-OH、-NH 2、-CN、C 1-3烷基、C 1-3羥基烷基、C 1-3烷氧基、C 1-3鹵代烷基、C 2-4烯基、C 2-4炔基、C 2-4氘代炔基、氰基、(C 1-3烷氧基)C 1-3烷基、(C 1-3烷氧基)C 1-3烷氧基、(C 1-3羥基烷氧基)C 1-3烷氧基、3元環烷基或4元環烷基、或3元雜環烷基或4元雜環烷基；並且其中的每個獨立地任選地是未被取代的或獨立地任選地被1個、2個或3個-NH 2、F、Cl、氘、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基取代。 In certain embodiments of formula (I'), each of R 2x is independently selected from F, Cl, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 hydroxyalkane 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 Base) C 1-3 alkyl, (C 1-3 alkoxy) C 1-3 alkoxy, (C 1-3 hydroxyalkoxy) C 1-3 alkoxy, 3-membered cycloalkyl or 4-membered cycloalkyl, or 3-membered heterocycloalkyl or 4-membered heterocycloalkyl; and each of which is independently optionally unsubstituted or independently optionally replaced by 1, 2 or 3 Substituted by -NH 2 , F, Cl, deuterium, -CN, -OH, -C 1-3 alkyl or -C 1-3 alkoxy.

在某些式(I′)的實施方案中，R 2x中的每個獨立地選自F、Cl、-OH、-NH 2、-CN、甲基、乙基、甲氧基、環丙基、被3個F取代的甲基、被3個Cl取代的甲基、被3個F取代的乙基、乙烯基、乙炔基、被氘取代的乙炔基、或氰基；並且其中的每個獨立地任選地是未被取代的或獨立地任選地被1個、2個或3個-NH 2、F、Cl、氘、-CN、-OH、甲基或甲氧基取代。 In certain embodiments of formula (I′), each of R 2x is independently selected from F, Cl, —OH, —NH 2 , —CN, methyl, ethyl, methoxy, cyclopropyl , methyl substituted by 3 F, methyl substituted by 3 Cl, ethyl substituted by 3 F, vinyl, ethynyl, ethynyl substituted by deuterium, or cyano; and each of independently optionally unsubstituted or independently optionally substituted with 1, 2 or 3 -NH2, F , Cl, deuterium, -CN, -OH, methyl or methoxy.

在某些式(I′)的實施方案中，R 2x中的每個獨立地選自F、Cl、-OH、甲基、被3個F取代的甲基、乙烯基、乙炔基或環丙基；並且其中的每個獨立地任選地是未被取代的或獨立地任選地被3個F、3個氘或甲基取代。 In certain embodiments of formula (I′), each of R 2x is independently selected from F, Cl, —OH, methyl, methyl substituted with 3 F, vinyl, ethynyl, or cyclopropane and each of which is independently optionally unsubstituted or independently optionally substituted with 3 F, 3 deuterium or methyl.

在某些式(I′)的實施方案中，X 3獨立地選自H、F、Cl、C 1-3烷基或C 1-3烷氧基。 In certain embodiments of formula (I'), X 3 is independently selected from H, F, Cl, C 1-3 alkyl or C 1-3 alkoxy.

在某些式(I′)的實施方案中，X 3獨立地選自H、F、Cl、甲基或甲氧基。 In certain embodiments of formula (I'), X3 is independently selected from H, F, Cl, methyl or methoxy.

在某些式(I′)的實施方案中，X 3獨立地選自F。 In certain embodiments of formula (I'), X3 is independently selected from F.

在某些式(I′)的實施方案中，“

Figure 02_image017
”是單鍵。 In certain embodiments of formula (I'), "
Figure 02_image017
" is a single key.

在某些式(I′)的實施方案中，“

Figure 02_image017
”是雙鍵。 In certain embodiments of formula (I'), "
Figure 02_image017
" is a double bond.

在某些式(I′)的實施方案中， 5X是N，“

Figure 02_image017
”是雙鍵；或 5X是C(R 7) 2，“
Figure 02_image017
”是單鍵。 In certain embodiments of formula (I'), 5 X is N,"
Figure 02_image017
" is a double bond; or 5 X is C(R 7 ) 2 , "
Figure 02_image017
" is a single key.

在某些式(I′)的實施方案中， 5X是CR 7，R 7獨立地是H、F、Cl、-C 1-3烷基或被1個、2個或3個F、Cl、氘、-OH或NH 2取代的-C 1-3烷基。 In some embodiments of formula (I′), 5 X is CR 7 , R 7 is independently H, F, Cl, -C 1-3 alkyl or replaced by 1, 2 or 3 F, Cl , deuterium, -OH or NH 2 substituted -C 1-3 alkyl.

在某些式(I′)的實施方案中， 5X是CR 7，R 7獨立地是H、F、Cl、甲基或被1個、2個或3個F、Cl、氘、-OH或NH 2取代的甲基。 In certain embodiments of formula (I′), 5 X is CR 7 , and R 7 is independently H, F, Cl, methyl or replaced by 1, 2 or 3 F, Cl, deuterium, -OH or NH2 substituted methyl.

在某些式(I′)的實施方案中，R 7和R 7連同它們各自被附接至的C原子形成3元環烷基、4元環烷基、5元環烷基或6元環烷基、3元雜環、4元雜環、5元雜環或6元雜環。 In certain embodiments of formula (I'), R7 and R7 , 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 ring An alkyl group, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle or a 6-membered heterocycle.

在某些式(I′)的實施方案中，R 7和R 7連同它們各自被附接至的C原子形成5元環烷或6元環烷基，或5元雜環或6元雜環。 In certain embodiments of formula (I′), R and R , together with the C atom to which they are each attached, form a 5-membered cycloalkane or a 6-membered cycloalkyl, or a 5-membered heterocycle or a 6-membered heterocycle .

在某些式(I′)的實施方案中，兩個R 7連同兩個R 7兩者均被附接至的C原子形成氧代(=O)，此處氧代連同X 2被附接至的N原子形成具有一個N或兩個N的4元、5元或6元內醯胺。 In certain embodiments of formula (I′), two R 7 along with the C atom to which both R 7 are attached form oxo (=O), where oxo along with X 2 is attached The N atoms to form 4-, 5- or 6-membered lactamides with one N or two Ns.

在某些式(I′)的實施方案中， 5X是N，並且“

Figure 02_image017
”是雙鍵。 In certain embodiments of formula (I'), 5 X is N, and "
Figure 02_image017
" is a double bond.

在某些式(I′)的實施方案中，W是NR w，並且R w是H、氘或C 1-3烷基。 In certain embodiments of formula (I'), W is NRw , and Rw is H, deuterium, or C1-3 alkyl.

在某些式(I′)的實施方案中，W是NR w，並且R w是H、氘、甲基或乙基。 In certain embodiments of formula (I'), W is NRw , and Rw is H, deuterium, methyl or ethyl.

在某些式(I′)的實施方案中，W是NR w，並且R w是H。 In certain embodiments of formula (I'), W is NRw , and Rw is H.

在某些式(I′)的實施方案中，W是O。In certain embodiments of formula (I'), W is O.

在某些式(I′)的實施方案中，R N中的每個獨立地是H、氘、F、Cl、-NH 2、-CN、-OH、-CH 2NHC(O)NHC 1-3烷基、-CH 2NHC(O)N(C 1-3烷基) 2、-CH 2OH、-CH 2OC(O)NHC 1-3烷基、-CH 2OC(O)N(C 1-3烷基) 2、

Figure 02_image044
、-C 1-3烷基、-C 1-3烷氧基或
Figure 02_image052
。 In certain embodiments of formula (I'), each of R N is independently H, deuterium, F, Cl, -NH2 , -CN, -OH, -CH2NHC (O) NHC1- 3 alkyl, -CH 2 NHC(O)N(C 1-3 alkyl) 2 , -CH 2 OH, -CH 2 OC(O)NHC 1-3 alkyl, -CH 2 OC(O)N( C 1-3 alkyl) 2 ,
Figure 02_image044
, -C 1-3 alkyl, -C 1-3 alkoxy or
Figure 02_image052
.

在某些式(I′)的實施方案中，R N中的每個獨立地是H、氘、F、Cl、-NH 2、-CH 2NHC(O)NHMe、-CH 2NHC(O)N(Me) 2、-CH 2OH、-CH 2OC(O)NHMe、-CH 2OC(O)NMe、甲基、甲氧基或

Figure 02_image052
。 In certain embodiments of formula (I′), each of R N 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 02_image052
.

在某些式(I′)的實施方案中，R N中的每個獨立地是H、氘、F或

Figure 02_image052
。 In certain embodiments of formula (I′), each of R N is independently H, deuterium, F, or
Figure 02_image052
.

在某些式(I′)的實施方案中，一個R N是H、氘或F；其他R N是

Figure 02_image052
；並且Y是C(R N) 2。 In certain embodiments of formula (I'), one R N is H, deuterium, or F; the other R N is
Figure 02_image052
; and Y is C(R N ) 2 .

在某些式(I′)的實施方案中，R N是

Figure 02_image052
；並且Y是NR N。 In certain embodiments of formula (I'), R N is
Figure 02_image052
; and Y is NR N .

此外，本發明公開的示例性化合物(示例性化合物)在下文列出：In addition, exemplary compounds (exemplary compounds) disclosed in the present invention are listed below:

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪(pyrrolizin)-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazine( pyrrolizin)-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl )phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizine- 7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol ;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizine- 7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizine- 7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2 -phenol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-methyl pyrrolidin-2-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-methyl Pyrrolidin-2-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-methyl Pyrrolidin-2-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-methyl Pyrrolidin-2-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-( Trifluoromethyl)phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- Fluorinaphth-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((S)-1-(methyl Base-d 3 ) pyrrolidin-2-yl) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene -2-phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- Fluorinaphth-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((S)-1-(methyl Base-d 3 ) pyrrolidin-2-yl) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚；3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl base) phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚；4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene- 2-phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((S)-1-(methyl Base-d 3 )pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚；4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2- phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚；4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-(甲基-d 3)-吡咯烷-2-基)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((S)-1-(methyl Base-d 3 )-pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6- Difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl -6-fluoronaphthalene-2-ol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5- Chloro-4-(trifluoromethyl)phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5- Ethyl-6-fluoronaphthalen-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5, 6-Difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5- Ethynyl-6-fluoronaphthalen-2-ol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4 - (trifluoromethyl)phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl- 6-fluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-di Fluorinaphth-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl- 6-fluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((S)-1-(methyl Base-d 3 ) pyrrolidin-2-yl) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-4-(tri Fluoromethyl)phenol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-4- (Trifluoromethyl)phenol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoro Methyl)phenol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazine- 7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)phenol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy- d2 )pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)phenol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl )phenol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚；3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)phenol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(pyrrolidin-1- methyl)cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(pyrrolidin-1- methyl)cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(pyrrolidin-1- methyl)cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(pyrrolidin-1- methyl)cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 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-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 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-fluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 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-fluoronaphthalene-2-ol;

3-(4-((1R,5S)-8-氧雜-3-氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrole Azin-7a(5H)-yl)methoxy- d2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol;

4-(4-(3,6-二氮雜雙環並[3.2.1]庚烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(3,6-diazabicyclo[3.2.1]heptane-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl ) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octane-2-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl ) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl)methoxy- d2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octane-2-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octane-2-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl ) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octane-2-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl ) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl ) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl ) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol ;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol ;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((S)-1-(methyl-d 3 )pyrrole Alk-2-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol ;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((S)-1-(methyl-d 3 )pyrrole Alk-2-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚；3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚；4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((S)-1-(methyl-d 3 )pyrrole Alk-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚；4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚；4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((S)-1-(methyl-d 3 )pyrrole Alk-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl base) phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2- phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene- 2-phenol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(tri Fluoromethyl)phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoro Naphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene- 2-phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphthalene-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl )phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2 -phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol ;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((S)-1-(methyl-d 3 )pyrrole Alk-2-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)phenol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl) phenol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2,5,5- d3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)phenol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octane-2-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl ) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)phenol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)phenol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)phenol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚；3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)phenol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropane Base) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropane Base) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropane Base) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropane Base) methoxy-d 2 ) pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy Base-d 2 )-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]oct-2-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy Base-d 2 )-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]oct-2-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy Base- d 2 )-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]oct-2-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy Base-d 2 )-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-7-基)-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-7-yl)-8(7H) -ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-7-基)-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidine- 7-yl)-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-7-基)-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-7-yl)-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidine-8(7H )-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidine-8 (7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidine-8 (7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[3,4- d] pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[3,4-d ]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[3,4-d]pyrimidine -8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[3,4-d ]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((S)-1-(methyl-d 3 )pyrrolidin-2-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidine-8(7H)- ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[3,4-d]pyrimidine -8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[3,4-d]pyrimidine- 8(7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[3,4-d]pyrimidine-8( 7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[3,4-d]pyrimidine- 8(7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((S)-1-(methyl-d 3 )pyrrolidin-2-yl)methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[3, 4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[ 3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[3, 4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[3,4 -d] pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[3,4-d ]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[3,4 -d] pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[3,4- d] pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[3, 4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrido[3,4-d]pyrimidine -8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrido[3,4-d ]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy- d 2 )pyrido[3 ,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[3, 4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrido[3,4- d] pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrido[3,4-d ]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine- 8(7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido [3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine-8(7H )-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3, 4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine-8 (7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[ 3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine-8 (7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[ 3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]pyrimidine- 8(7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]pyrimidine-8(7H )-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine-8 (7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine-8 (7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )-6-(trifluoromethane Base) pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )-6-(trifluoromethyl ) pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )-6-(trifluoromethyl)pyridine And[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )-6-(trifluoromethyl ) pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-6-(trifluoromethyl)pyridine And[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-6-(trifluoromethyl)pyrido [3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]pyrimidine-8 (7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-6-(trifluoromethyl)pyrido[3 ,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-6-(trifluoromethyl)pyrido [3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((S)-1-(methyl-d 3 )pyrrolidin-2-yl)methoxy)-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine -8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )-6-(tri Fluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )-6- (Trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)-6-(tri Fluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)-6-(trifluoro Methyl)pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)-6-(trifluoromethyl ) pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)-6-(trifluoro Methyl)pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )-6-(trifluoromethane Base) pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)-6-(trifluoromethyl)pyridine And[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )-6-( Trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)-6-(trifluoromethane Base) pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙基-7-氟-3-羥基萘-1-基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine- 8(7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]pyrimidine -8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]pyrimidine-8( 7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine- 8(7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙基-7-氟-3-羥基萘-1-基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 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]pyrimidine- 8(7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine -8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-((1-((dimethylamino)methyl)cyclopropyl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine-8( 7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 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]pyrimidine- 8(7H)-ketone;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((tetrahydro-1H-pyrrolizine-7a(5H) -yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro-4-(trifluoromethyl)phenol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro-4 - (trifluoromethyl)phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((tetrahydro-1H-pyrrolizine-7a(5H) -yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalen-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-di Fluorinaphth-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((tetrahydro-1H-pyrrolizine-7a(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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((tetrahydro-1H-pyrrolizine-7a(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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-7(8H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalene-2- phenol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 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-difluoronaphthalene-2 -phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-yl)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5 ,6-Difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5 - Ethynyl-6-fluoronaphthalen-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 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-phenol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚；3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro- 4-(trifluoromethyl)phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚；4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-2-d)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl -6-fluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 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-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚；4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6- Difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚；4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-2-d)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl -6-fluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 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- phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H) -yl)-5,6-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H) -yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl) -5-chloro-4-(trifluoromethyl)phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl) -5-Ethyl-6-fluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl) -5,6-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl) -5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl )-5,6-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5 ,6-Difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5 - Ethynyl-6-fluoronaphthalen-2-ol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 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-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 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-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazine -8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazine-8( 7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazine- 8(7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazine- 8(7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalene-1 -yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrimido[4,5- d] pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrimido[4,5-d ]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrimido[4,5-d]pyridine Azin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrimido[4,5-d ]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((S)-1-(methyl-d 3 )pyrrolidin-2-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazine-8(7H) -ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮；4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrimido[4,5-d]pyridine Azin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮；4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrimido[4,5-d]pyridazine -8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮；4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrimido[4,5-d]pyridazine-8 (7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮；4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrimido[4,5-d]pyridazine -8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((S)-1-(methyl-d 3 )pyrrolidin-2-yl)methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrimido[4, 5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrimido[ 4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrimido[4, 5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrimido[4,5 -d] pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrimido[4,5-d ]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrimido[4,5 -d] pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrimido[4,5- d] pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrimido[4, 5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrimido[4,5-d]pyridine Azin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrimido[4,5-d ]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy- d 2 )pyrimido[4 ,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrimido[4, 5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrimido[4,5- d] pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrimido[4,5-d ]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙基-7-氟-3-羥基萘-1-基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- ((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one ;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((tetra Hydrogen-1H-pyrrolidin-7a(5H)-yl)methoxy- d2 )pyrido[3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( (tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( (tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[3,4-d]pyrimidine-8( 7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[3,4-d]pyrimidine-8(7H )-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[3,4-d]pyrimidine-8(7H)- ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[3,4-d]pyrimidine-8(7H )-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[3,4-d]pyrimidine-8(7H)- ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl-2-d)methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one ;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl-2-d)methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl-2-d)methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one ;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[3,4-d]pyrimidine- 8(7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[3,4-d] Pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[3,4-d]pyrimidine- 8(7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[3,4-d]pyrimidine-8 (7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[3,4-d]pyrimidine-8(7H )-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[3,4-d]pyrimidine-8 (7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[3,4-d]pyrimidine-8( 7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[3,4-d]pyrimidine- 8(7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrido[3,4-d]pyrimidine-8(7H)- ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrido[3,4-d]pyrimidine-8(7H )-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[3,4-d]pyrimidine -8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[3,4-d]pyrimidine- 8(7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrido[3,4-d]pyrimidine-8( 7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrido[3,4-d]pyrimidine-8(7H )-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- ((Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one ;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d ]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((tetra Hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy- d2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine- 8(7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( (tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy- d2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d] Pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( (tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy- d2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d] Pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3 ,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3, 4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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]pyrimidine-8(7H) -ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4- d] pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3, 4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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]pyrimidine-8( 7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-6-(trifluoromethyl)pyrido[3,4- d] pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-6-(trifluoromethyl)pyrido[3,4-d ]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine -8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮；4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-6-(trifluoromethyl)pyrido[3,4-d ]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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]pyrimidine-8(7H)- ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )-6-(trifluoromethyl)pyrido [3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )-6-(trifluoromethyl) Pyrido[3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)-6-(trifluoromethyl)pyrido [3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)-6-(trifluoromethyl)pyrido[ 3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5- d3 )methoxy)-6-(trifluoromethyl)pyrido[3, 4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)-6-(trifluoromethyl)pyrido[ 3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )-6-(trifluoromethyl)pyrido[3 ,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)-6-(trifluoromethyl)pyrido[3,4- d] pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )-6-(trifluoromethyl)pyridine And[3,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)-6-(trifluoromethyl)pyrido[3 ,4-d]pyrimidin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙基-7-氟-3-羥基萘-1-基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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]pyrimidine-8(7H)- ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙基-7-氟-3-羥基萘-1-基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- ((1-((dimethylamino)methyl)cyclopropyl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine-8(7H)- ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy -d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro-4-(trifluoromethyl)phenol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro-4-(trifluoromethyl )phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy -d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol ;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy -d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthalene-2 -phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy -d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-7(8H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy -d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2-d)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro-4-( Trifluoromethyl)phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2-d)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6- Fluorinaphth-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((S)-1-(methyl-d 3 )pyrrolidin-2- Base) methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2-d)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene -2-phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2-d)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6- Fluorinaphth-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((S)-1-(methyl-d 3 )pyrrolidin-2- Base) methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚；3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2-d)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro-4-(trifluoromethyl base) phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚；4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2-d)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalene- 2-phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((S)-1-(methyl-d 3 )pyrrolidin-2- Base)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚；4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2-d)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2- phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚；4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2-d)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthalene- 2-phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((S)-1-(methyl-d 3 )pyrrolidin-2- Base)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2,5,5-d 3 )methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5, 6-Difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2,5,5-d 3 )methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5- Ethynyl-6-fluoronaphthalen-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2,5,5-d 3 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro-4 - (trifluoromethyl)phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2,5,5-d 3 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl- 6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2,5,5-d 3 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-di Fluorinaphth-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2,5,5-d 3 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl- 6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-5,5-d 2 )methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6- Difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-5,5-d 2 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene -2-phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-5,5-d 2 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6- Fluorinaphth-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-5,5-d 2 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro-4-( Trifluoromethyl)phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-5,5-d 2 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6- Fluorinaphth-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy Base-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy Base-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro-4-(trifluoromethyl)phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy Base-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy Base-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]oct-2-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy Base-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy Base-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro-4-(trifluoromethyl)phenol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]oct-2-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy Base-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-diazabicyclo[2.2.2]oct-2-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy Base-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- ((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazine-8(7H)- ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((tetra Hydrogen-1H-pyrrolizin-7a(5H)-yl)methoxy- d2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( (tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one ;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( (tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one ;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrimido[4,5-d]pyridazine-8 (7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrimido[4,5-d]pyridazine-8( 7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy- d 2 )pyrimido[4,5-d]pyridazine-8(7H) -ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrimido[4,5-d]pyridazine-8( 7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮；4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrimido[4,5-d]pyridazine-8(7H) -ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮；4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrimido[4,5-d]pyridazine-8(7H)- ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮；4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl-2-d)methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮；4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrimido[4,5-d]pyridazine-8(7H)- ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrimido[4,5-d]pyridazine -8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrimido[4,5-d] Pyridazin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrimido[4,5-d]pyridazine -8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrimido[4,5-d]pyridazine- 8(7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrimido[4,5-d]pyridazine-8( 7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrimido[4,5-d]pyridazine- 8(7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrimido[4,5-d]pyridazine-8 (7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrimido[4,5-d]pyridazine -8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrimido[4,5-d]pyridazine-8(7H) -ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrimido[4,5-d]pyridazine-8( 7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrimido[4,5-d]pyridine Azin-8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrimido[4,5-d]pyridazine -8(7H)-one;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrimido[4,5-d]pyridazine-8 (7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrimido[4,5-d]pyridazine-8( 7H)-ketone;

4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙基-7-氟-3-羥基萘-1-基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-diazabicyclo[2.2.2]octan-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-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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-(trifluoromethane base) phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2- phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(((R)- 3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene- 2-phenol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基(morpholino)甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(morpholino )methyl)cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(morpholinylmethyl )cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(morpholinylmethyl )cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(morpholinylmethyl )cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(morpholinylmethyl -d 2 ) cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(morpholinylmethyl -d 2 ) cyclopropyl)methoxy- d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(morpholinylmethyl -d 2 ) cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(((R)- 3-fluoropyrrolidin-1-yl)methyl-d2)cyclopropyl)methoxy- d2 )pyrido[4,3- d ]pyrimidin-7-yl)-5-chloro-4-( Trifluoromethyl)phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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-difluoronaphthalene -2-phenol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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- Fluorinaphth-2-ol;

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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- Fluorinaphth-2-ol;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy-d 2 )-6-(trifluoromethyl)pyridine And[3,4-d]pyrimidin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-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)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((1-(morpholinomethyl)cyclopropyl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine-8(7H )-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine-8( 7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-((1-(morpholinomethyl)cyclopropyl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine-8(7H)- ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((1-(morpholinomethyl)cyclopropyl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine-8(7H )-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy-d 2 )pyrimido[4,5-d]pyridazine -8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]pyridine Azin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]pyridazine-8 (7H)-ketone;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy-d 2 )pyrimido[4,5-d]pyridazine -8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((1-(morpholinylmethyl)cyclopropyl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl) Phenyl)-2-((1-(morpholinylmethyl)cyclopropyl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl) -2-((1-(morpholinylmethyl)cyclopropyl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-2-((1-(morpholinylmethyl)cyclopropyl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one;

3-(4-(1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-環丙基苯酚；3-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclo Propylphenol;

3-(4-(1R，5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-環丙基-5-氟苯酚；3-(4-(1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-cyclopropyl-5 - fluorophenol;

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-環丙基苯酚；或3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol; or

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-環丙基-5-氟苯酚。3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-cyclopropyl-5-fluorophenol.

此外，本發明公開了一種藥物組合物，所述藥物組合物包含治療有效量的至少一種化合物如上文定義的或其藥學上可接受的鹽、前驅藥、溶劑化物、水合物、互變異構體及異構體，乙基藥學上可接受的賦形劑。Furthermore, the present invention discloses a pharmaceutical composition comprising a therapeutically effective amount of at least one compound as defined above or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer thereof And isomers, ethyl pharmaceutically acceptable excipients.

在某些藥物組合物的實施方案中，藥物組合物包含治療有效量的至少一種如式(I)所定義的化合物、如上文定義的其藥學上可接受的鹽、前驅藥、水合物、互變異構體和異構體，以及藥學上可接受的賦形劑。In certain embodiments of the pharmaceutical composition, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound as defined in formula (I), a pharmaceutically acceptable salt thereof, a prodrug, a hydrate, an interchangeable compound as defined above Variants and isomers, and pharmaceutically acceptable excipients.

在某些藥物組合物的實施方案中，藥物組合物包含治療有效量的至少一種如式(I’)所定義的化合物、如上文定義的其藥學上可接受的鹽、前驅藥、水合物、互變異構體和異構體，以及藥學上可接受的賦形劑。In certain embodiments of the pharmaceutical composition, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound as defined by formula (I'), a pharmaceutically acceptable salt thereof, a prodrug, a hydrate, as defined above, Tautomers and isomers, and pharmaceutically acceptable excipients.

在某些藥物組合物的實施方案中，藥物組合物包含治療有效量的至少一種如示例性化合物所定義的化合物、或如上文定義的其藥學上可接受的鹽、前驅藥、水合物、互變異構體和異構體，以及藥學上可接受的賦形劑。In certain embodiments of the pharmaceutical composition, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound as defined by Exemplary Compounds, or a pharmaceutically acceptable salt, prodrug, hydrate, interactive compound thereof, as defined above. Variants and isomers, and pharmaceutically acceptable excipients.

此外，本發明公開了抑制細胞中KRAS G12D活性的方法，所述方法包括使其中期望抑制KRAS G12D活性的細胞與治療有效量的至少一種如上文定義的化合物或其藥學上可接受的鹽、前驅藥、溶劑化物、水合物、互變異構體和異構體接觸。Furthermore, the present invention discloses a method for inhibiting KRAS G12D activity in a cell, said method comprising subjecting a cell in which it is desired to inhibit KRAS G12D activity with a therapeutically effective amount of at least one compound as defined above or a pharmaceutically acceptable salt, precursor thereof Drugs, solvates, hydrates, tautomers and isomers.

在某些方法的實施方案中，用於抑制細胞中KRAS G12D活性的方法包括使其中期望抑制KRAS G12D活性的細胞與治療有效量的至少一種如式(I)所定義的化合物、如上文定義的其藥學上可接受的鹽、前驅藥、水合物、互變異構體和異構體接觸。In certain method embodiments, the method for inhibiting KRAS G12D activity in a cell comprises subjecting the 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), as defined above Pharmaceutically acceptable salts, prodrugs, hydrates, tautomers and isomers thereof.

在某些方法的實施方案中，用於抑制細胞中KRAS G12D活性的方法包括使其中期望抑制KRAS G12D活性的細胞與治療有效量的至少一種如式(I′)所定義的化合物、如上文定義的其藥學上可接受的鹽、前驅藥、水合物、互變異構體和異構體接觸。In certain method embodiments, the method for inhibiting KRAS G12D activity in a cell comprises subjecting the cell, in which inhibition of KRAS G12D activity is desired, to a therapeutically effective amount of at least one compound as defined in formula (I′), as defined above its pharmaceutically acceptable salts, prodrugs, hydrates, tautomers and isomers.

在某些方法的實施方案中，用於抑制細胞中KRAS G12D活性的方法包括使其中期望抑制KRAS G12D活性的細胞與治療有效量的至少一種如示例性化合物所定義的化合物、如上文定義的其藥學上可接受的鹽、前驅藥、水合物、互變異構體和異構體接觸。In certain method embodiments, the method for inhibiting KRAS G12D activity in a cell comprises subjecting the cell wherein it is desired to inhibit KRAS G12D activity with a therapeutically effective amount of at least one compound as defined in Exemplary Compounds, other compounds as defined above Pharmaceutically acceptable salts, prodrugs, hydrates, tautomers and isomers contact.

此外，本發明公開了用於治療KRAS G12D相關癌症的方法，所述方法包括向需要其的患者施用治療有效量的至少一種如上文定義的化合物或其藥學上可接受的鹽、前驅藥、溶劑化物、水合物、互變異構體和異構體。Furthermore, the present invention discloses a method for treating KRAS G12D-associated cancer, said method 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, solvent thereof compounds, hydrates, tautomers and isomers.

在某些方法的實施方案中，用於治療KRAS G12D相關癌症的方法包括向需要其的患者施用治療有效量的至少一種如式(I)所定義的化合物、如上文定義的其藥學上可接受的鹽、前驅藥、水合物、互變異構體和異構體。In certain method embodiments, the method for treating a KRAS G12D-associated cancer comprises administering to a patient in need thereof a therapeutically effective amount of at least one compound as defined by formula (I), a pharmaceutically acceptable compound thereof as defined above salts, prodrugs, hydrates, tautomers and isomers.

在某些方法的實施方案中，用於治療KRAS G12D相關癌症的方法包括向需要其的患者施用治療有效量的至少一種如式(I’)所定義的化合物、如上文定義的其藥學上可接受的鹽、前驅藥、水合物、互變異構體和異構體。In certain method embodiments, the method for treating KRAS G12D-associated cancer comprises administering to a patient in need thereof a therapeutically effective amount of at least one compound as defined in formula (I′), a pharmaceutically acceptable compound as defined above Accepted salts, prodrugs, hydrates, tautomers and isomers.

在某些方法的實施方案中，用於治療KRAS G12D相關癌症的方法包括向需要其的患者施用治療有效量的至少一種如示例性化合物所定義的化合物、如上文定義的其藥學上可接受的鹽、前驅藥、水合物、互變異構體和異構體。In certain method embodiments, the method for treating a KRAS G12D-associated cancer comprises administering to a patient in need thereof a therapeutically effective amount of at least one compound as defined by Exemplary Compounds, a pharmaceutically acceptable compound thereof as defined above Salts, prodrugs, hydrates, tautomers and isomers.

在某些方法的實施方案中，如上文定義的方法，治療有效量的化合物是在約0.01 mg/kg/天至100 mg/kg/天之間。In certain method embodiments, methods as defined above, the therapeutically effective amount of the compound is between about 0.01 mg/kg/day to 100 mg/kg/day.

在某些方法的實施方案中，如上文定義的方法，治療有效量的化合物是在約0.1 mg/kg/天至50 mg/kg/天之間。In certain method embodiments, methods as defined above, the therapeutically effective amount of the compound is between about 0.1 mg/kg/day to 50 mg/kg/day.

在某些方法的實施方案中，如上文所定義的方法，KRAS G12D相關癌症選自由以下組成的組：心臟：肉瘤(血管肉瘤(angiosarcoma)、纖維肉瘤、橫紋肌肉瘤(rhabdomyosarcoma)、脂肪肉瘤(liposarcoma))、黏液瘤(myxoma)、橫紋肌瘤(rhabdomyoma)、纖維瘤、脂肪瘤和畸胎瘤(teratoma)；肺：支氣管原癌(bronchogenic carcinoma)(鱗狀細胞(squamous cell)、未分化的小細胞、未分化的大細胞、腺癌(adenocarcinoma))、肺泡(細支氣管)癌、支氣管腺瘤、肉瘤、淋巴瘤、肺軟骨瘤性錯構瘤(chondromatous hamartoma)、間皮瘤(mesothelioma)；腸胃：食道癌(鱗狀細胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃癌(癌、淋巴瘤、平滑肌肉瘤)、胰腺癌(導管腺瘤(ductal adenocarcinoma)、胰島瘤(insulinoma)、胰高血糖素瘤(glucagonoma)、胃泌素瘤(gastrinoma)、類癌腫瘤(carcinoid tumors)、血管活性腸肽瘤(vipoma))、小腸(腺癌、淋巴瘤、類癌腫瘤、卡波西氏肉瘤(Kaposi's sarcoma)、平滑肌肉瘤)；泌尿生殖道：腎(腺癌、威爾姆氏瘤(Wilm's tumor)(腎母細胞瘤(nephroblastoma))、淋巴瘤、白血病)、膀胱和尿道(鱗狀細胞癌、移行細胞癌(transitional cell carcinoma)、腺癌)、***(腺癌、肉瘤)、睾丸(精原細胞瘤(seminoma)、畸胎瘤(teratoma)、胚胎性癌(embryonal carcinoma)、畸胎癌(teratocarcinoma)、絨毛膜癌(choriocarcinoma)、肉瘤、間質細胞癌、纖維瘤、纖維腺瘤(fibroadenoma)、腺瘤樣腫瘤(adenomatoid tumors)、淋巴瘤)；肝細胞瘤(肝細胞癌)、膽管瘤、肝母細胞瘤(hepatoblastoma)、血管肉瘤、肝細胞腺瘤、血管瘤(hemangioma)；膽管：膽囊癌、壺腹癌(ampullary carcinoma)、膽管癌；骨：骨原性肉瘤(骨肉瘤)、纖維肉瘤、惡性纖維組織細胞瘤、軟骨肉瘤、尤文氏肉瘤(Ewing's sarcoma)、惡性淋巴瘤(網狀細胞肉瘤(reticulum cell sarcoma))、多發性骨髓瘤、惡性巨大細胞瘤(malignant giant cell tumor)、脊索瘤(chordoma)、骨軟骨瘤(骨軟骨性外生骨疣(osteocartilaginous exostoses))、良性軟骨瘤(benign chondroma)、軟骨母細胞瘤(chondroblastoma)、軟骨肌瘤樣纖維瘤(chondromyxofibroma)、骨樣骨瘤(osteoid osteoma)以及巨大細胞瘤(giant cell tumors)；神經系統：顱骨(骨瘤、血管瘤、肉芽瘤(granuloma)、黃色瘤(xanthoma)、畸形性骨炎(osteitis deformans))、腦膜(meninges)(腦膜瘤(meningioma)、腦膜肉瘤(meningiosarcoma)、神經膠質瘤(gliomatosis))、腦(星形細胞瘤(astrocytoma)、髓母細胞瘤(medulloblastoma)、神經膠質瘤(glioma)、室管膜瘤(ependymoma)、生殖細胞瘤(germinoma)(松果體瘤(pinealoma))、多形性膠質母細胞瘤(glioblastoma multiform)、少突神經膠質瘤(oligodendroglioma)、施萬細胞瘤(schwannoma)、視網膜母細胞瘤(retinoblastoma)、先天性腫瘤(congenital tumors))、脊髓神經纖維瘤(spinal cord neurofibroma)、腦膜瘤、神經膠質瘤、肉瘤；婦科：子宮(子宮內膜癌、(漿液性囊腺癌(serous cystadenocarcinoma)、黏液性囊腺癌(mucinous cystadenocarcinoma)、未分類的癌)、粒層鞘細胞腫瘤(granulosa-thecal cell tumors)、Sertoli-Leydig細胞瘤(Sertoli-Leydig cell tumors)、無性細胞瘤(dysgerminoma)、惡性畸胎瘤)、外陰(鱗狀細胞癌、上皮內癌(intraepithelial carcinoma)、腺癌、纖維肉瘤、黑色素瘤)、***(透明細胞癌(clear cell carcinoma)、鱗狀細胞癌、葡萄樣肉瘤(botryoid sarcoma)、(胚胎型橫紋肌肉瘤(embryonal rhabdomyosarcoma))、輸卵管(癌))；血液：血(骨髓樣白血病(急性的和慢性的)、急性淋巴母細胞白血病(acute lymphoblastic leukemia)、慢性淋巴細胞白血病、骨髓增生性疾病、多發性骨髓瘤、骨髓增生異常綜合征(myelodysplastic syndrome))、霍奇金氏疾病(Hodgkin's disease)、非霍奇金氏淋巴瘤(惡性淋巴瘤)；皮膚：惡性黑色素瘤、基底細胞癌、鱗狀細胞癌、卡波西氏肉瘤、痣、發育不良痣(moles dysplastic nevi)、淋巴瘤、血管瘤、皮膚纖維瘤(dermatofibroma)、瘢痕瘤(keloids)、銀屑病；以及腎上腺：神經母細胞瘤。In certain method embodiments, the method as defined above, the KRAS G12D-associated cancer is selected from the group consisting of: cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma )), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole) carcinoma, bronchial adenoma, sarcoma, lymphoma, pulmonary chondromatous hamartoma, mesothelioma; Gastrointestinal: Esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, pancreatic hyperplasia) Glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma (Kaposi's sarcoma, leiomyosarcoma); urogenital tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell Carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma) Carcinoma (teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroid, fibroadenoma, adenomatoid tumors, lymphoma); hepatocellular carcinoma (liver cell carcinoma) , cholangioma, hepatoblastoma, hemangiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; bone: osteogenic sarcoma (osteosarcoma) tumor), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor cell tumor), chordoma, osteochondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyomatous fibroma ( chondromyxofibroma), osteoid osteoma, and giant cell tumors; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma (glioma), ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schizophrenia schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma; gynecology: uterus (endometrium Carcinoma, (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors (Sertoli-Leydig cell tumors) Leydig cell tumors), dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma ( clear cell carcinoma), squamous cell carcinoma, botryoid sarcoma, (embryonal rhabdomyosarcoma), fallopian tube (cancer)); blood: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin King's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, moles dysplastic nevi, lymphoma, hemangioma, skin fibers dermatofibroma, keloids, psoriasis; and adrenal: neuroblastoma.

在某些方法的實施方案中，如上文定義的方法，癌症是非小細胞肺癌、小細胞肺癌、結直腸癌、直腸癌或胰腺癌。In certain embodiments of the methods, methods as defined above, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

此外，本發明公開了用於治療需要其的患者中癌症的方法，所述方法包括(a)確定癌症與KRAS G12D突變相關(例如，KRAS G12D相關癌症)；以及(b)向患者施用治療有效量的至少一種如上文定義的化合物。Additionally, disclosed are methods for treating cancer in a patient in need thereof comprising (a) determining that the cancer is associated with a KRAS G12D mutation (eg, KRAS G12D-associated cancer); and (b) administering to the patient a therapeutically effective amount of at least one compound as defined above.

在某些用於治療需要其的患者中癌症的方法的實施方案中，所述方法包括(a)確定癌症與KRAS G12D突變相關(例如，KRAS G12D相關癌症)；以及(b)向患者施用治療有效量的至少一種如上文定義的化合物。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., a KRAS G12D-associated cancer); and (b) administering the treatment to the patient An effective amount of at least one compound as defined above.

在某些用於治療需要其的患者中癌症的方法的實施方案中，所述方法包括(a)確定癌症與KRAS G12D突變相關(例如，KRAS G12D相關癌症)；以及(b)向患者施用治療有效量的至少一種如式I、式I’或示例性化合物定義的化合物。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., a KRAS G12D-associated cancer); and (b) administering the treatment to the patient An effective amount of at least one compound as defined by Formula I, Formula I' or an exemplary compound.

在某些用於治療需要其的患者中癌症的方法的實施方案中，所述方法包括(a)確定癌症與KRAS G12D突變相關(例如，KRAS G12D相關癌症)；以及(b)向患者施用治療有效量的如上文定義的藥物組合物。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., a KRAS G12D-associated cancer); and (b) administering the treatment to the patient An effective amount of a pharmaceutical composition as defined above.

在某些用於治療需要其的患者中癌症的方法的實施方案中，其中施用經由選自由以下組成的組的途徑來進行：腸胃外施用、腹腔施用、經皮施用、心內施用、心室內施用、顱內施用、腦脊髓內施用(intracerebrospinal administration)、滑膜內施用、鞘內施用、肌肉內注射、玻璃體內注射(intravitreous injection)、靜脈注射、動脈內注射、口服施用、鼻內施用、含服(buccal)、舌下施用(sublingual administration)、經皮施用、局部施用、氣管內施用、直腸內施用、皮下施用以及局部施用。In certain embodiments of the method for treating cancer in a patient in need thereof, wherein administering is via a route selected from the group consisting of: parenteral administration, intraperitoneal administration, transdermal administration, intracardiac administration, intraventricular administration administration, intracranial administration, intracerebrospinal administration, intrasynovial administration, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intraarterial injection, oral administration, intranasal administration, Buccal, sublingual administration, transdermal administration, topical administration, intratracheal administration, intrarectal administration, subcutaneous administration and topical administration.

在某些用於治療需要其的患者中癌症的方法的實施方案中，施用經由靜脈注射來進行。In certain embodiments of the methods for treating cancer in a patient in need thereof, the administering is via intravenous injection.

在某些用於治療需要其的患者中癌症的方法的實施方案中，施用經由肌肉內注射來進行。In certain embodiments of the methods for treating cancer in a patient in need thereof, the administering is via intramuscular injection.

在某些用於治療需要其的患者中癌症的方法的實施方案中，施用經由肌肉內注射來進行。In certain embodiments of the methods for treating cancer in a patient in need thereof, the administering is via intramuscular injection.

在某些用於治療需要其的患者中癌症的方法的實施方案中，施用包括採用遞送裝置。In certain embodiments of the methods for treating cancer in a patient in need thereof, administering comprises employing a delivery device.

在某些用於治療需要其的患者中癌症的方法的實施方案中，施用經由醫院設施(hospital setting)來進行。In certain embodiments of the methods for treating cancer in a patient in need thereof, the administration is via a hospital setting.

應理解，本發明可以以其他具體的形式來實施，而不偏離其精神或本質屬性。本發明涵蓋本文中提到的本發明的方面和/或實施方案的全部組合。還應理解，實施方案中的每個單獨的要素意指與來自任何實施方案的任何要素和全部其他要素組合以描述另外的實施方案。It should be understood that the present invention may be embodied in other specific forms without departing from its spirit or essential attributes. The present invention covers 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 meant to be combined with any element from any embodiment and all other elements to describe a further embodiment.

定義definition

在本公開內容被認為是所要求保護的主題的示例的理解下做出以下描述，並且不意圖將所附申請專利範圍限制為示出的具體實施方案。為了便利，設置本公開內容中使用的標題，並且不認為以任何方式限制申請專利範圍。在任何標題下示出的實施方案可以與任何其他示出的標題實施方案組合。The following description is made with the understanding that the disclosure is considered to be an example of the claimed subject matter, and is not intended to limit the scope of the appended application to the specific embodiments shown. The headings used in this disclosure are set for convenience and are not considered to limit the scope of claims in any way. An embodiment shown under any heading may be combined with any other shown heading embodiment.

除非另外定義，否則本文使用的所有技術術語和科學術語具有與本領域普通技術人員通常理解相同的含義。應注意到，如本公開內容中使用的，單數形式“一(a)”、“和(and)”以及“該(the)”包括複數指示物，除非上下文另外清楚地說明。因此，“該化合物(the compound)”包括多個這樣的化合物並且“測定法(the assay)”包括一種或更多種測定法，以及諸如此類。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," and "the" include plural referents unless the context clearly dictates otherwise. Thus, reference to "the compound" includes a plurality of such compounds and "the assay" includes one or more assays, and the like.

如本公開內容中使用的，除了在其中使用它們的上下文中另外說明的程度上，以下詞語(words)、措辭(phrases)和符號通常意圖具有與下文列出的詞語、措辭和符號相同的含義。As used in this disclosure, the following words, phrases and symbols are generally intended to have the same meaning as the words, phrases and symbols listed below, except to the extent otherwise indicated in the context in which they are used .

為了便利，在化學基團的前面或末端處使用短線(dash)“-”以指示取代基的附接點(point of attachment)。例如-OH通過碳原子附接；可以用或不用一個或更多個短線來描述化學基團，而不失去其常用含義。通過結構中的線畫出的波浪線(wavy line)指示基團的附接點。除非化學上或結構上有要求，否則方向性不通過其中書寫或命名化學基團的順序來指示或意指。來自環的中心的實線(solid line)指示環上的取代基的附接點可以在任何環原子處。例如，以下結構中的X 1可以被附接至碳環原子中的任何，包括橋碳原子：

Figure 02_image066
For convenience, a dash "-" is used at the front or terminus of a chemical group to indicate the point of attachment of a substituent. For example -OH is attached through a carbon atom; one or more dashes may or may not be used to describe a chemical group without losing its usual meaning. Wavy lines drawn through lines in structures indicate points of attachment of groups. Unless chemically or structurally required, directionality is not indicated or implied by the order in which chemical groups are written or named. A solid line from the center of a ring indicates that the point of attachment of a substituent on the ring can be at any ring atom. For example, X in the following structure can be attached to any of the carbon ring atoms, including bridging carbon atoms:
Figure 02_image066

首碼“C m-n”指示以下基團具有從m個至n個碳原子。例如，“C 1-8烷基”指示烷基基團具有從1個至8個碳原子。以類似的方式，術語“m元-n元”環，其中m和n是數值範圍，例如“3元-12元雜環基”，指的是包含3個-12個原子的環，其中多達80%可以是雜原子，例如N、O、S、P，並且其餘的原子是碳。 The prefix "C mn " indicates that the following group has from m to n carbon atoms. For example, "C 1-8 alkyl" indicates an alkyl group having from 1 to 8 carbon atoms. In a similar manner, the term "m-membered-n-membered" ring, where m and n are numerical ranges, such as "3-membered-12-membered heterocyclyl", refers to rings containing 3-12 atoms, in which more Up to 80% can be heteroatoms, such as N, O, S, P, with the remaining atoms being carbon.

另外，可以使用或可以不使用某些常用的可選擇的化學名稱。例如，諸如二價“烷基”基團、二價“芳基”基團等的二價基團還可以分別地被稱為“亞烷基”基團或“亞烯基”基團或亞炔基基團、“亞芳基(arylene)”基團或“亞芳基(arylenyl)”基團或“亞芳基(arylyl)”基團。Additionally, certain common alternative chemical names may or may not be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" groups or "alkenylene" groups or alkylene groups, respectively. An alkynyl group, an "arylene" group or an "arylenyl" group or an "arylyl" group.

“本文提供的化合物”或“本文描述的化合物”或“本文公開的化合物”或“本公開內容的化合物”指的是式(I)的化合物、式(I′)的化合物、(II-a)式的化合物、式(II-b)的化合物、式(III-a)的化合物、式(III-b)的化合物、式(IV-a)的化合物、式(IV-b)的化合物、式(V-a)的化合物和式(V-b)的化合物，其還用於實施例1至實施例38的具體化合物或前面提及的示例性化合物。"Compounds provided herein" or "compounds described herein" or "compounds disclosed herein" or "compounds of the disclosure" refer to compounds of formula (I), compounds of formula (I'), (II-a ) compound of formula, compound of formula (II-b), compound of formula (III-a), compound of formula (III-b), compound of formula (IV-a), compound of formula (IV-b), Compounds of formula (V-a) and compounds of formula (V-b), which are also used for the specific compounds of Examples 1 to 38 or the aforementioned exemplary compounds.

在某些實施方案中，涉及值或參數自身的術語“約”包括所指示的量±10%、±5%或±1%。另外，術語“約X”包括“X”的描述。In certain embodiments, the term "about" in reference to a value or parameter per se includes ±10%, ±5%, or ±1% of the indicated amount. Additionally, the term "about X" includes the description "X".

如本文使用的，“鄰接原子(adjoining atoms)”指的是彼此緊密接近的原子。例如，在“C1-C2-C3-C4”中，原子C1與原子C2鄰接，原子C2與原子C1和原子C3鄰接，諸如此類。As used herein, "adjoining atoms" refers to atoms that are 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.

術語“烷基”指的是非支鏈的(unbranched)或支鏈的飽和的烴鏈。如本文使用的，烷基具有1個至6個碳原子(即，C 1-6烷基)或1個至10個碳原子(即，C 1-10烷基)。烷基基團包括甲基、乙基、丙基、異丙基、正丁基、仲丁基、異丁基、叔丁基、戊基、2-戊基、異戊基、新戊基、己基、2-己基、3-己基以及3-甲基戊基。當具有特定數目的碳的烷基基團通過化學名稱來命名或通過分子式來確定時，可以包括具有該數目的碳的所有位置異構體(positional isomers)，因此，作為實例，“丁基”包括正丁基(即，-(CH 2) 3CH 3)、仲丁基(即，-CH(CH 3)CH 2CH 3)、異丁基(即，-CH 2CH(CH 3) 2)以及叔丁基(即，-C(CH 3) 3)，並且“丙基”包括正丙基(即，-(CH 2) 2CH 3)和異丙基(即，-CH(CH 3) 2)。 The term "alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 6 carbon atoms (ie, C 1-6 alkyl) or 1 to 10 carbon atoms (ie, 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 specific number of carbons is named by a chemical name or identified by a molecular formula, all positional isomers with that number of carbons can be included, thus, as an example, "butyl" Including n-butyl (ie, -(CH 2 ) 3 CH 3 ), sec-butyl (ie, -CH(CH 3 )CH 2 CH 3 ), isobutyl (ie, -CH 2 CH(CH 3 ) 2 ) and tert-butyl (ie, -C(CH 3 ) 3 ), and "propyl" includes n-propyl (ie, -(CH 2 ) 2 CH 3 ) and isopropyl (ie, -CH(CH 3 ) 2 ).

術語“烯基”指的是包含至少一個碳-碳雙鍵(C=C)並且具有從2個至15個碳原子(即，C 2-15烯基)或從2個至4個碳原子(即，C 2-4烯基)的脂肪族基團。烯基基團的實例包括乙烯基、丙烯基、丁二烯基(包括1,2-丁二烯基和1,3-丁二烯基)。 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., C2-15 alkenyl) or from 2 to 4 carbon atoms (ie, C 2-4 alkenyl) aliphatic group. Examples of alkenyl groups include vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

術語“炔基”指的是包含至少一個碳-碳三鍵(C≡C)並且具有從2個至10個碳原子(即，C 2-10炔基)或從2個至4個碳原子(即，C 2-4炔基)等的脂肪族基團。術語“炔基”還包括具有一個三鍵和一個雙鍵的那些基團。 The term "alkynyl" refers to a group containing at least one carbon-carbon triple bond (C≡C) and having from 2 to 10 carbon atoms (i.e., C2-10 alkynyl) or from 2 to 4 carbon atoms (ie, C 2-4 alkynyl) and the like aliphatic group. The term "alkynyl" also includes those groups having one triple bond and one double bond.

術語“烷氧基”指的是基團“-O-烷基”，例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基以及1,2-二甲基丁氧基。術語“鹵代烷氧基”指的是如上文指示的烷氧基基團，其中一個或更多個氫原子被鹵素取代。The term "alkoxy" refers to the group "-O-alkyl" such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butyl oxy, n-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy. The term "haloalkoxy" refers to an alkoxy group as indicated above, wherein one or more hydrogen atoms are replaced by a halogen.

術語“醯基”指的是基團-C(=O)R，此處R是氫、烷基、環烷基、雜環基、芳基、雜烷基或雜芳基，並且其中的每個可以是任選地被取代的，如本文定義的。醯基基團的實例包括甲醯基、乙醯基、環己基羰基、環己基甲基羰基以及苯甲醯基等。The term "acyl" refers to the group -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, and each of Each can be optionally substituted, as defined herein. Examples of the acyl group include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and the like.

術語“醯胺基(amido)”指的是“C-醯胺基”基團和“N-醯胺基”基團兩者，所述“C-醯胺基”基團指的是基團-C(=O)NR aR b，所述“N-醯胺基”基團指的是基團-NR aC(=O)R b，其中R a和R b獨立地選自由以下組成的組：氫、烷基、芳基、鹵代烷基、雜芳基、環烷基以及雜環基；並且其中的每個可以是任選地被取代的。 The term "amido" refers to both a "C-amido" group and an "N-amido" group, the "C-amido" group referring to the group -C(=O)NR a R b , the "N-amido" group refers to the group -NR a C(=O)R b , wherein R a and R b are independently selected from the group consisting of The group of: hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, and heterocyclyl; and each of which may be optionally substituted.

“氨基”指的是基團-NR aR b，此處R a和R b獨立地選自由以下組成的組：氫、烷基、鹵代烷基、芳基、雜芳基、環烷基以及雜環基；並且其中的每個可以是任選地被取代的。 "Amino" refers to the group -NR a R b , where Ra and R b are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and hetero and each of which may be optionally substituted.

術語“芳基”指的是芳香族碳環基團，所述芳香族碳環基團具有單個環(例如，單環的(monocyclic))或包括稠合體系的多環(例如，雙環的(bicyclic)或三環的(tricyclic))。如本文使用的實例，芳基具有6個至20個環碳原子(即，C 6-20芳基)、6個至12個碳環原子(即，C 6-12芳基)等。芳基基團的某些實例包括苯基、萘基、芴基和蒽基。本文中，芳基不以任何方式涵蓋如下文定義的雜芳基並且不以任何方式與如下文定義的雜芳基重疊。如果一個或更多個芳基基團與雜芳基環稠合，那麼產生的環體系是雜芳基。 The term "aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic (monocyclic)) or polycyclic rings including fused systems (e.g., bicyclic ( bicyclic) or tricyclic (tricyclic)). As an example used herein, aryl has 6 to 20 ring carbon atoms (ie, C6-20 aryl), 6 to 12 carbon ring atoms (ie, C6-12 aryl), and the like. Some examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracenyl. Herein, aryl does not in any way encompass and overlap in any way with heteroaryl as defined below. If one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is heteroaryl.

術語“氰基”基團或“腈(carbonitrile)”基團由-CN代表。The term "cyano" group or "carbonitrile" group is represented by -CN.

術語“環烷基”指的是具有單個環或多環的飽和的或部分飽和的環狀烷基基團(cyclic alkyl group)，所述多環包括稠合環體系、橋接環體系和螺環體系。術語“環烷基”還包括環烯基基團(即，具有至少一個雙鍵的環狀基團(cyclic group))。如本文使用的，環烷基具有從3個至20個環碳原子(即，C 3-20環烷基)、從3個至8個環碳原子(即，C 3-8環烷基)或從3個至5個環碳原子(即，C 3-5環烷基)等。實例包括環丙基、環丁基、環戊基和環己基。 The term "cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused ring systems, bridged ring systems and spiro rings system. The term "cycloalkyl" also includes cycloalkenyl groups (ie, cyclic groups having at least one double bond). As used herein, cycloalkyl has 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 (ie, C 3-5 cycloalkyl) and the like. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

術語“橋接的”指的是環稠合(ring fusion)，在所述環稠合中環上非鄰近的原子通過二價取代基連接，所述二價取代基例如烯基基團、包含一個或兩個雜原子的烯基基團或單個雜原子。橋接環體系的實例包括奎寧環基(quinuclidinyl)和金剛烷基(admantanyl)。The term "bridged" refers to a ring fusion in which non-adjacent atoms on the ring are linked by a divalent substituent, such as an alkenyl group, comprising one or An alkenyl group of two heteroatoms or a single heteroatom. Examples of bridged ring systems include quinuclidinyl and admantanyl.

術語“稠合的”指的是結合至鄰近環的環。The term "fused" refers to rings that are bonded to adjacent rings.

術語“螺環(spiro)”指的是在相同碳原子處通過兩個鍵連接的環取代基。螺環基團的某些實例包括1,1-二乙基環戊烷、二甲基二氧六環和4-苄基-4-甲基呱啶，其中環戊烷和呱啶分別是螺環取代基。The term "spiro" refers to a ring substituent joined by two bonds at the same carbon atom. Some examples of spiro groups include 1,1-diethylcyclopentane, dimethyldioxane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro ring substituents.

“鹵素(halogen)或“鹵素(halo)”包括氟(F)、氯(Cl)、溴(Br)和碘(I)。“鹵代烷基”包括如上文定義的非支鏈的或支鏈的烷基基團，其中一個或更多個氫原子被鹵素取代。如果殘基(residue)被多於一個鹵素取代，那麼其可以被稱為通過使用對應於所附接的鹵素部分的數目的首碼(prefix)。二鹵代烷基(dihaloalkyl)和三鹵代烷基(trihaloalkyl)指的是被兩個(two)(“二(di)”)鹵素基團或三個(three)(“三(tri)”)鹵素基團取代的烷基，所述兩個鹵素基團和三個鹵素基團可以，但不必須，是相同的鹵素。鹵代烷基的某些實例包括二氟甲基(-CHF 2)和三氟甲基(-CF 3)。 "Halogen" or "halo" includes fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). "Haloalkyl" includes unbranched or branched as defined above. Alkyl group, wherein one or more hydrogen atoms are replaced by halogen. If the residue (residue) is replaced by more than one halogen, then it can be called by using the first corresponding to the number of halogen moieties attached Code (prefix). Dihaloalkyl (dihaloalkyl) and trihaloalkyl (trihaloalkyl) refer to two (two) ("two (di)") halogen groups or three (three) ("three (tri) ”) alkyl substituted by halo groups, the two halo groups and the three halo groups may, but need not, be the same halo. Some examples of haloalkyl groups include difluoromethyl (-CHF 2 ) and trifluoromethyl (-CF 3 ).

術語“雜芳基”指的是具有單個環、多環或多個稠合環的芳香族基團，所述芳香族基團具有一個或更多個獨立地選自N、O和S的環雜原子。如本文使用的實例，雜芳基包括雜芳基包括1個至20個碳環原子(即，C 1-20雜芳基)、3個至12個碳環原子(即，C 3-20雜芳基)等，以及該數目的環雜原子，如其中使用的，所述雜原子獨立地選自氮、氧和硫。雜芳基基團的實例包括嘧啶基、嘌呤基、吡啶基、噠嗪基、苯並噻唑基和吡唑基。術語“雜芳基”不涵蓋如上文定義的“芳基”並且不與如上文定義的“芳基”重疊。 The term "heteroaryl" refers to an aromatic group having a single ring, multiple rings or multiple fused rings having one or more rings independently selected from N, O and S heteroatoms. As used herein by way of example, heteroaryl includes heteroaryl 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), aryl) and the like, and the number of ring heteroatoms, as used therein, independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl and pyrazolyl. The term "heteroaryl" does not encompass and does not overlap with "aryl" as defined above.

“羥基(hydroxy)”或“羥基(hydroxyl)”指的是基團-OH。"Hydroxy" or "hydroxyl" refers to the group -OH.

“氧代”指的是基團(=O)或(O)。"Oxo" refers to the group (=O) or (O).

除非另外指示，否則在所有基團以單個鍵合的氮原子終止的情況下，該基團代表-NH基團。類似地，除非另外表述，否則鑒於本領域技術人員的知識，必然包含(imply)氫原子並且在必要時氫原子被認為是存在的，以完成價(valency)或提供穩定性。Unless otherwise indicated, where all groups terminate with a single bonded nitrogen atom, the group represents an -NH group. Similarly, unless stated otherwise, hydrogen atoms are implied and are considered to be present where necessary to accomplish valency or provide stability, given the knowledge of those skilled in the art.

“任選的”或“任選地”意指隨後描述的事件或情形可以發生或可以不發生，並且該描述包括其中所述事件或情形存在的情況以及其中所述事件或情形不存在的情況。另外，術語“任選地被取代的”意指指定的原子或基團上的任何一個或更多個氫原子可以被除了氫之外的部分取代或可以不被除了氫之外的部分取代。"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 exists and instances where it does not . Additionally, the term "optionally substituted" means that any one or more hydrogen atoms on the designated atom or group may or may not be substituted with moieties other than hydrogen.

“被取代的”意指在不超過指定的原子的正常價(normal valence)的條件下，指定的原子或基團上的一個或更多個氫原子被一個或更多個除了氫之外的取代基取代。取代基包括，但不限於，烷基、烯基、炔基、烷氧基、醯基、氨基、醯胺基、脒基(amidino)、芳基、疊氮基、氨甲醯基(carbamoyl)、羰基、羰基酯、氰基、胍基、鹵素、鹵代烷基、雜烷基、雜芳基、雜環基、羥基、肼基、亞氨基、氧代、硝基、烷基亞磺醯基(alkylsulfinyl)、磺酸、烷基磺醯基、硫氰酸酯(thiocyanate)、硫醇、硫酮(thione)或其組合。本文不意圖包括通過用附加至無窮大的另外的取代基定義取代基獲得的類似不確定結構(例如，具有被取代的烷基的被取代的芳基，所述被取代的烷基自身被被取代的芳基基團取代，所述被取代的芳基基團另外被被取代的雜烷基基團取代等)。除非另外提到，否則本文描述的化合物中的連續取代(serial substitutions)的最大數目是三。例如，具有兩個其他被取代的芳基基團的被取代的芳基基團的連續取代限於((被取代的芳基)被取代的芳基)被取代的芳基。類似地，以上定義不意圖包括不可能的取代類型(substitution pattern)(例如，被5個氟取代的甲基或具有兩個鄰近氧環原子的雜芳基基團)。這樣的不可能的取代類型對本領域技術人員是熟知的。在所有用於修飾化學基團的情況下，“被取代的”可以描述本文定義的其他化學基團。例如，術語“被取代的芳基”包括，但不限於，“烷基芳基”。除非另外明確規定，否則如果基團被描述為任選地被取代的，那麼該基團的任何取代基本身是未被取代的。"Substituted" means that one or more hydrogen atoms on the designated atom or group are replaced by one or more hydrogen atoms other than hydrogen without exceeding the designated atom's normal valence. Substituents replace. Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl , carbonyl, carbonyl ester, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxyl, hydrazino, imino, oxo, nitro, alkylsulfinyl ( alkylsulfinyl), sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. It is not intended herein to include similar undefined structures obtained by defining substituents with additional substituents appended to infinity (eg, substituted aryl with substituted alkyl which itself is substituted substituted by an aryl group which is additionally substituted by a substituted heteroalkyl group, etc.). Unless otherwise mentioned, the maximum number of serial substitutions in the compounds described herein is three. For example, sequential substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include impossible substitution patterns (eg, a methyl group substituted with 5 fluorines or a heteroaryl group with two adjacent oxygen ring atoms). Such improbable substitution patterns are well known to those skilled in the art. "Substituted" in all cases used to modify a chemical group may describe other chemical groups as defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl". Unless expressly stated otherwise, if a group is described as being optionally substituted, then any substituents for that group are themselves unsubstituted.

在某些情況下，“被取代的烷基”指的是具有一個或更多個取代基的烷基基團，所述取代基包括羥基、鹵素、氨基、烷氧基、環烷基、雜環基、芳基和雜芳基。在另外的情況下，“被取代的環烷基”指的是具有一個或更多個取代基的環烷基基團，所述取代基包括烷基、鹵代烷基、環烷基、雜環基、芳基、雜芳基、氨基、烷氧基、鹵素、氧代和羥基；通過“被取代的雜環基”，其指的是具有一個或更多個取代基的雜環基基團，所述取代基包括烷基、氨基、鹵代烷基、雜環基、環烷基、芳基、雜芳基、烷氧基、鹵素、氧代和羥基；術語“被取代的芳基”指的是具有一個或更多個取代基的芳基基團，所述取代基包括鹵素、烷基、氨基、鹵代烷基、環烷基、雜環基、雜芳基、烷氧基和氰基；術語“被取代的雜芳基”指的是具有一個或更多個取代基的芳基基團，所述取代基包括鹵素、烷基、氨基、鹵代烷基、環烷基、雜環基、雜芳基、烷氧基和氰基；術語“被取代的雜芳基”指的是具有一個或更多個取代基的雜芳基基團，所述取代基包括鹵素、氨基、烷基、鹵代烷基、環烷基、芳基、雜環基、雜芳基、烷氧基和氰基；並且術語“被取代的磺醯基”指的是基團-S(O) 2R，此處R被一個或更多個取代基取代，所述取代基包括烷基、環烷基、雜環基、芳基和雜芳基。在其他情況下，一個或更多個取代基可以另外被以下取代：鹵素、烷基、鹵代烷基、羥基、烷氧基、環烷基、雜環基、芳基或雜芳基，其中的每個是被取代的。在其他情況下，取代基可以另外被以下取代：鹵素、烷基、鹵代烷基、烷氧基、羥基、環烷基、雜環基、芳基或雜芳基，其中的每個是未被取代的。 In some instances, "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxy, halo, amino, alkoxy, cycloalkyl, hetero Cyclic, 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, halogen, oxo, and hydroxy; by "substituted heterocyclyl" it is meant a heterocyclyl group having one or more substituents, Such substituents include alkyl, amino, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halogen, oxo, and hydroxy; the term "substituted aryl" refers to An aryl group having one or more substituents including halogen, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy and cyano; the term ""Substitutedheteroaryl" refers to an aryl group having one or more substituents including halo, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl , alkoxy, and cyano; the term "substituted heteroaryl" refers to a heteroaryl group 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) 2R , where R is replaced by one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. In other cases, one or more substituents may additionally be substituted by halogen, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which one is replaced. 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 of.

在某些實施方案中，被取代的環烷基、被取代的雜環基、被取代的芳基和/或被取代的雜芳基包括在環原子上具有取代基的環烷基、雜環基、芳基和/或雜芳基，所述環烷基、雜環基、芳基和/或雜芳基的所述環原子被附接至化合物的其餘部分(rest)。例如，在以下部分中，苯環被間氯基團取代：

Figure 02_image068
In certain embodiments, substituted cycloalkyl, substituted heterocyclyl, substituted aryl and/or substituted heteroaryl include cycloalkyl, heterocyclic radical, aryl and/or heteroaryl, said ring atoms of said cycloalkyl, heterocyclyl, aryl and/or heteroaryl are attached to the rest of the compound. For example, in the following moieties, the benzene ring is replaced by a meta-chloro group:
Figure 02_image068

本文中，公開的化合物或其藥學上可接受的鹽可以包括一個或更多個不對稱中心並且從而產生互變異構體、非對映異構體和其他立體異構形式，對於氨基酸，根據絕對立體化學，所述互變異構體、非對映異構體和其他立體異構形式可以被定義為(R)-或(S)-或被定義為(D)-或(L)-。本公開內容包括所有這樣的可能的異構體，以及其外消旋形式或光學上純的形式。光學上活性的(+)異構體和(-)異構體、(R)-異構體和(S)-異構體或(D)-異構體和(L)-異構體可以使用手性合成子(synthon)或手性試劑來製備，或通過常規的技術例如色譜法(chromatography)和分段結晶(fractional crystallization)來拆分。用於單獨的互變異構體的製備、分離的傳統技術包括從合適的光學上純的前體(precursor)手性合成或使用例如手性高效液相色譜法(HPLC)來拆分外消旋體(鹽或衍生物的外消旋體)。當本文公開的化合物包含烯烴雙鍵或幾何非對稱的其他中心時，並且除非另外明確規定，否則這些化合物包括E幾何異構體和Z幾何異構體兩者。同樣地，還意圖包括所有互變異構形式。在所有以化合物的手性形式表示化合物的情況下，應理解實施方案包括，但不限於，具體的非對映異構地或互變異構地富集的形式。在沒有明確規定手性但手性存在的情況下，應理解實施方案意圖包括具體的非對映異構地或互變異構地富集的形式；或這樣的化合物的外消旋混合物或非外消旋(scalemic)混合物。“非外消旋混合物”是立體異構體以除了1:1之外的比率的混合物。The compounds disclosed herein, or pharmaceutically acceptable salts thereof, may include one or more asymmetric centers and thereby give rise to tautomers, diastereoisomers and other stereoisomeric forms, for amino acids, according to the absolute Stereochemistry, the tautomers, diastereoisomers and other stereoisomeric forms may be defined as (R)- or (S)- or as (D)- or (L)-. The present disclosure includes all such possible isomers, as well as their racemic or optically pure forms. Optically active (+) isomers and (-) isomers, (R)-isomers and (S)-isomers or (D)-isomers and (L)-isomers can be Prepared using chiral synthons or chiral reagents, or resolved by conventional techniques such as chromatography and fractional crystallization. Traditional techniques for the preparation, isolation, of individual tautomers include chiral synthesis from suitable optically pure precursors or resolution of racemic tautomers using, for example, chiral high performance liquid chromatography (HPLC). Body (racemate of salt or derivative). When the compounds disclosed herein contain olefinic double bonds or other centers of geometric asymmetry, and unless expressly stated otherwise, such compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. In all cases where a compound is represented in its chiral form, it is to be understood that the embodiments include, but are not limited to, the particular diastereomerically or tautomerically enriched form. Where chirality is not expressly stated, but exists, it is to be understood that the embodiments are intended to include specific diastereomerically or tautomerically enriched forms; or racemic mixtures or non-exomeric mixtures of such compounds. Racemic (scalemic) mixture. A "non-racemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

術語“立體異構體”指的是包含相同原子但具有不同的三維結構的不可互變的化合物，所述相同的原子通過相同的鍵來鍵合。本公開內容涵蓋多種立體異構體及其混合物，並且包括“互變異構體”，所述互變異構體指的是兩個立體異構體，所述兩個異構體的分子是彼此的不可重疊的鏡像。The term "stereoisomer" refers to noninterconvertible compounds containing identical atoms bonded by identical bonds but having different three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "tautomers," which refers to two stereoisomers whose molecules are relative to each other. Non-overlapping mirror images.

術語“互變異構體”代表一對立體異構體，所述立體異構體是彼此的不可重疊的鏡像。一對互變異構體的1:1混合物是“外消旋”混合物。互變異構體以除了1:1的比率的混合物是“非外消旋”混合物。The term "tautomers" denotes a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of tautomers is a "racemic" mixture. A mixture of tautomers in a ratio other than 1:1 is a "non-racemic" mixture.

術語“非對映異構體”代表具有至少兩個非對稱原子、但不是彼此的鏡像的立體異構體，。The term "diastereomer" denotes stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other.

術語“PROTAC”代表蛋白水解靶向嵌合體(proteolysis-targeting chimeras)。The term "PROTAC" stands for proteolysis-targeting chimeras.

溶劑和化合物的相互作用形成“溶劑化物”。在本文中，溶劑化物還包括公開的化合物的鹽的溶劑化物以及本文提供的化合物的水合物。Solvents and compounds interact to form "solvates". As used herein, solvates also include solvates of the salts of the disclosed compounds as well as hydrates of the compounds provided herein.

本公開內容包括式(I)的化合物、式(I′)的化合物、式(II-a)的化合物、式(II-b)的化合物、式(III-a)的化合物、式(III-b)的化合物、式(IV-a)的化合物、式(IV-b)的化合物、式(V-a)的化合物和式(V-b)的化合物，其中，被附接至分子中的碳原子的R 1至R 6，它們中的至少一個是氘原子(D)。這樣的化合物具有增強的對代謝的抗性(resistance)並且因此用於增加被施用至哺乳動物特別是人類的式(I)的任何化合物、式(I′)的任何化合物、式(II-a)的任何化合物、式(II-b)的任何化合物、式(III-a)的任何化合物、式(III-b)的任何化合物、式(IV-a)的任何化合物、式(IV-b)的任何化合物、式(V-a)的任何化合物和式(V-b)的任何化合物的半衰期(Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984))。這樣的化合物的合成通過本領域熟知的手段，例如通過採用其中一個或更多個氫已經被氘取代的起始材料來實現。 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 (Va) and compounds of formula (Vb), wherein R attached to a carbon atom in the molecule 1 to R 6 , at least one of which is a deuterium atom (D). Such compounds have enhanced resistance to metabolism and are therefore useful for increasing any compound of formula (I), any compound of formula (I′), formula (II-a) administered to mammals, especially humans. ), 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 (Va) and any compound of formula (Vb) half-life (Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 ( 1984)). The synthesis of such compounds is achieved by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

本公開內容的被氘取代的治療性化合物可以具有改進的DMPK(藥物代謝和藥代動力學)性質，涉及吸收、分佈、代謝和***(ADME)。由較強代謝穩定性產生的某些治療優點例如增加的體內半衰期、減少的劑量需求(dosage requirement)和/治療指數(therapeutic index)的改進可以通過用諸如氘的較重同位素取代來實現。應澄清，在本上下文中，氘被認為是R 1基團至R 6基團中的至少一個，式(I)的化合物、式(I′)的化合物、式(II-a)的化合物、式(II-b)的化合物、式(III-a)的化合物、式(III-b)的化合物、式(IV-a)的化合物、式(IV-b)的化合物、式(V-a)的化合物和式(V-b)的化合物中的取代基是D。 The deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (Drug Metabolism and Pharmacokinetics) properties related to absorption, distribution, metabolism and excretion (ADME). Certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirement and/or improvement in 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 at least one of the groups R1 to R6 , 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 (Va) The substituent in the compound and the compound of formula (Vb) is D.

同位素富集因數(isotopic enrichment factor)可以用於定義這樣的較重同位素特別地氘的濃度。應理解，在本公開的化合物中，不具體指定為特定同位素的任何原子意指代表該原子的任何穩定的同位素。如果位置被特定地指定為“H”或“氫”，那麼該位置被理解為具有以其天然富含同位素組成的氫。因此，在本公開的化合物中，被特定地指定為氘(D)的任何原子意指代表氘。An isotopic enrichment factor can be used to define the concentration of such heavier isotopes, particularly 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," then that position is understood to have hydrogen in its naturally enriched isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

在許多情況下，借助於氨基基團或與之類似的基團的存在，本公開的化合物能夠形成酸鹽(acid salts)。In many cases, the compounds of the present disclosure are capable of forming acid salts by virtue of the presence of an amino group or a group similar thereto.

術語“藥學上可接受的鹽”指的是由藥學上可接受的無毒的鹼或酸製備的鹽。在本發明的化合物是酸性的情況下，其對應的鹽可以由藥學上可接受的無毒的鹼來常規地製備，所述藥學上可接受的無毒的鹼包括無機鹼和有機鹼。在本發明的化合物是鹼性的情況下，其對應的鹽可以由藥學上可接受的無毒的酸來常規地製備，所述藥學上可接受的無毒的酸包括無機酸和有機酸。由於的式(I)的化合物、式(I′)的化合物、式(II-a)的化合物、式(II-b)的化合物、式(III-a)的化合物、式(III-b)的化合物、式(IV-a)的化合物、式(IV-b)的化合物、式(V-a)的化合物和式(V-b)的化合物意圖用於藥物用途，它們優選地以大體上純的形式被提供，例如至少60%純的，更合適地至少75%純的、尤其是至少98%純的(%是以重量與重量為基礎的)。The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conventionally prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conventionally prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Due to 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) are intended for pharmaceutical use, they are preferably in substantially pure form Provided, for example, is at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight to weight basis).

本發明的藥物組合物包含作為活性成分的由式(I)、式(I′)、式(II-a)、式(II-b)、式(III-a)、式(III-b)、式(IV-a)、式(IV-b)、式(V-a)和式(V-b)代表的化合物(或其藥學上可接受的鹽)、藥學上可接受的載體以及任選地其他治療成分或佐劑(adjuvant)。儘管在任何給出的情況下，最合適的途徑將取決於具體的宿主(host)和活性成分被施用於的狀況的性質和嚴重程度，但是組合物包括適合於口服施用、直腸施用、局部施用和腸胃外(包括皮下、肌肉內和靜脈)施用的組合物。藥物組合物可以以單位劑型常規地提供並且通過藥學領域熟知的方法中的任何來製備。The pharmaceutical composition of the present invention comprises formula (I), formula (I'), formula (II-a), formula (II-b), formula (III-a), formula (III-b) as active ingredient , a compound represented by 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 treatments ingredient or adjuvant. Although in any given case the most suitable route will depend on the particular host and the nature and severity of the condition to which the active ingredient is administered, compositions include those suitable for oral, rectal, topical, and compositions for parenteral (including subcutaneous, intramuscular and intravenous) administration. Pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

在實踐中，根據常規的藥物混合技術(conventional pharmaceutical compounding technique)，本發明的通過式(I)、式(I′)、式(II-a)、式(II-b)、式(III-a)、式(III-b)、式(IV-a)、式(IV-b)、式(V-a)和式(V-b)代表的化合物或其前驅藥或其代謝物或其藥學上可接受的鹽可以作為活性成分與藥物載體在緊密摻合物(intimate admixture)中組合。取決於期望用於施用的製劑(preparation)的形式，載體可以採取多種形式，所述施用例如口服施用或腸胃外施用(包括靜脈內施用)。因此，本發明的藥物組合物可以作為適合於口服施用的離散單元(discrete unit)被提供，例如膠囊、扁囊劑(cachet)或片劑，各自包含預先確定的量的活性成分。另外，組合物可以作為粉末、作為顆粒劑、作為溶液、作為含水液體中的懸浮液、作為非含水液體、作為水包油乳液或作為油包水液體乳液被提供。除了上文列出的常用劑型之外，通過式I或式I’代表的化合物或其藥學上可接受的鹽還可以通過控釋手段(controlled release mean)和/或遞送裝置來施用。組合物可以通過藥學的方法中的任何來製備。通常，這樣的方法包括促使活性成分與由一種或更多種必要的成分構成的載體締合(association)的步驟。通常，組合物通過將活性成分與液體載體或細分的(finely divided)固體載體或兩者均勻地且緊密地摻合來製備。然後，將產物常規地成型為期望的呈遞形式(presentation)。In practice, according to the conventional pharmaceutical compounding technique (conventional pharmaceutical compounding technique), the formula (I), formula (I'), formula (II-a), formula (II-b), formula (III- a), the compound represented by formula (III-b), formula (IV-a), formula (IV-b), formula (V-a) and formula (V-b) or its prodrug or its metabolite or its pharmaceutically acceptable Salts of can be combined as active ingredient with pharmaceutical carrier in intimate admixture. The carrier can take a variety of forms depending on the form of preparation desired for administration, eg, oral administration or parenteral (including intravenous administration). Accordingly, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient. Additionally, 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 listed above, the compound represented by Formula I or Formula I', or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product is then conventionally shaped into the desired presentation.

因此，本發明的藥物組合物可以包含藥學上可接受的載體和式I或式I’的化合物或其藥學上可接受的鹽。式I或式I’的化合物或其藥學上可接受的鹽還可以與一種或更多種其他治療活性化合物組合而被包含在藥物組合物中。Therefore, the pharmaceutical composition 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. A 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.

所使用的藥物載體可以是例如固體、液體或氣體。固體載體的實例包括乳糖、石膏粉(terra alba)、蔗糖、滑石(talc)、明膠、瓊脂、果膠、***膠(acacia)、硬脂酸鎂以及硬脂酸。液體載體的實例是糖漿、花生油、橄欖油和水。氣體載體的實例包括二氧化碳和氮氣。在製備用於口服劑型的組合物中，可以使用任何常規的藥物媒介物(media)。例如，水、乙二醇類、油類、醇類、調味劑(flavoring agent)、防腐劑、著色劑及類似物可以用於形成口服液體製劑(oral liquid preparation)，例如懸浮劑、酏劑(elixir)和溶液；而諸如澱粉、糖、微晶纖維素(microcrystalline cellulose)、稀釋劑、成粒劑(granulating agent)、潤滑劑、黏合劑、崩解劑及類似物的載體可以用於形成口服固體製劑(oral solid preparation)，例如粉劑、膠囊和片劑。由於片劑和膠囊易於施用，它們是優選的口服劑型，從而採用固體藥物載體。任選地，片劑可以通過標準含水技術或非含水技術來包衣。The pharmaceutical carrier used may be, for example, solid, liquid or gaseous. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any conventional pharmaceutical media may be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs ( elixir) and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, and the like can be used to form oral Oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage forms employing solid pharmaceutical carriers. Tablets may optionally be coated by standard aqueous or non-aqueous techniques.

包含本發明的組合物的片劑可以通過任選地與一種或更多種輔助成分(accessory ingredient)或佐劑壓制(compression)或模製(molding)來製備。壓制的片劑可以通過以下來製備：在合適的儀器中將任選地與黏合劑、潤滑劑、惰性稀釋劑、表面活性劑或分散劑混合的呈自由流動形式的活性成分例如粉劑或顆粒劑壓制。模製的片劑可以通過在合適的儀器中將用惰性液體稀釋劑潤濕的粉狀化合物的混合物模製來製備。每個片劑優選地包含從約0.05mg至約5g的活性成分，並且每個酏劑或膠囊優選地包含從約0.05mg至約5g的活性成分。例如意圖用於口服施用至人類的製劑可以包含從約0.5mg至約5g的活性成分，所述活性成分與合適且方便量的載體材料混合(compound)，所述載體材料可以從總組合物的約0.05%至約95%而變化。單位劑型將通常包含在從約0.01mg至約2g的活性成分之間，典型地0.01mg、0.02mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、25mg、50mg、l00mg、200mg、300mg、400mg、500mg、600mg、800mg或l000mg。Tablets comprising compositions of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by bringing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. suppress. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of active ingredient, and each elixir or capsule preferably contains from about 0.05 mg to about 5 g of active ingredient. For example, formulations intended for oral administration to humans may contain from about 0.5 mg to about 5 g of active ingredient compounded with a suitable and convenient amount of carrier material which can be derived from the total composition. Varies from about 0.05% to about 95%. Unit dosage forms will generally contain from about 0.01 mg to about 2 g of active ingredient, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg , 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg.

本發明適合於腸胃外施用的藥物組合物可以被製備為活性化合物在水中的溶液或懸浮液。可以包含合適的表面活性劑，比如例如羥丙基纖維素。分散劑(dispersion)還可以在甘油、液體聚乙二醇及其在油中的混合物中被製備。另外，可以包含防腐劑以防止有害的微生物生長。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, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Additionally, a preservative can be included to prevent the growth of harmful microorganisms.

本發明適合於可注射用途的藥物組合物包括無菌含水溶液或無菌含水分散劑。此外，組合物可以呈無菌粉劑的形式，用於這樣的無菌可注射的溶液或分散劑的現場製備(extemporaneous preparation)。在所有情況下，最終的可注射形式必須是無菌的並且必須實際上是易於可注射性(syringability)的流體。藥物組合物在製造和儲存的條件下必須是穩定的；從而，優選地應當被保護免受諸如細菌和真菌的微生物的污染動作。載體可以是包含例如水、乙醇、多元醇(例如，甘油、丙二醇和液體聚乙二醇)、植物油和其合適的混合物的溶劑或分散媒介物。Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or sterile aqueous dispersions. Furthermore, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be practically fluid for easy syringability. Pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be protected against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion vehicle containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

本發明的藥物組合物可以呈適合於局部用途的形式，比如例如氣霧劑(aerosol)、乳膏(cream)、軟膏(ointment)、洗劑(lotion)、撒粉劑(dusting powder)或類似物。另外，組合物可以呈適合於在經皮裝置(transdermal devices)中使用的形式。這些製劑可以利用通過本發明的式(I)、式(I′)、式(II-a)、式(II-b)、式(III-a)、式(III-b)、式(IV-a)、式(IV-b)、式(V-a)和式(V-b)代表的化合物或其藥學上可接受的鹽，經由常規的加工方法來製備。作為實例，通過將親水性材料和水連同約0.05wt%至約10wt%的化合物摻合以產生具有期望的黏度的乳膏或軟膏來製備乳膏或軟膏The pharmaceutical composition of the invention may be in a form suitable for topical use, such as for example an aerosol, cream, ointment, lotion, dusting powder or the like . Additionally, the compositions may be in a form suitable for use in transdermal devices. These formulations can utilize formula (I), formula (I'), formula (II-a), formula (II-b), formula (III-a), formula (III-b), formula (IV) through the present invention -a), the compound represented by formula (IV-b), formula (V-a) and formula (V-b), or a pharmaceutically acceptable salt thereof, is prepared by conventional processing methods. As an example, a cream or ointment is prepared by blending a hydrophilic material and water along with about 0.05% to about 10% by weight of the compound to produce a cream or ointment with the desired viscosity

本發明的藥物組合物可以呈適合於直腸施用的形式，其中載體是固體。優選的是混合物形成單位劑量栓劑。合適的載體包括可哥脂和本領域常用的其他材料。可以通過首先將組合物與軟化的或熔融的載體摻合，隨後通過在模具中冷凍或成型來常規地形成栓劑。The pharmaceutical compositions of this invention may be in a form suitable for rectal administration wherein the carrier is a solid. Preferably the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories may be conventionally formed by first admixing the composition with a softened or molten carrier, followed by freezing or shaping in molds.

除了前面提及的載體成分之外，上文描述的藥物製劑還可以根據需要包含一種或更多種另外的載體成分，例如稀釋劑、緩衝劑、調味劑、黏合劑、表面活性劑、增稠劑、潤滑劑、防腐劑(包括抗氧化劑)及類似物。此外，可以包含其他佐劑以致使製劑與意圖的受試者(recipient)的血液等滲(isotonic)。包含通過式I或式I’描述的化合物或其藥學上可接受的鹽的組合物還可以以粉劑或液體濃縮物形式來製備。In addition to the aforementioned carrier components, the pharmaceutical formulations described above may also contain one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, etc. additives, 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 recipient. Compositions comprising a compound described by Formula I or Formula I', or a pharmaceutically acceptable salt thereof, may also be prepared in powder or liquid concentrate form.

通常，在從約0.001mg/kg體重/天至約150mg/kg體重/天、或可選擇地約0.05mg/患者/天至約7g/患者/天的級別的劑量水準用於治療上文指示的狀況。例如，癌症可以通過施用從約0.001 mg化合物/kg體重/天至50mg化合物/kg體重/天或可選擇地從約0.05mg/患者/天至約3.5g/患者/天來有效地治療。Generally, dosage levels on the order of from about 0.001 mg/kg body weight/day to about 150 mg/kg body weight/day, or alternatively about 0.05 mg/patient/day to about 7 g/patient/day for the treatment indicated above status. For example, cancer can be effectively treated by administering from about 0.001 mg compound/kg body weight/day to 50 mg compound/kg body weight/day, or alternatively from about 0.05 mg/patient/day to about 3.5 g/patient/day.

然而，應理解任何特定患者的具體劑量水準將取決於多種因素，包括年齡、體重、健康狀況(general health)、性別、飲食、施用時間、施用途徑、***率(rate of excretion)、藥物組合以及正在經歷療法的具體疾病的嚴重程度。It is to be understood, however, that specific dosage levels for any particular patient will depend on a variety of factors, including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and The severity of the specific disease being treated.

術語“KRAS G12D”突變體指的是哺乳動物KRAS蛋白的突變體形式，該突變體包括在氨基酸位置12處用天冬氨酸對甘氨酸進行氨基酸取代。人類KRAS的氨基酸密碼子和氨基酸殘基的定位(positioning)基於通過UniProtKB/Swiss-Prot P01116: Variant p.Gly12Asp確定的氨基酸序列。The term "KRAS G12D" mutant refers to a mutant form of the 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 is based on the amino acid sequence determined by UniProtKB/Swiss-Prot P01116: Variant p.Gly12Asp.

術語“抑制”指的是生物活性或生物過程的基線活性(baseline activity)的降低。其“KRAS G12D的活性的抑制”指的是相比於在本公開內容的化合物不存在下該酶的活性，KRAS G12D活性的降低。The term "inhibition" refers to a reduction in the baseline activity of a biological activity or biological process. By "inhibition of the activity of KRAS G12D" is meant a decrease in the activity of KRAS G12D compared to the activity of the enzyme in the absence of a compound of the present disclosure.

本公開內容化合物可以結合至KRAS G12D，然後通過多種分子機制抑制或負性地調節KRAS G12D活性，非限制性實例包括示出：(a)KRAS的GTPase活性的降低；(b)GTP結合親和力的降低或GDP結合親和力的增加；(c)GTP的K 解離(K off)的降低或GDP的K 解離的降低；(d)鳥苷酸轉換因數(GEFs，guanine nucleotide exchange factors)的結合的降低，所述鳥苷酸轉換因數包括但不限於SOS1；(e)效應器或下游信號傳導分子的結合的降低，所述下游信號傳導分子包括但不限於Raf。 Compounds of the present disclosure can bind to KRAS G12D and then inhibit or negatively regulate KRAS G12D activity through a variety of molecular mechanisms, non-limiting examples include those showing: (a) reduction of the GTPase activity of KRAS; Reduction or increase of GDP binding affinity; (c) reduction of K dissociation (K off ) of GTP or reduction of K dissociation of GDP; (d) reduction of binding of guanine nucleotide conversion factors (GEFs, guanine nucleotide exchange factors), The guanylate conversion factors include, but are not limited to, SOS1; (e) reduction in binding of effectors or downstream signaling molecules, including, but not limited to, Raf.

通過負性地調節KRAS G12D的活性，本文公開的主題可以用於抑制非期望的細胞增殖和/或不依賴支援物的細胞生長(anchorage-independent cell growth)。By negatively modulating the activity of KRAS G12D, the subject matter disclosed herein can be used to inhibit undesired cell proliferation and/or anchorage-independent cell growth.

本公開內容的式(I)/式(I’)的氘代化合物或其鹽展示出KRAS G12D相對於野生型KRAS的優良的選擇性，這使得這樣的氘代化合物或其鹽選擇性接近KRAS G12D介導的癌細胞，繞過(sparing)KRAS野生型細胞。因此，本發明的氘代化合物或其藥學上可接受的鹽，其前驅藥、代謝物或衍生物可以用作針對KRAS G12D介導的腫瘤的治療劑(therapeutic)，具有改進的安全性概況。The deuterated compound of formula (I)/formula (I') or salt thereof of the present disclosure exhibits excellent selectivity of KRAS G12D relative to wild-type KRAS, which makes such deuterated compound or salt thereof selectivity close to KRAS G12D-mediated cancer cells, sparing KRAS wild-type cells. Therefore, the deuterated compounds of the present invention or pharmaceutically acceptable salts thereof, prodrugs, metabolites or derivatives thereof can be used as therapeutic agents against KRAS G12D-mediated tumors with improved safety profile.

術語“KRAS G12D相關的疾病或紊亂”指的是與KRAS G12D突變相關的或通過KRAS G12D突變介導的或具有KRAS G12D突變的疾病或紊亂。實例包括但不限於KRAS G12D相關的癌症。The term "KRAS G12D-associated disease or disorder" refers to a disease or disorder associated with or mediated by or having a KRAS G12D mutation. Examples include, but are not limited to, KRAS G12D-associated cancers.

術語“受試者”、“個體(individual)”或“患者”可互換地使用，並且指的是任何哺乳動物，包括諸如小鼠、大鼠、其他齧齒動物、兔、犬、貓、豬、牛、羊、馬、靈長類動物以及人類的哺乳動物。在某些實施方案中，患者是人類。在某些實施方案中，受試者已經被認為或已經被診斷為具有KRAS G12D突變陽性癌症(例如，癌症通過由管理機構例如美國食品藥品管理局(FDA)批准的測量方法來確定)。在某些實施方案中，受試者被懷疑具有KRAS G12D基因相關的癌症。The terms "subject", "individual" or "patient" are used interchangeably and refer to any mammal, including such as mice, rats, other rodents, rabbits, dogs, cats, pigs, Cattle, sheep, horses, primates and human mammals. 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 (eg, the cancer is determined by a measurement approved by a regulatory agency, such as the US Food and Drug Administration (FDA)). In certain embodiments, the subject is suspected of having a KRAS G12D gene-related cancer.

術語“疾病”指的是任何疾病、不適、病患(illness)、症狀或適應症，並且可以是與術語“紊亂”或“狀況”可互換的。The term "disease" refers to any disease, disorder, illness, symptom or indication, and may be interchangeable with the term "disorder" or "condition".

術語“癌症”涵蓋所有形式的癌症，包括但不限於所有形式的癌(carcinomas)、黑色素瘤、母細胞瘤(blastomas)、肉瘤、淋巴瘤和白血病。實例包括但不限於乳腺癌、膀胱癌、膀胱癌(bladder carcinoma)、尿道癌、腦部腫瘤、宮頸癌、結直腸癌、食道癌(esophageal cancer)、子宮內膜癌、肝癌(包括HCC)、喉癌、肺癌、骨肉瘤(osteosarcoma)、卵巢癌、胰腺癌、***癌、腎癌(renal carcinoma)、腎癌(kidney cancer)(包括RCC)、甲狀腺癌、急性淋巴性白血病、急性骨髓性白血病、室管膜瘤(ependymoma)、尤文氏肉瘤(Ewing’s sarcoma)、膠質母細胞瘤(glioblastoma)、髓母細胞瘤(medulloblastoma)、神經母細胞瘤(neuroblastoma)、骨肉瘤、橫紋肌肉瘤(rhabdomyosarcoma)、橫紋肌樣癌(rhabdoid cancer)以及腎母細胞瘤(nephroblastoma)(威爾姆氏腫瘤(Wilm’s tumor))。The term "cancer" encompasses all forms of cancer including, but not limited to, all forms of carcinomas, melanomas, blastomas, sarcomas, lymphomas and leukemias. Examples include, but are not limited to, breast cancer, bladder cancer, bladder cancer, urethral cancer, brain tumors, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, liver cancer (including HCC), Laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma, kidney cancer (including RCC), thyroid cancer, acute lymphoblastic leukemia, acute myeloid leukemia , ependymoma, Ewing's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Rhabdoid cancer and nephroblastoma (Wilm's tumor).

在某些這樣的實施方案中，本文公開的主題可以用於抑制、阻斷、減少或降低KRAS G12D活化，KRAS G12D活化用於減少腫瘤生長和/或腫瘤轉移(tumor metastasis)，其中方法包括向所述受試者施用有效量的式I或式I’的化合物或本文描述的藥物組合物。In certain such embodiments, the subject matter disclosed herein can be used to inhibit, block, reduce or reduce KRAS G12D activation for reducing tumor growth and/or tumor metastasis, wherein the methods comprise introducing The subject is administered an effective amount of a compound of Formula I or Formula I' or a pharmaceutical composition described herein.

在某些這樣的實施方案中，本文詳述的化合物或其藥學上可接受的鹽、前驅藥、代謝物或衍生物還可以與另外的療法組合使用。另外的療法可以任選地包括一種或更多種治療劑、放射療法、手術(例如，腫塊切除術(lumpectomy)和***切除術(mastectomy))、化療、基因療法、DNA療法、病毒療法、RNA療法、免疫療法、骨髓移植、奈米療法(nanotherapy)、單克隆抗體療法或前述的組合。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. Additional therapy may optionally include one or more therapeutic agents, radiation therapy, surgery (e.g., lumpectomy and 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.

製備方法Preparation

本發明的化合物可以由有機化學領域的技術人員通過多種方法合成，並且本文描述了用於製備本發明的化合物的一般合成方案。這些方案是示例性的並且不意指將本領域技術人員的可能的方法限於製備本文公開的化合物。製備本公開的化合物的不同的方法對於本領域技術人員將是明顯的。製備本發明的化合物的一般方案在下文列出的實施例部分中給出。純手性實施例的製備可以通過對本領域技術人員已知的技術來實現。例如純手性化合物可以通過手性相製備型HPLC(chiral phase preparative HPLC)分離外消旋產物或非對映異構體來製備。可選擇地，實施例化合物可以通過已知給出互變異構地或非對映異構地富集的產物的方法來製備。The compounds of the invention can be synthesized by a variety of methods by those skilled in the art of organic chemistry, and general synthetic schemes for the preparation of the compounds of the invention are described herein. These schemes are exemplary and are not meant to limit the methods available to those skilled in the art to prepare the compounds disclosed herein. Various methods for preparing the disclosed compounds will be apparent to those skilled in the art. General schemes for the preparation of compounds of the invention are given in the Examples section set forth below. The preparation of homochiral examples can be accomplished by techniques known to those skilled in the art. For example, homochiral compounds can be prepared by separation of racemic products or diastereomers by chiral phase preparative HPLC. Alternatively, the compounds of the examples may be prepared by methods known to give tautomerically or diastereomerically enriched products.

本部分中下文公開的反應和技術在適於所採用的試劑和材料的溶劑中進行，並且適合於將要產生的轉化。另外，應理解所有提出的反應條件被選擇為對於該反應標準的條件，所述反應條件包括溶劑的選擇、反應氣氛(reaction atmosphere)、反應溫度、實驗持續時間以及後處理常式(work up procedure)，這應當由本領域技術人員容易地實現。有機合成領域的技術人員還應理解，分子的多個部分(portion)上存在的官能團必須與所選擇的試劑和反應相容。在存在所要求的可選物可能與取代基不相容的情況下，與反應條件相容的取代基的限制對於本領域技術人員將是明顯的。有時，需要修改合成步驟的順序或相對於另一種具體路徑選擇一種具體路徑的判斷，以便獲得本發明的期望的化合物。還將理解，本領域中任何合成路徑的計畫將涵蓋用於保護本發明中描述的化合物中存在的反應性官能團的保護基團的判斷性選擇(Wuts and Greene, Greene’s Protective Groups in Organic Synthesis, Fourth Edition, Wiley and Sons (2007))。The reactions and techniques disclosed hereinafter in this section are performed in solvents appropriate to the reagents and materials employed and are appropriate for the transformations to be produced. In addition, it should be understood that all presented reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment, and work up procedure, were selected as conditions standard for this reaction. ), which should be easily realized by a person skilled in the art. Those skilled in the art of organic synthesis will also understand that the functional groups present on the various portions of the molecule must be compatible with the chosen reagents and reactions. Limitations of substituents that are compatible with the reaction conditions will be apparent to those skilled in the art, where there are claimed alternatives that may be incompatible with the substituents. Occasionally, modification of the order of synthetic steps or judgment in choosing one particular route over another will be required in order to obtain the desired compound of the invention. It will also be understood that the planning of any synthetic route in the art will encompass the judgmental choice of protecting groups used to protect the reactive functional groups present in the compounds described in this invention (Wuts and Greene, Greene's Protective Groups in Organic Synthesis, Fourth Edition, Wiley and Sons (2007)).

反應方案和實施例Reaction Schemes and Examples

本發明的公開的化合物可以由可商購的試劑使用本文描述的合成方法和反應方案，或使用本領域技術人員熟知的其他試劑和常規方法，來製備。例如本發明的化合物可以使用一般反應方案I-VIII來製備，所述一般反應方案I-VIII可以隨後是脫保護步驟以將保護基團脫去以獲得公開的化合物。The disclosed compounds of this invention can be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and routine methods well known to those skilled in the art. For example, compounds of the invention can be prepared using general reaction schemes I-VIII which can be followed by a deprotection step to remove protecting groups to obtain disclosed compounds.

一般反應方案General Reaction Scheme

式(II-a)的化合物，其中n、W、X 0至X 3、R 1至R 6如上文所定義，可以根據方案I來製備： Compounds of formula (II-a), wherein n, W, X 0 to X 3 , R 1 to R 6 are as defined above, can be prepared according to Scheme I:

方案I

Figure 02_image070
Figure 02_image072
Option I
Figure 02_image070
Figure 02_image072

在升高的溫度，例如100℃，在POCl 3、鹼例如DIEA的存在下，處理化合物(1)提供三氯化物(2)。在0℃，在胺(3)、鹼如DIEA和溶劑例如DCM的存在下，三氯化物(2)的選擇性取代生成化合物(4)。在醇(5)的存在下，在鹼例如DIEA的存在下，在溶劑如1,4-二氧六環中，二氯化物(4)的選擇性親核取代提供化合物(6)。隨後，在Suzuki偶聯條件下，氯化物(6)與雜芳香族硼酸頻哪醇酯(aromatic pinacoborate)(7)的Suzuki偶聯提供式(II-a)的化合物。 Treatment of compound (1 ) at elevated temperature, eg 100°C, in the presence of POCl3 , a base such as DIEA affords trichloride (2). Selective substitution of trichloride (2) in the presence of amine (3), a base such as DIEA and a solvent such as DCM at 0°C leads to compound (4). 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 affords compound (6). Subsequent Suzuki coupling of chloride (6) with heteroaromatic pinacoborate (7) under Suzuki coupling conditions affords compounds of formula (II-a).

式(II-b)的化合物，其中W、X 0至X 3、R 1至R 6如上文所定義，可以根據如方案I中概述的適用於式(II-a)的化合物的合成類似的程式和/或在必要的修改的情況下，通過用胺(A)替代胺(3)來製備：

Figure 02_image074
、
Figure 02_image076
Compounds of formula (II-b), wherein W, X 0 to X 3 , R 1 to R 6 are as defined above, can be synthesized analogously to compounds of formula (II-a) as outlined in Scheme I Formula and/or with mutatis mutandis, prepared by substituting amine (A) for amine (3):
Figure 02_image074
,
Figure 02_image076

式(III-a)的化合物，其中m、n、W、X 0至X 3、Y、R 1至R 5如上文所定義，可以根據如方案II概述的程式來製備： Compounds of formula (III-a), wherein m, n, W, X 0 to X 3 , Y, R 1 to R 5 are as defined above, can be prepared according to the formula as outlined in Scheme II:

方案II

Figure 02_image078
Scheme II
Figure 02_image078

在醇(8)的存在下，在鹼例如DIEA的存在下，在溶劑如1,4-二氧六環中，二氯化物(4)的選擇性親核取代提供化合物(9)。隨後，在Suzuki偶聯條件下，氯化物(9)與雜芳香族硼酸頻哪醇酯或雜芳香族硼酸頻哪醇酯(7)的Suzuki偶聯提供式(III-a)的化合物。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 affords compound (9). Subsequent Suzuki coupling of chloride (9) with heteroaromatic pinacol boronic acid esters or heteroaromatic pinacol boronic acid esters (7) under Suzuki coupling conditions affords compounds of formula (III-a).

除了用胺(A)替代胺(3)，式(III-b)的化合物，其中m、W、X 0至X 3、R 1至R 5如上文所定義，可以根據與方案II中適用於式(III-a)的化合物的合成類似的程式和/或在合適的修改的情況下，來製備：

Figure 02_image080
、
Figure 02_image081
Except substituting amine (3) with amine (A), compounds of formula (III-b), wherein m, W, X 0 to X 3 , R 1 to R 5 are as defined above, can be adapted to Synthesis of compounds of formula (III-a) is prepared analogously and/or with suitable modifications:
Figure 02_image080
,
Figure 02_image081

式(IV-a-1)的化合物，其中n、W、X 0至X 3和R 1至R 7如上文所定義，可以根據如方案III中概述的程式來製備： Compounds of formula (IV-a-1), wherein n, W, X to X and R to R are as defined above, can be prepared according to the formula as outlined in Scheme III:

方案III

Figure 02_image083
Figure 02_image085
Scheme III
Figure 02_image083
Figure 02_image085

在鹼例如TEA和溶劑例如DCM的存在下，胺(10)用醯氯(a)進行N-醯化提供化合物(11)。在有機鹼如DBU和溶劑例如THF的存在下，中間體(11)與可商購的試劑(b)例如(E)-4-乙氧基-1,1,1-三氟丁-3-烯-2-酮的偶聯反應提供化合物(12)。在p-TsOH和甲苯的存在下，中間體(12)的回流生成中間體(13)。在鹼例如1N含水NaOH和溶劑如THF的存在下，中間體(13)的水解提供化合物(14)。 隨後，在TEA、作為溶劑的t-BuOH和試劑如疊氮磷酸二苯酯(diphenyl azidophosphate)的存在下，中間體(14)的處理(克爾蒂斯重排(Curtius Rearangement))給出胺(15)。在NBS的存在下，(15)的溴化生成溴化物(16)。在升高的溫度在合適的溶劑例如NMP中，溴化物(16)與CuCN反應給出氰化物中間體(17)。在升高的溫度在酸性條件例如含水的H 2SO 4(1M)下，氰化物(17)的水解提供化合物(18)。 在試劑例如CDI的存在下，中間體(18)的環化(cyclization)提供化合物(19)。隨後，在升高的溫度，在POCl 3的存在下，中間體(19)的處理提供氯化物(20)。在胺(20)、鹼例如TEA和溶劑如DCM的存在下，氯化物的選擇性取代生成中間體(21)。隨後，在升高的溫度，在醇(5)、有機鹼例如DIEA和溶劑如1,4-二氧六環的存在下，化合物(21)的處理提供式(IV-a-1)的化合物。 N-acylation of amine (10) with amide chloride (a) in the presence of a base such as TEA and a solvent such as DCM affords compound (11). In the presence of an organic base such as DBU and a solvent such as THF, intermediate (11) with a commercially available reagent (b) such as (E)-4-ethoxy-1,1,1-trifluorobutan-3- Coupling reaction of en-2-ones 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 such as IN aqueous NaOH and a solvent such as THF affords compound (14). Subsequent treatment of intermediate (14) in the presence of TEA, t-BuOH as solvent and reagents such as diphenyl azidophosphate (Curtius Rearangement) gives the amine ( 15). Bromination of (15) in the presence of NBS leads to the bromide (16). Bromide (16) reacts with CuCN at elevated temperature in a suitable solvent such as NMP to give cyanide intermediate (17). Hydrolysis of cyanide (17) at elevated temperature under acidic conditions such as aqueous H2SO4 (1M) affords compound (18). Cyclization of intermediate (18) in the presence of a reagent such as CDI affords compound (19). Subsequent treatment of intermediate (19) in the presence of POCl3 at elevated temperature affords chloride (20). Selective substitution of chlorides in the presence of amine (20), base such as TEA and solvent such as DCM leads to intermediate (21). Subsequent treatment of compound (21) at elevated temperature in the presence of alcohol (5), an organic base such as DIEA and a solvent such as 1,4-dioxane affords compounds of formula (IV-a-1) .

除了胺(3)被胺(A)替代，式(IV-b-1)的化合物，其中W、X 0至X 2和R 1至R 7如上文所定義，可以根據如方案III中概述的類似的程式/或如有必要，在合適的修改的情況下來製備。

Figure 02_image087
Except that amine (3) is replaced by amine (A), compounds of formula (IV-b-1), wherein W, X 0 to X 2 and R 1 to R 7 are as defined above, can be obtained according to the formula as outlined in Scheme III Similar procedures and/or preparations were made with appropriate modifications, if necessary.
Figure 02_image087

式(V-a-1)的化合物，其中m、n、W、X 0至X 2、Y、R 1至R 5和R 7如上文所定義，可以根據如方案IV中概述的程式來製備： Compounds of formula (Va-1), wherein m, n, W, X 0 to X 2 , Y, R 1 to R 5 and R 7 are as defined above, can be prepared according to the formula as outlined in Scheme IV:

方案IV

Figure 02_image089
Plan IV
Figure 02_image089

在升高的溫度，在醇(8)、有機鹼例如DIEA和溶劑如1,4-二氧六環的存在下，化合物(21)的處理提供(V-a-1)。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).

除了鹼(3)被鹼(A)替代，式(V-b-1)的化合物，其中m、W、X 0至X 2、R 1至R 5和R 7如上文所定義，可以根據如方案IV中概述的類似的程式來製備。

Figure 02_image091
Compounds of formula (Vb-1), wherein m, W, X 0 to X 2 , R 1 to R 5 and R 7 are as defined above, can be obtained according to Scheme IV, except that base (3) is replaced by base (A). prepared by a similar procedure as outlined in .
Figure 02_image091

式(IV-a-2)的化合物，其中n、q、W、X 0至X 2和R 1至R 7如上文所定義，可以根據如方案IV中概述的程式來製備。 Compounds of formula (IV-a-2), wherein n, q, W, X 0 to X 2 and R 1 to R 7 are as defined above, can be prepared according to the formula as outlined in Scheme IV.

方案IV

Figure 02_image093
Plan IV
Figure 02_image093

在升高的溫度，在胺(3)、鹼例如DIEA和溶劑如DMSO的存在下，二氯化物(22)的選擇性親核取代提供中間體(23)。隨後，在升高的溫度，在醇(5)、t-BuONa、BINAP、催化劑例如Pd(OAc) 2和溶劑如甲苯的存在下，中間體(23)的處理生成中間體(24)。保護基團P例如-Cbz或Boc在合適的條件下例如Pd/C、H 2，其中P是Cbz；或TFA/DCM，其中P是Boc-，脫保護提供中間體(25)。隨後，在升高的溫度，在芳基溴化物或雜芳基溴化物(d)、Buchwald偶聯條件例如RuPhos、Pd 2(dba) 3、t-BuOna，和溶劑如甲苯的存在下，中間體(25)的Buchwald偶聯反應提供式(IV-a-2)的化合物。 Selective nucleophilic substitution of dichloride (22) in the presence of amine (3), base such as DIEA and solvent such as DMSO at elevated temperature affords intermediate (23). Subsequent treatment of intermediate (23) at elevated temperature in the presence of alcohol (5), t-BuONa, BINAP, catalyst such as Pd(OAc) 2 and solvent such as toluene leads to intermediate (24). Deprotection of a protecting group P such as -Cbz or Boc under suitable conditions such as Pd/C, H2 , where P is Cbz; or TFA/DCM, where P is Boc-, affords intermediate (25). Subsequently, at elevated temperature, in the presence of aryl bromide or heteroaryl bromide (d), Buchwald coupling conditions such as RuPhos, Pd 2 (dba) 3 , t-BuOna, and solvents such as toluene, intermediate Buchwald coupling reaction of the body (25) affords compounds of formula (IV-a-2).

除了鹼(3)被鹼(A)替代，式(IV-b-2)的化合物，其中q、W、X 0至X 2和R 1至R 7如上文所定義，可以根據如方案IV中概述的類似的程式來製備：

Figure 02_image095
Except that base (3) is replaced by base (A), compounds of formula (IV-b-2), wherein q, W, X 0 to X 2 and R 1 to R 7 are as defined above, can be obtained according to A similar procedure outlined to prepare:
Figure 02_image095

式(V-a-2)的化合物，其中m、n、q、W、X 0至X 2、R 1至R 5和R 7如上文所定義，可以根據如方案IV中概述的類似的程式/或如有必要，在合適的修改的情況下來製備。

Figure 02_image097
Compounds of formula (Va-2), wherein m, n, q, W, X 0 to X 2 , R 1 to R 5 and R 7 are as defined above, can be obtained according to an analogous formula as outlined in Scheme IV/or Prepared with appropriate modifications if necessary.
Figure 02_image097

除了胺(3)被胺(A)替代，式(IV-b-2)的化合物，其中n、q、W、X 0至X 2和R 1至R 7如上文所定義，可以根據如方案IV中概述的類似的程式/或如有必要，在合適的修改的情況下來製備。

Figure 02_image099
Except that amine (3) is replaced by amine (A), the compound of formula (IV-b-2), wherein n, q, W, X 0 to X 2 and R 1 to R 7 are as defined above, can be obtained according to the scheme A similar procedure outlined in IV and/or if necessary, prepared with appropriate modifications.
Figure 02_image099

式(IV-a-3)的化合物，其中n、W、X 0至X 2和R 1至R 6如上文所定義，可以根據如方案V中概述的程式來製備。

Figure 02_image101
Compounds of formula (IV-a-3), wherein n, W, X 0 to X 2 and R 1 to R 6 are as defined above, can be prepared according to the scheme as outlined in Scheme V.
Figure 02_image101

方案VPlan V

在肼(27)、鹼例如DIEA和溶劑如DMF的存在下，醛(26)的處理提供異二氮烯(hydrazineylidene) (28)。在胺(3)、鹼例如TEA和溶劑如DMF的存在下，異二氮烯(28)的反應提供化合物(29)。在升高的溫度中間體(29)在CO(氣體)氣氛、鹼例如TEA、Pd(dppf)Cl 2和溶劑如MeOH中，中間體(29)的處理提供甲基酯(30)。在升高的溫度，在酸性條件下例如冰醋酸，中間體(30)的環化提供化合物(31)。在氧化試劑例如m-CPBA，在溶劑如DCM中，硫醚(31)的氧化提供亞碸(32)。在醇(5)的存在下，亞碸(32)的取代反應生成式(IV-a-3)的化合物。 Treatment of aldehydes (26) in the presence of hydrazine (27), a base such as DIEA and a solvent such as DMF affords hydrazineylidenes (28). Reaction of isodiazenes (28) in the presence of amines (3), a base such as TEA and a solvent such as DMF affords compounds (29). Treatment of intermediate (29) at elevated temperature in a CO (gas) atmosphere, a base such as TEA, Pd(dppf) Cl2 and a solvent such as MeOH affords the methyl ester (30). Cyclization of intermediate (30) under acidic conditions such as glacial acetic acid at elevated temperature affords compound (31). Oxidation of thioether (31 ) in an oxidizing reagent such as m-CPBA in a solvent such as DCM affords sulfide (32). In the presence of alcohol (5), the substitution reaction of aridine (32) leads to the compound of formula (IV-a-3).

除了鹼(3)被鹼(A)替代，式(IV-b-3)的化合物，其中W、X 0至X 2和R 1至R 6如上文所定義，可以根據如方案V中概述的類似的程式來製備：

Figure 02_image103
Compounds of formula (IV-b-3), wherein W, X 0 to X 2 and R 1 to R 6 are as defined above, can be obtained according to A similar procedure to prepare:
Figure 02_image103

式(V-a-3)的化合物，其中m、n、W、X 0至X 2、R 1至R 5和Y如上文所定義，可以根據如方案VI中概述的程式來製備： Compounds of formula (Va-3), wherein m, n, W, X 0 to X 2 , R 1 to R 5 and Y are as defined above, can be prepared according to the formula as outlined in Scheme VI:

方案VI

Figure 02_image105
Scheme VI
Figure 02_image105

在醇(8)的存在下，亞碸(32)的取代反應生成式(V-a-3)的化合物。In the presence of alcohol (8), the substitution reaction of aridine (32) leads to the compound of formula (V-a-3).

除了鹼(3)被鹼(A)替代，式(V-b-3)的化合物，其中m、W、X 0至X 2和R 1至R 5如上文所定義，可以根據如方案VI中概述的類似的程式來製備：

Figure 02_image107
Compounds of formula (Vb-3), wherein m, W, X to X and R to R are as defined above, can be obtained according to the formula as outlined in Scheme VI, except that base (3) is replaced by base (A). A similar procedure to prepare:
Figure 02_image107

實施例Example

本文提供的實施例描述了本文公開的化合物以及用於製備化合物的中間體的合成。應理解本文描述的單獨的步驟可以組合。還應理解單獨批次的化合物可以組合並且然後在接下來的合成步驟中實施。The Examples provided herein describe the synthesis of the compounds disclosed herein as well as intermediates used to prepare the compounds. It should be understood that individual steps described herein may be combined. It is also understood that separate batches of compounds may be combined and then carried out in subsequent synthetic steps.

在以下實施例的描述中，描述了具體的實施方案。足夠詳細地描述了這些實施方案以能夠使本領域技術人員實踐本公開內容的某些實施方案。可以使用其他實施方案並且可以在不偏離本公開內容的範圍的情況下做出邏輯變化和其他變化。因此以下描述不意圖限制本公開內容的範圍，本公開內容的範圍而是由所附申請專利範圍明確規定。In the description of the examples below, 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 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 present disclosure, which is rather defined by the appended claims.

表1示出本發明的部分縮寫表1 表1 aq. 含水的 Bn 苄基 BnBr 溴化苄 BnCl 氯化苄 Boc 叔丁氧羰基 Boc 2O 二碳酸二叔丁酯 (Bpin) 2 雙(頻哪醇合)二硼烷 Cs 2CO 3 碳酸銫 CuI 碘化亞銅 DAST 二乙基氨基三氟化硫 DCM 二氯甲烷 DEA 二乙胺 DIAD 偶氮二羧酸二異丙酯 DIPEA或DIEA N,N-二異丙基乙胺 DMAP 4-二甲基氨基吡啶 DMF N,N-二甲基甲醯胺 DMSO 二甲基亞碸 DPPA 偶氮磷酸二苯酯 DPPE 1,2-雙(二苯基膦基)乙烷 DTAD 偶氮二羧酸二叔丁酯 dtbpy  (4,4-二叔丁基-2,2-聯吡啶)甲基碘化鈀(II) EA或EtOAc 乙酸乙酯 equiv. 當量 EtOH 乙醇 Et 2O *** Et 3N 三乙胺 g 克 H或hr 小時 HBPin 頻哪醇硼烷 HCl 鹽酸 HOAc 乙酸 H 2O 2 過氧化氫 HPLC 高效液相色譜法 iPrOH 異丙醇 (Ir(OMe) (cod)) 2 雙(1,5-環辛二烯)-二-μ-甲氧基二銥(I) KOAc 乙酸鉀 K 2CO 3 碳酸鉀 K 3PO 4 磷酸鉀 KOtBu 叔丁醇鉀 LC/MS或LC-MS 液相色譜法-質譜法 LDA 二異丙基氨基鋰 LiAlD 4 氘代氫化鋁鋰 LiAlH 4 氫化鋁鋰 LiHMDS 雙(三甲基矽烷基)氨基鋰 MeCN 乙腈 MeI 碘甲烷 MeOH 甲醇 Me-THF 2-甲基四氫呋喃 min 分鐘 mL 毫升 mmol 毫摩爾 Mn(TMHD) 3 三(2,2,6,6-四甲基-3,5-庚二酮酸)錳(III) MOMBr 溴甲基甲基醚 MOMCl 氯甲基甲基醚 MTBE 甲基叔丁基醚 NaBH 4 硼氫化鈉 NaBD 4 氘代硼氫化鈉 NaOH 氫氧化鈉 NaHCO 3 碳酸氫鈉 NaHMDS 雙(三甲基矽烷基)氨基鈉 Na 2SO 3 亞硫酸鈉 Na 2SO 4 硫酸鈉 NIS N-碘代丁二醯亞胺 n-BuLi 正丁基鋰 NH 4OAc 乙酸銨 NH 4Cl 氯化銨 O/N 過夜 PdCl 2(dppf)•CH 2Cl 2  [1,1’-雙(二苯基膦)二茂鐵]二氯化鈀(II)與二氯甲烷的絡合物 Pd(OAc) 2 乙酸鈀(II) Pd(Ph 3P) 4 四(三苯基膦)鈀(0) Pd(dppf)Cl 2  [1,1’-雙(二苯基膦)二茂鐵]二氯化鈀(II) PE 聚醚 pinBH 頻哪醇硼烷 POCl 3 磷醯氯 Prep-TLC 製備型薄層色譜法 Rt或r.t. 室溫 RT 保留時間 RuPhos Pd G3 第三代(G3)Buchwald預催化劑(third generation (G3) Buchwald precatalyst) sat. 飽和的 SEMCl 2-(三甲基矽基)乙氧基甲基氯 TEA 三乙胺 THF 四氫呋喃 TLC 薄層色譜法 TMSN 3 三甲基甲矽烷基疊氮化物 Table 1 shows some abbreviations of the present invention Table 1 Table 1 aq. watery Bn Benzyl BrB Benzyl bromide BnCl Benzyl chloride Boc tert-butoxycarbonyl Boc 2 O Di-tert-butyl dicarbonate (Bpin) 2 Bis(pinacolate)diborane Cs 2 CO 3 cesium carbonate CuI Cuprous iodide DAST Diethylaminosulfur trifluoride DCM Dichloromethane DEA Diethylamine DIAD Diisopropyl azodicarboxylate DIPEA or DIEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO DMSO DPPA diphenyl azophosphate DPPE 1,2-bis(diphenylphosphino)ethane DTAD Di-tert-butyl azodicarboxylate dtbpy (4,4-di-tert-butyl-2,2-bipyridyl)methylpalladium(II) iodide EA or EtOAc ethyl acetate equiv. equivalent EtOH ethanol Et 2 O Ether Et 3 N Triethylamine g gram H or hr Hour HBPin pinacol borane HCl hydrochloric acid HOAc Acetic acid H2O2 _ hydrogen peroxide HPLC HPLC iGO Isopropanol (Ir(OMe)(cod)) 2 Bis(1,5-cyclooctadiene)-di-μ-methoxydiiridium(I) KOAc Potassium acetate K 2 CO 3 potassium carbonate K 3 PO 4 potassium phosphate KO Potassium tert-butoxide LC/MS or LC-MS Liquid Chromatography-Mass Spectrometry LDA lithium diisopropylamide LiAlD4 Deuterated Lithium Aluminum Hydride LiAlH4 lithium aluminum hydride LiHMDS Lithium bis(trimethylsilyl)amide MeCN Acetonitrile MeI Iodomethane MeOH Methanol Me-THF 2-Methyltetrahydrofuran min minute mL ml mmol Millimoles Mn(TMHD) 3 Tris(2,2,6,6-tetramethyl-3,5-heptanedionate) manganese(III) MOMBr Bromomethyl methyl ether MOMCl Chloromethyl methyl ether MTBE methyl tert-butyl ether NaBH 4 sodium borohydride NaBD 4 Sodium deuterated borohydride NaOH sodium hydroxide NaHCO 3 sodium bicarbonate NaHMDS Sodium bis(trimethylsilyl)amide Na 2 SO 3 Sulfite Na 2 SO 4 sodium sulfate NIS N-iodobutanediamide n-BuLi n-BuLi NH 4 OAc Ammonium acetate NH 4 Cl ammonium chloride O/N overnight PdCl 2 (dppf) CH 2 Cl 2 Complexes of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and dichloromethane Pd(OAc) 2 Palladium(II) acetate Pd(Ph 3 P) 4 Tetrakis(triphenylphosphine)palladium(0) Pd(dppf)Cl 2 [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride PE polyether pinBH pinacol borane POCl3 Phosphoryl chloride Prep-TLC Preparative TLC Rt or rt room temperature RT keep time RuPhos Pd G3 The third generation (G3) Buchwald precatalyst (third generation (G3) Buchwald precatalyst) sat. Saturated SEMCl 2-(Trimethylsilyl)ethoxymethyl chloride TEA Triethylamine THF Tetrahydrofuran TLC TLC TMSN 3 trimethylsilyl azide

中間體製備Intermediate preparation

中間體1和中間體2Intermediate 1 and Intermediate 2

2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲醇(非對映異構體-A)2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methanol (diastereoisomer-A)

和and

2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲醇(非對映異構體-B)

Figure 02_image109
非對映異構體-a   非對映異構體-b                     中間體1              中間體2 非對映異構體-a     非對映異構體-b 2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methanol (diastereoisomer-B)
Figure 02_image109
Diastereomer-a Diastereomer-b Intermediate 1 Intermediate 2 Diastereomer-a Diastereomer-b

步驟1：2-羥基四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯-2-dStep 1: 2-Hydroxytetrahydro-1H-pyrrolazine-7a(5H)-carboxylate ethyl ester-2-d

在0℃在N 2下，向2,5-二氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯(19.0 g，89.9 mmol，1當量)在無水EtOH (100.0 mL)中的溶液分批次地添加NaBD 4(1.13 g，26.9 mmol，0.3當量)。在0℃在N 2下攪拌反應混合物持續10 min。基於LCMS，轉化完成。在0℃，反應用含水NH 4Cl(4 mL)小心地猝滅並且在該溫度攪拌持續30 min。然後，將混合物傾倒在分液漏斗中，在鹽水和EtOAc之間分配。在分離之後，水層用EtOAc (2×)萃取。合併的有機層經無水Na 2SO 4乾燥，並且在旋轉蒸發儀上濃縮以給出殘餘物。產生的油通過柱色譜法(用DCM/MeOH = 2%-5%洗脫)純化以提供作為無色油的預計的2-羥基-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯-2-d (15.0 g，70%收率)。  LC-MS [M+H] += 201.1。 2,5-Dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate ethyl ester (19.0 g, 89.9 mmol, 1 equiv) in anhydrous EtOH (100.0 mL) at 0 °C under N2 The solution in NaBD 4 (1.13 g, 26.9 mmol, 0.3 equiv) was added portionwise. The reaction mixture was stirred at 0 °C for 10 min under N2 . Based on LCMS, the conversion was complete. The reaction was carefully quenched with aqueous NH4Cl (4 mL) at 0 °C and stirred at this temperature for 30 min. Then, the mixture was poured into a separatory funnel and partitioned between brine and EtOAc. After separation, the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over anhydrous Na 2 SO 4 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 afford the expected 2-hydroxy-5-oxotetrahydro-1H-pyrrolazine-7a(5H) as a colorless oil -Ethylcarboxylate-2-d (15.0 g, 70% yield). LC-MS [M+H] + = 201.1.

步驟2：2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯-2-dStep 2: 2-Fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate ethyl ester-2-d

在-70℃在N 2下在5 min內，向2-羥基-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯-2-d(15.0 g，70.0 mol，1.0當量)在DCM(80 mL)中的溶液逐滴地添加DAST (16.9 g，105.0 mol，1.5當量)。將反應混合物逐漸地加溫至rt並且攪拌持續16h。基於LCMS，轉化完成。將反應混合物在冰-水浴中冷卻，在逐滴地添加MeOH (4 mL)的情況下猝滅，並且用H 2O (156 mL)稀釋。將反應混合物傾倒在分液漏斗中並且用DCM (200 mL×3)萃取。合併的有機層用鹽水(200 mL)洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用PE/EtOAc =2/1洗脫)純化以提供作為淺色油(light oil)的非對映異構體2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯-2-d的混合物(4.90 g，29%收率)。LC-MS [M+H] += 217.1。 To 2 -hydroxy-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate ethyl ester-2-d (15.0 g, 70.0 mol, 1.0 equiv) in DCM (80 mL) was added DAST (16.9 g, 105.0 mol, 1.5 equiv) dropwise. The reaction mixture was gradually warmed to rt and stirred for 16 h. Based on LCMS, the conversion was complete. The reaction mixture was cooled in an ice-water bath, quenched with the dropwise addition of MeOH (4 mL), and diluted with H 2 O (156 mL). The reaction mixture was poured into a separatory funnel and extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , collected by filtration, and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (eluting with PE/EtOAc = 2/1) to afford the diastereomer 2-fluoro-5-oxotetrahydro-1H- as a light oil. Mixture of pyrrolizine-7a(5H)-ethyl carboxylate-2-d (4.90 g, 29% yield). LC-MS [M+H] + = 217.1.

步驟3：手性SFCStep 3: Chiral SFC

非對映異構體的混合物(4.90 g，22.6 mmol)通過手性SFC(Daicel Chiralpak IB SFC 4.6 mm×250 mm×5µm；在MeOH中的0.1% NH 4OH；CO 2%: 70%，10 min)純化。收集對應於兩個峰的級份，合併並且在減壓下濃縮，以提供兩種組分。 The mixture of diastereomers (4.90 g, 22.6 mmol) was analyzed by chiral SFC (Daicel Chiralpak IB SFC 4.6 mm × 250 mm × 5 µm; 0.1% NH 4 OH in MeOH; CO 2 %: 70%, 10 min) purification. Fractions corresponding to the two peaks were collected, combined and concentrated under reduced pressure to provide two components.

非對映異構體-a：峰1，RT = 4.1 min，1.8 g，36% 收率，作為無色油；LC-MS [M+H] += 217.1。 1H NMR (400 MHz, CDCl 3) δ 4.22 – 4.13 (m, 3H), 3.21– 3.09 (m, 1H), 2.82 – 2.70 (m, 2H), 2.63 (dd, J = 32.8, 15.2 Hz, 1H), 2.44 – 2.37 (m, 1H), 2.26 – 2.15 (m, 1H), 2.14 – 2.06 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H)。 Diastereomer-a: Peak 1, RT = 4.1 min, 1.8 g, 36% yield as colorless oil; LC-MS [M+H] + = 217.1. 1 H NMR (400 MHz, CDCl 3 ) δ 4.22 – 4.13 (m, 3H), 3.21 – 3.09 (m, 1H), 2.82 – 2.70 (m, 2H), 2.63 (dd, J = 32.8, 15.2 Hz, 1H ), 2.44 – 2.37 (m, 1H), 2.26 – 2.15 (m, 1H), 2.14 – 2.06 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H).

非對映異構體-b：峰2，RT = 5.9 min，1.8 g，35%收率，作為無色油。LC-MS [M+H] += 217.1。 1H NMR (400 MHz, CDCl 3) δ 4.23 – 4.14 (m, 3H), 3.21– 3.10 (m, 1H), 2.83 – 2.70 (m, 2H), 2.64 (dd, J = 32.8, 15.2 Hz, 1H), 2.45 – 2.38 (m, 1H), 2.27 – 2.16 (m, 1H), 2.13 – 2.07 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H)。 Diastereomer-b: Peak 2, RT = 5.9 min, 1.8 g, 35% yield as colorless oil. LC-MS [M+H] + = 217.1. 1 H NMR (400 MHz, CDCl 3 ) δ 4.23 – 4.14 (m, 3H), 3.21 – 3.10 (m, 1H), 2.83 – 2.70 (m, 2H), 2.64 (dd, J = 32.8, 15.2 Hz, 1H ), 2.45 – 2.38 (m, 1H), 2.27 – 2.16 (m, 1H), 2.13 – 2.07 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H).

步驟4：(2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲醇(中間體1，非對映異構體-A)和(2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲醇(中間體2，非對映異構體-B)Step 4: (2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methanol (Intermediate 1, Diastereomer-A) and (2-Fluorotetrahydro-1H -pyrrolazin-7a(5H)-yl-2-d)methanol (intermediate 2, diastereoisomer-B)

平行地合成兩種非對映異構體A和B。The two diastereomers A and B were synthesized in parallel.

在20℃在N 2氣氛下，向2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯-2-d(峰1，500 mg，2.3 mmol，1.0當量)在THF(5.5 mL)中的溶液一次性地添加LiAlH 4(131 mg，3.46 mmol，1.5當量)。反應混合物用冷凝器逐漸地加溫至回流並且攪拌持續2h。基於LCMS，轉化完成。將反應混合物冷卻至0℃並且在逐滴地添加含水NaOH (0.3 mL, 1 N)的情況下小心地猝滅。混合物在和飽和的含水NH 4Cl和DCM之間分配。  在分離之後，水層用DCM(2×)萃取。合併的有機層經無水Na 2SO 4乾燥，通過過濾收集，並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/ MeOH = 30/1(包含1%NH 3•H 2O)洗脫)純化以提供作為淺色油的(2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲醇(非對映異構體A，200mg，52%收率)。LC-MS [M+H] += 161.1。 1H NMR (400 MHz, CD 3OD) δ 3.35 (d, J = 10.4 Hz, 1H), 3.31 – 3.29 (m, 1H), 3.27 (d, J = 10.4 Hz, 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)。 2 -Fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate ethyl ester-2-d (peak 1, 500 mg, 2.3 mmol, 1.0 eq) in THF (5.5 mL) was added LiAlH4 (131 mg, 3.46 mmol, 1.5 eq) in one portion. The reaction mixture was gradually warmed to reflux with a condenser and stirred for 2 h. Based on LCMS, the conversion was complete. The reaction mixture was cooled to 0 °C and quenched carefully with the dropwise addition of aqueous NaOH (0.3 mL, 1 N). The mixture was partitioned between saturated aqueous NH4Cl and DCM. After separation, the aqueous layer was extracted with DCM (2x). The combined organic layers were dried over anhydrous Na2SO4 , collected by filtration, and concentrated on a rotary evaporator . The resulting oil was purified by column chromatography (eluting with DCM/MeOH = 30/1 (containing 1% NH 3 ·H 2 O)) to afford (2-fluorotetrahydro-1H-pyrrolazine- 7a(5H)-yl-2-d) Methanol (Diastereomer A, 200 mg, 52% yield). LC-MS [M+H] + = 161.1. 1 H NMR (400 MHz, CD 3 OD) δ 3.35 (d, J = 10.4 Hz, 1H), 3.31 – 3.29 (m, 1H), 3.27 (d, J = 10.4 Hz, 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).

將非對映異構體-b(峰2，500mg，2.31mmol)轉化成作為淺色油的(2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲醇(非對映異構體B：176mg，43%)。LC-MS [M+H] += 161.1。 1H NMR (400 MHz, CD 3OD) δ 3.35 (d, J = 10.4 Hz, 1H), 3.31 – 3.29 (m, 1H), 3.27 (d, J = 10.4 Hz, 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)。 Diastereomer-b (peak 2, 500 mg, 2.31 mmol) was converted to (2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methanol as a pale oil ( Diastereomer B: 176 mg, 43%). LC-MS [M+H] + = 161.1. 1 H NMR (400 MHz, CD 3 OD) δ 3.35 (d, J = 10.4 Hz, 1H), 3.31 – 3.29 (m, 1H), 3.27 (d, J = 10.4 Hz, 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).

中間體3Intermediate 3

(2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲-d2-醇

Figure 02_image111
非對映異構體-b                                                                                                                 中間體3 (2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methanol-d2-ol
Figure 02_image111
Diastereomer-b Intermediate 3

在0℃在N 2下，向2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯-2-d (1.0 g，4.6 mmol)在無水EtOH (10.0 mL)中的溶液分批次地添加NaBD 4(0.21 g，5.1 mmol)。將混合物加溫至rt並且在N 2下攪拌持續20 min。基於LCMS，轉化完成。反應在冰浴中冷卻並且通過在攪拌的情況下逐滴地添加含水NH 4Cl (1 mL)來猝滅。在30 min攪拌之後，混合物在水和DCM之間分配。在分離之後，水相用DCM (2×)萃取。合併的有機層經無水Na 2SO 4乾燥，通過過濾收集並且在旋轉蒸發儀上濃縮，以給出殘餘物。產生的油通過柱色譜法(用DCM/MeOH(30/1)洗脫)純化以提供作為黃色油的標題化合物6-氟-7a-(羥基甲基-d 2)六氫-3H-吡咯嗪-3-酮-6-d(720 mg，收率：80.4%)。LC-MS [M+H] += 177.2。 To 2 -fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate ethyl ester-2-d (1.0 g, 4.6 mmol) in anhydrous EtOH (10.0 mL) was added NaBD4 (0.21 g, 5.1 mmol) in portions. The mixture was warmed to rt and stirred under N2 for 20 min. Based on LCMS, the conversion was complete. The reaction was cooled in an ice bath and quenched by the dropwise addition of aqueous NH4Cl (1 mL) with stirring. After stirring for 30 min, the mixture was partitioned between water and DCM. After separation, the aqueous phase was extracted with DCM (2x). The combined organic layers were dried over anhydrous Na2SO4 , 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 afford the title compound 6-fluoro-7a-(hydroxymethyl-d 2 )hexahydro-3H-pyrrolazine as a yellow oil -3-Keto-6-d (720 mg, yield: 80.4%). LC-MS [M+H] + =177.2.

步驟2:氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲-d 2-醇 Step 2: Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methan- d2 -ol

在rt在N 2下，向6-氟-7a-(羥基甲基-d 2)六氫-3H-吡咯嗪-3-酮-6-d (720 mg，4.09 mmol)在無水THF (7 ml)中的溶液分批次地添加LiAlH 4(233 mg, 6.13 mmol)。反應混合物在冷凝器的情況下加溫至回流並且攪拌持續2 h。基於LC-MS，轉化完成。將反應混合物冷卻至0℃並且在逐滴地添加含水NaOH (0.2 mL, 1 M)的情況下小心地猝滅。混合物在水和DCM之間分配。在分離之後，水層用DCM(2×)萃取。合併的有機層經無水Na 2SO 4乾燥，通過過濾收集，並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/(在MeOH中的NH 3)(30/1)洗脫)純化以提供作為無色油的標題化合物(2-氟四氫-1H-吡咯嗪-7a(5H)-基)-2-d)甲-d 2-醇(449.04 mg，收率：58.53%)。LC-MS [M+H] += 163.1。 1H NMR (400 MHz, CDCl 3) δ 3.22 – 2.88 (m, 4H), 2.15 – 2.04 (m, 2H), 1.98 – 1.71(m, 4H)。 To 6-fluoro-7a-(hydroxymethyl- d 2 ) hexahydro-3H-pyrrolidin-3-one-6-d (720 mg, 4.09 mmol) in anhydrous THF (7 ml ) was added LiAlH 4 (233 mg, 6.13 mmol) in portions. The reaction mixture was warmed to reflux with a condenser and stirred for 2 h. Based on LC-MS, the conversion was complete. The reaction mixture was cooled to 0 °C and quenched carefully with the 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 (2x). The combined organic layers were dried over anhydrous Na2SO4 , collected by filtration , and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (eluting with DCM/( NH3 in MeOH) (30/1)) to afford the title compound (2-fluorotetrahydro-lH-pyrrolazine-7a ( 5H)-yl)-2-d)metha-d 2 -ol (449.04 mg, yield: 58.53%). LC-MS [M+H] + =163.1. 1 H NMR (400 MHz, CDCl 3 ) δ 3.22 – 2.88 (m, 4H), 2.15 – 2.04 (m, 2H), 1.98 – 1.71 (m, 4H).

中間體4Intermediate 4

(2-氟四氫-1H-吡咯嗪-7a(5H)-基-5.5-d2)甲醇

Figure 02_image113
非對映異構體-a   非對映異構體-b
Figure 02_image115
非對映異構體-b                                                             中間體4 (2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5.5-d2)methanol
Figure 02_image113
Diastereomer-a Diastereomer-b
Figure 02_image115
Diastereomer-b Intermediate 4

步驟1: 2-羥基四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯Step 1: 2-Hydroxytetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester

在0℃在N 2下在1 min內，向2,5-二氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯(19.0 g，89.9 mmol，1當量)在無水EtOH (100.0 mL)中的溶液分批次地添加NaBD 4(1.13 g，26.9 mmol，0.3當量)。在0℃在N 2下攪拌反應混合物持續10 min。基於LCMS，轉化完成。在0℃，反應用含水NH 4Cl (4 mL)小心地猝滅，並且在該溫度攪拌持續30 min。然後將混合物傾倒在分液漏斗中，在鹽水和EtOAc之間分配。在分離之後，水層用EtOAc (2×)萃取。合併的有機層經無水Na 2SO 4乾燥，並且在旋轉蒸發儀上濃縮，以給出殘餘物。產生的油通過柱色譜法(用DCM/MeOH = 2%-5%洗脫)純化以提供作為無色油的預計的標題化合物(15.0 g，70%收率)。  LC-MS [M+H] += 200.1。 To 2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate ethyl ester (19.0 g, 89.9 mmol, 1 equiv) in anhydrous EtOH at 0 °C under N2 within 1 min (100.0 mL) was added NaBD 4 (1.13 g, 26.9 mmol, 0.3 equiv) in portions. The reaction mixture was stirred at 0 °C for 10 min under N2 . Based on LCMS, the conversion was complete. The reaction was carefully quenched with aqueous NH4Cl (4 mL) at 0 °C and stirred at this temperature for 30 min. The mixture was then poured into a separatory funnel and partitioned between brine and EtOAc. After separation, the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over anhydrous Na2SO4 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 afford the expected title compound (15.0 g, 70% yield) as a colorless oil. LC-MS [M+H] + = 200.1.

步驟2: 2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯Step 2: 2-Fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester

在-70℃在N 2下在5 min內，向2-羥基四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯(15.0 g，70.0 mol，1.0當量)在DCM (80 mL)中的溶液逐滴地添加DAST (16.9 g，105.0 mol，1.5當量)。將反應混合物逐漸地加溫至rt並且攪拌持續16h。基於LCMS，轉化完成。將反應混合物在冰-水浴中冷卻，在逐滴地添加MeOH (4 mL)的情況下猝滅，並且用H 2O (156 mL)稀釋。將反應混合物傾倒在分液漏斗中並且用DCM (200 mL×3)萃取。合併的有機層用鹽水(200 mL)洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用PE/EtOAc =2/1洗脫)純化以提供作為無色油的非對映異構體2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯的混合物(5.40 g，32.0%收率)。LC-MS [M+H] += 216.1。 Add 2-hydroxytetrahydro-1H-pyrrolazine-7a(5H)-carboxylate ethyl ester (15.0 g, 70.0 mol, 1.0 equiv) in DCM (80 mL) at -70 °C under N for 5 min DAST (16.9 g, 105.0 mol, 1.5 equiv) was added dropwise to the solution in . The reaction mixture was gradually warmed to rt and stirred for 16 h. Based on LCMS, the conversion was complete. The reaction mixture was cooled in an ice-water bath, quenched with the dropwise addition of MeOH (4 mL), and diluted with H 2 O (156 mL). The reaction mixture was poured into a separatory funnel and extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , collected by filtration, and concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (eluting with PE/EtOAc = 2/1) to afford the diastereomer 2-fluoro-5-oxotetrahydro-1H-pyrrolazine-7a as a colorless oil ( 5H) - mixture of ethyl carboxylates (5.40 g, 32.0% yield). LC-MS [M+H] + = 216.1.

步驟3: 手性SFC製備Step 3: Chiral SFC preparation

非對映異構體2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯的混合物(132 g, 612 mmol)，通過手性SFC(柱：CHIRALPAK AY-3(AY30CD-TJ004) 4.6 mm×150 mm×0.2 µm；流動相：EtOH；流速：0.5 ml/min；10 min)分離。將對應於兩個峰的級份分別合併，並且在減壓下濃縮，以提供兩種組分。A mixture of diastereomeric 2-fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate ethyl ester (132 g, 612 mmol) was analyzed by chiral SFC (column: CHIRALPAK AY -3 (AY30CD-TJ004) 4.6 mm×150 mm×0.2 µm; mobile phase: EtOH; flow rate: 0.5 ml/min; 10 min) separation. Fractions corresponding to the two peaks were combined separately and concentrated under reduced pressure to provide two components.

非對映異構體-a：峰1，化合物9，RT = 5.7 min，60.8 g，46%收率，作為無色油；Diastereomer-a: peak 1, compound 9, RT = 5.7 min, 60.8 g, 46% yield, as colorless oil;

非對映異構體-b：峰2，化合物10，RT = 7.5 min，58.8 g，45%收率，作為黃色油；Diastereomer-b: peak 2, compound 10, RT = 7.5 min, 58.8 g, 45% yield, as a yellow oil;

步驟4: 6-氟-7a-(羥基甲基)六氫-3H-吡咯嗪-3-酮Step 4: 6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolidin-3-one

在0℃在N 2下，向2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯(化合物10，非對映異構體-b，1 g，4.6 mmol)在無水EtOH (10.0 mL)中的溶液分批次地添加NaBH 4(0.19 g，5.1 mmol)。將反應混合物逐漸地加溫至rt並且在N 2下攪拌持續20 min。基於LCMS，轉化完成。在0℃，反應在逐滴地添加含水NH 4Cl (1 mL)的情況下小心地猝滅，並且攪拌持續30 min。然後，混合物在水和DCM之間分配。在分離之後，水層用DCM (2×)萃取。合併的有機層經無水Na 2SO 4乾燥，通過過濾收集並且在旋轉蒸發儀上濃縮，以給出殘餘物。產生的油通過柱色譜法(用DCM/MeOH(30/1)洗脫)純化以提供作為黃色油的標題化合物6-氟-7a-(羥基甲基)六氫-3H-吡咯嗪-3-酮(680 mg，收率：76.1%)。LC-MS [M+H] += 174.2。 2 -Fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (compound 10, diastereoisomer-b, 1 g, 4.6 mmol) in anhydrous EtOH (10.0 mL) was added NaBH4 (0.19 g, 5.1 mmol) in portions. The reaction mixture was gradually warmed to rt and stirred under N 2 for 20 min. Based on LCMS, the conversion was complete. At 0 °C, the reaction was quenched carefully with the dropwise addition of aqueous NH4Cl (1 mL), and stirring was continued for 30 min. Then, the mixture was partitioned between water and DCM. After separation, the aqueous layer was extracted with DCM (2x). The combined organic layers were dried over anhydrous Na2SO4 , 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 afford the title compound 6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolazine-3- as a yellow oil. Ketone (680 mg, yield: 76.1%). LC-MS [M+H] + = 174.2.

步驟5: 2-氟四氫-1H-吡咯啉-7a(5H)-基-5.5-d 2)甲醇 Step 5: 2-Fluorotetrahydro-1H-pyrroline-7a(5H)-yl-5.5- d2 )methanol

在rt在N 2下，向6-氟-7a-(羥基甲基)六氫-3H-吡咯嗪-3-酮(680 mg，3.88 mmol)在Me-THF (7 ml)中的溶液分批次地添加LiAlD 4(342 mg, 8.15 mmol)。反應混合物在冷凝器的情況下加溫至90℃，攪拌持續2 h。反應通過LCMS來監測。在完成之後，將反應混合物冷卻至0℃並且在逐滴地添加含水NaOH (7 mL, 1 mol/L)的情況下小心地猝滅。混合物在水和DCM之間分配。在分離之後，水層用DCM(2×)萃取。合併的有機層經無水Na 2SO 4乾燥，通過過濾收集，並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/(在MeOH中的NH 3)(30/1)洗脫)純化以提供作為無色油的標題化合物(418 mg，收率：60%)。LC-MS [M+H] += 162.2。 1H NMR (400 MHz, CDCl 3) δ 5.23 (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)。 To a solution of 6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolidin-3-one (680 mg, 3.88 mmol) in Me-THF (7 ml) portionwise at rt under N LiAlD 4 (342 mg, 8.15 mmol) was added in portions. The reaction mixture was warmed to 90 °C with a condenser and stirred for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to 0 °C and quenched carefully with the 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 (2x). The combined organic layers were dried over anhydrous Na2SO4 , collected by filtration, and concentrated on a rotary evaporator . The resulting oil was purified by column chromatography (eluting with DCM/(NH 3 in MeOH) (30/1 )) to afford the title compound (418 mg, yield: 60%) as a colorless oil. LC-MS [M+H] + =162.2. 1 H NMR (400 MHz, CDCl 3 ) δ 5.23 (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).

中間體5Intermediate 5

(2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲-d2-醇

Figure 02_image117
非對映異構體-b                                                  11                                                            中間體5 (2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methan-d2-ol
Figure 02_image117
Diastereomer-b 11 Intermediate 5

步驟1: 6-氟-7a-(羥基甲基-d 2)六氫-3H-吡咯嗪-3-酮 Step 1: 6-fluoro-7a-(hydroxymethyl-d 2 )hexahydro-3H-pyrrolidin-3-one

在0℃在N 2下，向2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯(化合物10，1 g，4.6 mmol)在無水EtOH (10.0 mL)中的溶液分批次地添加NaBD 4(0.21 g，5.1 mmol)。將反應混合物加溫至rt並且在N 2下攪拌持續20 min。反應通過LCMS來監測。在轉化完成之後，將反應在冰-水浴中冷卻，並且在逐滴地添加飽和的含水NH 4Cl (0.2 mL)的情況下小心地猝滅。在攪拌持續30 min之後，混合物在水和DCM之間分配。在分離之後，水層用DCM (2×)萃取。合併的有機層用鹽水洗滌，經無水Na 2SO 4乾燥，並且通過過濾收集。濾液在旋轉蒸發儀上濃縮，以給出殘餘物。產生的油通過柱色譜法(用DCM/MeOH (30/1)洗脫)純化以提供作為黃色油的標題化合物(700 mg，收率：78%)。LC-MS [M+H] += 176.1。 Add ethyl 2-fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (compound 10, 1 g, 4.6 mmol) in anhydrous EtOH (10.0 mL) at 0 °C under N2 ) was added NaBD 4 (0.21 g, 5.1 mmol) in portions. The reaction mixture was warmed to rt and stirred under N2 for 20 min. The reaction was monitored by LCMS. After the conversion was complete, the reaction was cooled in an ice-water bath and quenched carefully with the dropwise addition of saturated aqueous NH4Cl (0.2 mL). After stirring for 30 min, the mixture was partitioned between water and DCM. After separation, the aqueous layer was extracted with DCM (2x). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 , 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 afford the title compound (700 mg, yield: 78%) as a yellow oil. LC-MS [M+H] + =176.1.

步驟2: (2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲-d 2-醇 Step 2: (2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methan- d2 -ol

在rt在N 2下，向6-氟-7a-(羥基甲基-d 2)六氫-3H-吡咯嗪-3-酮(300 mg，1.71 mmol)在無水THF (7 ml)中的溶液分批次地添加LiAlH 4(97.5 mg, 2.57 mmol)。反應混合物在冷凝器的情況下加溫至回流並且攪拌持續2 h。基於LCMS，轉化完成。將反應混合物冷卻至0℃並且在逐滴地添加含水NaOH (0.2 mL, 1 mol/L)的情況下小心地猝滅。反應混合物在水和DCM之間分配。在分離之後，水層用DCM (2×)萃取。合併的有機層經無水Na 2SO 4乾燥，並且通過過濾收集。濾液在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/(在MeOH中的NH 3)(30/1)洗脫)純化以提供作為無色油的標題化合物(199 mg，收率：64%)。LC-MS [M+H] += 162.1。 1H NMR (400 MHz, CDCl 3) δ 5.27 – 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)。 To a solution of 6-fluoro-7a-(hydroxymethyl- d2 )hexahydro-3H-pyrrolidin-3-one (300 mg, 1.71 mmol) in anhydrous THF (7 ml) at rt under N2 LiAlH 4 (97.5 mg, 2.57 mmol) was added in portions. The reaction mixture was warmed to reflux with a condenser and stirred for 2 h. Based on LCMS, the conversion was complete. The reaction mixture was cooled to 0 °C and quenched carefully with the 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 (2x). The combined organic layers were dried over anhydrous Na 2 SO 4 and collected by filtration. The filtrate was concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (eluting with DCM/(NH 3 in MeOH) (30/1 )) to afford the title compound (199 mg, yield: 64%) as a colorless oil. LC-MS [M+H] + = 162.1. 1 H NMR (400 MHz, CDCl 3 ) δ 5.27 – 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).

中間體6Intermediate 6

(2-氟四氫-1H-吡咯嗪-7a(5H)-基-5.5-d2)甲-d2-醇

Figure 02_image119
11                                                            中間體6 (2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5.5-d2)methan-d2-ol
Figure 02_image119
11 Intermediate 6

在rt在N 2下，向6-氟-7a-(羥基甲基-d2)六氫-3H-吡咯嗪-3-酮(化合物11，400 mg，2.28 mmol)在無水Me-THF (8 ml)中的溶液分批次地添加LiAlH 4(210 mg, 5.02 mmol)。反應混合物在冷凝器的情況下加溫至90℃並且攪拌持續2 h。反應通過LCMS來監測。在完成之後，將反應混合物冷卻至0℃並且在逐滴地添加含水NaOH (0.2 mL, 1 mol/L)的情況下小心地猝滅。混合物在水和DCM之間分配。在分離之後，水層用DCM (2x)萃取。合併的有機層經無水Na 2SO 4乾燥，並且通過過濾收集。濾液在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/(在MeOH中的NH 3)(30/1)洗脫)純化以提供作為無色油的標題化合物(185 mg，收率：45%)。LC-MS [M+H] += 164.1。 1H NMR (400 MHz, CDCl 3) δ 5.27 – 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)。 To 6-fluoro-7a-(hydroxymethyl- d2 )hexahydro-3H-pyrrolidin-3-one (compound 11, 400 mg, 2.28 mmol) in anhydrous Me-THF (8 ml ) was added LiAlH 4 (210 mg, 5.02 mmol) in batches. The reaction mixture was warmed to 90 °C with a condenser and stirred for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to 0 °C and quenched carefully with the dropwise addition of aqueous NaOH (0.2 mL, 1 mol/L). The mixture was partitioned between water and DCM. After separation, the aqueous layer was extracted with DCM (2x). The combined organic layers were dried over anhydrous Na 2 SO 4 and collected by filtration. The filtrate was concentrated on a rotary evaporator. The resulting oil was purified by column chromatography (eluting with DCM/(NH 3 in MeOH) (30/1 )) to afford the title compound (185 mg, yield: 45%) as a colorless oil. LC-MS [M+H] + = 164.1. 1 H NMR (400 MHz, CDCl 3 ) δ 5.27 – 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).

中間體7Intermediate 7

(四氫-1H-吡咯嗪-7a(5H)-基)甲-d2-醇

Figure 02_image121
12                                                  中間體7 (Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methan-d2-ol
Figure 02_image121
12 Intermediate 7

在0℃在N 2下在2 min內，向四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯12 (5.0 g，27.3 mmol)在無水THF (30 mL)中的溶液分批次地添加NaBD 4(1.25 g，30.0 mmol)。將產生的混合物緩慢地加溫至rt並且攪拌持續30 min。基於LC/MS，轉化完成。將反應混合物在冰-水浴中冷卻，在逐滴地添加MeOH的情況下小心地猝滅，並且在飽和的含水NH 4Cl (30 mL)和DCM (50 mL)之間分配。在分離之後，水層用DCM (2×)萃取。合併的有機層用鹽水洗滌，經無水Na 2SO 4乾燥，通過過濾收集並且在旋轉蒸發儀上濃縮，以提供作為無色油的預計的粗製化合物(3.64 g，93%收率， 25.4 mmol)，所述粗製化合物對於在下一步中使用是足夠純的。LC-MS [M+H] += 144。 To a solution of ethyl tetrahydro-1H-pyrrolazine-7a(5H)-carboxylate 12 (5.0 g, 27.3 mmol) in anhydrous THF (30 mL) in 2 min at 0 °C under N2 NaBD4 (1.25 g, 30.0 mmol) was added in portions. The resulting mixture was slowly warmed to rt and stirred for 30 min. Based on LC/MS, the conversion was complete. The reaction mixture was cooled in an ice-water bath, quenched carefully with the dropwise addition of MeOH, and partitioned between saturated aqueous NH 4 Cl (30 mL) and DCM (50 mL). After separation, the aqueous layer was extracted with DCM (2x). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 , collected by filtration and concentrated on a rotary evaporator to provide the expected crude compound (3.64 g, 93% yield, 25.4 mmol) as a colorless oil, The crude compound was pure enough to be used in the next step. LC-MS [M+H] + =144.

中間體8Intermediate 8

((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲醇

Figure 02_image123
5                                                         13                                               中間體8 ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)methanol
Figure 02_image123
5 13 Intermediate 8

步驟1: (6R,7aS)-6-氟-7a-(羥基甲基)六氫-3H-吡咯嗪-3-酮-6-dStep 1: (6R,7aS)-6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolidin-3-one-6-d

在0℃在N 2下，向(2R,7aS)-2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯-2-d (2 g，9.25 mmol)在無水EtOH (20.0 mL)中的溶液分批次緩慢地添加NaBH 4(421 mg，11.1 mmol)。在rt在N 2下攪拌混合物持續10 min。反應通過LC/MS來監測。在轉化完成之後，在5℃，反應用NH 4Cl (1 mL)小心地猝滅並且在該溫度攪拌持續30 min。然後，將混合物在旋轉蒸發儀上濃縮，以給出殘餘物。產生的油通過柱色譜法(用DCM/MeOH (20/1)洗脫)純化以提供作為黃色油的標題化合物(1.6 g，收率：90%)。LC-MS [M+H] += 175.2。 To ( 2R ,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate ethyl ester-2-d (2 g, 9.25 mmol ) in anhydrous EtOH (20.0 mL) was slowly added NaBH 4 (421 mg, 11.1 mmol) in portions. The mixture was stirred at rt under N for 10 min. The reaction was monitored by LC/MS. After the conversion was complete, the reaction was carefully quenched with NH4Cl (1 mL) at 5 °C and stirred at this temperature for 30 min. Then, the mixture was concentrated on a rotary evaporator to give a residue. The resulting oil was purified by column chromatography (eluting with DCM/MeOH (20/1 )) to afford the title compound (1.6 g, yield: 90%) as a yellow oil. LC-MS [M+H] + =175.2.

步驟2: ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲醇 Step 2: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methanol

在rt在N 2下，向(6R,7aS)-6-氟-7a-(羥基甲基)六氫-3H-吡咯嗪-3-酮-6-d (900 mg，5.1 mmol)在Me-THF (10 ml)中的溶液小心地分批次添加LiAlD 4(450.3 mg, 10.7 mmol)。將反應混合物加溫至90℃並且攪拌持續2 h。反應通過LCMS來監測。在轉化完成之後，將反應混合物冷卻至0℃並且在添加NaOH的水溶液(0.9 mL, 1 N)的情況下小心地猝滅，過濾並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/MeOH (30/1)洗脫)純化以提供作為黃色油的標題化合物(540 mg，收率：65%)。LC-MS [M+H] += 163.1。 1H NMR (400 MHz, CDCl 3) δ 3.43 (s, 1H), 3.27 (s, 2H), 3.20 – 2.99 (m, 2H), 2.17 – 1.97 (m, 2H), 1.95 – 1.71 (m, 4H)。 To (6R, 7aS )-6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolidin-3-one-6-d (900 mg, 5.1 mmol) in Me- A solution in THF (10 ml) was carefully added in portions with LiAlD4 (450.3 mg, 10.7 mmol). The reaction mixture was warmed to 90 °C and stirred for 2 h. The reaction was monitored by LCMS. After conversion was complete, the reaction mixture was cooled to 0 °C and quenched carefully 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 afford the title compound (540 mg, yield: 65%) as a yellow oil. LC-MS [M+H] + =163.1. 1 H NMR (400 MHz, CDCl 3 ) δ 3.43 (s, 1H), 3.27 (s, 2H), 3.20 – 2.99 (m, 2H), 2.17 – 1.97 (m, 2H), 1.95 – 1.71 (m, 4H) ).

中間體9Intermediate 9

((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲-d2-醇

Figure 02_image125
5                                                         14                                                中間體9 ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)methan-d2-ol
Figure 02_image125
5 14 Intermediate 9

步驟1:  (6R,7aS)-6-氟-7a-(羥基甲基-d 2)六氫-3H-吡咯嗪-3-酮-6-d Step 1: (6R,7aS)-6-fluoro-7a-(hydroxymethyl-d 2 )hexahydro-3H-pyrrolidin-3-one-6-d

在0℃在N 2下，向(2R,7aS)-2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯-2-d (1 g，4.6 mmol)在絕對EtOH (10.0 mL)中的溶液分批次緩慢地添加NaBD 4(0.21 g，5.1 mmol)。在rt在N 2下攪拌混合物持續20 min。反應通過LCMS來監測。在轉化完成之後，在5℃，反應用飽和的含水NH 4Cl (1 mL)小心地猝滅，並且在該溫度攪拌持續30 min。然後，將混合物在旋轉蒸發儀上濃縮，以給出殘餘物。產生的油通過柱色譜法(用DCM/MeOH (30/1)洗脫)純化以提供作為黃色油的標題化合物(720 mg，收率：80%)。  LC-MS [M+H] += 177.2。 To ( 2R ,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate ethyl ester-2-d (1 g, 4.6 mmol ) in absolute EtOH (10.0 mL) was slowly added NaBD4 (0.21 g, 5.1 mmol) in portions. The mixture was stirred at rt under N for 20 min. The reaction was monitored by LCMS. After the conversion was complete, the reaction was carefully quenched with saturated aqueous NH4Cl (1 mL) at 5 °C and stirred at this temperature for 30 min. Then, the mixture 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 afford the title compound (720 mg, yield: 80%) as a yellow oil. LC-MS [M+H] + =177.2.

步驟2:  ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲-d 2-醇 Step 2: ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methan- d 2 -ol

在rt在N 2下，向(6R,7aS)-6-氟-7a-(羥基甲基-d 2)六氫-3H-吡咯嗪-3-酮-6-d (650 mg，3.7 mmol)在Me-THF (10 mL)中的溶液小心地添加LiAlD 4(328 mg, 7.8 mmol)。將反應混合物加溫至90℃並且攪拌持續2 h。反應通過LCMS來監測。在轉化完成之後，將反應混合物冷卻至0℃並且用含水NaOH (0.9 mL, 1 N)小心地猝滅，過濾並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/MeOH (30/1)洗脫)純化以提供作為黃色油的標題化合物(360 mg，收率：59%)。LC-MS [M+H] += 165.0。 1H NMR (400 MHz, CDCl 3) δ 3.54 (s, 1H), 3.26 – 2.97 (m, 2H), 2.17 – 1.96 (m, 2H), 1.95 – 1.69 (m, 4H)。 To (6R,7aS)-6-fluoro-7a-(hydroxymethyl- d2 )hexahydro-3H-pyrrolidin-3-one-6-d (650 mg, 3.7 mmol) at rt under N2 A solution in Me-THF (10 mL) was carefully added LiAlD4 (328 mg, 7.8 mmol). The reaction mixture was warmed to 90 °C and stirred for 2 h. The reaction was monitored by LCMS. After conversion was complete, the reaction mixture was cooled to 0 °C 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 afford the title compound (360 mg, yield: 59%) as a yellow oil. LC-MS [M+H] + = 165.0. 1 H NMR (400 MHz, CDCl 3 ) δ 3.54 (s, 1H), 3.26 – 2.97 (m, 2H), 2.17 – 1.96 (m, 2H), 1.95 – 1.69 (m, 4H).

中間體10Intermediate 10

((2S,7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲醇

Figure 02_image127
4                                                           15                                            中間體10 ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methanol
Figure 02_image127
4 15 Intermediate 10

步驟1: (6S,7aR)-6-氟-7a-(羥基甲基)六氫-3H-吡咯嗪-3-酮-6-dStep 1: (6S,7aR)-6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolidin-3-one-6-d

在0℃在N 2下，向(2S,7aR)-2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯-2-d (2 g，9.3 mmol)在絕對EtOH (20.0 mL)中的溶液分批次緩慢地添加NaBH 4(421 mg，11.1 mmol)。在rt在N 2下攪拌混合物持續10 min。反應通過LCMS來監測。在轉化完成之後，在5℃，反應用飽和的含水NH 4Cl (1 mL)小心地猝滅，並且在該溫度攪拌持續30 min。然後將混合物在旋轉蒸發儀上濃縮以給出殘餘物。產生的油通過柱色譜法(用DCM/MeOH (30/1)洗脫)純化以提供作為黃色油的標題化合物(1.6 g，收率：89%)。  LC-MS [M+H] +=  175.2 To ( 2S ,7aR)-2-fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate ethyl ester-2-d (2 g, 9.3 mmol ) in absolute EtOH (20.0 mL) was slowly added NaBH 4 (421 mg, 11.1 mmol) in portions. The mixture was stirred at rt under N for 10 min. The reaction was monitored by LCMS. After the conversion was complete, the reaction was carefully quenched with saturated aqueous NH4Cl (1 mL) at 5 °C and stirred at this temperature for 30 min. 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 afford the title compound (1.6 g, yield: 89%) as a yellow oil. LC-MS [M+H] + = 175.2

步驟2:  (6S,7aR)-6-氟-7a-(羥基甲基)六氫-3H-吡咯嗪-3-酮-6-dStep 2: (6S,7aR)-6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolidin-3-one-6-d

在0℃在N 2下，向(6S,7aR)-6-氟-7a-(羥基甲基)六氫-3H-吡咯嗪-3-酮-6-d (700 mg，4.01 mmol)在THF (10 ml)中的溶液小心地分批次添加LiAlH 4(226 mg, 5.96 mmol)。將反應混合物加溫至70℃並且攪拌持續2 h。反應通過LCMS來監測。在轉化完成之後，將反應混合物冷卻至0℃並且用含水NaOH (0.9 mL, 1 N)小心地猝滅，過濾並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/(在MeOH中的NH 3)(30/1)洗脫)純化以提供作為無色油的標題化合物(450 mg，收率：70%)。LC-MS [M+H] += 161.1。 1H NMR (400 MHz, CDCl 3) δ 3.53 (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)。 To (6S,7aR)-6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolidin-3-one-6-d (700 mg, 4.01 mmol) in THF at 0 °C under N (10 ml) was carefully added LiAlH 4 (226 mg, 5.96 mmol) in portions. The reaction mixture was warmed to 70 °C and stirred for 2 h. The reaction was monitored by LCMS. After conversion was complete, the reaction mixture was cooled to 0 °C 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/(NH 3 in MeOH) (30/1 )) to afford the title compound (450 mg, yield: 70%) as a colorless oil. LC-MS [M+H] + = 161.1. 1 H NMR (400 MHz, CDCl 3 ) δ 3.53 (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).

中間體11Intermediate 11

((2S,7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲醇

Figure 02_image129
15                                                    中間體11 ((2S,7aR)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)methanol
Figure 02_image129
15 intermediate 11

在0℃在N 2下，向(6S,7aR)-6-氟-7a-(羥基甲基)六氫-3H-吡咯嗪-3-酮-6-d (900 mg，5.11 mmol)在Me-THF (10 ml)中的溶液小心地添加LiAlD 4(450 mg, 10.73 mmol)。將反應混合物加溫至90℃並且攪拌持續2 h。反應通過LC/MS來監測。在轉化完成之後，將反應混合物冷卻至0℃並且用含水NaOH (0.9 mL, 1 N)小心地猝滅，過濾並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/(在MeOH中的NH 3)(30/1)洗脫)純化以提供作為無色油的標題化合物(540 mg，收率：65%)。LC-MS [M+H] += 163.1。 1H NMR (400 MHz, CDCl 3) δ 3.43 (s, 1H), 3.27 (s, 2H), 3.20 – 2.98 (m, 2H), 2.17 – 1.97 (m, 2H), 1.95 – 1.69 (m, 4H)。 To (6S,7aR)-6-fluoro-7a-( hydroxymethyl )hexahydro-3H-pyrrolidin-3-one-6-d (900 mg, 5.11 mmol) in Me - solution in THF (10 ml) was added LiAlD4 (450 mg, 10.73 mmol) carefully. The reaction mixture was warmed to 90 °C and stirred for 2 h. The reaction was monitored by LC/MS. After conversion was complete, the reaction mixture was cooled to 0 °C 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/(NH 3 in MeOH) (30/1 )) to afford the title compound (540 mg, yield: 65%) as a colorless oil. LC-MS [M+H] + =163.1. 1 H NMR (400 MHz, CDCl 3 ) δ 3.43 (s, 1H), 3.27 (s, 2H), 3.20 – 2.98 (m, 2H), 2.17 – 1.97 (m, 2H), 1.95 – 1.69 (m, 4H) ).

中間體12Intermediate 12

((2S,7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲-d2-醇

Figure 02_image131
4                                                        16                                                  中間體12 ((2S,7aR)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)methan-d2-ol
Figure 02_image131
4 16 Intermediate 12

步驟1:  (6S,7aR)-6-氟-7a-(羥基甲基-d2)六氫-3H-吡咯嗪-3-酮-6-dStep 1: (6S,7aR)-6-fluoro-7a-(hydroxymethyl-d2)hexahydro-3H-pyrrolidin-3-one-6-d

在0℃在N 2下，向(2S,7aR)-2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯-2-d (2.0 g，9.25 mmol)在絕對EtOH (20.0 mL)中的溶液分批次緩慢地添加NaBD 4(430 mg，10.2 mmol)。在rt在N 2下攪拌混合物持續10 min。反應通過LCMS來監測。在轉化完成之後，在5℃，反應用飽和的含水NH 4Cl (1 mL)小心地猝滅，並且在該溫度攪拌持續30 min。然後，將混合物在旋轉蒸發儀上濃縮，以給出殘餘物。產生的油通過柱色譜法(用DCM/MeOH (20/1)洗脫)純化以提供作為黃色油的標題化合物(1.30 g，收率：71%)。  LC-MS [M+H] += 177.1 To ( 2S ,7aR)-2-fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate ethyl ester-2-d (2.0 g, 9.25 mmol ) in absolute EtOH (20.0 mL) was slowly added NaBD 4 (430 mg, 10.2 mmol) in portions. The mixture was stirred at rt under N for 10 min. The reaction was monitored by LCMS. After the conversion was complete, the reaction was carefully quenched with saturated aqueous NH4Cl (1 mL) at 5 °C and stirred at this temperature for 30 min. Then, the mixture was concentrated on a rotary evaporator to give a residue. The resulting oil was purified by column chromatography (eluting with DCM/MeOH (20/1 )) to afford the title compound (1.30 g, yield: 71%) as a yellow oil. LC-MS [M+H] + = 177.1

步驟2:    ((2S,7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲-d 2-醇 Step 2: ((2S,7aR)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-d 3 )methan- d 2 -ol

在0℃在N 2下，向(6S,7aR)-6-氟-7a-(羥基甲基-d 2)六氫-3H-吡咯嗪-3-酮-6-d (650 mg，3.7 mmol)在Me-THF (10 ml)中的溶液小心地添加LiAlD 4(420 mg, 10 mmol)。將反應混合物加溫至90℃並且攪拌持續2 h。反應通過LCMS來監測。在轉化完成之後，將反應混合物冷卻至0℃並且用含水NaOH (0.9 mL, 1 N)小心地猝滅，過濾並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/(在MeOH中的NH 3)(30/1)洗脫)純化以提供作為無色油的標題化合物(360 mg，收率：60%)。LC-MS [M+H] += 165.0。 1H NMR (400 MHz, CDCl 3) δ 3.54 (s, 1H), 3.19 – 2.98 (m, 2H), 2.17 – 1.96 (m, 2H), 1.95 – 1.68 (m, 4H)。 To (6S,7aR)-6-fluoro-7a-(hydroxymethyl- d 2 ) hexahydro-3H-pyrrolidin-3-one-6-d (650 mg, 3.7 mmol ) in Me-THF (10 ml) was carefully added LiAlD 4 (420 mg, 10 mmol). The reaction mixture was warmed to 90 °C and stirred for 2 h. The reaction was monitored by LCMS. After conversion was complete, the reaction mixture was cooled to 0 °C 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/(NH 3 in MeOH) (30/1 )) to afford the title compound (360 mg, yield: 60%) as a colorless oil. LC-MS [M+H] + = 165.0. 1 H NMR (400 MHz, CDCl 3 ) δ 3.54 (s, 1H), 3.19 – 2.98 (m, 2H), 2.17 – 1.96 (m, 2H), 1.95 – 1.68 (m, 4H).

中間體13Intermediate 13

((2S，7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲-d2-醇

Figure 02_image133
16                                                                    中間體13 ((2S,7aR)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methanol-d2-ol
Figure 02_image133
16 Intermediate 13

在0℃在N 2下，向(6S,7aR)-6-氟-7a-(羥基甲基-d 2)六氫-3H-吡咯嗪-3-酮-6-d (650 mg，3.7 mmol)在THF (10 ml)中的溶液小心地添加LiAlH 4(213 mg, 5.6 mmol)。將反應混合物加溫至70℃並且攪拌持續2 h。反應通過LC/MS來監測。在轉化完成之後，將反應混合物冷卻至0℃並且用含水NaOH (0.5 mL, 1 N)小心地猝滅，過濾並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/(在MeOH中的NH 3)(30/1)洗脫)純化以提供作為黃色油的標題化合物(340 mg，收率：56%)。LC-MS [M+H] += 163.1。 1H NMR (400 MHz, CDCl 3) δ 3.34 (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)。 To (6S,7aR)-6-fluoro-7a-(hydroxymethyl- d 2 ) hexahydro-3H-pyrrolidin-3-one-6-d (650 mg, 3.7 mmol ) in THF (10 ml) was carefully added LiAlH 4 (213 mg, 5.6 mmol). The reaction mixture was warmed to 70 °C and stirred for 2 h. The reaction was monitored by LC/MS. After conversion was complete, the reaction mixture was cooled to 0 °C 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 (eluting with DCM/(NH 3 in MeOH) (30/1 )) to afford the title compound (340 mg, yield: 56%) as a yellow oil. LC-MS [M+H] + =163.1. 1 H NMR (400 MHz, CDCl 3 ) δ 3.34 (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).

中間體14Intermediate 14

((2S，7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲-d2-醇

Figure 02_image135
9                                                    17                                                  中間體14 ((2S,7aR)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol-d2-ol
Figure 02_image135
9 17 Intermediate 14

步驟1:    (6S,7aR)-6-氟-7a-(羥基甲基-d 2)六氫-3H-吡咯嗪-3-酮 Step 1: (6S,7aR)-6-fluoro-7a-(hydroxymethyl-d 2 )hexahydro-3H-pyrrolidin-3-one

在0℃在N 2下，向(2S,7aR)-2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯(2.0 g，9.3 mmol)在無水EtOH (20.0 mL)中的溶液分批次緩慢地添加NaBD 4(430 mg，10.2 mmol)。在rt在N 2下攪拌混合物持續10 min。反應通過LC/MS來監測。在轉化完成之後，在5℃，反應用飽和的含水NH 4Cl (1 mL)小心地猝滅，並且在該溫度攪拌持續30 min。然後，將混合物在旋轉蒸發儀上濃縮，以給出殘餘物。產生的油通過柱色譜法(用DCM/MeOH (20/1)洗脫)純化以提供作為黃色油的標題化合物(1.6 g，收率：88%)。  LC-MS [M+H] +=  176.1 To (2S,7aR)-2-fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (2.0 g, 9.3 mmol) in anhydrous EtOH at 0 °C under N2 (20.0 mL) was slowly added NaBD 4 (430 mg, 10.2 mmol) in portions. The mixture was stirred at rt under N for 10 min. The reaction was monitored by LC/MS. After the conversion was complete, the reaction was carefully quenched with saturated aqueous NH4Cl (1 mL) at 5 °C and stirred at this temperature for 30 min. Then, the mixture was concentrated on a rotary evaporator to give a residue. The resulting oil was purified by column chromatography (eluting with DCM/MeOH (20/1 )) to afford the title compound (1.6 g, yield: 88%) as a yellow oil. LC-MS [M+H] + = 176.1

步驟2: ((2S，7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲-d 2-醇 Step 2: ((2S,7aR)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methan- d2 -ol

在0℃在N 2下，向(6S,7aR)-6-氟-7a-(羥基甲基-d 2)六氫-3H-吡咯嗪-3-酮(800 mg，4.6 mmol)在THF (10 ml)中的溶液小心地添加LiAlH 4(263 mg, 6.9 mmol)。將反應混合物在70℃攪拌持續2 h。反應通過LCMS來監測。在轉化完成之後，將反應混合物冷卻至0℃並且用含水NaOH (0.5 mL, 1 N)小心地猝滅，過濾並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/(在MeOH中的NH 3)(30/1)洗脫)純化以提供作為無色油的標題化合物(480 mg，收率：65%)。LC-MS [M+H] += 162.1。 1H NMR (400 MHz, CDCl 3) δ 5.29 – 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)。 To (6S,7aR)-6-fluoro-7a-(hydroxymethyl- d 2 ) hexahydro-3H-pyrrolidin-3-one (800 mg, 4.6 mmol) in THF ( 10 ml) was carefully added LiAlH 4 (263 mg, 6.9 mmol). The reaction mixture was stirred at 70 °C for 2 h. The reaction was monitored by LCMS. After conversion was complete, the reaction mixture was cooled to 0 °C 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 (eluting with DCM/(NH 3 in MeOH) (30/1 )) to afford the title compound (480 mg, yield: 65%) as a colorless oil. LC-MS [M+H] + = 162.1. 1 H NMR (400 MHz, CDCl 3 ) δ 5.29 – 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).

中間體15Intermediate 15

((2S,7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d2)甲-d2-醇

Figure 02_image137
17                                                                   中間體15 ((2S,7aR)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d2)methan-d2-ol
Figure 02_image137
17 Intermediate 15

在0℃在N 2下，向(6S,7aR)-6-氟-7a-(羥基甲基-d2)六氫-3H-吡咯嗪-3-酮-d (800 mg，4.6 mmol)在Me-THF (10 ml)中的溶液添加LiAlD 4(407 mg, 9.7 mmol)。將反應混合物在90℃攪拌持續2 h。反應通過LCMS來監測。在完成之後，將反應混合物冷卻至0℃並且用NaOH (0.9 mL,1 mol/L)猝滅，過濾並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/(在MeOH中的NH 3)(30/1)洗脫)純化以提供作為無色油的標題化合物，((2S,7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)-5,5-d2)甲-d2-醇(480 mg，收率：64%)。LC-MS [M+H] += 164.1。 1H NMR (400 MHz, CDCl3) δ 5.28 – 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)。 To (6S,7aR)-6-fluoro-7a-(hydroxymethyl- d2 )hexahydro-3H-pyrrolidin-3-one-d (800 mg, 4.6 mmol) in Me - solution in THF (10 ml) was added LiAlD 4 (407 mg, 9.7 mmol). The reaction mixture was stirred at 90 °C for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to 0 °C 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 (eluting with DCM/( NH3 in MeOH) (30/1)) to afford the title compound, ((2S,7aR)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl)-5,5-d2)methan-d2-ol (480 mg, yield: 64%). LC-MS [M+H] + = 164.1. 1 H NMR (400 MHz, CDCl3) δ 5.28 – 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).

中間體16Intermediate 16

((2S,7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇

Figure 02_image139
9                                                            18                                            中間體16 ((2S,7aR)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol
Figure 02_image139
9 18 Intermediate 16

步驟1:  (6S,7aR)-6-氟-7a-(羥基甲基)六氫-3H-吡咯嗪-3-酮Step 1: (6S,7aR)-6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolidin-3-one

在0℃在N 2下，向(2S,7aR)-2-氟-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯(2.0 g，9.3 mmol)在無水EtOH (20 mL)中的溶液緩慢地添加NaBH 4(421 mg，11.1 mmol)。在室溫在N 2下攪拌混合物持續10 min。反應通過LCMS來監測。在完成之後，在5℃，反應用NH 4Cl (1 mL)稀釋並且在該溫度攪拌持續30 min。然後，將混合物在旋轉蒸發儀上濃縮，以給出殘餘物。產生的油通過柱色譜法(用DCM/MeOH (30/1)洗脫)純化以提供作為黃色油的標題化合物(1.6 g，收率：89%)。  LC-MS [M+H] += 174.1。 To (2S,7aR)-2-fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (2.0 g, 9.3 mmol) in anhydrous EtOH at 0 °C under N2 (20 mL) was added NaBH4 (421 mg, 11.1 mmol) slowly. The mixture was stirred at room temperature under N 2 for 10 min. The reaction was monitored by LCMS. After completion, the reaction was diluted with NH4Cl (1 mL) at 5 °C and stirred at this temperature for 30 min. Then, the mixture 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 afford the title compound (1.6 g, yield: 89%) as a yellow oil. LC-MS [M+H] + = 174.1.

步驟2: ((2S,7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇Step 2: ((2S,7aR)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol

在20℃在N 2下，向(6S,7aR)-6-氟-7a-(羥基甲基)六氫-3H-吡咯嗪-3-酮-d (800 mg，4.62 mmol)在THF (7 ml)中的溶液添加LiAlH 4(263 mg, 6.93 mmol)。將反應混合物在70℃攪拌持續2 h。反應通過LCMS來監測。在轉化完成之後，將反應混合物冷卻至0℃並且用含水NaOH (0.5 mL, 1 N)小心地猝滅，過濾並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/(在MeOH中的NH 3)(30/1)洗脫)純化以提供作為無色油的標題化合物(460 mg，收率：56%)。LC-MS [M+H] += 160.1。 To (6S, 7aR )-6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolidin-3-one-d (800 mg, 4.62 mmol) in THF (7 ml) was added LiAlH 4 (263 mg, 6.93 mmol). The reaction mixture was stirred at 70 °C for 2 h. The reaction was monitored by LCMS. After conversion was complete, the reaction mixture was cooled to 0 °C 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 (eluting with DCM/(NH 3 in MeOH) (30/1 )) to afford the title compound (460 mg, yield: 56%) as a colorless oil. LC-MS [M+H] + =160.1.

1H NMR (400 MHz, CDCl 3) δ 5.29 – 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)。 1 H NMR (400 MHz, CDCl 3 ) δ 5.29 – 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).

中間體17Intermediate 17

((2S,7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d2)甲醇

Figure 02_image141
18                                                                      中間體17 ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d2)methanol
Figure 02_image141
18 Intermediate 17

在20℃在N 2下，向(6S,7aR)-6-氟-7a-(羥基甲基)六氫-3H-吡咯嗪-3-酮(800 mg，4.62 mmol)在Me-THF (7 ml)中的溶液小心地添加LiAlD 4(407 mg, 9.70 mmol)。將反應混合物加溫至90℃並且攪拌持續2 h。反應通過LCMS來監測。在轉化完成之後，將反應混合物冷卻至0℃並且用含水NaOH (0.5 mL, 1 N)小心地猝滅，過濾並且在旋轉蒸發儀上濃縮。產生的油通過柱色譜法(用DCM/(在MeOH中的NH 3)(30/1)洗脫)純化以提供作為無色油的標題化合物(470 mg，收率：57%)。LC-MS [M+H] += 162.1。 1H NMR (400 MHz, CDCl 3) δ 5.28 – 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)。 To (6S, 7aR )-6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolidin-3-one (800 mg, 4.62 mmol) in Me-THF (7 ml) was carefully added LiAlD 4 (407 mg, 9.70 mmol). The reaction mixture was warmed to 90 °C and stirred for 2 h. The reaction was monitored by LCMS. After conversion was complete, the reaction mixture was cooled to 0 °C 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 (eluting with DCM/(NH 3 in MeOH) (30/1 )) to afford the title compound (470 mg, yield: 57%) as a colorless oil. LC-MS [M+H] + = 162.1. 1 H NMR (400 MHz, CDCl 3 ) δ 5.28 – 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).

中間體18Intermediate 18

2,4,7-三氯-8-氟吡啶並[4,3-d]嘧啶

Figure 02_image143
19                                                      中間體18 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine
Figure 02_image143
19 intermediate 18

在rt，向7-氯-8-氟吡啶並[4,3-d]嘧啶-2,4-二醇(4.61 g, 21.4 mmol)在POCl 3(76.0 g, 496 mmol)中的溶液緩慢地添加DIEA (14.0 g, 108 mmol)。將混合物在110℃加熱持續3小時。反應通過LCMS來監測。在完成之後，將混合物在真空下濃縮,以提供2,4,7-三氯-8-氟吡啶並[4,3-d]嘧啶(4 g，粗品)，2,4,7-三氯-8-氟吡啶並[4,3-d]嘧啶在下一步直接使用，而不另外純化。LC-MS [M+H] += 354.2。 At rt, a solution of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (4.61 g, 21.4 mmol) in POCl (76.0 g, 496 mmol) was slowly added to Add DIEA (14.0 g, 108 mmol). The mixture was heated at 110 °C for 3 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under vacuum to provide 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (4 g, crude), 2,4,7-trichloro -8-Fluoropyrido[4,3-d]pyrimidine was used directly in the next step without additional purification. LC-MS [M+H] + = 354.2.

實施例1Example 1

4-(4-(3,6-二氮雜雙環並[3.2.1]庚烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚

Figure 02_image145
4-(4-(3,6-diazabicyclo[3.2.1]heptane-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
Figure 02_image145

步驟1: 7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1,3-二酚Step 1: 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol

在N 2下，向7-氟萘-1,3-二酚(12 g，67.3 mmol，1當量)、2-溴乙炔基(三異丙基)甲矽烷(18.5 g，70.7 mmol，1.05當量)和KOAc (13.2 g，134 mmol，2.0當量)在1,4-二氧六環(80 mL)中的混合物添加二氯化釕和1-異丙基-4-甲基苯二聚體(4.13 g，6.74 mmol，0.1當量)。將產生的混合物加溫至110℃並且在N 2下攪拌持續2 h。基於LC/MS，轉化完成。將反應混合物冷卻至rt並且在鹽水和EtOAc之間分配。在分離之後，水層用EtOAc (2×)萃取。合併的有機層經無水Na 2SO 4乾燥，通過過濾收集。將濾液濃縮以給出殘餘物，所述殘餘物通過柱色譜法(SiO 2，PE/EtOAc = 1/0至5/1)純化以給出作為黑色油的標題化合物(15.6 g，65%收率)。LC-MS [M-H] -= 357.2。 Under N 2 , 7-fluoronaphthalene-1,3-diol (12 g, 67.3 mmol, 1 equiv), 2-bromoethynyl (triisopropyl) silane (18.5 g, 70.7 mmol, 1.05 equiv ) and KOAc (13.2 g, 134 mmol, 2.0 equiv) in 1,4-dioxane (80 mL) were added with ruthenium dichloride and 1-isopropyl-4-methylbenzene dimer ( 4.13 g, 6.74 mmol, 0.1 equiv). The resulting mixture was warmed to 110 °C and stirred under N2 for 2 h. Based on LC/MS, the conversion was complete. The reaction mixture was cooled to rt and partitioned between brine and EtOAc. After separation, the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over anhydrous Na2SO4 and collected by filtration. The filtrate was concentrated to give a residue which was purified by column chromatography ( Si02 , PE/EtOAc = 1/0 to 5/1) to give the title compound as a black oil (15.6 g, 65% yield Rate). LC-MS [MH] - = 357.2.

步驟2: 7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-酚Step 2: 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol

在0℃在N 2下，向7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-l,3-二酚(37 g，103.2 mmol)和DIEA (40 g，309.6 mmol，3當量)在DCM (370 mL)中的混合物添加MOMCl (10.8 g，134 mmol)。將混合物加溫至rt並且攪拌持續0.5 h。基於LC/MS，反應轉化完成。反應混合物用冰-水(200 mL)稀釋並且用EtOAc (100 mL×3)萃取。合併的有機層用鹽水(200 mL)洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且濃縮以給出殘餘物。殘餘物通過柱色譜法(SiO 2，PE/EtOAc = 1/0至50/1)純化以給出作為黃色油的標題化合物(29 g，70%收率)。LCMS[M+H] += 403.2。 7-Fluoro-8-(( triisopropylsilyl )ethynyl)naphthalene-l,3-diol (37 g, 103.2 mmol) and DIEA (40 g, 309.6 A mixture of mmol, 3 equiv) in DCM (370 mL) was added MOMCl (10.8 g, 134 mmol). The mixture was warmed to rt and stirred for 0.5 h. Based on LC/MS, the reaction conversion was complete. 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 , collected by filtration, and concentrated to give a residue. The residue was purified by column chromatography ( Si02 , PE/EtOAc = 1/0 to 50/1) to give the title compound (29 g, 70% yield) as yellow oil. LCMS[M+H] + = 403.2.

步驟3: 7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基三氟甲磺酸酯Step 3: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl triflate

在-40℃在N 2下，向7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-l-酚(29.0 g，72 mmol)和DIEA (27.9 g，10.4 mL，129 mmol)在DCM (200 mL)中的溶液添加Tf 2O (30.5 g，108.0 mmol，17.9 mL，1.5當量)。在N 2下攪拌反應混合物持續0.5 h。基於LC/MS，轉化完成。反應混合物用冰-水(200 mL)稀釋並且DCM (400 mL )萃取。有機相用鹽水洗滌，經無水Na 2SO 4乾燥，並且通過過濾收集。濾液在旋轉蒸發儀上濃縮。殘餘物通過柱色譜法(SiO 2，PE/EtOAc = 1/0至60/1)純化以提供作為黃色油的標題化合物(38.0 g，99%收率)。LCMS[M+H] += 535.1。 7-Fluoro-3-( methoxymethoxy )-8-((triisopropylsilyl)ethynyl)naphthalene-l-phenol (29.0 g, 72 mmol) and DIEA (27.9 g, 10.4 mL, 129 mmol) in DCM (200 mL) was added Tf2O (30.5 g, 108.0 mmol, 17.9 mL, 1.5 equiv). The reaction mixture was stirred under N 2 for 0.5 h. Based on LC/MS, the conversion 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 Na2SO4 , and collected by filtration. The filtrate was concentrated on a rotary evaporator. The residue was purified by column chromatography ( Si02 , PE/EtOAc = 1/0 to 60/1) to afford the title compound (38.0 g, 99% yield) as yellow oil. LCMS[M+H] + = 535.1.

步驟4: ((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-l,3,2-二氧雜硼烷-2-基)萘-1-基)乙炔基)三異丙基甲矽烷Step 4: ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl )naphthalene-1-yl)ethynyl)triisopropylsilane

向7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基三氟甲磺酸酯(8 g，15.0 mmol，1當量)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-l,3,2-二氧雜硼烷-2-基)-l,3,2-二氧雜硼烷(16.0 g，63.0 mmol，4.2當量)和KOAc (4.80 g，48.9 mmol，3.26當量)在脫氣的甲苯(200 mL)中的混合物添加Pd(dppf)Cl 2(1.20 g，1.64 mmol，0.11當量)。將混合物抽真空，用N 2填充並且裝配有冷凝器和N 2氣球。將產生的混合物在130℃油浴中加溫並且在N 2下攪拌持續12 h。基於LC/MS，轉化完成。將反應混合物冷卻至rt，在水和EtOAc之間分配。在分離之後，水層用EtOAc (2×)萃取。合併的有機層用鹽水洗滌，經無水Na 2SO 4乾燥，並且通過過濾收集。濾液在旋轉蒸發儀上濃縮。殘餘物通過柱色譜法(SiO2，PE/EtOAc = 100/1至50/1)純化以給出作為淺黃色油的標題化合物(1.0 g，17%收率)。LCMS[M+H] += 513。 1H NMR (400 MHz, CDCl 3) δ 7.68 (dd, J = 9.0, 5.8 Hz, 1H), 7.52 (d, J = 2.6 Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 5.29 (s, 2H), 3.52 (s, 3H), 1.45 (s, 12H), 1.18 (d, J = 2.4 Hz, 21H)。 To 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl trifluoromethanesulfonate (8 g, 15.0 mmol, 1 equivalent), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3 , a mixture of 2-dioxaborane (16.0 g, 63.0 mmol, 4.2 equiv) and KOAc (4.80 g, 48.9 mmol, 3.26 equiv) in degassed toluene (200 mL) was added with Pd(dppf)Cl 2 ( 1.20 g, 1.64 mmol, 0.11 equiv). The mixture was evacuated, filled with N2 and fitted with a condenser and N2 balloon. The resulting mixture was warmed in a 130 °C oil bath and stirred under N2 for 12 h. Based on LC/MS, the conversion was complete. The reaction mixture was cooled to rt, partitioned between water and EtOAc. After separation, the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 , and collected by filtration. The filtrate was concentrated on a rotary evaporator. The residue was purified by column chromatography (Si02, PE/EtOAc = 100/1 to 50/1) to give the title compound (1.0 g, 17% yield) as pale yellow oil. LCMS[M+H] + =513. 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (dd, J = 9.0, 5.8 Hz, 1H), 7.52 (d, J = 2.6 Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 5.29 (s, 2H), 3.52 (s, 3H), 1.45 (s, 12H), 1.18 (d, J = 2.4 Hz, 21H).

步驟5：3-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-3,6-二氮雜雙環並[3.1.1]庚烷-6-羧酸叔丁酯Step 5: 3-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6 - tert-butyl carboxylate

在rt，向2,4,7-三氯-8-氟吡啶並[4,3-d]嘧啶(中間體18，3.4 g，13.55 mmol，1當量)在乾燥的DCM (40.0 mL)中的溶液添加DIEA (13.4 mL，81.30 mmol，6當量)。然後，將混合物冷卻至-40℃，在N 2下在10 min內，逐滴地添加3,6-二氮雜雙環並[3.1.1]庚烷-6-羧酸叔丁酯(2.68 g，13.55 mmol，1當量)的溶液並且攪拌持續0.5 h。基於LC/MS，轉化完成。反應用水(30.0 mL)猝滅。產生的反應混合物用EtOAc (30.0 mL×3)萃取。合併的有機層用鹽水洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在減壓下濃縮。產生的殘餘物通過在矽膠柱(silica gel column )上的快速色譜法(flash chromatography)(PE/EtOAc =40/1至20/1)純化以提供作為白色固體的3-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-3,6-二氮雜雙環並[3.1.1]庚烷-6-羧酸叔丁酯(1.9 g，34%收率，4.6 mmol)。LC-MS [M+H] += 414.1。 Add 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (Intermediate 18, 3.4 g, 13.55 mmol, 1 equiv) in dry DCM (40.0 mL) at rt. To the solution was added DIEA (13.4 mL, 81.30 mmol, 6 equiv). Then, the mixture was cooled to −40 °C, and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate ( 2.68 g , 13.55 mmol, 1 equiv) and stirring was continued for 0.5 h. Based on LC/MS, the conversion was complete. The reaction was quenched with water (30.0 mL). The resulting reaction mixture was extracted with EtOAc (30.0 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 , collected by filtration , and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on a silica gel column (PE/EtOAc = 40/1 to 20/1) to afford 3-(2,7-bis Chloro-8-fluoropyrido[4,3-d]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.

步驟6：3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d2)吡啶並[4,3-d]嘧啶-4-基)-3,6-二氮雜雙環並[3.1.1]庚烷-6-羧酸叔丁酯Step 6: 3-(7-Chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidine- 4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

在N 2下，向3-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-3,6-二氮雜雙環並[3.1.1]庚烷-6-羧酸叔丁酯(500 mg，1.21 mol，1當量)在乾燥的1,4-二氧六環(4 mL)中的溶液添加(四氫-1H-吡咯嗪-7a(5H)-基)甲-d 2-醇(中間體7，342 mg，2.4 mmol)和DIEA (0.6 mL，3.63 mmol，3當量)。將反應加溫至80℃並且攪拌過夜。基於LC/MS，轉化完成。將反應混合物冷卻至rt，用水(50.0 mL)稀釋並且隨後添加EtOAc (50.0 mL)。將兩層分離並且水層用EtOAc (2×)萃取。合併的有機層經無水Na 2SO 4乾燥，通過過濾收集，並且在減壓下濃縮。產生的殘餘物通過在矽膠柱上的快速色譜法(DCM/MeOH =20/1)純化，以提供預計的3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,6-二氮雜雙環並[3.1.1]庚烷-6-羧酸叔丁酯(530 mg，84%收率，1.0 mmol)。LC-MS [M+H] += 521.2。 Under N2 , to 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]hept A solution of tert-butyl alkane-6-carboxylate (500 mg, 1.21 mol, 1 equiv) in dry 1,4-dioxane (4 mL) was added (tetrahydro-1H-pyrrolazine-7a (5H )-yl)metha- d2 -ol (Intermediate 7, 342 mg, 2.4 mmol) and DIEA (0.6 mL, 3.63 mmol, 3 equiv). The reaction was warmed to 80 °C and stirred overnight. Based on LC/MS, the conversion was complete. The reaction mixture was cooled to rt, diluted with water (50.0 mL) and then EtOAc (50.0 mL) was added. The two layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over anhydrous Na2SO4 , collected by filtration , and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel column (DCM/MeOH=20/1) to provide the expected 3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazine -7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6- tert-Butyl carboxylate (530 mg, 84% yield, 1.0 mmol). LC-MS [M+H] + = 521.2.

步驟7：3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,6-二氮雜雙環並[3.1.1]庚烷-6-羧酸叔丁酯 Step 7: 3-(8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- 2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo And [3.1.1] tert-butyl heptane-6-carboxylate

向3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,6-二氮雜雙環並[3.1.1]庚烷-6-羧酸叔丁酯(530 mg，1.02 mmol)在二氧六環(3.0 mL)和H 2O (1.0 mL)的脫氣的混合溶劑中的溶液添加((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)萘-1-基)乙炔基)三異丙基甲矽烷(787.9 mg，2.05 mmol，2當量)、Cs 2CO 3(668 mg，2.05 mmol)和Pd(dppf)Cl 2(150 mg，0.20 mmol)。將混合物抽真空，用N 2填充，並且該程式重複三次。將容器密封。將產生的混合物加溫至110並且攪拌持續1 h。基於LC/MS，轉化完成。反應混合物用水(20 mL)稀釋並且用EtOAc (20 mL×3)萃取。合併的有機層通過無水Na 2SO 4乾燥並且通過過濾收集。將濾液在減壓下濃縮。產生的殘餘物通過在矽膠柱上的快速色譜法(DCM/MeOH =10/1)純化，以提供標題化合物(217 mg，26%收率，0.25 mmol)。LC-MS [M+H] += 871.4。 To 3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidine-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 O (1.0 mL) of degassed mixed solvent solution was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (787.9 mg, 2.05 mmol, 2 equiv), Cs 2 CO 3 (668 mg, 2.05 mmol) and Pd( dppf) Cl2 (150 mg, 0.20 mmol). The mixture was evacuated, filled with N2 , and the procedure was repeated three times. Keep container tightly closed. The resulting mixture was warmed to 110 and stirred for 1 h. Based on LC/MS, the conversion was complete. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4 and collected by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel column (DCM/MeOH = 10/1 ) to afford the title compound (217 mg, 26% yield, 0.25 mmol). LC-MS [M+H] + = 871.4.

步驟8：3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,6-二氮雜雙環並[3.1.1]庚烷-6-羧酸叔丁酯 Step 8: 3-(7-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazine -7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6- tert-butyl carboxylate

在rt，向3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,6-二氮雜雙環並[3.1.1]庚烷-6-羧酸叔丁酯(217 mg，0.25 mmol)在DMF (2.0 mL)中的溶液添加CsF (190 mg，1.25 mmol)。將產生的混合物攪拌持續1 h，用水(20.0 mL)稀釋並且用EtOAc (20.0 mL×3)萃取。合併的有機層經無水Na 2SO 4乾燥，通過過濾收集並且在減壓下濃縮，以給出作為黃色油的預計的標題化合物(300 mg，粗品)，所述標題化合物直接使用而不另外純化。LC-MS [M+H] += 715.3。 At rt, to 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl) -2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazepine To a solution of tert-butyl bicyclo[3.1.1]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 1 h, diluted with water (20.0 mL) and extracted with EtOAc (20.0 mL×3). The combined organic layers were dried over anhydrous Na2SO4 , 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 further purification . LC-MS [M+H] + = 715.3.

步驟10：4-(4-(3,6-二氮雜雙環並[3.2.1]庚烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚 Step 10: 4-(4-(3,6-Diazabicyclo[3.2.1]heptan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazine-7a(5H )-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

在rt，向3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,6-二氮雜雙環並[3.1.1]庚烷-6-羧酸叔丁酯(300 mg，0.42 mmol)在MeCN (2.0 mL)中的溶液添加4N HCl/MeOH (2.0 mL)。將反應混合物攪拌持續1 h，用飽和的NaHCO 3調節至pH ~ 7，用水(20 mL)稀釋並且用EtOAc (20 mL×3)萃取。合併的有機層用鹽水洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在減壓下濃縮。殘餘物通過製備型HPLC (Prep-HPLC) (流動相A：0.1%FA；流動相B：MeCN；梯度：在55分鐘內30%-70% B；流速：70 mL/min)純化，以給出作為白色固體的標題化合物(8 mg，0.14 mmol，3%收率)。LC-MS [M+H] += 571.2。 At rt, to 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrole Azin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6 - A solution of tert-butyl 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 1 h, adjusted to pH~7 with saturated NaHCO 3 , diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 , 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 in 55 minutes; flow rate: 70 mL/min) to give The title compound (8 mg, 0.14 mmol, 3% yield) was obtained as a white solid. LC-MS [M+H] + = 571.2.

實施例2Example 2

3-(4-(8-氧雜-3-氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚

Figure 02_image147
3-(4-(8-oxa-3-azabicyclo[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
Figure 02_image147

步驟1：2-(3-溴-5-氯-4-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷Step 1: 2-(3-Bromo-5-chloro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane

在N 2下，向1-溴-3-氯-2-(三氟甲基)苯(5.0 g，19.3 mmol)和4,4,5,5-四甲基-1,3,2-二氧雜硼烷(4.93 g，38.5 mmol)在THF(60.0 mL)中的溶液添加dtbbpy (621 mg，2.31 mmol)和(Ir(OMe) (cod)) 2(1.28 g，1.93 mmol，0.1當量)。產生的混合物用N 2的流沖洗持續1 min，密封，加溫至60℃並且持續2小時。基於TLC，轉化完成。將反應混合物冷卻至rt，在鹽水和DCM之間分配。在分離之後，將有機相在真空中濃縮，以給出作為黑色油的標題中間體(12.0 g，粗品)，所述標題中間體直接用於下一步，而不另外純化。LCMS[M+H] += 385.0。 1 -Bromo-3-chloro-2-(trifluoromethyl)benzene (5.0 g, 19.3 mmol) and 4,4,5,5-tetramethyl-1,3,2-bis To a solution of oxaborane (4.93 g, 38.5 mmol) in THF (60.0 mL) was added dtbbpy (621 mg, 2.31 mmol) and (Ir(OMe)(cod)) 2 (1.28 g, 1.93 mmol, 0.1 equiv) . The resulting mixture was flushed with a flow of N2 for 1 min, sealed, and warmed to 60 °C for 2 h. Based on TLC, the transformation was complete. The reaction mixture was cooled to rt, partitioned between brine and DCM. After separation, the organic phase was concentrated in vacuo to give the title intermediate as a black oil (12.0 g, crude), which was used directly in the next step without further purification. LCMS [M+H] + = 385.0.

步驟2: 3-溴-5-氯-4-(三氟甲基)苯酚Step 2: 3-Bromo-5-chloro-4-(trifluoromethyl)phenol

向5-氯-4-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(12.0 g，31.1 mmol)在THF (100.0 mL)和H 2O (50.0 mL)中的溶液添加AcOH (74.8 g，1.25 mol)。然後，在0℃，將H 2O 2(70.6 g，623 mmol，30%)逐滴地添加到混合物中持續20 min。將混合物在0℃攪拌持續1 h。基於TLC，反應轉化完成。添加水(200 mL)和EtOAc (200 mL)。將兩相分離。有機相用Na 2SO 3溶液(200.0 mL×2)、鹽水(100 mL×2)洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在旋轉蒸發儀上濃縮。殘餘物在矽膠柱上純化(PE/EtOAc = 40:1至5:1)，以給出作為淺棕色油的3-溴-5-氯-4-(三氟甲基)苯酚(5.2 g，經兩步83%收率)。LC-MS [M+H] +=275。 To 5-chloro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (12.0 g, 31.1 mmol) in THF ( 100.0 mL) and H2O (50.0 mL) was added AcOH (74.8 g, 1.25 mol). Then, H 2 O 2 (70.6 g, 623 mmol, 30%) was added dropwise to the mixture at 0° C. for 20 min. The mixture was stirred at 0 °C for 1 h. Based on TLC, the reaction conversion was complete. Water (200 mL) and EtOAc (200 mL) were added. The two phases were separated. The organic phase was washed with Na 2 SO 3 solution (200.0 mL×2), brine (100 mL×2), dried over anhydrous Na 2 SO 4 , 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 after two steps). LC-MS [M+H] + =275.

步驟3: 5-(苄基氧基)-1-溴-3-氯-2-(三氟甲基)苯Step 3: 5-(Benzyloxy)-1-bromo-3-chloro-2-(trifluoromethyl)benzene

向3-溴-5-氯-4-(三氟甲基)苯酚(5 g，18.15 mmol，1.0當量)在CH 3CN (125 mL)中的溶液添加苄基溴(3.73 g，21.78 mmol，1.2當量)和K 2CO 3(7.53 g，54.46 mmol，3.0當量)。將產生的混合物攪拌持續2 h。基於LC/MS，轉化完成。將反應混合物通過矽藻土(celite)過濾並且用CH 3CN (100 mL)洗滌。將濾液在真空中濃縮並且殘餘物通過矽膠柱色譜法(PE/EtOAc=1:0)、隨後是反相製備型HPLC (流動相A：0.1%FA；流動相B：ACN；梯度：在55分鐘內60%-90% B；流速：70 mL/min)來純化，以給出作為淺黃色液體的5-(苄基氧基)-1-溴-3-氯-2-(三氟甲基)苯(4.5 g，68%收率)。LC-MS [M+H] +=366。 1H NMR (60 MHz, CDCl 3): δ 7.67-6.84 (m, 7H), 5.15 (s, 2H)。 To a solution of 3-bromo-5-chloro-4-(trifluoromethyl)phenol (5 g, 18.15 mmol, 1.0 equiv) in CH 3 CN (125 mL) was added benzyl bromide (3.73 g, 21.78 mmol, 1.2 eq) and K2CO3 (7.53 g, 54.46 mmol, 3.0 eq) . The resulting mixture was stirred for 2 h. Based on LC/MS, the conversion was complete. The reaction mixture was filtered through celite and washed with CH 3 CN (100 mL). The filtrate was concentrated in vacuo and the residue was subjected to silica gel column chromatography (PE/EtOAc=1:0) followed by reverse phase preparative HPLC (mobile phase A: 0.1% FA; mobile phase B: ACN; gradient: at 55 60%-90% B in minutes; flow rate: 70 mL/min) to give 5-(benzyloxy)-1-bromo-3-chloro-2-(trifluoromethane yl) benzene (4.5 g, 68% yield). LC-MS [M+H] + =366. 1 H NMR (60 MHz, CDCl 3 ): δ 7.67-6.84 (m, 7H), 5.15 (s, 2H).

步驟4: 2-(5-(苄基氧基)-3-氯-2-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷Step 4: 2-(5-(Benzyloxy)-3-chloro-2-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-di Oxaborane

在N 2下，向5-(苄基氧基)-1-溴-3-氯-2-(三氟甲基)苯(2.01 g，5.47 mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-l,3,2-二氧雜硼烷-2-基)-l,3,2-二氧雜硼烷(4.17 g，16.4 mmol)和KOAc (1.62 g，16.4 mmol)在脫氣的1,4-二氧六環(80.0 mL)中的混合物添加Pd(dppf)Cl 2(0.90 g，1.10 mmol，0.2當量)。混合物用N 2沖洗(purge)持續10秒，裝配有冷凝器和N 2氣球。將產生的反應混合物在110℃油浴中攪拌持續12 h。基於LC/MS，轉化完成。將反應混合物冷卻至rt，過濾並且將濾液濃縮以給出殘餘物，所述殘餘物用EtOAc (100 mL)和水(80 mL)稀釋。在分離之後，水層用EtOAc (2×)萃取。合併的有機層用鹽水洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在真空中濃縮。殘餘物通過矽膠柱色譜法(PE/EtOAc = 100/1至20/1)純化，以給出作為白色固體的標題中間體2-(5-(苄基氧基)-3-氯-2-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(1.2 g，53%收率)。LC-MS [M+H] += 413。 1H NMR (60 MHz, CDCl 3): δ 7.49-7.46 (m, 5H), 7.15-7.03 (m, 2H), 5.17(s, 2H)1.45 (s, 12H)。 5-(Benzyloxy)-1-bromo-3-chloro-2-(trifluoromethyl)benzene (2.01 g, 5.47 mmol), 4,4,5,5 - tetramethyl yl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4.17 g, 16.4 mmol) and KOAc (1.62 g, 16.4 mmol) in degassed 1,4-dioxane (80.0 mL) was added Pd(dppf) Cl2 (0.90 g, 1.10 mmol, 0.2 equiv). The mixture was purged with N2 for 10 sec, equipped with a condenser and N2 balloon. The resulting reaction mixture was stirred in a 110 °C oil bath for 12 h. Based on LC/MS, the conversion was complete. The reaction mixture was cooled to rt, filtered and the filtrate was 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 (2x). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 , 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)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (1.2 g, 53% yield). LC-MS [M+H] + =413. 1 H NMR (60 MHz, CDCl 3 ): δ 7.49-7.46 (m, 5H), 7.15-7.03 (m, 2H), 5.17(s, 2H)1.45 (s, 12H).

步驟5: 3-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-8-氧雜-3-氮雜雙環並[3.2.1]辛烷Step 5: 3-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

在rt，向2,4,7-三氯-8-氟吡啶並[4,3-d]嘧啶(中間體18，2 g，7.9 mmol)在DCM (30 mL)中的溶液添加DIEA (5.8 mL，35.5 mmol)。混合物用N 2氣體的流沖洗持續10秒，然後冷卻至-40℃，隨後在N 2下添加8-氧雜-3-氮雜雙環並[3.2.1]辛烷(中間體7，0.81 g，7.1 mmol，1.0當量)。將產生的反應混合物攪拌持續1 h。基於LC/MS，轉化完成。反應混合物用DCM (50 mL)稀釋並且傾倒在水(20 mL )中。在分離之後，有機層用鹽水洗滌，經Na 2SO 4乾燥，通過過濾收集，並且在旋轉蒸發儀上濃縮。殘餘物通過矽膠柱色譜法(PE/EtOAc = 3:1)純化，以給出作為黃色固體的標題化合物(1.4 g，54%收率)。LC-MS [M+H] += 329.0。 To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (Intermediate 18, 2 g, 7.9 mmol) in DCM (30 mL) was added DIEA (5.8 mL, 35.5 mmol). The mixture was flushed with a stream of N2 gas for 10 s , then cooled to −40 °C, followed by the addition of 8-oxa-3-azabicyclo[3.2.1]octane (Intermediate 7, 0.81 g , 7.1 mmol, 1.0 equiv). The resulting reaction mixture was stirred for 1 h. Based on LC/MS, the conversion 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 , 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.

步驟6: 3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-8-氧雜-3-氮雜雙環並[3.2.1]辛烷 Step 6: 3-(7-Chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidine -4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

向3-{2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基}-8-氧雜-3-氮雜雙環並[3.1.1]辛烷(1.4 g，4.2 mmol)在1,4-二氧六環(20 mL)中的溶液按順序地添加(四氫-1H-吡咯嗪-7a(5H)-基)甲-d 2-醇(0.90 g，6.4 mmol)和DIEA (2.1 mL，12.7 mmol)。將反應混合物加溫至80℃並且在N 2下攪拌持續12 h。將反應混合物冷卻至rt，用EtOAc (100 mL)和H 2O (50 mL)稀釋。在分離之後，有機層用鹽水洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在真空中濃縮。殘餘物通過矽膠色譜法(PE/EtOAc=1:1至DCM/MeOH=10:1 (包含0.1% Et 3N))純化以給出作為黃色固體的標題化合物(1.40 g，76%收率)。LC-MS [M+H] +=436.2。 To 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-8-oxa-3-azabicyclo[3.1.1]octane (1.4 g, 4.2 mmol) in 1,4-dioxane (20 mL) was added sequentially to (tetrahydro-1H-pyrrolazin-7a(5H)-yl)methan- d2 -ol (0.90 g , 6.4 mmol) and DIEA (2.1 mL, 12.7 mmol). The reaction mixture was warmed to 80 °C and stirred under N2 for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL) and H2O (50 mL). After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4 , collected by filtration , and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc=1:1 to DCM/MeOH=10:1 (containing 0.1% Et3N )) to give the title compound (1.40 g, 76% yield) as a yellow solid . LC-MS [M+H] + =436.2.

步驟7: 3-(7-(5-(苄基氧基)-3-氯-2-(三氟甲基)苯基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-8-氧雜-3-氮雜雙環並[3.2.1]辛烷 Step 7: 3-(7-(5-(Benzyloxy)-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizine- 7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

向3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-8-氧雜-3-氮雜雙環並[3.2.1]辛烷(200 mg，0.46 mmol)在脫氣的1,4-二氧六環(9.0 mL)和H 2O (3.0 mL)的懸浮液添加Cs 2CO 3(300 mg, 0.92 mmol)、Pd(dppf)Cl 2(33.7 mg，0.0461 mmol)和2-[5-(苄基氧基)-3-氯-2-(三氟甲基)苯基]-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(190 mg，0.460 mmol)。將混合物抽真空，用N 2填充並且裝配有冷凝器和N 2氣球。將產生的反應混合物加溫至110℃並且攪拌持續2 h。基於LC/MS，反應轉化完成。將反應混合物冷卻至rt並且用EtOAc (100 mL)和H 2O (50 mL)稀釋。將兩層分離。有機層用鹽水洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在真空中濃縮。殘餘物通過矽膠柱色譜法(PE/ EtOAc =1:1至EtOAc (包含0.1% Et 3N))純化，以給出作為黃色固體的標題化合物(110 mg，35%收率)。LC-MS [M+H] +=686.2。 To 3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidine-4 -yl)-8-oxa-3-azabicyclo[3.2.1]octane (200 mg, 0.46 mmol) in degassed 1,4-dioxane (9.0 mL) and H 2 O ( 3.0 mL) to a suspension of Cs 2 CO 3 (300 mg, 0.92 mmol), Pd(dppf)Cl 2 (33.7 mg, 0.0461 mmol) and 2-[5-(benzyloxy)-3-chloro-2 -(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (190 mg, 0.460 mmol). The mixture was evacuated, filled with N2 and fitted with a condenser and N2 balloon. The resulting reaction mixture was warmed to 110 °C and stirred for 2 h. Based on LC/MS, the reaction conversion was complete. The reaction mixture was cooled to rt and diluted with EtOAc (100 mL) and H 2 O (50 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 by silica gel column chromatography (PE/EtOAc = 1:1 to EtOAc (containing 0.1% Et 3 N)) to give the title compound (110 mg, 35% yield) as a yellow solid. LC-MS [M+H] + =686.2.

步驟8: 3-(4-(8-氧雜-3-氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚 Step 8: 3-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol

向3-(7-(5-(苄基氧基)-3-氯-2-(三氟甲基)苯基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-8-氧雜-3-氮雜雙環並[3.2.1]辛烷(110 mg，0.16 mmol)在CH 3OH (5 mL)中的溶液添加Pd/C (11.0 mg，10% wt)。將混合物在真空中脫氣，用H 2填充，並且該程式重複三次。將混合物在H 2氣氛氣球下攪拌持續1 h。基於LC/MS，反應轉化完成。將產生的反應混合物通過矽藻土的薄層(a thin pad of celite)用EtOAc (30 mL)過濾。將濾液在真空中濃縮以給出粗製產物。粗製產物通過製備型HPLC (流動相A：0.1%FA；流動相B：ACN；梯度：在55分鐘內30%-80% B；流速：70 mL/min)純化並且凍乾，以給出作為白色固體的標題化合物3-(4-(-8-氧雜-3-氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚(14.3 mg，經兩步5%收率)。LC-MS [M+H] += 596.2。 1H NMR (400 MHz, CD 3OD) δ 9.09 (s, 1H), 8.55 (s, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.71 (d, J = 2.4 Hz, 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)。 To 3-(7-(5-(benzyloxy)-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizine-7a( 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 CH3OH (5 mL) was added Pd/C (11.0 mg, 10% wt). The mixture was degassed in vacuo, filled with H2 , and the procedure was repeated three times. The mixture was stirred under a H 2 atmosphere balloon for 1 h. Based on LC/MS, the reaction conversion was complete. The resulting reaction mixture was filtered through a thin pad of celite with EtOAc (30 mL). The filtrate was concentrated in vacuo to give 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 minutes; flow rate: 70 mL/min) and lyophilized to give as The title compound 3-(4-(-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrole Azin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol (14.3 mg, via 5% yield in two steps). LC-MS [M+H] + = 596.2. 1 H NMR (400 MHz, CD 3 OD) δ 9.09 (s, 1H), 8.55 (s, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.71 (d, J = 2.4 Hz, 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).

實施例3Example 3

4-(4-(3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚

Figure 02_image149
4-(4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
Figure 02_image149

步驟1：3-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯Step 1: 3-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 - tert-butyl carboxylate

在-40℃在N 2下，向2,4,7-三氯-8-氟吡啶並[4-d]嘧啶(中間體18，5.6 g，22.18 mmol，1當量)在DCM (30.0 mL)中的溶液添加DIEA (18.3 mL，110.91 mmol，5當量)和3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(4.24 g，20.0 mmol)。將反應混合物在-40℃攪拌持續1 h。將反應混合物傾倒在DCM (100 mL)和水(100 mL)中。將兩層分離。有機層用鹽水洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在真空中濃縮。殘餘物使用用(PE:EtOAc =5/1至3/1)洗脫的矽膠柱色譜法來純化，以給出作為黃色固體的3-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(5.2 g，55%收率，12.1mmol)。LC-MS [M+H] +=428.1。 To 2,4,7-trichloro-8-fluoropyrido[4-d]pyrimidine (Intermediate 18, 5.6 g, 22.18 mmol, 1 equiv) in DCM (30.0 mL) at -40 °C under N2 To the solution in DIEA (18.3 mL, 110.91 mmol, 5 equiv) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.24 g, 20.0 mmol) were added. The reaction mixture was stirred at -40 °C for 1 h. 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 3-(2,7-dichloro-8-fluoropyrido[ tert-butyl 4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.2 g, 55% yield, 12.1 mmol). LC-MS [M+H] + = 428.1.

步驟2：3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯 Step 2: 3-(7-Chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy- d2 )pyrido[4,3-d]pyrimidine -4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

向3-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(1.00 g，2.33 mmol)在1,4-二氧六環(15.0 mL)中的溶液添加(四氫-1H-吡咯嗪-7a(5H)-基)甲-d 2-醇(中間體7，659 mg，4.67 mmol)和DIEA (1.2 mL，7 mmol)。將反應混合物加溫至80℃並且攪拌持續6 h。基於LC/MS，反應完成。將反應混合物冷卻至rt，用EtOAc (50 mL)和水(50 mL)稀釋。將有機層分離，用鹽水洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在真空中濃縮。殘餘物通過矽膠柱色譜法(PE/EtOAc=1:1至DCM/MeOH=10:1 (包含0.1% Et 3N))純化，以給出作為黃色固體的標題化合物(960 mg，77%收率，1.80 mmol)。LC-MS [M+H] +=535.2。 To 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy A solution of tert-butyl acid ester (1.00 g, 2.33 mmol) in 1,4-dioxane (15.0 mL) was added to (tetrahydro-1H-pyrrolazin-7a(5H)-yl)methan- d2 -ol (Intermediate 7, 659 mg, 4.67 mmol) and DIEA (1.2 mL, 7 mmol). The reaction mixture was warmed to 80 °C and stirred for 6 h. Based on LC/MS, the reaction was complete. The reaction mixture was cooled to rt, diluted with EtOAc (50 mL) and water (50 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 , collected by filtration , and concentrated in vacuo. The residue was purified by silica gel column chromatography (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 rate, 1.80 mmol). LC-MS [M+H] + =535.2.

步驟3：3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯 Step 3: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- 2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo And[3.2.1] tert-butyl octane-8-carboxylate

向3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(485 mg，0.909 mmol)在脫氣的1,4-二氧六環(15.0 mL)和H 2O (5.0 mL)中的溶液添加Cs 2CO 3(611 mg，1.87 mmol)、Pd(dppf)Cl 2(68.6 mg，0.0909 mmol，0.1當量)和((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)萘-1-基)乙炔基)三異丙基甲矽烷(來自實施例1，步驟4，424 mg，0.826 mmol)。將混合物抽真空，用N 2填充，並且該順序重複三次。產生的反應容器裝配有冷凝器和N 2氣球，並且在110℃攪拌持續5 h。基於LC/MS，反應完成。將反應混合物冷卻至rt，用EtOAc (30 mL)和水(30 mL)稀釋。將有機層分離，用鹽水(20 mL)洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在真空中濃縮。殘餘物通過矽膠柱色譜法(PE/EtOAc=1:1至DCM/MeOH=10:3)純化以提供作為黑色固體的標題化合物(677 mg，82%收率，0.76 mmol)。LC-MS [M+H] +=885.4。 To 3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidine-4 -yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (485 mg, 0.909 mmol) in degassed 1,4-dioxane (15.0 mL ) and H 2 O (5.0 mL) were added Cs 2 CO 3 (611 mg, 1.87 mmol), Pd(dppf)Cl 2 (68.6 mg, 0.0909 mmol, 0.1 eq) and ((2-fluoro-6- (Methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)tri Isopropylsilane (from Example 1, Step 4, 424 mg, 0.826 mmol). The mixture was evacuated, filled with N2 , and this sequence was repeated three times. The resulting reaction vessel was fitted with a condenser and N balloon and stirred at 110 °C for 5 h. 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), dried over anhydrous Na 2 SO 4 , collected by filtration, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc=1:1 to DCM/MeOH=10:3) to afford the title compound (677 mg, 82% yield, 0.76 mmol) as a black solid. LC-MS [M+H] + =885.4.

步驟4：3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯 Step 4: 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazine -7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- tert-butyl carboxylate

在rt，向3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(1.95 g，2.21 mmol)在DMF (25 mL)中的溶液添加CsF (1.68 g，11.0 mmol)。將反應攪拌持續1 h。基於LC/MS，反應完成。將反應混合物傾倒在EtOAc (20 mL)和鹽水(20 mL)中。在分離之後，有機層經無水Na 2SO 4乾燥，通過過濾收集，在真空中濃縮，以給出作為棕色固體的標題化合物(2.3 g，粗品)。LC-MS [M+H] += 729.3。 At rt, to 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl) -2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine To a solution of tert-butyl bicyclo[3.2.1]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 1 h. 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 dried over anhydrous Na2SO4 , collected by filtration, concentrated in vacuo to give the title compound (2.3 g, crude) as a brown solid. LC-MS [M+H] + = 729.3.

步驟5: 4-(4-(3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚 Step 5: 4-(4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazine-7a(5H )-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

向3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(2.3 g，3.16 mmol，1當量)在乙腈(2.0 mL)中的溶液添加1,4-二氧六環中的1N HCl(40 mL)。將反應在室溫攪拌持續1 h。基於LC/MS，反應完成。在小心地添加飽和的含水NaHCO 3的情況下，將反應混合物調節至pH~7。 將混合物傾倒在水和DCM中。在分離之後，有機相用鹽水洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在真空中濃縮。殘餘物通過製備型HPLC (流動相A：0.1%FA；流動相B：ACN；梯度：在55分鐘內30%-80% B；流速：70 mL/min)純化。將溶液凍乾以給出作為白色固體的預計的標題化合物(100 mg，0.17 mmol，經兩步8%收率)。LC-MS [M+H] += 585.3。 1H NMR (400 MHz, CD 3OD-d 6) δ 9.08 (s, 1H), 8.51 (s, 1H), 7.88 (dd, J = 8.0 Hz, 4.0 Hz 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)。 To 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizine-7a (5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid A solution of tert-butyl ester (2.3 g, 3.16 mmol, 1 eq) in acetonitrile (2.0 mL) was added 1 N HCl in 1,4-dioxane (40 mL). The reaction was stirred at room temperature for 1 h. Based on LC/MS, the reaction was complete. The reaction mixture was adjusted to pH ~7 with the careful addition of saturated aqueous NaHCO 3 . The mixture was poured into water and DCM. After separation, the organic phase was washed with brine, dried over anhydrous Na 2 SO 4 , 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 minutes; flow rate: 70 mL/min). The solution was lyophilized to give the expected title compound (100 mg, 0.17 mmol, 8% yield over two steps) as a white solid. LC-MS [M+H] + = 585.3. 1 H NMR (400 MHz, CD 3 OD-d 6 ) δ 9.08 (s, 1H), 8.51 (s, 1H), 7.88 (dd, J = 8.0 Hz, 4.0 Hz 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).

實施例4Example 4

4-(4-(3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚

Figure 02_image151
4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2-fluorotetrahydro-1H-pyrrolizine-7a(5H )-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
Figure 02_image151

步驟1: 3-(7-氯-8-氟-2-((2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯Step 1: 3-(7-Chloro-8-fluoro-2-((2-fluorotetrahydro-1H-pyrrolazin-7a(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

向3-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(762 mg，1.78 mmol)在1,4-二氧六環(15.0 mL)中的溶液添加(2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲醇(中間體1，190 mg，1.19 mmol)和DIEA (460.00 mg，3.56 mmol，3當量)。 將反應混合物在80℃攪拌持續6 h。基於LC/MS，反應完成。將反應混合物冷卻至rt，用EtOAc (20.0 mL)和水(20.0 mL)稀釋。在分離之後，有機層用鹽水洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在真空中濃縮。殘餘物通過矽膠柱色譜法(PE/EtOAc=1:1至DCM/MeOH=10:1 (包含0.1% Et 3N))純化，以給出作為黃色固體的標題化合物(230 mg，35%收率，0.41 mmol)。LC-MS [M+H] += 552.2。 To 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy To a solution of tert-butyl ester (762 mg, 1.78 mmol) in 1,4-dioxane (15.0 mL) was added (2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d ) methanol (Intermediate 1, 190 mg, 1.19 mmol) and DIEA (460.00 mg, 3.56 mmol, 3 equiv). The reaction mixture was stirred at 80 °C for 6 h. Based on LC/MS, the reaction was complete. The reaction mixture was cooled to rt, diluted with EtOAc (20.0 mL) and water (20.0 mL). After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4 , collected by filtration , and concentrated in vacuo. The residue was purified by silica gel column chromatography (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 rate, 0.41 mmol). LC-MS [M+H] + = 552.2.

步驟2：3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-((2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯Step 2: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- 2-((2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- tert-butyl diazabicyclo[3.2.1]octane-8-carboxylate

向3-(7-氯-8-氟-2-((2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(180 mg，0.33 mmol)在脫氣的1,4-二氧六環(9.0 mL)和H 2O (3.0 mL)中的溶液添加((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)萘-1-基)乙炔基)三異丙基甲矽烷(來自實施例1，步驟4，334 mg，0.65 mmol,)、Cs 2CO 3(212 mg，0.65 mmol)和Pd(dppf)Cl 2(23.9 mg，0.0301 mmol)。將混合物抽真空，用N 2填充，並且該順序重複三次。產生的混合物裝配有冷凝器和N 2氣球，在110℃攪拌過夜。基於LC/MS，反應完成。將反應混合物冷卻至rt，用EtOAc (30 mL)和水(30 mL)稀釋。在分離之後，有機層用鹽水(20 mL)洗滌，經無水Na 2SO 4乾燥，通過過濾收集，並且在真空中濃縮。殘餘物通過矽膠柱色譜法(PE/EtOAc=1:1至DCM/MeOH=10:3)純化，以給出作為黑色固體的標題化合物(200 mg，68%收率，0.22 mmol)。LC-MS [M+H] += 902.4。 To 3-(7-chloro-8-fluoro-2-((2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (180 mg, 0.33 mmol) in degassed 1,4-dioxahexa A solution in ring (9.0 mL) and H2O (3.0 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolin-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (from Example 1, Step 4, 334 mg, 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, filled with N2 , and this sequence was repeated three times. The resulting mixture was fitted with a condenser and N balloon and stirred overnight at 110 °C. 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 , collected by filtration, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc=1:1 to DCM/MeOH=10:3) to give the title compound (200 mg, 68% yield, 0.22 mmol) as a black solid. LC-MS [M+H] + = 902.4.

步驟3：3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯Step 3: 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((2-fluorotetrahydro-1H -pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane tert-butyl alkane-8-carboxylate

向3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-((2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(260 mg，0.29 mmol)在DMF (2 mL)中的溶液添加CsF (219 mg，1.44 mmol)。將反應混合物在rt攪拌持續1 h。基於LC/MS，反應完成。反應混合物用EtOAc (10.0 mL)和水(10.0 mL)稀釋。在分離之後，將有機層在真空中濃縮，以給出標題中間體(215 mg，粗品)。LC-MS [M+H] += 746.3。 To 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2- ((2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine To a solution of tert-butyl heterobicyclo[3.2.1]octane-8-carboxylate (260 mg, 0.29 mmol) in DMF (2 mL) was added CsF (219 mg, 1.44 mmol). The reaction mixture was stirred at rt for 1 h. Based on LC/MS, the reaction was complete. The reaction mixture was diluted with EtOAc (10.0 mL) and water (10.0 mL). After separation, the organic layer was concentrated in vacuo to give the title intermediate (215 mg, crude). LC-MS [M+H] + = 746.3.

步驟4: 4-(4-(3,8-二氮雜雙環並[3.2.1]辛烷-2-基)-8-氟-2-((2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚Step 4: 4-(4-(3,8-diazabicyclo[3.2.1]octan-2-yl)-8-fluoro-2-((2-fluorotetrahydro-1H-pyrrolazine- 7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

向(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(215 mg，0.29 mmol)在MeCN (7.0 mL)中的溶液添加1,4-二氧六環中的 HCl(7.0 mL，4M)。將反應混合物在rt攪拌持續1 h。基於LC/MS，反應完成。將溶劑在真空中除去。殘餘物通過製備型HPLC (流動相A：0.1%FA；流動相B：ACN；梯度：在55分鐘內30%-70% B；流速：70 mL/min)純化並且凍乾，以給出預計的標題化合物(8.1 mg，0.013 mmol，經兩步5%收率)。LC-MS [M+H] += 602.3。 1H NMR (400 MHz, CD 3OD) δ 9.08 (s, 1H), 8.51 (s, 1H),7.89 (dd, J = 9.2, 5.6 Hz, 1H), 7.38-7.33 (m, 2H), 7.23 (d, J = 2.6 Hz, 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 = 4.4 Hz, 1H), 3.26-3.21 (m, 1H), 2.55-1.94 (m, 10H)。 To (7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((2-fluorotetrahydro-1H-pyrrolazine- 7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- A solution of tert-butyl carboxylate (215 mg, 0.29 mmol) in MeCN (7.0 mL) was added with HCl in 1,4-dioxane (7.0 mL, 4M). The reaction mixture was stirred at rt for 1 h. 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 minutes; flow rate: 70 mL/min) and lyophilized to give the expected The title compound (8.1 mg, 0.013 mmol, 5% yield over two steps). LC-MS [M+H] + = 602.3. 1 H NMR (400 MHz, CD 3 OD) δ 9.08 (s, 1H), 8.51 (s, 1H), 7.89 (dd, J = 9.2, 5.6 Hz, 1H), 7.38-7.33 (m, 2H), 7.23 (d, J = 2.6 Hz, 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 = 4.4 Hz, 1H), 3.26-3.21 (m, 1H), 2.55-1.94 (m, 10H).

實施例5Example 5

4-(4-(3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(實施例4的非對映異構體)

Figure 02_image153
4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2-fluorotetrahydro-1H-pyrrolizine-7a(5H )-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (diastereoisomeric Construct)
Figure 02_image153

用實施例4平行地合成實施例5的化合物，實施例4的非對映異構體。LC-MS [M+H] += 602.3。 1H NMR (400 MHz, CD 3OD) δ 9.08 (s, 1H), 8.51 (s, 1H), 7.89 (dd, J = 8.0, 4.0 Hz, 1H), 7.39-7.33 (m, 2H), 7.23 (d, J = 2.6 Hz, 1H), 4.74 (s, 2H), 4.54-4.44 (m, 2H), 3.91 (d, J = 44 Hz, 2H), 3.68-3.52 (m, 3H), 3.37 (d, J = 4.0 Hz, 1H), 3.28-3.20 (m, 1H), 2.56-1.89 (m, 10H)。 The compound of Example 5, the diastereoisomer of Example 4, was synthesized in parallel using Example 4. LC-MS [M+H] + = 602.3. 1 H NMR (400 MHz, CD 3 OD) δ 9.08 (s, 1H), 8.51 (s, 1H), 7.89 (dd, J = 8.0, 4.0 Hz, 1H), 7.39-7.33 (m, 2H), 7.23 (d, J = 2.6 Hz, 1H), 4.74 (s, 2H), 4.54-4.44 (m, 2H), 3.91 (d, J = 44 Hz, 2H), 3.68-3.52 (m, 3H), 3.37 ( d, J = 4.0 Hz, 1H), 3.28-3.20 (m, 1H), 2.56-1.89 (m, 10H).

實施例6/實施例7Example 6/Example 7

3-(4-(3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚 3-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy -d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro-4-(trifluoromethyl)phenol

和and

3-(4-(3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-4-(三氟甲基)苯酚

Figure 02_image155
3-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy -d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-4-(trifluoromethyl)phenol
Figure 02_image155

步驟1: 2,4-二氯-5,6,7,8-四氫吡啶並[3,4-d]嘧啶Step 1: 2,4-Dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

向2,4-二氯-5,8-二氫吡啶[3,4-d]嘧啶-7(6H)-羧酸叔丁酯(2.0 g，6.6 mmol)在DCM (20.0 mL)中的溶液添加TFA (7.0 mL)，並且將反應在rt攪拌持續3小時。將反應在減壓下濃縮，以提供作為黃色油的2,4-二氯-5,6,7,8-四氫吡啶並[3,4-d]嘧啶(3.5 g，粗品)，2,4-二氯-5,6,7,8-四氫吡啶並[3,4-d]嘧啶直接用於下一步。LC-MS [M+H] +=204.0。 To a solution of tert-butyl 2,4-dichloro-5,8-dihydropyridin[3,4-d]pyrimidine-7(6H)-carboxylate (2.0 g, 6.6 mmol) in DCM (20.0 mL) TFA (7.0 mL) was added, and the reaction was stirred at rt for 3 hours. The reaction was concentrated under reduced pressure to provide 2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (3.5 g, crude) as a yellow oil, 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.

步驟2: 2,4-二氯-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-羧酸苄酯Step 2: Benzyl 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

在0℃，向2,4-二氯-5,6,7,8-四氫吡啶並[3,4-d]嘧啶(3.50 g，17.2 mmol，1當量)在THF (50.0 mL)中的溶液添加DIEA (4.45 g，34.5 mmol)和CbzCl (2.93 g，17.24 mmol).將反應在rt攪拌持續1 h。將混合物在真空中濃縮。殘餘物在EtOAc (100 mL)和H 2O (100 mL)之間分配。在分離之後，將有機層在真空中濃縮。殘餘物通過柱色譜法(PE/EtOAc = 5/1至3/1)純化，以給出作為黃色油的標題中間體(2.10 g，6.23 mmol，經兩步94%收率)。LC-MS [M+H] += 338.0。 To 2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (3.50 g, 17.2 mmol, 1 equiv) in THF (50.0 mL) at 0°C The solution was added DIEA (4.45 g, 34.5 mmol) and CbzCl (2.93 g, 17.24 mmol). The reaction was stirred at rt for 1 h. The mixture was concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and H2O (100 mL). After separation, the organic layer was concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc = 5/1 to 3/1) to give the title intermediate as a yellow oil (2.10 g, 6.23 mmol, 94% yield over two steps). LC-MS [M+H] + = 338.0.

步驟3: 4-(8-(叔丁氧基羰基)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-氯-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-羧酸苄酯Step 3: 4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-chloro-5,8-dihydropyrido [3,4-d]pyrimidine-7(6H)-carboxylate benzyl ester

向2,4-二氯-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-羧酸苄酯(2.10 g，6.23 mmol)在DMSO (30.0 mL)中的溶液添加DIEA (2.01 g，15.6 mmol)和3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(1.32 g，6.23 mmol，1當量)，並且將反應在55℃攪拌持續12小時。將反應冷卻至rt，用EtOAc (100 mL)和H 2O (50 mL)稀釋。在分離之後，有機層用鹽水洗滌，經無水Na 2SO 4乾燥，過濾，並且在真空中濃縮。殘餘物通過柱色譜法(PE/EtOAc = 5/1至3/1)純化，以給出作為黃色固體的4-(8-(叔丁氧基羰基)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-氯-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-羧酸苄酯(2.10 g，65%收率，4.09 mmol)。LC-MS [M+H] += 514.3。 To a solution of benzyl 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (2.10 g, 6.23 mmol) in DMSO (30.0 mL) DIEA (2.01 g, 15.6 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.32 g, 6.23 mmol, 1 equiv) were added and the reaction was stirred at 55 Stirring at °C was continued for 12 hours. The reaction was cooled to rt, diluted with EtOAc (100 mL) and H2O (50 mL). After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4 , 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 as a yellow solid [3.2.1] Octane-3-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate benzyl ester (2.10 g, 65% yield rate, 4.09 mmol). LC-MS [M+H] + = 514.3.

步驟4: 4-(8-(叔丁氧基羰基)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-羧酸苄酯 Step 4: 4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((tetrahydro-1H-pyrrolizine- 7a(5H)-yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester

向4-(8-(叔丁氧基羰基)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-氯-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-羧酸苄酯(1.40 g，2.73 mmol)在脫氣的甲苯(80 mL)中的溶液添加(四氫-1H-吡咯嗪-7a(5H)-基)甲-d 2-醇(中間體 7，770 mg，5.4 mmol)、t-BuONa (656 mg，6.83 mmol6)、Pa 2(dba) 3(2476 mg，0.27 mmol6)和BINAP (3426 mg，0.55 mmol6)。混合物用N 2脫氣6持續1 min。將裝配有冷凝器和N 2氣球的混合物在110℃攪拌持續3 h。將反應混合物冷卻至rt，用EtOAc和H 2O稀釋。在分離之後，有機層經無水Na 2SO 4乾燥，過濾，並且濃縮。殘餘物通過製備型HPLC (流動相A：0.1%FA；流動相B：ACN；梯度：在55分鐘內50%-90% B；流速：70 mL/min)純化，以給出作為黃色固體的4-(8-(叔丁氧基羰基)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-羧酸苄酯(0.62 g，36%收率，1.0 mmol)。LC-MS [M+H] += 621.3。 To 4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-chloro-5,8-dihydropyrido[3 ,4-d] A solution of pyrimidine-7(6H)-carboxylate benzyl ester (1.40 g, 2.73 mmol) in degassed toluene (80 mL) was added (tetrahydro-1H-pyrrolazine-7a(5H)- base) methyl-d 2 -alcohol (intermediate 7, 770 mg, 5.4 mmol), t-BuONa (656 mg, 6.83 mmol6), Pa 2 (dba) 3 (2476 mg, 0.27 mmol6) and BINAP (3426 mg, 0.55 mmol6). The mixture was degassed with N2 for 6 for 1 min. The mixture equipped with a condenser and N balloon was stirred at 110 °C for 3 h. The reaction mixture was cooled to rt, diluted with EtOAc and H2O . After separation , the organic layer was dried over anhydrous Na2SO4 , filtered, and concentrated. Residual objects through preparation HPLC (flow phase A: 0.1%FA; flow phase B: ACN; gradient: 50%-90%b in 55 minutes; flow rate: 70 ml/min) purification 4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((tetrahydro-1H-pyrrolizine-7a(5H )-yl)methoxy-d2)-benzyl 5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (0.62 g, 36% yield, 1.0 mmol). LC-MS [M+H] + = 621.3.

步驟5：3-(2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,6,7,8-四氫吡啶並[3,4-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯 Step 5: 3-(2-((tetrahydro-1H-pyrrolazin-7a(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

向4-(8-(叔丁氧基羰基)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-羧酸苄酯在MeOH (20.0 mL)中的溶液添加NH 3/MeOH溶液(20 mL)和Pd/C (0.20 g)。將混合物抽真空並且用H 2填充。將混合物在rt在H 2氣氛下攪拌持續4 h。TLC示出起始材料被完全消耗並且將反應過濾。將濾液在真空中濃縮，以提供作為黃色固體的標題化合物(470 mg，60%收率，0.6 mmol)。LC-MS [M+H] += 487.3。 To 4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((tetrahydro-1H-pyrrolazine-7a( A solution of 5H)-yl)methoxy- d2 )-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate benzyl ester in MeOH (20.0 mL) was added with NH 3 /MeOH solution (20 mL) and Pd/C (0.20 g). The mixture was evacuated and filled with H2 . The mixture was stirred at rt under H2 atmosphere for 4 h. TLC showed complete consumption of starting material and the reaction was filtered. The filtrate was concentrated in vacuo to provide the title compound (470 mg, 60% yield, 0.6 mmol) as a yellow solid. LC-MS [M+H] + = 487.3.

步驟6：3-(7-(3-氯-5-(甲氧基甲氧基)-2-(三氟甲基)苯基)2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,6,7,8-四氫吡啶並[3,4-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯 Step 6: 3-(7-(3-Chloro-5-(methoxymethoxy)-2-(trifluoromethyl)phenyl)2-((tetrahydro-1H-pyrrolazine-7a(5H )-yl)methoxy-d 2 )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] tert-butyl octane-8-carboxylate

在rt在N 2下，向3-(2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,6,7,8-四氫吡啶並[3,4-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(230 mg，0.48 mmol)在脫氣的甲苯(8.0 mL)中的溶液添加RuPhos (46.6 mg，0.10 mmol)、Cs 2CO 3(469 mg，1.44 mmol)、1-溴-3-氯-5-(甲氧基甲氧基)-2-(三氟甲基)苯(來自實施例2，步驟3，154 mg, 0.48 mmol)和Pd 2(dba) 3(45.8 mg，0.050 mmol)。將混合物在真空中脫氣並且用N 2填充。將裝配有冷凝器和N 2氣球的混合物在110℃攪拌持續8小時。LCMS示出起始材料被完全消耗，將反應冷卻至rt，用EtOAc (30.0 mL)和水(30.0 mL)稀釋。在分離之後，有機層用鹽水(20.0 mL)洗滌，經無水Na 2SO 4乾燥，過濾，並且在真空中濃縮。殘餘物通過柱色譜法(DCM/MeOH = 3/1至1/1)純化，以給出作為棕色固體的標題中間體(340 mg，71%收率)。LC-MS [M+H] += 725。氘代化合物，3-(7-(5-(甲氧基甲氧基)-2-(三氟甲基)苯基)2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6,7,8-四氫吡啶並[3,4-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯LC-MS [M+H] += 689。 To 3-( 2 -((tetrahydro-1H-pyrrolazin-7a(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 (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, 154 mg, 0.48 mmol) and Pd2 (dba) 3 (45.8 mg, 0.050 mmol). The mixture was degassed in vacuo and filled with N2 . The mixture equipped with a condenser and N balloon was stirred at 110 °C for 8 h. LCMS showed complete consumption of the starting material, the reaction was cooled to rt, diluted 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 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH = 3/1 to 1/1) to give the title intermediate (340 mg, 71% yield) as a brown solid. LC-MS [M+H] + =725. Deuterated compound, 3-(7-(5-(methoxymethoxy)-2-(trifluoromethyl)phenyl) 2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 - tert-butyl carboxylate LC-MS [M+H] + = 689.

步驟7: 3-(4-(3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚和3-(4-(3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-4-(三氟甲基)苯酚 Step 7: 3-(4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl) Methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro-4-(trifluoromethyl)phenol and 3-( 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-4-(trifluoromethyl)phenol

在壓力管(pressure tube)中，向3-(7-(3-氯-5-(甲氧基甲氧基)-2-(三氟甲基)苯基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d2)-5,6,7,8-四氫吡啶並[3,4-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(340 mg，0.47 mmol)在MeOH (25.0 mL)中的溶液添加4N HCl (25.0 mL)。將反應在70℃攪拌持續8小時。將混合物冷卻至rt，在真空中濃縮。殘餘物通過製備型HPLC (流動相A：0.1%FA；流動相B：ACN；梯度：在55分鐘內30%-80% B；流速：70 mL/min)純化，以提供：In a pressure tube, 3-(7-(3-chloro-5-(methoxymethoxy)-2-(trifluoromethyl)phenyl)-2-((tetrahydro- 1H-Pyrrolazin-7a(5H)-yl)methoxy-d2)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-di To a solution of tert-butyl azabicyclo[3.2.1]octane-8-carboxylate (340 mg, 0.47 mmol) in MeOH (25.0 mL) was added 4N HCl (25.0 mL). The reaction was stirred at 70 °C for 8 hours. The mixture was cooled to rt, 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 minutes; flow rate: 70 mL/min) to provide:

實施例6，P1：作為白色固體的3-(4-(3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚(16.0 mg，經兩步6%收率)。LC-MS [M+H] += 581.3。 1H NMR (400 MHz, CD 3OD) δ 6.78 (d, J = 4.0 Hz, 1H), 6.73 (d, J = 4.0 Hz, 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 6, P1: 3-(4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-((tetrahydro-1H-pyrrolazine- 7a(5H)-yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-chloro-4-(trifluoromethane base) phenol (16.0 mg, 6% yield over two steps). LC-MS [M+H] + = 581.3. 1 H NMR (400 MHz, CD 3 OD) δ 6.78 (d, J = 4.0 Hz, 1H), 6.73 (d, J = 4.0 Hz, 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);

實施例7，P2：作為白色固體的3-(4-(3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-4-(三氟甲基)苯酚(8.0 mg，經兩步3%收率)。 LC-MS [M+H] += 547.3. 1H NMR (400 MHz, CD 3OD) δ 7.61 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.44(dd, J = 8.8 Hz, 2.4 Hz, 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 = 5.6 Hz, 2H), 3.16 (q, d, J = 5.6 Hz, 2H), 2.85(q, d, J = 5.2 Hz, 2H), 2.33-2.25 (m, 2H). 2.23-2.14 (m, 4H).2.10-2.03 (m, 6H)。 Example 7, P2: 3-(4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-((tetrahydro-1H-pyrrolazine- 7a(5H)-yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-4-(trifluoromethyl)phenol ( 8.0 mg, 3% yield in two steps). LC-MS [M+H] + = 547.3. 1 H NMR (400 MHz, CD 3 OD) δ 7.61 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.44( dd, J = 8.8 Hz, 2.4 Hz, 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 = 5.6 Hz, 2H), 3.16 (q, d, J = 5.6 Hz, 2H), 2.85(q, d, J = 5.2 Hz, 2H), 2.33-2.25 (m, 2H). 2.23-2.14 (m, 4H). 2.10-2.03 (m, 6H).

使用如實施例4描述的類似程式合成以下表2中的化合物： 表2 化合物 ID 結構 LC-MS [M+H]和H-NMR 實施例 8

Figure 02_image157
LC-MS [M+H] +=595.2。 1H NMR (400 MHz, DMSO-d 6): δ 9.08 (s, 1H), 8.23 (s, 2H), 7.18 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 4.43 (t, J = 9.6Hz, 2H), 3.74-3.56 (m, 2H), 3.63-3.61 (m, 2H), 3.07-3.02 (m, 2H), 2.70-2.64 (m, 2H), 1.96-1.78 (m,6H), 1.70-1.59 (m,6H)。 實施例9
Figure 02_image159
 LC-MS [M+H] += 595.3。 1H NMR (400 MHz, DMSO-d 6): δ 9.16 (s, 1H), 8.27 (s, 2H), 7.18 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 4.91 (s, 1H), 4.23 (s, 1H), 3.35-3.29 (m, 2H), 3.16-3.12 (m, 2H), 3.00-2.96 (m, 2H), 2.63-2.58 (m, 2H), 1.95-1.87 (m,4H), 1.84-1.73(m,4H), 1.64-1.57 (m,2H)。 The compounds in Table 2 below were synthesized using a similar procedure as described in Example 4: Table 2 Compound ID structure LC-MS [M+H] and H-NMR Example 8
Figure 02_image157
 LC-MS [M+H] + =595.2. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.08 (s, 1H), 8.23 (s, 2H), 7.18 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H ), 4.43 (t, J = 9.6Hz, 2H), 3.74-3.56 (m, 2H), 3.63-3.61 (m, 2H), 3.07-3.02 (m, 2H), 2.70-2.64 (m, 2H), 1.96-1.78 (m,6H), 1.70-1.59 (m,6H). Example 9
Figure 02_image159
 LC-MS [M+H] + = 595.3. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.16 (s, 1H), 8.27 (s, 2H), 7.18 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H ), 4.91 (s, 1H), 4.23 (s, 1H), 3.35-3.29 (m, 2H), 3.16-3.12 (m, 2H), 3.00-2.96 (m, 2H), 2.63-2.58 (m, 2H ), 1.95-1.87 (m,4H), 1.84-1.73(m,4H), 1.64-1.57 (m,2H).

實施例10Example 10

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚

Figure 02_image161
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl- 6-fluoronaphthalene-2-ol
Figure 02_image161

EX.10EX.10

步驟1：(1R,5S)-3-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯Step 1: (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] tert-butyl octane-8-carboxylate

在-40℃在N 2下，向2,4,7-三氯-8-氟吡啶並[4,3-d]嘧啶(中間體18，5.01 g，19.8 mmol)在DCM (30 mL)中的溶液添加DIEA (18.3 mL，111 mmol)和(1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(4.24 g，20.0 mmol)。將反應混合物在-40℃攪拌持續1 h。將反應混合物傾倒在DCM (100 mL)和水(100 mL)中。將兩層分離。有機層用鹽水洗滌，經無水Na2SO4乾燥，通過過濾收集，並且在真空中濃縮。使用用(PE/ EtOAc = 5:1至3:1)洗脫的矽膠柱色譜法純化殘餘物，以給出作為黃色固體的標題化合物(5.21 g,61%收率)。LC-MS [M+H]+ =428.1。 To 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (Intermediate 18, 5.01 g, 19.8 mmol) in DCM (30 mL) at -40 °C under N A solution of DIEA (18.3 mL, 111 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.24 g, 20.0 mmol) were added. The reaction mixture was stirred at -40 °C for 1 h. 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 (5.21 g, 61% yield) as a yellow solid. LC-MS [M+H]+ = 428.1.

步驟2：(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-3.8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯 Step 2: (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2, 5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3.8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

將(1R,5S)-3-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(180 mg，0.420 mmol)、((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲醇(中間體8，74.8 mg，0.461 mmol)和Cs 2CO 3(410 mg，1.26 mmol)在1,4-二氧六環(10 mL)中的混合物加溫至95℃並且在N 2氣氛下攪拌持續12 h。反應通過LCMS來監測。在完成之後，允許混合物冷卻下來至rt並且在減壓下濃縮。殘餘物通過用[MeOH:DCM] (1:100 – 1:20)洗脫的矽膠柱色譜法純化，以提供作為黃色固體的標題中間體(100 mg，收率43%)。LC-MS [M+H] +=554.3 (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] Octane-8-carboxylate tert-butyl ester (180 mg, 0.420 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 ) A mixture of methanol (Intermediate 8 , 74.8 mg, 0.461 mmol) and Cs2CO3 (410 mg, 1.26 mmol) in 1,4-dioxane (10 mL) was warmed to 95 °C and heated under N Stirring was continued for 12 h under 2 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 silica gel column chromatography eluting with [MeOH:DCM] (1:100 - 1:20) to afford the title intermediate (100 mg, 43% yield) as a yellow solid. LC-MS [M+H] + =554.3

步驟3：(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-3.8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯 Step 3: (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene -1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[ tert-butyl 4,3-d]pyrimidin-4-yl)-3.8-diazabicyclo[3.2.1]octane-8-carboxylate

將(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-3.8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(350 mg，0.632 mmol)、((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)萘-1-基)乙炔基)三異丙基甲矽烷(來自實施例1，步驟4，646 mg，1.26 mmol)和K 2CO 3(261 mg，1.89 mmol)在1,4-二氧六環(4.0 mL)和H 2O (0.8 mL)中的混合物抽真空，用N 2回填(backfill)，並且該順序重複三次。在N 2的流中，向產生的混合物添加RuPhos Pd G3 (52.7 mg，0.0630 mmol)。將混合物密封，加溫至90℃並且在N 2氣氛下攪拌持續2 h。反應通過LCMS來監測。在完成之後，允許混合物冷卻下來至rt並且在減壓下濃縮。殘餘物通過用[MeOH:DCM] (1:100 – 1:20)洗脫的矽膠柱色譜法純化，以提供作為棕色固體的標題中間體(300 mg，收率53%)。LC-MS [M+H] +=904.5 (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5, 5-d3)Methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3.8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (350 mg, 0.632 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2- yl)naphthalen-1-yl)ethynyl)triisopropylsilane (from Example 1, Step 4, 646 mg, 1.26 mmol) and K 2 CO 3 (261 mg, 1.89 mmol) in 1,4-di The mixture in oxane (4.0 mL) and H 2 O (0.8 mL) was evacuated, backfilled with N 2 , and the sequence was repeated three times. To the resulting mixture was added RuPhos Pd G3 (52.7 mg, 0.0630 mmol) under a flow of N2 . The mixture was sealed, warmed to 90 °C and stirred under N2 atmosphere for 2 h. 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 silica gel column chromatography eluting with [MeOH:DCM] (1:100 - 1:20) to afford the title intermediate (300 mg, 53% yield) as a brown solid. LC-MS [M+H] + =904.5

步驟4: 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-6-氟-5-((三異丙基甲矽烷基)乙炔基)萘-2-酚 Step 4: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6- Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol

在0℃在N 2氣氛下，向(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-3.8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(300 mg,0.332 mmol)在MeCN (5.0 mL)中的攪拌的混合物一次性地添加HCl (4N，在二氧六環中) (1.0 mL)。將反應混合物在rt攪拌持續1 h。反應通過LCMS來監測。在完成之後，將殘餘物在減壓下濃縮，以給出標題化合物(300 mg粗品)，所述標題化合物在下一步中使用，而不另外純化。LC-MS [M+H] +=760.4 To (1R, 5S )-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethyl) Silyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 ) Methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3.8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300 mg, 0.332 mmol) in To the stirred mixture 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 1 h. The reaction was 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 further purification. LC-MS [M+H] + =760.4

步驟5: 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚 Step 5: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- Ethynyl-6-fluoronaphthalen-2-ol

在N 2氣氛下，向4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-6-氟-5-((三異丙基甲矽烷基)乙炔基)萘-2-酚(300 mg，粗品)在DMF (4 mL)中的混合物一次性地添加CsF (200 mg，1.32 mmol)。將混合物在rt攪拌過夜。反應通過LC/MS來監測。在完成之後，混合物通過製備型-HPLC (柱：Gemini 5um C18 150*21.2mm，流動相：水(0.05% NH 3-H 2O)-ACN；B%：20%-95%，20 min)純化，以提供作為黃色固體的標題化合物(55.1 mg，收率28%(兩步))。LC-MS [M+H] += 604.3。 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.03 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.31 (d, J = 12.0 Hz, 1H), 4.10 (dd, J = 10.4, 3.2 Hz, 1H), 4.00 (dd, J = 10.4, 2.4 Hz, 1H), 3.93 (s, 1H), 3.68 – 3.49 (m, 4H), 3.08 (q, J = 13.6 Hz, 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)。 Under N2 atmosphere, to 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((( 2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]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). The mixture was stirred overnight at rt. The reaction was monitored by LC/MS. After completion, the mixture was passed through 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) Purification provided the title compound (55.1 mg, 28% yield (two steps)) as a yellow solid. LC-MS [M+H] + = 604.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.03 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H ), 7.38 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.31 (d, J = 12.0 Hz, 1H), 4.10 (dd, J = 10.4, 3.2 Hz, 1H), 4.00 (dd, J = 10.4, 2.4 Hz, 1H), 3.93 (s, 1H), 3.68 – 3.49 (m, 4H), 3.08 (q, J = 13.6 Hz, 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).

實施例11Example 11

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(2-乙基-5-(丙-1-烯-2-基)苯基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d2)吡啶並[4,3-d]嘧啶

Figure 02_image163
4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(2-ethyl-5-(prop-1-ene-2- Base) phenyl) -8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidine
Figure 02_image163

EX.11EX.11

步驟1:  (1R,5S)-3-(7-(2-乙基-5-(2-羥基丙-2-基)苯基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯 Step 1: (1R,5S)-3-(7-(2-Ethyl-5-(2-hydroxypropan-2-yl)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrole Azin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 - tert-butyl carboxylate

將2-[4-乙基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基]丙-2-醇(來自EX.37的步驟4，162 mg，0.560 mmol)、(1R,5S)-3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(來自EX.3的步驟4，200 mg，0.373 mmol )和K 2CO 3(155 mg，1.12 mmol)在1,4-二氧六環/H2O (v/v=5:1，5 mL)中的混合物脫氣。然後，添加RuPhos Pd G3 (31.2 mg，0.0373 mmol)。將混合物抽真空，用N2回填，並且該順序重複三次。將產生的混合物加溫至90℃並且在N 2氣氛下攪拌持續4 h。反應通過LCMS來監測。在完成之後，允許混合物冷卻下來至rt並且在減壓下濃縮。殘餘物通過用[MeOH:DCM] (1:100 – 1:20)洗脫的矽膠柱色譜法純化，以提供為黃色固體(100 mg，43 %收率)。LC-MS [M+H] += 663.4。 2-[4-Ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol (from Step 4 of EX.37, 162 mg, 0.560 mmol), (1R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(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 from step 4 , a mixture of 200 mg, 0.373 mmol) and K2CO3 (155 mg, 1.12 mmol) in 1,4-dioxane/H2O (v/v=5:1, 5 mL) outgassing. 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 °C and stirred under N2 atmosphere for 4 h. 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 silica gel column chromatography eluting with [MeOH:DCM] (1:100 - 1:20) to provide as a yellow solid (100 mg, 43% yield). LC-MS [M+H] + = 663.4.

步驟2: 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(2-乙基-5-(丙-1-烯-2-基)苯基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶 Step 2: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(2-ethyl-5-(prop-1-ene -2-yl)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidine

在rt，將(1R,5S)-3-(7-(2-乙基-5-(2-羥基丙-2-基)苯基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(44.0 mg，0.0663 mmol)和TMSI (26.5 mg，0.133 mmol)在MeCN (5.0 mL)中的混合物攪拌持續1h。反應通過LCMS來監測。在完成之後，將反應混合物濃縮以給出殘餘物，所述殘餘物通過在矽膠上的柱色譜法(用DCM/MeOH，0至15%洗脫)純化，以提供預計的產物，所述產物另外用製備型-HPLC (在DCM中的5% MeOH)純化，以提供作為黃色固體的標題化合物(15.0 mg，41 %收率)。LC-MS [M+H] += 545.3。 At rt, (1R,5S)-3-(7-(2-ethyl-5-(2-hydroxypropan-2-yl)phenyl)-8-fluoro-2-((tetrahydro-1H- Pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- A mixture of tert-butyl 8-carboxylate (44.0 mg, 0.0663 mmol) and TMSI (26.5 mg, 0.133 mmol) in MeCN (5.0 mL) was stirred for 1 h. 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 Additional purification with prep-HPLC (5% MeOH in DCM) provided the title compound (15.0 mg, 41 % yield) as a yellow solid. LC-MS [M+H] + = 545.3.

1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.58 (dd, J = 8.0, 1.6 Hz, 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 = 7.6 Hz, 3H)。 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.58 (dd, J = 8.0, 1.6 Hz, 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 = 7.6 Hz, 3H).

遵循實施例10的類似程式，除了使用其對應的氘代蝴蝶醇(butterfly alcohol)，合成表3中的實施例12-實施例21。 表3 化合物ID 結構 LC-MS；H-NMR EX.12

Figure 02_image165
LC-MS [M+H] +=603.5 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.96 (dd, J = 9.2, 6.0 Hz, 1H), 7.45 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 5.27 (d, J = 54.0 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.30 (d, J = 12.0 Hz, 1H), 4.11 (dd, J = 10.4, 4.0 Hz, 1H), 4.00 (dd, J = 10.4, 3.2 Hz, 1H), 3.89 (s, 1H), 3.06 (9, J = 14.0 Hz, 1H), 3.00 (s, 1H), 2.16 – 1.95 (m, 3H), 1.85 – 1.59 (m, 7H). EX.13
Figure 02_image167
 LC-MS [M+H] +=603.2 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.94 – 7.85 (m, 1H), 7.40 (t, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.14 (d, J = 2.0 Hz, 1H), 5.27 (d, J = 53.6 Hz, 1H), 4.46 (d, J = 12.4 Hz, 1H), 4.31 (d, J = 12.4 Hz, 1H), 3.89 (s, 1H), 3.65 – 3.50 (m, 4H), 3.14 – 3.01 (m, 3H), 2.85 – 2.79 (m, 1H), 2.57 (s, 1H), 2.15 – 1.97 (m, 3H), 1.87 – 1.74 (m, 3H), 1.65 (s, 3H). EX.14
Figure 02_image169
 LC-MS [M+H] +=604.2 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.03 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 4.47 (d, J = 12.8 Hz, 1H), 4.31 (d, J = 12.4 Hz, 1H), 3.93 (s, 1H), 3.68 – 3.49 (m, 4H), 3.14 – 2.99 (m, 3H), 2.83 (dd, J = 14.4, 8.4 Hz, 1H), 2.17 – 1.96 (m, 3H), 1.89 – 1.74 (m, 3H), 1.66 (s, 4H). EX.15
Figure 02_image171
 LC-MS [M+H] +=606.2 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.88 (dd, J = 9.2, 6.0 Hz, 1H), 7.39 (t, J = 9.2 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.31 (d, J = 12.0 Hz, 1H), 3.87 (s, 1H), 3.64 – 3.53 (m, 4H), 3.14 – 2.98 (m, 2H), 2.16 – 1.96 (m, 3H), 1.83 – 1.70 (m, 3H), 1.65 (s, 4H). EX.16
Figure 02_image173
 LC-MS [M+H] +=603.3 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.92 (dd, J = 9.2, 6.0 Hz, 1H), 7.43 (t, J = 9.2 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 5.28 (d, J = 54.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.32 (d, J = 12.0 Hz, 1H), 3.89 (s, 1H), 3.68 – 3.58 (m, 4H),  3.15 – 3.04 (m, 2H), 3.02 (s, 1H), 2.83 (dd, J = 14.8, 8.8 Hz, 1H), 2.19 – 1.93 (m, 3H), 1.90 – 1.72 (m, 3H), 1.66 (s, 4H). EX.17
Figure 02_image175
 LC-MS [M+H] +=603.0 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.03 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 8.8 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 1.6 Hz, 1H), 5.28 (d, J = 54.0 Hz, 1H), 4.46 (d, J = 11.6 Hz, 1H), 4.31 (d, J = 12.4 Hz, 1H), 4.10 (dd, J = 10.3, 3.2 Hz, 1H), 4.00 (dd, J = 10.4, 2.0 Hz, 1H), 3.93 (s, 1H), 3.68 – 3.49 (m, 4H), 3.15 – 2.98 (m, 2H), 2.15 – 1.97 (m, 3H), 1.87 – 1.73 (m, 3H), 1.65 (s, 4H). EX.18
Figure 02_image177
 LC-MS [M+H] +=605.2 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.96 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 5.28 (d, J = 54.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.31 (d, J = 12.0 Hz, 1H), 3.93 (s, 1H), 3.66 – 3.51 (m, 4H), 3.11 – 2.99 (m, 2H), 2.60 (s, 1H), 2.14 – 1.95 (m, 3H), 1.85 – 1.72 (m, 3H), 1.65 (s, 4H). EX.19
Figure 02_image179
 LC-MS [M+H] +=604.3 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.80 (dd, J = 9.2, 6.0 Hz, 1H), 7.34 (t, J = 8.8 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.32 (d, J = 11.6 Hz, 1H), 3.82 (s, 1H), 3.68 – 3.55 (m, 4H), 3.14 – 2.98 (m, 3H), 2.87 – 2.78 (m, 1H), 2.18 – 1.96 (m, 3H), 1.88 – 1.74 (m, 3H), 1.65 (s, 4H). EX.20
Figure 02_image181
 LC-MS [M+H] +=604.3 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.86 (dd, J = 9.2, 6.0 Hz, 1H), 7.38 (t, J = 9.2 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 4.46 (d, J = 12.4 Hz, 1H), 4.32 (d, J = 12.4 Hz, 1H), 4.12 (dd, J = 10.4, 2.4 Hz, 1H), 4.01 (dd, J = 10.4, 2.4 Hz, 1H), 3.85 (m, 1H), 3.68 – 3.58 (m, 4H), 3.08 (q, J = 14.0 Hz, 1H), 3.01 (s, 1H), 2.18 – 1.94 (m, 3H), 1.89 – 1.71 (m, 3H), 1.65 (s, 4H). EX.21
Figure 02_image183
 LC-MS [M+H] +=604.3 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.03 (s, 1H), 7.97 (dd, J = 9.2, 6.0Hz, 1H), 7.46 (t, J = 8.8Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.31 (d, J = 12.0 Hz, 1H), 3.93 (s, 1H), 3.68 – 3.50 (m, 4H), 3.08 (q, J = 14.0 Hz, 1H), 3.00 (s, 1H), 2.16 – 1.94 (m, 3H), 1.85 – 1.76  (m, 3H), 1.66 (s, 4H). Following a similar procedure to Example 10, except using its corresponding deuterated butterfly alcohol, Examples 12-21 in Table 3 were synthesized. table 3 Compound ID structure LC-MS; H-NMR EX.12
Figure 02_image165
 LC-MS [M+H] + =603.5 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.96 (dd, J = 9.2, 6.0 Hz, 1H), 7.45 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 5.27 (d, J = 54.0 Hz, 1H), 4.45 (d, J = 12.0 Hz , 1H), 4.30 (d, J = 12.0 Hz, 1H), 4.11 (dd, J = 10.4, 4.0 Hz, 1H), 4.00 (dd, J = 10.4, 3.2 Hz, 1H), 3.89 (s, 1H) , 3.06 (9, J = 14.0 Hz, 1H), 3.00 (s, 1H), 2.16 – 1.95 (m, 3H), 1.85 – 1.59 (m, 7H). EX.13
Figure 02_image167
 LC-MS [M+H] + =603.2 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.94 – 7.85 (m, 1H), 7.40 (t, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.14 (d, J = 2.0 Hz, 1H), 5.27 (d, J = 53.6 Hz, 1H), 4.46 (d, J = 12.4 Hz, 1H), 4.31 (d, J = 12.4 Hz, 1H), 3.89 (s, 1H), 3.65 – 3.50 (m, 4H), 3.14 – 3.01 (m, 3H), 2.85 – 2.79 (m, 1H), 2.57 (s, 1H), 2.15 – 1.97 ( m, 3H), 1.87 – 1.74 (m, 3H), 1.65 (s, 3H). EX.14
Figure 02_image169
 LC-MS [M+H] + =604.2 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.03 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H) , 7.46 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 4.47 (d, J = 12.8 Hz, 1H), 4.31 (d, J = 12.4 Hz, 1H), 3.93 (s, 1H), 3.68 – 3.49 (m, 4H), 3.14 – 2.99 (m, 3H), 2.83 (dd, J = 14.4, 8.4 Hz, 1H), 2.17 – 1.96 (m, 3H), 1.89 – 1.74 (m, 3H), 1.66 (s, 4H). EX.15
Figure 02_image171
 LC-MS [M+H] + =606.2 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.88 (dd, J = 9.2, 6.0 Hz, 1H), 7.39 (t, J = 9.2 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.31 (d, J = 12.0 Hz , 1H), 3.87 (s, 1H), 3.64 – 3.53 (m, 4H), 3.14 – 2.98 (m, 2H), 2.16 – 1.96 (m, 3H), 1.83 – 1.70 (m, 3H), 1.65 (s , 4H). EX.16
Figure 02_image173
 LC-MS [M+H] + =603.3 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.92 (dd, J = 9.2, 6.0 Hz, 1H), 7.43 (t, J = 9.2 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 5.28 (d, J = 54.0 Hz, 1H), 4.46 (d, J = 12.0 Hz , 1H), 4.32 (d, J = 12.0 Hz, 1H), 3.89 (s, 1H), 3.68 – 3.58 (m, 4H), 3.15 – 3.04 (m, 2H), 3.02 (s, 1H), 2.83 ( dd, J = 14.8, 8.8 Hz, 1H), 2.19 – 1.93 (m, 3H), 1.90 – 1.72 (m, 3H), 1.66 (s, 4H). EX.17
Figure 02_image175
 LC-MS [M+H] + =603.0 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.03 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H) , 7.46 (t, J = 8.8 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 1.6 Hz, 1H), 5.28 (d, J = 54.0 Hz, 1H), 4.46 (d, J = 11.6 Hz, 1H), 4.31 (d, J = 12.4 Hz, 1H), 4.10 (dd, J = 10.3, 3.2 Hz, 1H), 4.00 (dd, J = 10.4, 2.0 Hz, 1H) , 3.93 (s, 1H), 3.68 – 3.49 (m, 4H), 3.15 – 2.98 (m, 2H), 2.15 – 1.97 (m, 3H), 1.87 – 1.73 (m, 3H), 1.65 (s, 4H) . EX.18
Figure 02_image177
 LC-MS [M+H] + =605.2 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.96 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 5.28 (d, J = 54.0 Hz, 1H), 4.46 (d, J = 12.0 Hz , 1H), 4.31 (d, J = 12.0 Hz, 1H), 3.93 (s, 1H), 3.66 – 3.51 (m, 4H), 3.11 – 2.99 (m, 2H), 2.60 (s, 1H), 2.14 – 1.95 (m, 3H), 1.85 – 1.72 (m, 3H), 1.65 (s, 4H). EX.19
Figure 02_image179
 LC-MS [M+H] + =604.3 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.80 (dd, J = 9.2, 6.0 Hz, 1H), 7.34 (t, J = 8.8 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.32 (d, J = 11.6 Hz , 1H), 3.82 (s, 1H), 3.68 – 3.55 (m, 4H), 3.14 – 2.98 (m, 3H), 2.87 – 2.78 (m, 1H), 2.18 – 1.96 (m, 3H), 1.88 – 1.74 (m, 3H), 1.65 (s, 4H). EX.20
Figure 02_image181
 LC-MS [M+H] + =604.3 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.86 (dd, J = 9.2, 6.0 Hz, 1H), 7.38 (t, J = 9.2 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 4.46 (d, J = 12.4 Hz, 1H), 4.32 (d, J = 12.4 Hz, 1H), 4.12 (dd, J = 10.4, 2.4 Hz, 1H), 4.01 (dd, J = 10.4, 2.4 Hz, 1H), 3.85 (m, 1H), 3.68 – 3.58 (m, 4H), 3.08 (q , J = 14.0 Hz, 1H), 3.01 (s, 1H), 2.18 – 1.94 (m, 3H), 1.89 – 1.71 (m, 3H), 1.65 (s, 4H). EX.21
Figure 02_image183
 LC-MS [M+H] + =604.3 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.03 (s, 1H), 7.97 (dd, J = 9.2, 6.0Hz, 1H), 7.46 (t, J = 8.8Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.31 ( d, J = 12.0 Hz, 1H), 3.93 (s, 1H), 3.68 – 3.50 (m, 4H), 3.08 (q, J = 14.0 Hz, 1H), 3.00 (s, 1H), 2.16 – 1.94 (m , 3H), 1.85 – 1.76 (m, 3H), 1.66 (s, 4H).

實施例22Example 22

7a-(((4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-8-氟吡啶並[4,3-d]嘧啶-2-基)氧基)甲基-d 2)六氫吡咯嗪4(1H)-氧化物

Figure 02_image185
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- d2 )hexahydropyrrolazine 4(1H)-oxide
Figure 02_image185

EX.22EX.22

步驟1: 2-[8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基]-4,4,5,5-四甲基-1,3,2-二氧雜硼烷Step 1: 2-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2- Dioxaborane

在rt，向{2-[2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)萘-1-基]乙炔基}三異丙基甲矽烷(來自實施例1，步驟4，200 mg，0.39 mmol)在DMF (5 mL)中的混合物添加CsF (593 mg，3.9 mmol)。將反應混合物在rt攪拌持續12 h。反應通過LC-MS來監測。在完成之後，產生的混合物用水(20 mL)稀釋並且用EtOAc (10 mL ×3)萃取。合併的有機層用鹽水(20 mL)洗滌，經Na 2SO 4乾燥，過濾，並且在旋轉蒸發儀上濃縮。殘餘物通過矽膠柱色譜法(用MeOH/DCM，1%至5%洗脫)純化以提供作為淺黃色油的標題化合物(120 mg，77%收率)。LC-MS [M+H] +=356.9 At rt, to {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborinane- 2-yl)naphthalen-1-yl]ethynyl}triisopropylsilane (from Example 1, Step 4, 200 mg, 0.39 mmol) in DMF (5 mL) was added CsF (593 mg, 3.9 mmol). The reaction mixture was stirred at rt for 12 h. The reaction was monitored by LC-MS. After completion, the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered, and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography (eluting with MeOH/DCM, 1% to 5%) to afford the title compound (120 mg, 77% yield) as a light yellow oil. LC-MS [M+H] + =356.9

步驟2: 2-[8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基]-4,4,5,5-四甲基-1,3,2-二氧雜硼烷Step 2: 2-[8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2- Dioxaborane

在rt在N 2氣體的流下，向2-[8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基]-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(120 mg，0.337 mmol)在EtOAc (10 mL)中的混合物添加Pd/C (120 mg，10 %)，並且在H 2(1 atm)氣氛下攪拌持續1.5 h。  反應通過LC-MS來監測。  在完成之後，將產生的混合物通過矽藻土過濾，並且將濾液在真空下濃縮。殘餘物通過矽膠柱色譜法(用EtOAc/PE，1%至10洗脫)純化，以提供作為淺黃色油的標題化合物(110 mg，81%收率)。LC-MS [M+H] +=361.2 To 2-[ 8 -ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl - A mixture of 1,3,2-dioxaborane (120 mg, 0.337 mmol) in EtOAc (10 mL) was added with Pd/C (120 mg, 10%), and the Stirring was continued for 1.5 h. The reaction was monitored by LC-MS. After completion, the resulting mixture was filtered through celite, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc/PE, 1% to 10) to afford the title compound (110 mg, 81% yield) as a pale yellow oil. LC-MS [M+H] + =361.2

步驟3: 7a-(((4-((1R,5S)-8-(叔丁氧基羰基)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶並[4,3-d]嘧啶-2-基)氧基)甲基-d 2)六氫吡咯嗪4(1H)-氧化物 Step 3: 7a-(((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7 -(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl group-d 2 ) hexahydropyrrolizine 4(1H)-oxide

將{3-[7-氯-8-氟-2-(六氫吡咯嗪-7a-基甲氧基)吡啶並[4,3-d]嘧啶-4-基]-3,8-二氮雜雙環並[3.2.1]辛烷-8-基}甲酸叔丁酯(來自實施例3的步驟2，100 mg，0.187 mmol)、2-[8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基]-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(101 mg，0.279 mmol)、K 2CO 3(77.3 mg，0.559 mmol)和RuPhos Pd G3 (15.6 mg，0.0186 mmol)在1,4-二氧六環(5 mL)和H 2O (1 mL)中的混合物在90℃在N 2氣氛下攪拌持續3 h。反應通過LC-MS來監測。在完成之後，允許混合物冷卻下來至rt並且在減壓下濃縮。殘餘物通過矽膠柱色譜法(用MeOH/DCM，1%至10洗脫)純化以提供作為黃色固體的標題化合物(80 mg，51%收率)。   LC-MS [M+H] +=749.4 {3-[7-Chloro-8-fluoro-2-(hexahydropyrrolidin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diaze Heterobicyclo[3.2.1]octan-8-yl}carboxylate tert-butyl (from step 2 of Example 3, 100 mg, 0.187 mmol), 2-[8-ethyl-7-fluoro-3-( Methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (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 H2O (1 mL) were stirred at 90 °C under N2 atmosphere last for 3 h. 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 afford the title compound (80 mg, 51% yield) as a yellow solid. LC-MS [M+H] + =749.4

步驟4: 7a-(((4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-8-氟吡啶並[4,3-d]嘧啶-2-基)氧基)甲基-d 2)六氫吡咯嗪4(1H)-氧化物 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- d2 )hexahydropyrrolazine 4(1H)-oxide

在rt，向7a-[({4-[8-(叔丁基-$l^{3}-氧基)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基]-7-[8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基]-8-氟吡啶並[4,3-d]嘧啶-2-基}氧基)甲基]-六氫吡咯嗪-4-鎓(ium)-4-氧化物(olate)(80 mg，0.107 mmol)在MeCN (2.5 mL)中的混合物添加在1,4-二氧六環中的HCl (0.5 mL，4N)並且攪拌持續1 h。反應通過LC-MS來監測。在完成之後，將混合物在減壓下濃縮。混合物通過製備型-HPLC純化，以提供作為黃色固體的7a-{[(4-{3,8-二氮雜雙環並[3.2.1]辛烷-3-基}-7-(8-乙基-7-氟-3-羥基萘-1-基)-8-氟吡啶並[4,3-d]嘧啶-2-基)氧基]甲基}-六氫吡咯嗪-4-鎓-4-氧化物(10.9 mg，16%收率(兩步))。LC-MS [M+H] += 605.2。 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 7.70 (dd, J = 8.8, 6.0 Hz, 1H), 7.42 – 7.14 (m, 2H), 6.94 (d, J = 2.4 Hz, 1H), 4.38 (t, J = 11.6 Hz, 2H), 3.77 – 3.66 (m, 2H), 3.58 – 3.43 (m, 6H), 2.37 – 2.28 (m, 1H), 2.24 – 2.04 (m, 5H), 2.01 – 1.87 (m, 4H), 1.64 – 1.50 (m, 4H), 0.70 (t, J = 7.2 Hz, 3H)。 At rt, to 7a-[({4-[8-(tert-butyl-$l^{3}-oxyl)-3,8-diazabicyclo[3.2.1]octan-3-yl ]-7-[8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-2-yl}oxy 1,4-dioxahexa HCl (0.5 mL, 4N) in a ring and stirring continued for 1 h. 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]octan-3-yl}-7-(8-ethane) as a yellow solid Base-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy]methyl}-hexahydropyrrolazin-4-ium- 4-oxide (10.9 mg, 16% yield (two steps)). LC-MS [M+H] + = 605.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 7.70 (dd, J = 8.8, 6.0 Hz, 1H), 7.42 – 7.14 (m, 2H), 6.94 (d, J = 2.4 Hz , 1H), 4.38 (t, J = 11.6 Hz, 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 = 7.2 Hz, 3H).

實施例23Example 23

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚

Figure 02_image187
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizine- 7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol
Figure 02_image187

EX.23EX.23

步驟1:   5,6-二氟-1,4-二氫-1,4-環氧基萘Step 1: 5,6-difluoro-1,4-dihydro-1,4-epoxynaphthalene

在-15℃在N 2氣氛下在2 h內，向1-溴-2,3,4-三氟苯(2000 g，9.48 mol)和呋喃(1286 g，19.0 mol)在甲苯(10 L)中的混合物逐滴地添加n-BuLi (1.6 M，7.10 L)將混合物在-15℃攪拌持續30分鐘，然後加溫至rt並且攪拌持續17小時。隨後，反應混合物用水(3 L)猝滅。將兩層分離。水層用EtOAc (2×2L)萃取。合併的有機層經無水Na 2SO 4乾燥，過濾，並且在減壓下濃縮。產生的殘餘物通過矽膠色譜法(PE/EA=50/1)純化，以給出作為棕色油的產物(750 g，4.17 mol，44%收率)。LC-MS [M-H] -= 179。 To 1-bromo-2,3,4-trifluorobenzene (2000 g, 9.48 mol) and furan (1286 g, 19.0 mol) in toluene (10 L) at -15 °C under N2 atmosphere within 2 h The mixture in was added n-BuLi (1.6 M, 7.10 L) dropwise and the mixture was stirred at -15 °C for 30 min, then warmed to rt and stirred for 17 h. Subsequently, the reaction mixture was quenched with water (3 L). The two layers were separated. The aqueous layer was extracted with EtOAc (2x2L). The combined organic layers were dried over anhydrous Na2SO4 , 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, 4.17 mol, 44% yield). LC-MS [MH] - =179.

步驟2: 7,8-二氟萘-1-酚Step 2: 7,8-Difluoronaphthalen-1-ol

在rt在1h內，向5,6-二氟-1,4-二氫-1,4-環氧基萘(750 g，4.17 mol)在EtOH (7.5 L)中的溶液添加含水HCl (4.9 L，12 M)。將混合物逐漸地加溫至回流並且攪拌持續2小時。將混合物冷卻至rt並且在真空下濃縮。殘餘物通過矽膠(PE/EA=100:1)純化。產生的固體用PE (200 mL)洗滌，以提供作為白色固體的7,8-二氟萘-1-酚(420 g，56%收率)。 LCMS (ESI -: 179)。To a solution of 5,6-difluoro-1,4-dihydro-1,4-epoxynaphthalene (750 g, 4.17 mol) in EtOH (7.5 L) was added aqueous HCl (4.9 L) over 1 h at rt. L, 12 M). 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-difluoronaphthalen-1-ol (420 g, 56% yield) as a white solid. LCMS (ESI-: 179).

步驟3: 1,2-二氟-8-(甲氧基甲氧基)萘Step 3: 1,2-Difluoro-8-(methoxymethoxy)naphthalene

在冰-H 2O浴中，向7,8-二氟萘-1-酚(395 g，2.19 mol)在DCM (4L)中的攪拌的溶液添加DIPEA (849 g，1.14 L，6.57 mol)並且隨後快速地逐滴地添加MOMBr (543 g，355 mL，4.38 mol)。將混合物在0℃攪拌持續0.5 h，允許加溫至周圍溫度(ambient temperature)，並且攪拌持續1.5 h。將反應混合物傾倒在飽和的含水Na 2CO 3中，用DCM (2L)萃取，經Na 2SO 4乾燥，過濾並且濃縮至黃色油。粗製殘餘物通過用PE中的5% EtOAc洗脫的矽膠色譜法純化，以提供作為黃色固體的標題化合物(450 g，92%收率)。LC/MS [M+H] +=225.1。 1H-NMR (400 MHz, CDCl 3) 7.55-7.51 (m, 1H), 7.46-7.43 (m, 1H), 7.36-7.28 (m, 2H), 7.15 (d, J=7.6 Hz, 1H), 5.35 (s, 2H), 3.57 (s, 3H)。 To a stirred solution of 7,8-difluoronaphthalen-1-ol (395 g, 2.19 mol) in DCM (4 L) was added DIPEA (849 g, 1.14 L, 6.57 mol) in an ice- H2O bath And then MOMBr (543 g, 355 mL, 4.38 mol) was added dropwise rapidly. The mixture was stirred at 0 °C for 0.5 h, allowed to warm to ambient temperature, and stirred for 1.5 h. The reaction mixture was poured into saturated aqueous Na 2 CO 3 , extracted with DCM (2 L), dried over Na 2 SO 4 , filtered and concentrated to a yellow oil. The crude residue was purified by silica gel chromatography eluting with 5% EtOAc in PE to afford the title compound (450 g, 92% yield) as a yellow solid. LC/MS [M+H] + =225.1. 1 H-NMR (400 MHz, CDCl 3 ) 7.55-7.51 (m, 1H), 7.46-7.43 (m, 1H), 7.36-7.28 (m, 2H), 7.15 (d, J=7.6 Hz, 1H), 5.35 (s, 2H), 3.57 (s, 3H).

步驟4: 2-(5.6-二氟-4-(甲氧基甲氧基)萘-2-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷Step 4: 2-(5.6-Difluoro-4-(methoxymethoxy)naphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborin alkyl

向1,2-二氟-8-(甲氧基甲氧基)萘(450 g，2.01 mol)在乾燥的甲苯(4.5 L)中的溶液添加[Ir(OMe)(cod) 2] 2(43.9 g，66.2 mmol)、4,4'-二叔丁基-2,2'-聯吡啶(64.5 g，239 mmol)和HBpin (641 g，5.01 mol)。將混合物抽真空，用N 2回填，並且該順序重複三次。將產生的混合物加溫至70℃並且攪拌持續2 h，以基於LC/MS，給出完全轉化。將反應混合物冷卻至rt，並且通過矽藻土的薄層。將濾液濃縮，以提供作為深棕色油的粗製產物(530 g，75%收率)。 [M+H] +=  351.2 To a solution of 1,2-difluoro-8-(methoxymethoxy)naphthalene (450 g, 2.01 mol) in dry toluene (4.5 L) was added [Ir(OMe)(cod) 2 ] 2 ( 43.9 g, 66.2 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (64.5 g, 239 mmol) and HBpin (641 g, 5.01 mol). The mixture was evacuated, backfilled with N2 , and the sequence was repeated three times. The resulting mixture was warmed to 70 °C and stirred for 2 h 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 afford the crude product (530 g, 75% yield) as a dark brown oil. [M+H] + = 351.2

步驟5: 5,6-二氟-4-(甲氧基甲氧基)萘-2-酚Step 5: 5,6-Difluoro-4-(methoxymethoxy)naphthalene-2-ol

在冰-H 2O浴中，向2-(5,6-二氟-4-(甲氧基甲氧基)萘-2-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(530 g，1.51 mol)在THF (2.0 L)中的攪拌的溶液添加HOAc (362 g，6.04 mol)，隨後在1 h內，逐滴地添加35% H 2O 2(1.99 kg，20.5 mol)。將混合物在0℃繼續攪拌持續0.5 h，允許加溫至周圍溫度，並且攪拌持續另一個1.5 h。反應用飽和的NaHSO 3(含水)猝滅，用EtOAc (1 L×2)萃取。合併的有機層經Na 2SO 4乾燥，過濾，並且濃縮。產生的殘餘物通過用PE中的5% EtOAc洗脫的矽膠色譜法純化，以給出標題化合物(185 g，51%收率)。LCMS (ESI -: 239)。 In an ice-H 2 O bath, 2-(5,6-difluoro-4-(methoxymethoxy)naphthalen-2-yl)-4,4,5,5-tetramethyl-1 , to a stirred solution of 3,2-dioxaborane (530 g, 1.51 mol) in THF (2.0 L) was added HOAc (362 g, 6.04 mol), followed by the addition of 35% H2O2 (1.99 kg , 20.5 mol). The mixture was continued to stir at 0 °C for 0.5 h, allowed to warm to ambient temperature, and stirred for another 1.5 h. The reaction was quenched with saturated NaHSO 3 (aq), extracted with EtOAc (1 L×2). The combined organic layers were dried over Na2SO4 , 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).

步驟6: 5,6-二氟-4-(甲氧基甲氧基)萘-2-基乙酸酯Step 6: 5,6-Difluoro-4-(methoxymethoxy)naphthalen-2-yl acetate

向5,6-二氟-4-(甲氧基甲氧基)萘-2-酚(185 g，1當量，770 mmol)在DCM (1.8 L)中的溶液添加Et 3N (156 g，1.54 mol)和DMAP (30 mg，0.245 mmol)。然後在0℃，逐滴地添加乙醯氯(121 g，1.54 mol)。將混合物加溫至rt並且攪拌持續0.5小時。在完成之後，反應混合物用水(1000 mL)稀釋並且用DCM (2×1L)萃取。合併的有機層經Na 2SO 4乾燥，過濾，並且在真空下濃縮。殘餘物通過柱色譜法(PE/EA = 100/1至20/1)純化，以提供作為黃色油的標題化合物(125 g，58%收率)。LC/MS [M+H] +=283.2。 To a solution of 5,6-difluoro-4-(methoxymethoxy)naphthalene-2-ol (185 g, 1 equiv, 770 mmol) in DCM (1.8 L) was added Et 3 N (156 g, 1.54 mol) and DMAP (30 mg, 0.245 mmol). Acetyl chloride (121 g, 1.54 mol) was then added dropwise at 0°C. The mixture was warmed to rt and stirred for 0.5 h. After completion, the reaction mixture was diluted with water (1000 mL) and extracted with DCM (2 x 1 L). The combined organic layers were dried over Na2SO4 , filtered, and concentrated under vacuum . The residue was purified by column chromatography (PE/EA = 100/1 to 20/1) to afford the title compound (125 g, 58% yield) as a yellow oil. LC/MS [M+H] + =283.2.

步驟7: 5,6-二氟-4-羥基萘-2-基乙酸酯Step 7: 5,6-Difluoro-4-hydroxynaphthalen-2-yl acetate

在-40℃，向乙酸5,6-二氟-4-(甲氧基甲氧基)萘-2-基酯(125 g，443 mmol)在EA (600 mL)中的溶液添加EA中的HC1 (4 M，1300 mL)，並且攪拌持續0.5小時，然後在0℃攪拌另一個0.5小時。在完成之後，反應混合物用水(300 mL)稀釋並且用EA (2×300mL)萃取。合併的有機層經Na 2SO 4乾燥，過濾，並且在真空下濃縮，這提供作為黃色粗製油的標題化合物(91 g，粗品)，所述標題化合物通過矽膠色譜法(PE/EA = 20/1)純化，以提供作為白色固體的標題化合物(68 g，64 %收率)。 To a solution of 5,6-difluoro-4-(methoxymethoxy)naphthalen-2-yl acetate (125 g, 443 mmol) in EA (600 mL) at -40 °C was added HCl (4 M, 1300 mL), and stirring was continued for 0.5 h, then another 0.5 h at 0 °C. After completion, the reaction mixture was diluted with water (300 mL) and extracted with EA (2 x 300 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in vacuo, which provided the title compound (91 g, crude) as a yellow crude oil, which was analyzed by silica gel chromatography (PE/EA=20/ 1) Purification to provide the title compound (68 g, 64% yield) as a white solid.

步驟8: 5,6-二氟-4-(((三氟甲基)磺醯基)氧基)萘-2-基乙酸酯Step 8: 5,6-Difluoro-4-(((trifluoromethyl)sulfonyl)oxy)naphthalen-2-ylacetate

在-78℃在N 2氣氛下在30 min內，向5,6-二氟-4-羥基萘-2-基乙酸酯(68 g，285 mol)和DIPEA (110 g，856 mmol)在DCM (660 mL)中的溶液逐滴地添加Tf 2O (96.5 g，342 mmol)，並且攪拌持續0.5小時。在完成之後，反應混合物用水(200 mL)稀釋，加溫至rt並且用DCM (2×200mL)萃取。合併的有機層經Na 2SO 4乾燥，過濾，並且在真空下濃縮。殘餘物通過柱色譜法(PE/EA = 1/10至20/1)純化，以提供作為黃色固體的標題化合物(40.1 g，38%收率)。 To 5,6-difluoro-4-hydroxynaphthalen-2-yl acetate (68 g, 285 mol) and DIPEA (110 g, 856 mmol) at -78 °C in 30 min under N atmosphere The solution in DCM (660 mL) was added Tf20 (96.5 g, 342 mmol) dropwise and stirred for 0.5 h. After completion, the reaction mixture was diluted with water (200 mL), warmed to rt and extracted with DCM (2 x 200 mL). The combined organic layers were dried over Na2SO4 , filtered, and concentrated under vacuum . The residue was purified by column chromatography (PE/EA = 1/10 to 20/1) to afford the title compound (40.1 g, 38% yield) as a yellow solid.

步驟9: 7,8-二氟-3-羥基萘-1-基三氟甲磺酸酯Step 9: 7,8-Difluoro-3-hydroxynaphthalen-1-yl triflate

在0℃，向5,6-二氟-4-(((三氟甲基)磺醯基)氧基)萘-2-基乙酸酯(40.1 g，108 mmol)在THF (420 mL)和H 2O (84 mL)中的溶液添加LiOH.H 2O (5.30 g, 130 mmol)。將混合物在0℃攪拌持續0.5小時。在完成之後，用AcOH，將反應混合物調節pH至約6。反應混合物用水(400 mL)稀釋並且用EA (2×400mL)萃取。合併的有機層經Na 2SO 4乾燥，過濾，並且在真空下濃縮，這提供作為棕色油的標題化合物(39 g，粗品)。LC/MS [M+]+ = 329.1 Add 5,6-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)naphthalen-2-yl acetate (40.1 g, 108 mmol) in THF (420 mL) at 0 °C and a solution in H 2 O (84 mL) was added LiOH.H 2 O (5.30 g, 130 mmol). The mixture was stirred at 0 °C for 0.5 h. After completion, the reaction mixture was adjusted to pH about 6 with AcOH. The reaction mixture was diluted with water (400 mL) and extracted with EA (2 x 400 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in vacuo, which provided the title compound (39 g, crude) as a brown oil. LC/MS [M+]+ = 329.1

步驟9: 7,8-二氟-3-(甲氧基甲氧基)萘-1-基三氟甲磺酸酯Step 9: 7,8-Difluoro-3-(methoxymethoxy)naphthalen-1-yl triflate

在0℃，向7,8-二氟-3-羥基萘-1-基三氟甲磺酸酯(39.0 g，120 mmol)在DCM (400 mL)中的溶液添加DIPEA (46.4 g, 360 mmol)，並且然後逐滴地添加MOMBr (18.0 g，144 mmol)。將混合物在0℃攪拌持續1小時。在完成之後，反應混合物用水(400 mL)稀釋並且用DCM (2×400mL)萃取。合併的有機層經Na 2SO 4乾燥，過濾，並且在真空下濃縮。殘餘物通過柱色譜法(PE/EA = 1/10至10/1)，隨後是製備型-HPLC純化，以提供標題化合物(8.01 g，18%收率)。  LC/MS [M+H]+ = 373.1。 1H-NMR (400 MHz, 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)。 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 0 °C. ), and then MOMBr (18.0 g, 144 mmol) was added dropwise. The mixture was stirred at 0 °C for 1 hour. After completion, the reaction mixture was diluted with water (400 mL) and extracted with DCM (2 x 400 mL). The combined organic layers were dried over Na2SO4 , filtered, and concentrated under vacuum . The residue was purified by column chromatography (PE/EA = 1/10 to 10/1) followed by prep-HPLC to provide the title compound (8.01 g, 18% yield). LC/MS [M+H]+ = 373.1. 1 H-NMR (400 MHz, 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).

步驟10:       2-(7.8-二氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷Step 10: 2-(7.8-Difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborin alkyl

向7,8-二氟-3-(甲氧基甲氧基)萘-1-基三氟甲磺酸酯(8.01 g，21.5 mmol)和4,4,5,5-四甲基-2-(4,4,5,5-四甲基-l,3,2-二氧雜硼烷-2-基)-l,3,2-二氧雜硼烷(6.55 g，25.8 mmol)在DMF (60 mL)中的溶液添加Pd(dppf)Cl 2.DCM (527 mg，0.645 mmol)和KOAc (64.5 mmol)。將混合物抽真空，用N2回填，並且該順序重複三次。將產生的混合物加溫至80℃並且在N 2氣氛下攪拌持續16小時。在完成之後，將反應混合物冷卻至rt，用水(100 mL)稀釋並且用EA (2×500mL)萃取。合併的有機層用鹽水(100 mL)洗滌，經Na 2SO 4乾燥，過濾，並且在真空下濃縮。殘餘物通過柱色譜法(PE/EA = 20/1)純化，以提供作為白色固體的標題化合物(3.20 g，43%收率)。LC/MS [M+H]+ = 351.1。 1H-NMR (400 MHz, 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)。 To 7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl triflate (8.01 g, 21.5 mmol) and 4,4,5,5-tetramethyl-2 -(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborinane (6.55 g, 25.8 mmol) in To a solution in DMF (60 mL) was added Pd(dppf)Cl 2 .DCM (527 mg, 0.645 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 °C and stirred under N2 atmosphere for 16 h. After completion, the reaction mixture was cooled to rt, diluted with water (100 mL) and extracted with EA (2 x 500 mL). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE/EA = 20/1) to afford the title compound (3.20 g, 43% yield) as a white solid. LC/MS [M+H]+ = 351.1. 1 H-NMR (400 MHz, 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).

步驟11: (1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯 Step 11: (1R,5S)-3-(7-(7,8-Difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane tert-butyl alkane-8-carboxylate

將(1R,5S)-3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(來自EX. 3的步驟2，100 mg，0.186 mmol)、2-[7,8-二氟-3-(甲氧基甲氧基)萘-1-基]-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(97.9 mg，0.279 mmol)、K 2CO 3(77.3 mg，0.556 mmol)、RuPhos Pd G3 (15.6 mg，0.0186 mmol)在二氧六環(5 mL)和H 2O (1 mL)中的混合物在90℃在N 2氣氛下攪拌持續4 h。反應通過LC-MS來監測。在完成之後，允許混合物冷卻下來至室溫並且在減壓下濃縮。殘餘物通過矽膠柱色譜法(用MeOH/DCM，1%至10%洗脫)純化，以提供作為黃色固體的 (3-{7-[7,8-二氟-3-(甲氧基甲氧基)萘-1-基]-8-氟-2-(六氫吡咯嗪-7a-基甲氧基)吡啶並[4,3-d]嘧啶-4-基}-3,8-二氮雜雙環並[3.2.1]辛烷-8-基)甲酸叔丁酯(70 mg，46%收率)。LC-MS [M+H] +=723.2 (1R,5S)-3-(7-Chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(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 of EX. 3, 100 mg, 0.186 mmol), 2-[7,8-Difluoro-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (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 O (1 mL) Stirring was continued for 4 h at 90 °C under N2 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 afford (3-{7-[7,8-difluoro-3-(methoxymethyl Oxy)naphthalen-1-yl]-8-fluoro-2-(hexahydropyrrolidin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl}-3,8-di Azabicyclo[3.2.1]octan-8-yl) tert-butyl carboxylate (70 mg, 46% yield). LC-MS [M+H] + =723.2

步驟12: 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚 Step 12: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H- Pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol

在rt，向(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(80.0 mg，0.111 mmol)在ACN (5 ml)中的攪拌的溶液添加1,4-二氧六環中的HCl (4N，1 mL)。然後，將反應混合物在rt攪拌持續1 h。將產生的混合物在真空下濃縮。粗製產物通過製備型-HPLC (0.05% NH 3-H 2O)-ACN；B%：20%-95%，20 min)純化，以提供作為白色固體的標題化合物(15.4 mg，23%收率)。LC-MS [M+H] += 759.3。 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.80 – 7.67 (m, 1H), 7.57 (dd, J = 17.2, 9.2 Hz, 1H), 7.39 (s, 1H), 7.24 (s, 1H), 4.42 (t, J = 11.2 Hz, 2H), 3.68 – 3.49 (m, 6H), 3.02 – 2.85 (m, 3H), 1.97 – 1.50 (m, 12H)。 At rt, to (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro -1H-pyrrolazin-7a(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 in 1,4-dioxane (4N, 1 mL). Then, the reaction mixture was stirred at rt for 1 h. 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 (15.4 mg, 23% yield) as a white solid ). LC-MS [M+H] + = 759.3. 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.80 – 7.67 (m, 1H), 7.57 (dd, J = 17.2, 9.2 Hz, 1H), 7.39 (s, 1H), 7.24 (s, 1H), 4.42 (t, J = 11.2 Hz, 2H), 3.68 – 3.49 (m, 6H), 3.02 – 2.85 (m, 3H), 1.97 – 1.50 (m, 12H).

遵循如EX.23類似的程式合成表4中的EX.24至EX.27。 表4 化合物ID 結構 LC/MS；H-NMR或MS [M+1] 24

Figure 02_image189
LC-MS [M+H] +=600.3 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.10 (s, 1H), 7.78 – 7.71 (m, 1H), 7.58 (dd, J = 17.6, 9.5 Hz, 1H), 7.39 (s, 1H), 7.24 (d, J = 2.4 Hz, 1H), 4.42 (t, J = 11.2 Hz, 2H), 3.65 – 3.50 (m, 4H), 3.13 – 2.98 (m, 2H), 2.67 (s, 1H), 2.18 – 2.09 (m, 1H), 2.08 – 1.95 (m, 2H), 1.86 – 1.72 (m, 3H), 1.68 – 1.56 (m, 4H)。 25
Figure 02_image191
 LC-MS [M+1]：598.6 26
Figure 02_image193
 LC-MS [M+1]：597.6 27
Figure 02_image195
 LC-MS [M+H] +=598.4 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.23 (s, 1H), 7.77 – 7.71 (m, 1H), 7.58 (dd, J = 17.6, 9.6 Hz, 1H), 7.39 (s, 1H), 7.23 (s, 1H), 4.88 (s, 1H), 4.35 – 3.95 (m, 4H), 3.32 – 3.22 (m, 2H), 3.17 – 3.02 (m, 3H), 3.00 (s, 1H), 2.19 – 1.64 (m, 10H)。 EX.24 to EX.27 in Table 4 were synthesized following a similar procedure as EX.23. Table 4 Compound ID structure LC/MS; H-NMR or MS [M+1] twenty four
Figure 02_image189
 LC-MS [M+H] + =600.3 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.10 (s, 1H), 7.78 – 7.71 (m, 1H), 7.58 (dd, J = 17.6, 9.5 Hz, 1H), 7.39 (s, 1H), 7.24 (d, J = 2.4 Hz, 1H), 4.42 (t, J = 11.2 Hz, 2H), 3.65 – 3.50 (m, 4H), 3.13 – 2.98 (m, 2H), 2.67 (s, 1H), 2.18 – 2.09 (m, 1H), 2.08 – 1.95 (m, 2H), 1.86 – 1.72 (m, 3H), 1.68 – 1.56 (m, 4H ). 25
Figure 02_image191
 LC-MS [M+1]: 598.6 26
Figure 02_image193
 LC-MS [M+1]: 597.6 27
Figure 02_image195
 LC-MS [M+H] + =598.4 1 H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.23 (s, 1H), 7.77 – 7.71 (m, 1H), 7.58 (dd, J = 17.6, 9.6 Hz, 1H), 7.39 (s, 1H), 7.23 (s, 1H), 4.88 (s, 1H), 4.35 – 3.95 (m, 4H), 3.32 – 3.22 (m, 2H), 3.17 – 3.02 (m, 3H), 3.00 (s, 1H), 2.19 – 1.64 (m, 10H).

實施例28Example 28

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-環丙基苯酚

Figure 02_image197
3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol
Figure 02_image197

EX.28EX.28

步驟1： 1-溴-3-氯-2-環丙基苯Step 1: 1-Bromo-3-chloro-2-cyclopropylbenzene

向1-溴-3-氯-2-碘苯(10.0 g，31.5 mmol)、K 3PO 4(24.7 g，11.3 mmol)和Pd(dppf)Cl 2(2.30 g，3.14 mmol)在1,4-二氧六環(180 mL)和H 2O (6 mL)中的混合物添加環丙基硼酸(3.52 g，40.9 mmol)。將混合物抽真空，用N2回填，並且該順序重複三次。將產生的混合物加溫至100℃並且在N 2下攪拌持續18小時。允許混合物冷卻下來至rt。將水(50 ml)添加至混合物。產生的混合物用EA (3×200 ml)萃取。合併的有機層經無水Na 2SO 4乾燥。在過濾之後，將濾液在減壓下濃縮。殘餘物通過用PE/EA (100/1)洗脫的矽膠柱色譜法純化，以提供作為無色油的標題化合物(4.70 g，58%收率)。  LC/MS [M+H]+ = 232.4。 1H NMR (400 MHz, CDCl 3) δ 7.46 (dd, J = 8.0, 1.2 Hz, 1H), 7.30 (dd, J = 8.0, 0.8 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 1.81 – 1.72 (m, 1H), 1.21 – 1.15 (m, 2H), 0.80 – 0.74 (m, 2H)。 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) at 1,4 - A mixture in dioxane (180 mL) and H2O (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 °C and stirred under N2 for 18 h. Allow the mixture to cool down to rt. Water (50 ml) was added to the mixture. The resulting mixture was extracted with EA (3 x 200 ml). The combined organic layers were dried over anhydrous Na2SO4 . 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 afford the title compound (4.70 g, 58% yield) as a colorless oil. LC/MS [M+H]+ = 232.4. 1 H NMR (400 MHz, CDCl 3 ) δ 7.46 (dd, J = 8.0, 1.2 Hz, 1H), 7.30 (dd, J = 8.0, 0.8 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H) , 1.81 – 1.72 (m, 1H), 1.21 – 1.15 (m, 2H), 0.80 – 0.74 (m, 2H).

步驟2: 2-(3-溴-5-氯-4-環丙基苯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷Step 2: 2-(3-Bromo-5-chloro-4-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane

將1-溴-3-氯-2-環丙基苯(4.70 g，20.3 mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-1,3,2-二氧雜硼烷(25.8 g，102 mmol)、[Ir(OMe)(1,5-cod)] 2(340 mg，0.513 mmol)和4,4'-二叔丁基-2,2'-聯吡啶(330 mg, 1.23 mmol)在己烷(100 mL)中的混合物脫氣並且用N 2沖洗3次。將混合物在60℃在N 2氣氛下攪拌持續4小時。反應通過TLC來監測。在轉化完成之後，將產生的混合物冷卻下來至rt並且在減壓下濃縮。粗製產物在下一步直接使用而不另外純化。 1-Bromo-3-chloro-2-cyclopropylbenzene (4.70 g, 20.3 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolin-2-yl)-1,3,2-dioxaborinane (25.8 g, 102 mmol), [Ir(OMe)(1,5-cod)] 2 (340 mg, 0.513 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (330 mg, 1.23 mmol) in hexane (100 mL) was degassed and flushed with N for 3 Second-rate. The mixture was stirred at 60 °C under N2 atmosphere for 4 h. The reaction was monitored by TLC. After conversion was complete, the resulting mixture was cooled down to rt and concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

殘餘物用THF (60 mL)和H 2O (30 mL)溶解。在0℃，向上述混合物添加AcOH (43.2 g，719 mmol)和H 2O 2(24.3 g，214 mmol)將產生的混合物在0℃攪拌另外的1 h。反應通過LCMS來監測。在轉化完成之後，將水(50 ml)添加至混合物。產生的混合物用EtOAc (3×150 ml)萃取。合併的有機層經無水Na 2SO 4乾燥。在過濾之後，將濾液在減壓下濃縮。粗製產物通過反相快速色譜法(柱，C18矽膠；流動相，ACN-水中0.1% FA，在10 min內10%至50%梯度；檢測器，UV 214 nm)純化，以提供作為黃色油的標題化合物(3.31 g，66 %收率)。 LC-MS [M-H] -= 247.1 The residue was dissolved with THF (60 mL) and H2O (30 mL). At 0°C, AcOH (43.2 g, 719 mmol) and H 2 O 2 (24.3 g, 214 mmol) were added to the above mixture and the resulting mixture was stirred at 0°C for an additional 1 h. 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 (3 x 150 ml). The combined organic layers were dried over anhydrous Na2SO4 . 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, ACN-0.1% FA in water, gradient 10% to 50% in 10 min; detector, UV 214 nm) to afford the The title compound (3.31 g, 66% yield). LC-MS [MH] - = 247.1

步驟3: 1-溴-3-氯-2-環丙基-5-(甲氧基甲氧基)苯Step 3: 1-Bromo-3-chloro-2-cyclopropyl-5-(methoxymethoxy)benzene

在0℃在N 2氣體的流下，向3-溴-5-氯-4-環丙基苯酚(11.2 g，45.2 mmol)在THF (200 mL)中的混合物分批次地添加NaH (60 %，在礦物油中，5.42 g，136 mmol)。將混合物加溫至rt並且攪拌持續0.5小時。然後，在5 min內，將1-1-溴-1-甲氧基甲烷(11.3 g，90.4 mmol)逐滴地添加至混合物，並且在rt攪拌持續1h。反應通過TLC來監測。在完成之後，反應通過在0℃添加飽和的含水NH 4Cl (100 ml)來猝滅。產生的混合物用EA (3×200 ml)萃取。合併的有機層經無水Na 2SO 4乾燥。在過濾之後，將濾液在減壓下濃縮，並且殘餘物通過柱色譜法(PE:EA =100:1-30:1)純化，以提供標題化合物(10.8 g，74%收率)。LC/MS [M+H] += 292.4。 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 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)。 To a mixture of 3-bromo-5-chloro-4-cyclopropylphenol (11.2 g, 45.2 mmol) in THF (200 mL) was added NaH (60% , in mineral oil, 5.42 g, 136 mmol). The mixture was warmed to rt and stirred for 0.5 h. Then, 1-1-bromo-1-methoxymethane (11.3 g, 90.4 mmol) was added dropwise to the mixture within 5 min and stirred at rt for 1 h. The reaction was monitored by TLC. After completion, the reaction was quenched by the addition of saturated aqueous NH4Cl (100 ml) at 0 °C. The resulting mixture was extracted with EA (3 x 200 ml). The combined organic layers were dried over anhydrous Na2SO4 . 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 (400 MHz, CDCl3) δ 7.19 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 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).

步驟4: 2-[3-氯-2-環丙基-5-(甲氧基甲氧基)苯基]-4,4,5,5-四甲基-1,3,2-二氧雜硼烷Step 4: 2-[3-Chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxo Borane

向1-溴-3-氯-2-環丙基-5-(甲氧基甲氧基)苯(10.8 g，37.7 mmol)、K 2CO 3(22.2 g，226 mmol)和4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-1,3,2-二氧雜硼烷(38.3 g，151 mmol)在1,4-二氧六環(100 mL)中的混合物添加Pd(dppf)Cl 2(2.76 g, 3.7 mmol)。將混合物抽真空，用N 2回填，並且該順序重複三次。將產生的混合物加溫至100℃並且在N 2氣氛下攪拌持續4小時。反應通過TLC來監測。在完成之後，將反應混合物冷卻至rt，添加水(50 mL)並且用EtOAc (3×300mL)萃取。有機層經Na 2S0 4乾燥，過濾，並且濃縮。殘餘物通過反相快速色譜法(C18柱；ACN-水中NH 3.H 2O，在20 min內0%至100%梯度；檢測器，UV 254 nm)純化，以提供作為棕色油的標題化合物(6.50 g，52 %收率)。LC/MS [M+H] += 339.7。 1H NMR (400 MHz, CDCl 3) δ 7.19 (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)。 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 4,4, 5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborin A mixture of alkanes (38.3 g, 151 mmol) in 1,4-dioxane (100 mL) was added Pd(dppf) Cl2 (2.76 g, 3.7 mmol). The mixture was evacuated, backfilled with N2 , and the sequence was repeated three times. The resulting mixture was warmed to 100 °C and stirred under N2 atmosphere for 4 h. 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 x 300 mL). The organic layer was dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by reverse phase flash chromatography (C18 column; ACN-NH 3 .H 2 O in water, gradient 0% to 100% in 20 min; detector, 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 (400 MHz, CDCl 3 ) δ 7.19 (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).

步驟5: 5-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-2,5-二氮雜雙環並[2.2.2]辛烷-2-羧酸叔丁酯Step 5: 5-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2 - tert-butyl carboxylate

在-40℃在N 2氣氛下，向2,4,7-三氯-8-氟吡啶並[4,3-d]嘧啶(粗製的中間體18，4.02 g，15.9 mmol)和DIEA (12.0 g，93.0  mmol)在DCM (100 mL)中的溶液逐滴地添加2,5-二氮雜雙環並[2.2.2]辛烷-2-羧酸叔丁酯(3.41 g，16.1 mmol)並且攪拌持續30 min。反應通過LCMS來監測。在完成之後，反應混合物通過添加H 2O (50 mL)來猝滅。然後，將混合物傾倒在分液漏斗中並且分離。水層用DCM (50 mL×3)萃取。合併的有機層用鹽水(50 mL)洗滌，經Na 2SO 4乾燥，過濾，並且在旋轉蒸發儀上濃縮。產生的油通過快速柱色譜法(DCM/MeOH = 50/1)純化，以提供作為黃色固體的標題化合物(4.12 g，61%收率)。LC-MS [M+H] += 428.2。 2,4,7- Trichloro -8-fluoropyrido[4,3-d]pyrimidine (crude intermediate 18, 4.02 g, 15.9 mmol) and DIEA (12.0 g, 93.0 mmol) in DCM (100 mL) was added dropwise tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (3.41 g, 16.1 mmol) and Stirring was continued for 30 min. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched by adding H2O (50 mL). Then, the mixture was poured into a separatory funnel and separated. The aqueous layer was extracted with DCM (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , 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 (4.12 g, 61% yield) as a yellow solid. LC-MS [M+H] + = 428.2.

步驟6：5-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-2.5-二氮雜雙環並[2.2.2]辛烷-2-羧酸叔丁酯 Step 6: 5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5- d3 )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2.5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester

將5-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-2,5-二氮雜雙環並[2.2.2]辛烷-2-羧酸叔丁酯(1.51 g，3.53 mmol)、((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲醇(中間體8，680 mg，4.19 mmol)和Cs 2CO 3(3.40 g，10.4 mmol)在1,4-二氧六環(30 mL)中的混合物在95℃在N 2氣氛下攪拌持續12 h。反應通過LCMS來監測。在完成之後，允許混合物冷卻下來至rt並且在減壓下濃縮。殘餘物通過矽膠柱色譜法(DCM/MeOH，1%至5%)純化，以給出作為黃色固體的標題化合物(1.5 g，68%收率)。LC-MS [M+H] +=554.4 5-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxy tert-butyl acid ester (1.51 g, 3.53 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methanol (intermediate 8,680 mg, 4.19 mmol) and Cs2CO3 (3.40 g, 10.4 mmol) in 1,4- dioxane (30 mL) was stirred at 95 °C under N2 atmosphere for 12 h. 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 silica gel column chromatography (DCM/MeOH, 1% to 5%) to give the title compound (1.5 g, 68% yield) as a yellow solid. LC-MS [M+H] + =554.4

步驟7: 5-(7-(3-氯-2-環丙基-5-(甲氧基甲氧基)苯基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-2.5-二氮雜雙環並[2.2.2]辛烷-2-羧酸叔丁酯 Step 7: 5-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2.5-diazabicyclo And[2.2.2]octane-2-carboxylate tert-butyl ester

將5-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-2.5-二氮雜雙環並[2.2.2]辛烷-2-羧酸叔丁酯(1.05 g，1.90 mmol)、2-(3-氯-2-環丙基-5-(甲氧基甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(來自步驟4，910 mg，2.69 mmol)、K 3PO 4(1.20 g，5.65 mmol)和RuPhos Pd G3 (150 mg，0.179 mmol)在1,4-二氧六環(20 mL)和H 2O (4 mL)中的混合物抽真空，用N 2回填，並且該順序重複三次。將產生的混合物加溫至60℃並且在N 2氣氛下攪拌持續2 h。反應通過LCMS來監測。在完成之後，允許混合物冷卻下來至rte並且在減壓下濃縮。殘餘物通過矽膠柱色譜法(用DCM/MeOH，1%至5%洗脫)純化，以提供作為黃色固體的標題化合物(650 mg，45%收率)。LC-MS [M+H] +=730.7 5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy Base) pyrido[4,3-d]pyrimidin-4-yl)-2.5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (1.05 g, 1.90 mmol), 2- (3-Chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (from Step 4, 910 mg, 2.69 mmol), K 3 PO 4 (1.20 g, 5.65 mmol) and RuPhos Pd G3 (150 mg, 0.179 mmol) in 1,4-dioxane (20 mL) and H 2 O ( 4 mL) was evacuated, backfilled with N 2 , and the sequence was repeated three times. The resulting mixture was warmed to 60 °C and stirred under N2 atmosphere for 2 h. 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 afford the title compound (650 mg, 45% yield) as a yellow solid. LC-MS [M+H] + =730.7

步驟8: 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-環丙基苯酚 Step 8: 3-(4-(2,5-Diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropane Phenol

在rt，向5-(7-(3-氯-2-環丙基-5-(甲氧基甲氧基)苯基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-2,5-二氮雜雙環並[2.2.2]辛烷-2-羧酸叔丁酯(650 mg，0.890 mmol)在MeCN (10mL)中的攪拌的混合物逐滴地添加1,4-二氧六環中的HCl (4N，2 mL)並且攪拌持續1h。反應通過LCMS來監測。在完成之後，將反應混合物濃縮以給出殘餘物，所述殘餘物通過矽膠柱色譜法(用DCM/MeOH，0至3%洗脫)純化，以提供作為白色固體的標題化合物(333 mg，60%收率)。LC-MS [M+H] += 586.4。 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.21 (s, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 4.86 (s, 1H), 4.25 – 4.05 (m, 3H), 4.02 (dd, J = 10.4, 2.4 Hz, 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 = 6.0 Hz, 2H), -0.02 (d, J = 5.6 Hz, 2H)。 At rt, to 5-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,5-di A stirred mixture of tert-butyl azabicyclo[2.2.2]octane-2-carboxylate (650 mg, 0.890 mmol) in MeCN (10 mL) was added dropwise to 1,4-dioxane HCl (4N, 2 mL) and stirring continued for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give a residue which was purified by silica gel column chromatography (eluting with DCM/MeOH, 0 to 3%) to afford the title compound as a white solid (333 mg, 60% yield). LC-MS [M+H] + = 586.4. 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.21 (s, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 4.86 (s, 1H), 4.25 – 4.05 (m, 3H), 4.02 (dd, J = 10.4, 2.4 Hz, 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 = 6.0 Hz, 2H), -0.02 (d, J = 5.6 Hz, 2H).

實施例29Example 29

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2S,7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-環丙基苯酚

Figure 02_image199
3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol
Figure 02_image199

EX.29EX.29

除了由中間體11替代中間體8，使用如實施例28概述的類似程式合成實施例29 (16.9 mg)。LC-MS [M+H] += 586.5。 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.21 (s, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 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 29 (16.9 mg) was synthesized using a similar procedure as outlined in Example 28, except that Intermediate 8 was replaced by Intermediate 11. LC-MS [M+H] + = 586.5. 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.21 (s, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 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).

實施例30Example 30

3-(4-(1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-環丙基苯酚

Figure 02_image201
3-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclo Propylphenol
Figure 02_image201

EX.30EX.30

除了由(1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷替代2,5-二氮雜雙環並[2.2.2]辛烷，使用如實施例28概述的類似程式合成實施例30 (425 mg)。 LC-MS [M+H] += 586.5。 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.08 (s, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 4.40 (d, J = 12.4 Hz, 2H), 4.11 (d, J = 10.4 Hz, 1H), 4.01 (d, J = 10.4 Hz, 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 = 6.8 Hz, 2H), -0.00 – -0.08 (m, 2H)。 Using a method similar to that outlined in Example 28, except that 2,5-diazabicyclo[2.2.2]octane was replaced by (1R,5S)-3,8-diazabicyclo[3.2.1]octane Example 30 (425 mg) was synthesized by formula. LC-MS [M+H] + = 586.5. 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.08 (s, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 4.40 (d, J = 12.4 Hz, 2H), 4.11 (d, J = 10.4 Hz, 1H), 4.01 (d, J = 10.4 Hz, 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 = 6.8 Hz, 2H), -0.00 – -0.08 (m , 2H).

實施例31Example 31

4-(4-((2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚

Figure 02_image203
4-(4-((2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H -pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -phenol
Figure 02_image203

EX.31EX.31

步驟1: 5-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-2.5-二氮雜雙環並[2.2.2]辛烷-2-羧酸叔丁酯 Step 1: 5-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d] Pyrimidin-4-yl)-2.5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester

將5-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-2.5-二氮雜雙環並[2.2.2]辛烷-2-羧酸叔丁酯(來自EX.28的步驟6，900 mg，1.62 mmol)、((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)萘-1-基)乙炔基)三異丙基甲矽烷(來自EX.1的步驟4，1.03 g，2.01 mmol)、K 2CO 3(672 mg，4.87 mmol)和RuPhos Pd G3 (135 mg, 0.161 mmol)在1,4-二氧六環(20 mL)和H 2O (4 mL)中的混合物抽真空，用N 2回填，並且該順序重複三次。將產生的混合物加溫至90℃並且在N 2氣氛下攪拌持續2 h。反應通過LCMS來監測。在完成之後，允許混合物冷卻下來至rt並且在減壓下濃縮。殘餘物通過反相快速色譜法(C18柱，用包含0.1% NH 3-H 2O的10%至100% MeCN/H 2O洗脫)純化，以提供作為黃色固體的標題化合物(900 mg，61 %收率)。 LC-MS [M+H] +=905.0 5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy Base) pyrido[4,3-d]pyrimidin-4-yl)-2.5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (step 6 from EX.28, 900 mg, 1.62 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborinane- 2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (from step 4 of EX.1, 1.03 g, 2.01 mmol), K2CO3 (672 mg, 4.87 mmol) and RuPhos Pd G3 (135 mg, 0.161 mmol) in 1,4-dioxane (20 mL) and H 2 O (4 mL) was evacuated, backfilled with N 2 , and the sequence was repeated three times. The resulting mixture was warmed to 90 °C and stirred under N2 atmosphere for 2 h. 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, eluting with 10% to 100% MeCN/ H2O containing 0.1% NH3 - H2O ) to afford the title compound as a yellow solid (900 mg, 61% yield). LC-MS [M+H] + =905.0

步驟2: 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-6-氟-5-((三異丙基甲矽烷基)乙炔基)萘-2-酚 Step 2: 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-(( Triisopropylsilyl)ethynyl)naphthalene-2-ol

在rt，向5-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-2,5-二氮雜雙環並[2.2.2]辛烷-2-羧酸叔丁酯(900 mg，0.995 mmol)在MeCN (20mL)中的攪拌的混合物添加1,4-二氧六環中的HCl (4N，10 mL)並且攪拌持續1 h。反應通過LCMS來監測。將產生的混合物用氫氧化銨溶液中和至PH 7-8。獲得的混合物通過反相快速色譜法(C18柱，用包含0.1% NH 3-H 2O的10%至80% MeCN/H 2O洗脫)純化，以提供作為灰白色固體的標題化合物(500 mg，66 %收率)。LC-MS [M+H] += 760.8。 At rt, to 5-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d A stirred mixture of ]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate tert-butyl ester (900 mg, 0.995 mmol) in MeCN (20 mL) was added HCl in 1,4-dioxane (4N, 10 mL) and stirring continued for 1 h. The reaction was monitored by LCMS. The resulting mixture was neutralized to pH 7-8 with ammonium hydroxide solution. The obtained mixture was purified by reverse phase flash chromatography (C18 column, eluting with 10% to 80% MeCN/ H2O containing 0.1% NH3 - H2O ) to afford the title compound (500 mg , 66% yield). LC-MS [M+H] + = 760.8.

步驟3: 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚 Step 3: 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphthalene-2-ol

在N 2氣氛下，向4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-6-氟-5-((三異丙基甲矽烷基)乙炔基)萘-2-酚(500 mg，0.658 mmol)在DMF (10 mL)中的混合物一次性地添加CsF (1.00 g，6.58 mmol)。將混合物加溫至50℃並且攪拌持續1 h。反應通過LCMS來監測。在完成之後，混合物通過製備型-HPLC(C18柱，用包含0.1% NH 3-H 2O的0%至50% MeCN/H 2O洗脫)純化，以提供作為黃色固體的標題化合物(300 mg，收率：76%)。 Under N 2 atmosphere, to 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro- A mixture of 5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (500 mg, 0.658 mmol) in DMF (10 mL) was added CsF (1.00 g, 6.58 mmol) in one portion. The mixture was warmed to 50 °C and stirred for 1 h. The reaction was monitored by LCMS. After completion, the mixture was purified by prep-HPLC (C18 column, eluting with 0% to 50% MeCN/ H2O containing 0.1% NH3 - H2O ) to afford the title compound as a yellow solid (300 mg, yield: 76%).

LC-MS [M+H] +=604.6。 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.47 (t, J = 8.8 Hz, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.17 (s, 1H), 4.83 (s, 1H), 4.36 – 3.90 (m, 5H), 3.28 (d, J = 10.8 Hz, 1H), 3.16 – 2.97 (m, 4H), 2.18 – 1.97 (m, 4H), 1.96 – 1.69 (m, 6H)。 LC-MS [M+H] + =604.6. 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.47 (t, J = 8.8 Hz, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.17 (s, 1H), 4.83 (s, 1H), 4.36 – 3.90 (m, 5H), 3.28 (d, J = 10.8 Hz, 1H), 3.16 – 2.97 (m, 4H) , 2.18 – 1.97 (m, 4H), 1.96 – 1.69 (m, 6H).

實施例32Example 32

3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-環丙基-5-氟苯酚

Figure 02_image205
3-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-cyclopropyl-5-fluorophenol
Figure 02_image205

EX.32EX.32

步驟1: 1-溴-2-環丙基-3-氟苯Step 1: 1-Bromo-2-cyclopropyl-3-fluorobenzene

將1-溴-3-氟-2-碘苯(5.50 g，18.3 mmol)、Pd(dppf)Cl 2(1.34 g，1.83 mmol)、環丙基硼酸(1.94 g，22.5 mmol)和K 3PO 4(13.6 g, 64.1 mmol)在1,4-二氧六環(80 mL)和H 2O (4 mL)中的混合物抽真空，用N 2回填，並且該順序重複三次。將產生的混合物加溫至100℃並且攪拌持續18小時。反應通過LCMS來監測。將反應混合物冷卻至rt，用水(100 mL)稀釋並且用EtOAc (150 mL×3)萃取。合併的有機層經Na 2SO 4乾燥，過濾，並且在減壓下濃縮。獲得的殘餘物通過用PE的快速色譜法純化，以提供作為黃色固體的標題化合物(3.01 g，46%收率)。LC-MS [M+H] += 302.1。 1H NMR (400 MHz, DMSO-d6) δ 7.46 – 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)。 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 A mixture of 4 (13.6 g, 64.1 mmol) in 1,4-dioxane (80 mL) and H 2 O (4 mL) was evacuated, backfilled with N 2 , and the sequence was repeated three times. The resulting mixture was warmed to 100°C 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 dried over Na2SO4 , filtered, and concentrated under reduced pressure . The obtained residue was purified by flash chromatography with PE to afford the title compound (3.01 g, 46% yield) as a yellow solid. LC-MS [M+H] + = 302.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.46 – 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).

步驟2: 3-溴-4-環丙基-5-氟苯酚Step 2: 3-Bromo-4-cyclopropyl-5-fluorophenol

將1-溴-2-環丙基-3-氟苯(3.30 g，15.3 mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧雜硼烷)(11.6 g，45.9 mmol)、[Ir(OMe)(1,5-cod)] 2(0.510 g，0.769 mmol)和4,4'-二叔丁基-2,2'-聯吡啶(0.250 g, 0.933 mmol)在(100 mL)中的混合物抽真空，用N 2回填，並且該順序重複三次。  將產生的反應混合物加溫至60℃並且在N 2氣氛下攪拌持續18 h。反應通過TLC來監測。將反應混合物在真空下濃縮，以提供作為黃色油的標題化合物(5.31 g，粗品)，將所述標題化合物溶解在THF (40 mL)和H 2O (20 mL)中，冷卻至0℃，並且添加AcOH (60.1 g，1.00 mol)和H 2O 2(10.1 g，298 mmol)。將產生的混合物在0℃攪拌持續1 h。反應通過LCMS來監測，用水(100 mL)稀釋並且用EtOAc (150 mL×3)萃取。合併的有機層經Na 2SO 4乾燥，過濾，並且在真空下濃縮。獲得的殘餘物通過快速色譜法(用PE/EtOAc，0至20%洗脫)純化，以提供作為黃色油的標題化合物(1.31 g，18%收率)。LC-MS [M-H] -= 231.0。 1-Bromo-2-cyclopropyl-3-fluorobenzene (3.30 g, 15.3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2 '-Bis(1,3,2-dioxaborinane) (11.6 g, 45.9 mmol), [Ir(OMe)(1,5-cod)] 2 (0.510 g, 0.769 mmol) and 4,4' - A mixture of di-tert-butyl-2,2'-bipyridine (0.250 g, 0.933 mmol) in (100 mL) was evacuated, backfilled with N2 , and the sequence was repeated three times. The resulting reaction mixture was warmed to 60 °C and stirred under N2 atmosphere for 18 h. The reaction was monitored by TLC. The reaction mixture was concentrated under vacuum to provide 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 0° C., And AcOH (60.1 g, 1.00 mol) and H 2 O 2 (10.1 g, 298 mmol) were added. The resulting mixture was stirred at 0 °C for 1 h. The reaction was monitored by LCMS, diluted with water (100 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were dried over Na2SO4 , filtered, and concentrated under vacuum . The residue obtained was purified by flash chromatography (eluting with PE/EtOAc, 0 to 20%) to afford the title compound (1.31 g, 18% yield) as a yellow oil. LC-MS [MH] - = 231.0.

步驟3: 1-溴-2-環丙基-3-氟-5-(甲氧基甲氧基)苯Step 3: 1-Bromo-2-cyclopropyl-3-fluoro-5-(methoxymethoxy)benzene

在0℃在N 2氣氛下，向3-溴-4-環丙基-5-氟苯酚(1.31 g，5.65 mmol)在THF (50 mL)中的溶液緩慢地分批次添加氫化鈉(60 %，在礦物油中，0.670 g，16.8 mmol)，並且攪拌持續30分鐘。然後在0℃，逐滴地添加溴(甲氧基)甲烷(1.41 g，11.2 mmol)。將產生的混合物緩慢地加溫至rt並且攪拌持續30分鐘。反應通過TLC來監測。將反應混合物濃縮以給出殘餘物，所述殘餘物通過快速色譜法(用PE/MeOH，0至5%洗脫)純化，以提供作為無色油的標題化合物(1.65 g，75%收率)。LC-MS[M-H] -= 273.2。 1H NMR (400 MHz, CDCl 3) δ 7.07 (t, J = 2 Hz 1H), 6.68 (dd, J = 12, 2.4 Hz, 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)。 To a solution of 3-bromo-4-cyclopropyl-5-fluorophenol (1.31 g, 5.65 mmol) in THF (50 mL) was slowly added portion-wise sodium hydride (60 mL) at 0 °C under N atmosphere. %, in mineral oil, 0.670 g, 16.8 mmol), and stirring continued for 30 minutes. Bromo(methoxy)methane (1.41 g, 11.2 mmol) was then added dropwise at 0°C. 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/MeOH, 0 to 5%) to afford the title compound (1.65 g, 75% yield) as a colorless oil . LC-MS [MH] - = 273.2. 1 H NMR (400 MHz, CDCl 3 ) δ 7.07 (t, J = 2 Hz 1H), 6.68 (dd, J = 12, 2.4 Hz, 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).

步驟4: 2-(2-環丙基-3-氟-5-(甲氧基甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷Step 4: 2-(2-Cyclopropyl-3-fluoro-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxo Borane

將(1-溴-2-環丙基-3-氟-5-(甲氧基甲氧基)苯(600 mg，2.18 mmol)、AcOK (642 mg，6.54 mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧雜硼烷) (1.11 g, 4.36 mmol)和Pd(dppf)Cl 2(159 g, 0.22 mmol)在1,4-二氧六環(10 mL)中的混合物抽真空，用N 2回填，並且該順序重複三次。將產生的混合物加溫至100℃並且在N 2氣氛下攪拌持續12小時。反應通過TLC來監測。在完成之後，將反應混合物冷卻至rt，用水(10 mL)稀釋並且用EtOAc (50 mL×3)萃取。合併的有機層經Na 2SO 4乾燥，過濾，並且在真空下濃縮。獲得的殘餘物通過反相快速色譜法純化，以提供作為黃色固體的標題化合物(386 mg，38%收率)。LC-MS [M-H]- = 321.3。 1H NMR (400 MHz, CD 3OD) δ 6.94 (d, J = 2.4 Hz, 1H), 6.65 (dd, J = 10.4, 2.4 Hz, 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)。 (1-Bromo-2-cyclopropyl-3-fluoro-5-(methoxymethoxy)benzene (600 mg, 2.18 mmol), AcOK (642 mg, 6.54 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborinane) (1.11 g, 4.36 mmol) and Pd(dppf)Cl 2 (159 g, 0.22 mmol) in 1,4-dioxane (10 mL) was evacuated, backfilled with N 2 , and the sequence was repeated three times. The resulting mixture was warmed to 100° C. Stirring was continued for 12 hours under 2 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 washed over Na 2 SO 4 was dried, filtered, and concentrated under vacuum. The residue obtained was purified by reverse phase flash chromatography to provide the title compound (386 mg, 38% yield) as a yellow solid. LC-MS [MH]-=321.3 .1 H NMR (400 MHz, CD 3 OD) δ 6.94 (d, J = 2.4 Hz, 1H), 6.65 (dd, J = 10.4, 2.4 Hz, 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).

步驟5: 5-(7-(2-環丙基-3-氟-5-羥基苯基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-2.5-二氮雜雙環並[2.2.2]辛烷-2-羧酸叔丁酯 Step 5: 5-(7-(2-cyclopropyl-3-fluoro-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine -7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2.5-diazabicyclo[2.2.2]octane tert-butyl alkane-2-carboxylate

將5-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-2.5-二氮雜雙環並[2.2.2]辛烷-2-羧酸叔丁酯(來自EX.28的步驟6，100 mg，0.180 mmol)、2-(2-環丙基-3-氟-5-(甲氧基甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(145 mg，0.450 mmol)、K 3PO 4(115 mg，0.542 mmol)和RuPhos Pd G3 (15.1 mg，0.018 mmol)在THF (2 mL)和H 2O (4 mL)中的混合物抽真空，用N 2回填，並且該順序重複三次。將產生的混合物加溫至40℃並且在N 2氣氛下攪拌持續2小時。反應通過LCMS來監測。反應混合物用水(3 mL)稀釋並且用EtOAc (10 mL)萃取。合併的有機層經Na 2SO 4乾燥，過濾，並且在減壓下濃縮。獲得的殘餘物通過矽膠柱色譜法(用DCM/MeOH，0%至20%洗脫)純化，以提供作為白色固體的標題化合物(105 mg，57%收率)。LC-MS [M+H] += 714.4。 5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy Base) pyrido[4,3-d]pyrimidin-4-yl)-2.5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (step 6 from EX.28, 100 mg, 0.180 mmol), 2-(2-cyclopropyl-3-fluoro-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2 - Dioxaborane (145 mg, 0.450 mmol), K 3 PO 4 (115 mg, 0.542 mmol) and RuPhos Pd G3 (15.1 mg, 0.018 mmol) in THF (2 mL) and H 2 O (4 mL) The mixture in was evacuated, backfilled with N2 , and this sequence was repeated three times. The resulting mixture was warmed to 40 °C and stirred under N2 atmosphere for 2 h. 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 dried over Na2SO4 , filtered, and concentrated under reduced pressure . The obtained residue was purified by silica gel column chromatography (eluting with DCM/MeOH, 0% to 20%) to afford the title compound (105 mg, 57% yield) as a white solid. LC-MS [M+H] + = 714.4.

步驟6: 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-環丙基-5-氟苯酚 Step 6: 3-(4-(2,5-Diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-cyclopropyl-5- Fluorophenol

在rt，向5-(7-(2-環丙基-3-氟-5-羥基苯基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-4-基)-2,5-二氮雜雙環並[2.2.2]辛烷-2-羧酸叔丁酯(100 mg，0.140 mmol)在ACN (1 mL)中的溶液添加1,4-二氧六環中的HCl (4N，0.2 mL)。將混合物在rt攪拌持續1小時。反應通過LCMS來監測。在完成之後，將反應混合物濃縮以給出殘餘物，所述殘餘物用製備型-HPLC純化，以提供作為白色固體的標題化合物(15.5 mg，12%收率)。LC-MS [M+H] += 570.4。 1H NMR (400 MHz, DMSO-d6) δ 9.96 (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, 2.4 Hz, 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 = 8.8 Hz, 2H), 0.15 (d, J = 4.4 Hz, 2H)。 At rt, to 5-(7-(2-cyclopropyl-3-fluoro-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azin-7a(5H)-yl-2,5,5-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 with 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 with prep-HPLC to provide the title compound (15.5 mg, 12% yield) as a white solid. LC-MS [M+H] + = 570.4. 1 H NMR (400 MHz, DMSO-d6) δ 9.96 (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, 2.4 Hz, 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 = 8.8 Hz, 2H), 0.15 (d, J = 4.4 Hz, 2H).

實施例33/實施例34Example 33/Example 34

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((3-(羥基甲基)四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(EX.33，非對映異構體1)4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(hydroxymethyl)tetra Hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol ( EX.33, diastereoisomers1)

和and

4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((3-(羥基甲基)四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(EX.34，非對映異構體2)

Figure 02_image207
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(hydroxymethyl)tetra Hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol ( EX.34, diastereoisomers 2)
Figure 02_image207

EX.33 (非對映異構體1)和EX.34 (非對映異構體2)EX.33 (Diastereomer 1) and EX.34 (Diastereomer 2)

步驟1: 1-苄基2-甲基2-(丁-3-烯-1-基)吡咯烷-1,2-二羧酸酯Step 1: 1-Benzyl 2-methyl 2-(but-3-en-1-yl)pyrrolidine-1,2-dicarboxylate

在-78℃在N 2氣氛下，向1-苄基2-甲基(S)-吡咯烷-1,2-二羧酸酯(100 g，0.380 mol)在乾燥的THF (200 mL)中的溶液逐滴地添加LHMDS (1.0 M，在THF中，0.456 L，0.456 mol)並且攪拌持續1 h。然後將4-溴丁-1-烯(51.3 g，0.380 mol)在-78℃逐滴地添加到反應混合物中。將反應混合物加溫至rt並且攪拌持續12 h。反應通過LCMS來監測。在完成之後，反應通過添加飽和的含水NH 4Cl (200 mL)來猝滅，傾倒在分液漏斗中並且分離。水層用EtOAc (500 mL)萃取兩次。合併的有機層用鹽水(200 mL)洗滌，經Na 2SO 4乾燥，並且通過過濾收集。  將濾液在減壓下濃縮。  殘餘物通過快速柱色譜法(PE/EtOAc = 10:1)純化，以給出作為黃色油的期望的化合物(80.0 g，66%收率)。 LC-MS [M+H] +=318.1 To 1-benzyl 2-methyl(S)-pyrrolidine-1,2-dicarboxylate (100 g, 0.380 mol) in dry THF (200 mL) at -78 °C under N atmosphere A solution of LHMDS (1.0 M in THF, 0.456 L, 0.456 mol) was added dropwise and stirred for 1 h. Then 4-bromobut-1-ene (51.3 g, 0.380 mol) was added dropwise to the reaction mixture at -78°C. The reaction mixture was warmed to rt and stirred for 12 h. The reaction was monitored by LCMS. After completion, the reaction was quenched by the addition of saturated aqueous NH4Cl (200 mL), 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), dried over Na 2 SO 4 , and collected by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (PE/EtOAc = 10:1) to give the desired compound (80.0 g, 66% yield) as yellow oil. LC-MS [M+H] + =318.1

步驟2: 1-苄基2-甲基2-(2-(環氧乙烷-2-基)乙基)吡咯烷-1,2-二羧酸酯Step 2: 1-Benzyl 2-methyl 2-(2-(oxiran-2-yl)ethyl)pyrrolidine-1,2-dicarboxylate

向1-苄基2-甲基2-(丁-3-烯-1-基)吡咯烷-1,2-二羧酸酯(20.0 g，63.0 mmol)在DCM (200 mL)中的溶液分批次添加m-CPBA (27.3 g，158 mmol)，將產生的混合物在周圍溫度攪拌持續5 h。反應通過LCMS來監測。在完成反應之後，反應用飽和的含水亞硫酸鈉猝滅，用EtOAc (500 mL×3)萃取。合併的有機相用鹽水洗滌，並且經Na 2SO 4乾燥。在過濾之後，將濾液在減壓下濃縮。殘餘物通過矽膠柱色譜法(PE/EtOAc = 4:1)純化，以給出作為無色油的標題化合物(19.0 g，90%收率)。 LC-MS [M+H] += 334.1 To a solution of 1-benzyl 2-methyl 2-(but-3-en-1-yl)pyrrolidine-1,2-dicarboxylate (20.0 g, 63.0 mmol) in DCM (200 mL) m-CPBA (27.3 g, 158 mmol) was added in batches and the resulting mixture was stirred at ambient temperature for 5 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction was quenched with saturated aqueous sodium sulfite, extracted with EtOAc (500 mL×3). The combined organic phases were washed with brine and dried over Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 4:1) to give the title compound (19.0 g, 90% yield) as a colorless oil. LC-MS [M+H] + = 334.1

步驟3: 3-(羥基甲基)四氫-1H-吡咯嗪-7a(5H)-羧酸甲酯(非對映異構體1)和(非對映異構體2)Step 3: Methyl 3-(hydroxymethyl)tetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (diastereomer 1) and (diastereomer 2)

向1-苄基2-甲基2-(2-(環氧乙烷-2-基)乙基)吡咯烷)-1,2-二羧酸酯(18.0 g，54.0 mmol)在MeOH (200 mL)中的溶液添加Pd/C (10 %，在碳上，1.8 g)將混合物抽真空，用氫氣回填，並且該順序重複三次)。將產生的混合物在rt在H 2(1 atm)的情況下攪拌持續16小時。反應通過LCMS來監測。在完成之後，將混合物小心地通過矽藻土的薄層過濾。將濾液在真空下濃縮。殘餘物通過在矽膠柱上的柱色譜法(用0至10% MeOH/DCM洗脫)純化，以提供3-(羥基甲基)四氫-1H-吡咯嗪-7a(5H)-羧酸甲酯的兩種非對映異構體(兩種異構體)： To 1-benzyl 2-methyl 2-(2-(oxiran-2-yl)ethyl)pyrrolidine)-1,2-dicarboxylate (18.0 g, 54.0 mmol) in MeOH (200 mL) was added Pd/C (10% on carbon, 1.8 g) the mixture was evacuated, backfilled with hydrogen, and the sequence was repeated three times). The resulting mixture was stirred at rt under H2 (1 atm) for 16 h. The reaction was monitored by LCMS. After completion, the mixture was carefully filtered through a thin layer of celite. The filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 0 to 10% MeOH/DCM) to provide 3-(hydroxymethyl)tetrahydro-1H-pyrrolazine-7a(5H)-carboxylate Two diastereoisomers (two isomers) of esters:

非對映異構體1：4.00 g，37 %收率，黃色油，LC-MS [M+H] += 200.1；和 Diastereomer 1: 4.00 g, 37 % yield, yellow oil, LC-MS [M+H] + = 200.1; and

非對映異構體2：4.90 g，46 %收率，作為黃色油。LC-MS [M+H] += 200.1 Diastereomer 2: 4.90 g, 46 % yield as yellow oil. LC-MS [M+H] + = 200.1

步驟4: 3-(((叔丁基二甲基甲矽烷基)氧基)甲基)四氫-1H-吡咯嗪-7a(5H)-羧酸甲酯(非對映異構體1)和3-(((叔丁基二甲基甲矽烷基)氧基)甲基)四氫-1H-吡咯嗪-7a(5H)-羧酸甲酯(非對映異構體2)Step 4: Methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (diastereomer 1) and 3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid methyl ester (diastereomer 2)

在室溫，向3-(羥基甲基)四氫-1H-吡咯嗪-7a(5H)-羧酸甲酯(非對映異構體1，7.49 g，37.6 mmol)和1H-咪唑(7.68 g，113 mmol)在DCM (100 mL)中的溶液添加TBSCl (8.50 g, 56.4 mmol)。將混合物在rt攪拌持續2 h。反應通過LCMS來監測。在完成之後，反應通過添加水(100mL)來猝滅。然後，將反應混合物傾倒在分液漏斗中並且分離。水層用EtOAc (100 mL×3)萃取。合併的有機層用鹽水洗滌，經無水Na 2SO 4乾燥 在過濾之後，將濾液在減壓下濃縮。殘餘物通過快速柱色譜法(DCM/MeOH=40:1)純化，以提供作為黃色油的期望的產物3-(((叔丁基二甲基甲矽烷基)氧基)甲基)四氫-1H-吡咯嗪-7a(5H)-羧酸甲酯(非對映異構體1，8.20 g，70 %收率)。LC-MS [M+H] += 314.1。 1H NMR (400 MHz, DMSO-d 6) δ 3.61 (s, 3H), 3.54 (dd, J =10.0, 6.0 Hz, 1H), 3.43 (dd, J = 10.0, 6.4 Hz, 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)。 3-(Hydroxymethyl)tetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid methyl ester (diastereoisomer 1, 7.49 g, 37.6 mmol) and 1H-imidazole (7.68 g, 113 mmol) in DCM (100 mL) was added TBSCl (8.50 g, 56.4 mmol). The mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. After completion, the reaction was quenched by adding water (100 mL). Then, the reaction mixture was poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM/MeOH=40:1) to afford the desired product 3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro as a yellow oil -1H-Pyrrolazine-7a(5H)-methyl carboxylate (diastereoisomer 1, 8.20 g, 70 % yield). LC-MS [M+H] + = 314.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.61 (s, 3H), 3.54 (dd, J =10.0, 6.0 Hz, 1H), 3.43 (dd, J = 10.0, 6.4 Hz, 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).

類似的程式適用於合成3-(((叔丁基二甲基甲矽烷基)氧基)甲基)四氫-1H-吡咯嗪-7a(5H)-羧酸甲酯(非對映異構體2)：A similar scheme was applied to the synthesis of methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (diastereoisomeric Body 2):

將3-(羥基甲基)四氫-1H-吡咯嗪-7a(5H)-羧酸甲酯(非對映異構體2，10.0 g，50.2 mmol)和1H-咪唑(10.3 g，151 mmol)轉化成作為黃色油的期望的產物3-(((叔丁基二甲基甲矽烷基)氧基)甲基)四氫-1H-吡咯嗪-7a(5H)-羧酸甲酯(非對映異構體2，9.50 g，60%收率)。LC-MS [M+H] += 314.1。 1H NMR (400 MHz, DMSO-d 6) δ 3.77 (dd, J = 10.4, 5.6 Hz, 1H), 3.69 (dd, J = 10.4, 5.6 Hz, 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)。 Methyl 3-(hydroxymethyl)tetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (diastereomer 2, 10.0 g, 50.2 mmol) and 1H-imidazole (10.3 g, 151 mmol ) into the desired product 3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid methyl ester (not Enantiomer 2, 9.50 g, 60% yield). LC-MS [M+H] + = 314.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.77 (dd, J = 10.4, 5.6 Hz, 1H), 3.69 (dd, J = 10.4, 5.6 Hz, 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).

步驟5: (3-(((叔丁基二甲基甲矽烷基)氧基)甲基)四氫-1H-吡咯嗪-7a(5H)-基)甲-d 2-醇(非對映異構體1) Step 5: (3-(((tert-Butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methan-d 2 -ol (diastereomeric Isomer 1)

在0℃在N 2氣氛下，向3-{[(叔丁基二甲基甲矽烷基)氧基]甲基}-六氫吡咯嗪-7a-羧酸甲酯(非對映異構體1，1.01 g，3.22 mmol)在THF (20 ml)中的攪拌的溶液添加NaBD 4(200 mg，4.78 mmol)和ZnCl 2(650 mg，4.77 mmol)。然後，將反應在rt攪拌過夜。反應通過在0℃添加飽和的含水NH 4Cl (20 ml)來猝滅。產生的混合物用EA (3×50 ml)萃取。將合併的有機層在減壓下濃縮。殘餘物通過矽膠柱色譜法(用DCM/MeOH (10:1)洗脫)純化，以提供作為白色固體的標題化合物(440 mg，47%收率)。LC-MS [M+H] +=288.0 3-{[(tert- butyldimethylsilyl )oxy]methyl}-hexahydropyrrolazine-7a-carboxylic acid methyl ester (diastereomer 1, 1.01 g, 3.22 mmol) in THF (20 ml) was added NaBD 4 (200 mg, 4.78 mmol) and ZnCl 2 (650 mg, 4.77 mmol). Then, the reaction was stirred overnight at rt. The reaction was quenched by the addition of saturated aqueous NH4Cl (20 ml) at 0 °C. The resulting mixture was extracted with EA (3 x 50 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM/MeOH (10:1 ) to afford the title compound (440 mg, 47% yield) as a white solid. LC-MS [M+H] + =288.0

步驟6： (1R,5S)-3-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯Step 6: (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] tert-butyl octane-8-carboxylate

在-40℃在N 2下，向2,4,7-三氯-8-氟吡啶並[4,3-d]嘧啶(中間體18，5.01 g，19.8 mmol)在DCM (30 mL)中的溶液添加DIEA (18.3 mL，111 mmol)和(1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(4.24 g，20.0 mmol)。將反應混合物在-40℃攪拌持續1 h。將反應混合物傾倒在DCM (100 mL)和水(100 mL)中。將兩層分離。有機層用鹽水洗滌，經無水Na2SO4乾燥，通過過濾收集，並且在真空中濃縮。使用用(PE/ EtOAc = 5:1至3:1)洗脫的矽膠柱色譜法純化殘餘物，以給出作為黃色固體的標題化合物(5.21 g,61%收率)。LC-MS [M+H]+ =428.1。 To 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (Intermediate 18, 5.01 g, 19.8 mmol) in DCM (30 mL) at -40 °C under N A solution of DIEA (18.3 mL, 111 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.24 g, 20.0 mmol) were added. The reaction mixture was stirred at -40 °C for 1 h. 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 (5.21 g, 61% yield) as a yellow solid. LC-MS [M+H]+ = 428.1.

步驟7: (1R,5S)-3-(2-((3-(((叔丁基二甲基甲矽烷基)氧基)甲基)四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-7-氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯)(非對映異構體1) Step 7: (1R,5S)-3-(2-((3-(((tert-Butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizine-7a(5H)- Base) methoxy-d 2 )-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- tert-Butyl 8-carboxylate) (Diastereomer 1)

在0℃在N 2下，向(3-(((叔丁基二甲基甲矽烷基)氧基)甲基)四氫-1H-吡咯嗪-7a(5H)-基)甲-d 2-醇(非對映異構體1，200 mg，0.696 mmol)在THF (4 mL)中的溶液緩慢地添加NaH (166.9 mg，6.9 mmol)。在添加之後，將產生的混合物緩慢地加溫至rt並且攪拌持續30分鐘。向上述混合物添加(1R,5S)-3-(2,7-二氯-8-氟吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(298 mg，0.696 mmol)。將產生的混合物在rt攪拌持續另外的16 h。反應通過LCMS來監測。在轉化完成之後，反應通過在0℃飽和的含水NH 4Cl來猝滅。 產生的混合物用EA (3×100 ml)萃取。合併的有機層經無水Na 2SO 4乾燥。在過濾之後，將濾液在減壓下濃縮。殘餘物通過用EA/PE (6:10)洗脫的矽膠柱色譜法純化，以提供作為灰白色固體的標題化合物(140 mg，27%收率)。 To (3-(( ( tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl-d at 0°C under N2 - A solution of the alcohol (Diastereomer 1, 200 mg, 0.696 mmol) in THF (4 mL) was slowly added NaH (166.9 mg, 6.9 mmol). After the addition, the resulting mixture was slowly warmed to rt and stirred for 30 minutes. To the above mixture was added (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]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 16 h. The reaction was monitored by LCMS. After the conversion was complete, the reaction was quenched by saturated aqueous NH4Cl at 0 °C. The resulting mixture was extracted with EA (3 x 100 ml). The combined organic layers were dried over anhydrous Na2SO4 . 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 afford the title compound (140 mg, 27% yield) as an off-white solid.

LC-MS [M+H] += 680.4。 LC-MS [M+H] + = 680.4.

步驟8： (1R,5S)-3-(2-((3-(((叔丁基二甲基甲矽烷基)氧基)甲基)四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯)(非對映異構體1) Step 8: (1R,5S)-3-(2-((3-(((tert-Butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizine-7a(5H)- Base) methoxy-d 2 )-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester) (diastereoisomeric Body 1)

將(3-{2-[(3-{[(叔丁基二甲基甲矽烷基)氧基]甲基}-六氫吡咯嗪-7a-基)甲氧基]-7-氯-8-氟吡啶[4,3-d]嘧啶-4-基}-3,8-二氮雜雙環並[3.2.1]辛烷-8-基)甲酸叔丁酯(120 mg，0.176 mmol)、{2-[2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)萘-1-基]乙炔基}三異丙基甲矽烷(90.4 mg，0.176 mmol)、K 2CO 3(73.1mg, 0.530 mmol)在1,4-二氧六環(3 mL)和H 2O (0.6 mL)中的混合物脫氣。然後添加RuPhos Pd G3 (14.8 mg，0.0177 mmol)。將混合物抽真空，用N 2回填，並且該順序重複三次。將產生的混合物加溫至90℃並且在N 2氣氛下攪拌持續2 h。反應通過LCMS來監測。在完成之後，允許混合物冷卻下來至rt並且在減壓下濃縮。殘餘物通過反相快速法(reverse phase flash)(NH 3H 2O:ACN 20-95%, 20 min)純化，以提供作為黃色固體的標題化合物(100 mg，50%收率)。LC-MS [M+H] += 1030.6。 (3-{2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-hexahydropyrrolizin-7a-yl)methoxy]-7-chloro-8 tert-butyl -fluoropyridin[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octan-8-yl)carboxylate (120 mg, 0.176 mmol), {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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. Then RuPhos Pd G3 (14.8 mg, 0.0177 mmol) was added. The mixture was evacuated, backfilled with N2 , and the sequence was repeated three times. The resulting mixture was warmed to 90 °C and stirred under N2 atmosphere for 2 h. 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 (NH 3 H 2 O:ACN 20-95%, 20 min) to afford the title compound (100 mg, 50% yield) as a yellow solid. LC-MS [M+H] + = 1030.6.

步驟9： (1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((3-(羥基甲基)四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(非對映異構體1) Step 9: (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((3 -(Hydroxymethyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine tert-Butyl Heterobicyclo[3.2.1]octane-8-carboxylate (Diastereomer 1)

在rt在N 2氣氛下，(1R,5S)-3-(2-((3-(((叔丁基二甲基甲矽烷基)氧基)甲基)四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(600 mg, 0.583 mmol)在DMF (6 mL)中的溶液添加CsF (442 mg, 2.91 mmol)，並且攪拌過夜。反應通過LCMS來監測。產生的混合物用水(50 mL)稀釋。產生的混合物用EtOAc (3×50 ml)萃取。合併的有機層經無水Na 2SO 4乾燥。在過濾之後，將濾液在減壓下濃縮。殘餘物通過反相快速法純化，以提供作為黃色固體的標題化合物(150 mg，31%收率)。LC-MS [M+H] += 759.4。 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.10 (dd, J = 9.2, 6.0 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.55 (t, J = 8.8 Hz, 1H), 7.38 (s, 1H), 5.38 (s, 2H), 4.55 (d, J = 12.8 Hz, 1H), 4.39 (d, J = 11.2 Hz, 1H), 4.31 (s, 2H), 3.99 (s, 1H), 3.64 (t, J = 14.0 Hz, 2H), 3.44 (d, J = 5.7 Hz, 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)。 (1R,5S)-3-( 2 -((3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine- 7a(5H)-yl)methoxy-d 2 )-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)acetylene Base)naphthalene-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (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 (3 x 50 ml). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash method to provide the title compound (150 mg, 31% yield) as a yellow solid. LC-MS [M+H] + = 759.4. 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.10 (dd, J = 9.2, 6.0 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.55 (t, J = 8.8 Hz, 1H), 7.38 (s, 1H), 5.38 (s, 2H), 4.55 (d, J = 12.8 Hz, 1H), 4.39 (d, J = 11.2 Hz, 1H), 4.31 (s, 2H ), 3.99 (s, 1H), 3.64 (t, J = 14.0 Hz, 2H), 3.44 (d, J = 5.7 Hz, 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).

步驟10: 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((3-(羥基甲基)四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(非對映異構體1) Step 10: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(hydroxymethyl Base) tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-Phenol (Diastereomer 1)

在rt，向(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((3-(羥基甲基)四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(100 mg，0.132 mmol)在ACN (5 ml)中的攪拌的溶液添加1,4-二氧六環中的4M HCl (1 mL)並且攪拌持續1h。反應通過LCMS來監測。在轉化完成之後，將產生的混合物在真空下濃縮，並且殘餘物通過製備型-HPLC (0.05% NH 3-H 2O)-ACN；B%：20%-95%，20 min)純化，以提供作為灰白色固體的標題化合物4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((3-(羥基甲基)四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(非對映異構體1，15.4 mg, 23%收率)。LC-MS [M+H] += 615.3。 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.04 (s, 1H), 7.98 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 4.50 (d, J = 13.2 Hz, 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)。 At rt, to (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(( 3-(Hydroxymethyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,8-di A stirred solution of tert-butyl azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.132 mmol) in ACN (5 ml) was added 4M HCl in 1,4-dioxane (1 mL) and stirring continued for 1 h. The reaction was monitored by LCMS. After the conversion was complete, the resulting mixture was concentrated under vacuum, and the residue was purified by prep-HPLC (0.05% NH 3 -H 2 O)-ACN; B%: 20%-95%, 20 min) to The title compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3 -(Hydroxymethyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluorin-2-ol (Diastereomer 1, 15.4 mg, 23% yield). LC-MS [M+H] + = 615.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.04 (s, 1H), 7.98 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H ), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 4.50 (d, J = 13.2 Hz, 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).

遵循如EX.33概述的來自步驟7至步驟10 (非對映異構體1)類似的程式，使用(3-(((叔丁基二甲基甲矽烷基)氧基)甲基)四氫-1H-吡咯嗪-7a(5H)-基)甲-d 2-醇(非對映異構體2)替代(3-(((叔丁基二甲基甲矽烷基)氧基)甲基)四氫-1H-吡咯嗪-7a(5H)-基)甲-d 2-醇(非對映異構體1)，合成EX.34的化合物(非對映異構體2)。   作為灰白色固體的EX.34 (非對映異構體2，12.6 mg，15%收率)。LC-MS [M+H] += 615.2。 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.03 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 4.59 (s, 1H), 4.47 (d, J = 11.6 Hz, 1H), 4.31 (d, J = 12.4 Hz, 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)。 Following a similar procedure from step 7 to step 10 (diastereoisomer 1) as outlined in EX.33, using (3-(((tert-butyldimethylsilyl)oxy)methyl)tetra Hydrogen-1H-pyrrolizin-7a(5H)-yl)methan- d2 -ol (diastereomer 2) in place of (3-(((tert-butyldimethylsilyl)oxy)methanol yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methan-d 2 -alcohol (diastereoisomer 1), and the compound of EX.34 (diastereoisomer 2) was synthesized. EX.34 (Diastereomer 2, 12.6 mg, 15% yield) as an off-white solid. LC-MS [M+H] + = 615.2. 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.03 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H ), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 4.59 (s, 1H), 4.47 (d, J = 11.6 Hz, 1H), 4.31 (d, J = 12.4 Hz, 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).

實施例35Example 35

4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(5-(二氟甲基)-2-乙基苯基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶

Figure 02_image209
4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(5-(difluoromethyl)-2-ethylphenyl) -8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidine
Figure 02_image209

EX.35EX.35

步驟1: 4-乙基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯甲醛

Figure 02_image211
Step 1: 4-Ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
Figure 02_image211

在室溫，向3-溴-4-乙基苯甲醛(500 mg，2.13 mmol)、B 2Pin 2(648 mg，2.55 mmol)和KOAc (626 mg，6.38 mmol)在1,4-二氧六環(5 mL)中的溶液一次性地添加Pd(dppf)Cl 2(109 mg，0.151 mmol)。將混合物抽真空，用N 2回填，並且該順序重複三次。將產生的混合物加溫至100℃並且在N 2氣氛下攪拌持續4 h。反應通過LCMS來監測。在完成之後，將混合物冷卻下來至rt並且在減壓下濃縮。殘餘物通過用[PE:EA] (1:100 – 60:1)洗脫的矽膠柱色譜法純化，以提供作為黃色油的標題化合物(250 mg，收率：45%)。LC-MS [M+H] +=261.1 Add 3-bromo-4-ethylbenzaldehyde (500 mg, 2.13 mmol), B 2 Pin 2 (648 mg, 2.55 mmol) and KOAc (626 mg, 6.38 mmol) in 1,4-dioxo To the solution in hexacyclone (5 mL) was added Pd(dppf) Cl2 (109 mg, 0.151 mmol) in one portion. The mixture was evacuated, backfilled with N2 , and the sequence was repeated three times. The resulting mixture was warmed to 100 °C and stirred under N2 atmosphere for 4 h. 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 silica gel column chromatography eluting with [PE:EA] (1:100 - 60:1) to afford the title compound (250 mg, yield: 45%) as a yellow oil. LC-MS [M+H] + =261.1

步驟2:  (1R,5S)-3-(7-(2-乙基-5-甲醯基苯基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯 Step 2: (1R,5S)-3-(7-(2-Ethyl-5-formylphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)- Base)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

將4-乙基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯甲醛(50.0 mg，0.192 mmol)、(1R,5S)-3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(來自實施例3的步驟2，124 mg，0.232 mmol)和K 2CO 3(79.7 mg，0.578 mmol)在1,4-二氧六環(2 mL)和H 2O (0.5 mL)中的混合物排氣(evacuate)並且用氮氣回填三次。然後添加RuPhos Pd G3 (16.1 mg，0.0192 mmol)。將混合物加溫至90℃並且在N 2氣氛下攪拌持續4 h。反應通過LCMS來監測。在完成之後，將混合物冷卻下來至rt並且在減壓下濃縮。殘餘物通過用[MeOH:DCM] (1:100 – 1:30)洗脫的矽膠柱色譜法純化，以提供作為黃色固體的標題化合物(60 mg，收率49%)。LC-MS [M+H] +=633.4 4-Ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (50.0 mg, 0.192 mmol), (1R, 5S)-3-(7-Chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidine -4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (from step 2 of Example 3, 124 mg, 0.232 mmol) and K 2 CO 3 (79.7 mg, 0.578 mmol) in 1,4-dioxane (2 mL) and H 2 O (0.5 mL) was evacuated and backfilled three times with nitrogen. Then RuPhos Pd G3 (16.1 mg, 0.0192 mmol) was added. The mixture was warmed to 90 °C and stirred under N2 atmosphere for 4 h. 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 silica gel column chromatography eluting with [MeOH:DCM] (1:100 - 1:30) to afford the title compound (60 mg, yield 49%) as a yellow solid. LC-MS [M+H] + =633.4

步驟3: (1R,5S)-3-(7-(5-(二氟甲基)-2-乙基苯基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯 Step 3: (1R,5S)-3-(7-(5-(Difluoromethyl)-2-ethylphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizine-7a( 5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary Butyl ester

在0℃在N 2氣氛下，向{3-[7-(2-乙基-5-甲醯基苯基)-8-氟-2-(六氫吡咯嗪-7a-基甲氧基)吡啶並[4,3-d]嘧啶-4-基]-3,8-二氮雜雙環並[3.2.1]辛烷-8-基}甲酸叔丁酯(50.1 mg，0.0792 mmol)在DCM (3 mL)中的溶液一次性地添加BAST (175 mg，0.795 mmol)。將反應混合物緩慢地加溫至rt並且攪拌持續16h。反應通過LCMS來監測。在完成之後，將殘餘物在減壓下濃縮，以給出標題粗製化合物(50 mg粗品)，所述標題粗製化合物在下一步中使用，而不另外純化。LC-MS [M+H] +=655.3 At 0°C under N2 atmosphere, to {3-[7-(2-ethyl-5-formylphenyl)-8-fluoro-2-(hexahydropyrrolidin-7a-ylmethoxy) tert-butyl pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-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 further purification. LC-MS [M+H] + =655.3

步驟4: 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(5-(二氟甲基)-2-乙基苯基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶 Step 4: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(5-(difluoromethyl)-2-ethyl Phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidine

在N 2氣氛下，向(1R,5S)-3-(7-(5-(二氟甲基)-2-乙基苯基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(50 mg粗品)在1,4-二氧六環(2 mL)中的混合物一次性地添加HCl (4N，在二氧六環中，1 mL)。將混合物在rt攪拌持續1h。反應通過LCMS來監測。在完成之後，將混合物濃縮並且殘餘物通過製備型-HPLC (柱：Gemini 5um C18 150*21.2mm，流動相：水(0.05% NH3-H2O)-ACN；B%：20%-95%，20 min)純化，以提供作為黃色固體的標題化合物(11 mg，25%收率)。LC-MS [M+H] += 555.4。 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.08 (t, J = 56.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 2H), 3.74 – 3.66 (m, 4H), 3.16 – 3.08 (m, 2H), 2.79 – 2.70 (m, 2H), 2.61 (q, J = 7.2 Hz, 2H), 2.01 – 1.81 (m, 6H), 1.79 – 1.63 (m, 6H), 1.07 (t, J = 7.6 Hz, 3H)。 Under N2 atmosphere, to (1R,5S)-3-(7-(5-(difluoromethyl)-2-ethylphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrole Azin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- A mixture of tert-butyl carboxylate (50 mg crude) in 1,4-dioxane (2 mL) was added in one portion with HCl (4N in dioxane, 1 mL). The mixture was stirred at rt for 1 h. The reaction was monitored by LCMS. After completion, the mixture was concentrated and the residue was passed through preparative-HPLC (column: Gemini 5um C18 150*21.2mm, mobile phase: water (0.05% NH3-H2O)-ACN; B%: 20%-95%, 20 min) to provide the title compound (11 mg, 25% yield) as a yellow solid. LC-MS [M+H] + = 555.4. 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.08 (t, J = 56.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 2H), 3.74 – 3.66 (m, 4H), 3.16 – 3.08 (m, 2H), 2.79 – 2.70 (m, 2H) , 2.61 (q, J = 7.2 Hz, 2H), 2.01 – 1.81 (m, 6H), 1.79 – 1.63 (m, 6H), 1.07 (t, J = 7.6 Hz, 3H).

實施例36Example 36

3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d2)吡啶並[4,3-d]嘧啶-7-基)-4-乙基苯酚

Figure 02_image213
3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazine- 7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-4-ethylphenol
Figure 02_image213

EX. 36EX. 36

步驟1: 3-氯-4-乙基苯酚Step 1: 3-Chloro-4-ethylphenol

在rt，向甲基4-溴-3-氯苯酚(1.00 g，4.82 mmol)和Pd(t-Bu 3P) 2(247 mg，0.482 mmol)在THF (20.0 mL)中的溶液逐滴地添加二乙基鋅(24.0 mL，24.0 mmol，1M在己烷中)將反應混合物抽真空，用N 2回填，並且該順序重複三次。  將產生的混合物加溫至50℃並且在N 2氣氛下攪拌持續18 h。反應通過TLC來監測。在完成之後，反應混合物用H 2O (50.0 mL)猝滅。然後，將混合物傾倒在分液漏斗中並且分離。水層用EtOAc (30 mL×3)萃取。合併的有機層用鹽水(30.0 mL)洗滌，經Na 2SO 4乾燥，過濾，並且在旋轉蒸發儀上濃縮。產生的粗製油通過矽膠色譜法(PE/MeOH = 100:1–2:1)純化，以提供作為黃色油的標題化合物(700 mg，92%收率)。LC-MS [M+H]+ = 157.4。 1H NMR (400 MHz, CDCl 3) δ 7.06 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.4, 2.4 Hz, 1H), 4.06 (s, 1H), 2.67 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H)。 To a solution of methyl 4-bromo-3-chlorophenol (1.00 g, 4.82 mmol) and Pd(t- Bu3P ) 2 (247 mg, 0.482 mmol) in THF (20.0 mL) was added dropwise at rt Diethylzinc (24.0 mL, 24.0 mmol, 1M in hexanes) was added to evacuate the reaction mixture, backfill with N2 , and this sequence was repeated three times. The resulting mixture was warmed to 50 °C and stirred under N2 atmosphere for 18 h. The reaction was monitored by TLC. After completion, the reaction mixture was quenched with H2O (50.0 mL). Then, the mixture was poured into a separatory funnel and separated. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30.0 mL), dried over Na 2 SO 4 , filtered, and concentrated on a rotary evaporator. The resulting crude oil was purified by silica gel chromatography (PE/MeOH = 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 (400 MHz, CDCl 3 ) δ 7.06 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.4, 2.4 Hz, 1H), 4.06 (s, 1H), 2.67 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H).

步驟2: 4-乙基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯酚Step 2: 4-Ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

將3-氯-4-乙基苯酚(500 mg，3.19 mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-1,3,2-二氧雜硼烷(1.21 g，4.78 mmol)、Cy 3P (107 mg，0.382 mmol)、KOAc (626 mg，6.38 mmol)和Pd 2(dba) 3(87.7 mg，0.0957 mmol)在DME (7.0 mL)中的混合物抽真空，用N 2回填，並且該順序重複三次。將產生的混合物在150℃在N 2氣氛下在微波反應器中處理持續2小時。反應通過TLC來監測。在完成之後，反應混合物通過添加水(20.0 mL)來猝滅並且用EtOAc (10 mL×3)萃取。合併的有機層用鹽水(20 mL)洗滌，經Na 2SO 4乾燥，過濾，並且在旋轉蒸發儀上濃縮。產生的粗製油通過矽膠色譜法(PE/MeOH = 100:1–2/1)純化，以提供作為黃色油的標題化合物(40.0 mg，5%收率)。LC-MS [M+H]+ = 249.0。 1H NMR (400 MHz, CDCl 3) δ 7.21 (d, J = 2.8 Hz, 1H), 7.06 (d, J = 8 Hz, 1H), 6.85 (dd, J = 8.4, 3.2 Hz, 1H), 2.83 (q, J = 7.2 Hz, 2H), 1.27 (d, J = 5.6 Hz, 12H), 1.15 (t, J = 7.6 Hz, 3H)。 3-Chloro-4-ethylphenol (500 mg, 3.19 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2 -dioxaborin-2-yl)-1,3,2-dioxaborinane (1.21 g, 4.78 mmol), Cy 3 P (107 mg, 0.382 mmol), KOAc (626 mg, 6.38 mmol) A mixture of Pd2 (dba) 3 (87.7 mg, 0.0957 mmol) in DME (7.0 mL) was evacuated, backfilled with N2 , and the sequence was repeated three times. The resulting mixture was treated in a microwave reactor at 150 °C under N2 atmosphere for 2 h. The reaction was monitored by TLC. After completion, the reaction mixture was quenched by adding water (20.0 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered, and concentrated on a rotary evaporator. The resulting crude oil was purified by silica gel chromatography (PE/MeOH = 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 (400 MHz, CDCl 3 ) δ 7.21 (d, J = 2.8 Hz, 1H), 7.06 (d, J = 8 Hz, 1H), 6.85 (dd, J = 8.4, 3.2 Hz, 1H), 2.83 (q, J = 7.2 Hz, 2H), 1.27 (d, J = 5.6 Hz, 12H), 1.15 (t, J = 7.6 Hz, 3H).

步驟3： (1R,5S)-3-(7-(2-乙基-5-羥基苯基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯 Step 3: (1R,5S)-3-(7-(2-Ethyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(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

將4-乙基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯酚(90.0 mg，0.362 mmol)、(1R,5S)-3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(來自實施例3的步驟2，96.8 mg，0.181 mmol)、Cs 2CO 3(354 mg, 1.08 mmol)和Pd(dppf)Cl 2(13.2 mg, 0.0181 mmol)在1,4-二氧六環/H 2O (4:1，2.0 mL)中的混合物抽真空，用N 2回填，並且該順序重複三次。將產生的混合物加溫至90℃並且在N 2氣氛下攪拌持續2 h。反應通過LC-MS來監測。在完成之後，將混合物冷卻至rt，並且將揮發物(volatile)在旋轉蒸發儀上移除。殘餘物通過矽膠色譜法(DCM/MeOH = 100:1–10:1)純化，以提供作為黃色固體的標題化合物(70.0 mg，62%收率)。LC-MS [M+H] +=621.3 4-Ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (90.0 mg, 0.362 mmol), (1R,5S )-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidine- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (from step 2 of Example 3, 96.8 mg, 0.181 mmol), Cs 2 CO 3 ( 354 mg, 1.08 mmol) and a mixture of Pd(dppf)Cl 2 (13.2 mg, 0.0181 mmol) in 1,4-dioxane/H 2 O (4:1, 2.0 mL) was evacuated with N 2 Backfill, and the sequence is repeated three times. The resulting mixture was warmed to 90 °C and stirred under N2 atmosphere for 2 h. The reaction was monitored by LC-MS. After completion, the mixture was cooled to rt and the volatiles were removed on a rotary evaporator. The residue was purified by silica gel chromatography (DCM/MeOH = 100:1 - 10:1) to afford the title compound (70.0 mg, 62% yield) as a yellow solid. LC-MS [M+H] + =621.3

步驟4: 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-乙基苯酚 Step 4: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((tetrahydro-1H- Pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-4-ethylphenol

在rt，向(1R,5S)-3-(7-(2-乙基-5-羥基苯基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(70.0 mg，0.113 mmol)在ACN (2.0 mL)中的溶液添加1,4-二氧六環中的HCl (0.4 mL,4M)並且攪拌持續1h。反應通過LCMS來監測。在完成之後，將反應混合物濃縮，以給出殘餘物，所述殘餘物通過反向快速色譜法(柱，C18矽膠，流動相：ACN - H 2O (0.1%NH 4OH)；梯度：55 – 65%)直接純化，以提供為白色固體(10.1 mg，17 %收率)。 At rt, to (1R,5S)-3-(7-(2-ethyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(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 (70.0 mg, 0.113 mmol) in ACN (2.0 mL) was added HCl in 1,4-dioxane (0.4 mL, 4M) and stirred for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give a residue which was subjected to reverse-phase flash chromatography (column, C18 silica gel, mobile phase: ACN—H 2 O (0.1% NH 4 OH); gradient: 55 −65%) was directly purified to provide as a white solid (10.1 mg, 17% yield).

LC-MS [M+H] += 521.3。 1H NMR (400 MHz, CD 3CN) δ 9.07 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.91 (dd, J = 8.4, 2.4 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H), 5.38 (t, J = 4.8 Hz, 2H), 4.51 (d, J = 10.8 Hz, 2H), 3.60 (d, J = 10.8 Hz, 5H), 3.17 (s, 2H), 2.79 (s, 3H), 2.50 (dd, J = 14.8, 7.6 Hz, 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 = 7.6 Hz, 3H)。 LC-MS [M+H] + = 521.3. 1 H NMR (400 MHz, CD 3 CN) δ 9.07 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.91 (dd, J = 8.4, 2.4 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H), 5.38 (t, J = 4.8 Hz, 2H), 4.51 (d, J = 10.8 Hz, 2H), 3.60 (d, J = 10.8 Hz, 5H), 3.17 (s, 2H), 2.79 (s, 3H), 2.50 (dd, J = 14.8, 7.6 Hz, 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 = 7.6 Hz, 3H).

實施例37Example 37

2-(3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d2)吡啶並[4,3-d]嘧啶-7-基)-4-乙基苯基)丙-2-醇

Figure 02_image215
2-(3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((tetrahydro-1H- Pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-4-ethylphenyl)propan-2-ol
Figure 02_image215

EX.37EX.37

步驟1: 3-溴-4-乙基苯甲酸Step 1: 3-Bromo-4-ethylbenzoic acid

在rt在1h內，向4-乙基苯甲酸(5.00 g，33.3 mmol)、硝酸(65 %，22 mL)、水(20 mL)、乙酸(120 mL)和溴(5.85 g，36.6 mmol)的溶液逐滴地添加AgNO 3(5.66 g，33.3 mmol )在水(20 mL)中的溶液。將產生的混合物在rt攪拌持續3 h。反應通過LCMS來監測。在完成之後，將反應混合物傾倒在冰-水中，並且沉澱物通過過濾來收集。固體用飽和的含水Na 2CO 3(100 ml)處理並且攪拌持續10 min。將剩餘的固體通過過濾移除。溶液用12 N HCl調節至pH 2-3。混合物用EtOAc (200 mL×2)萃取。合併的有機層經Na 2SO 4乾燥，過濾，並且在旋轉蒸發儀上濃縮。獲得的殘餘物通過快速色譜法(用MeOH/DCM，0至50%洗脫)純化，以提供作為白色固體的標題化合物(7.50 g，98%收率)。LC-MS [M+H] _= 229.1。 Add 4-ethylbenzoic acid (5.00 g, 33.3 mmol), nitric acid (65%, 22 mL), water (20 mL), acetic acid (120 mL) and bromine (5.85 g, 36.6 mmol) within 1 h at rt A solution of AgNO 3 (5.66 g, 33.3 mmol ) in water (20 mL) was added dropwise. The resulting mixture was stirred at rt for 3 h. The reaction was monitored by LCMS. After completion, the reaction mixture was poured into ice-water, and the precipitate was collected by filtration. The solid was treated with saturated aqueous Na 2 CO 3 (100 ml) and stirring continued for 10 min. The remaining solid was removed by filtration. The solution was adjusted to pH 2-3 with 12 N HCl. The mixture was extracted with EtOAc (200 mL×2). The combined organic layers were dried over Na2SO4 , filtered, and concentrated on a rotary evaporator . The residue obtained was purified by flash chromatography (eluting with MeOH/DCM, 0 to 50%) to afford the title compound (7.50 g, 98% yield) as a white solid. LC-MS [M+H ] = 229.1.

步驟2: 3-溴-4-乙基苯甲酸甲酯Step 2: Methyl 3-bromo-4-ethylbenzoate

向3-溴-4乙基苯甲酸(7.30 g，31.9 mmol)在MeOH (73.0 mL)中的溶液逐滴地添加濃H 2SO 4(0.73 mL)。將混合物加熱至回流並且攪拌過夜。反應通過LCMS來監測。將大部分的溶劑在減壓下移除。殘餘物在EtOAc和飽和的NaHCO 3水溶液之間分配並且分離。水層用EtOAc (200 mL)萃取。合併的有機層經Na2SO4乾燥，過濾，並且在真空下濃縮。獲得的殘餘物通過快速色譜法(用PE/EtOAc，0至20%洗脫)純化，以提供作為無色油的標題化合物(6.10 g，79%收率)。LC-MS [M+H] += 242.2。 To a solution of 3-bromo-4ethylbenzoic acid (7.30 g, 31.9 mmol) in MeOH (73.0 mL) was added concentrated H2SO4 (0.73 mL ) dropwise. 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 partitioned between EtOAc and saturated aqueous NaHCO 3 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 afford the title compound (6.10 g, 79% yield) as a colorless oil. LC-MS [M+H] + = 242.2.

步驟3: 2-(3-溴-4-乙基苯基)丙-2-醇Step 3: 2-(3-Bromo-4-ethylphenyl)propan-2-ol

在0℃在N 2氣氛下，向3-溴-4-乙基苯甲酸甲酯(3.00 g，12.3 mmol)在THF (15.0 mL)中的攪拌的溶液逐滴地添加MeMgBr (1.0 M在***中，24.6 mL)。然後允許混合物加溫至周圍溫度並且攪拌持續3.5 h。反應通過LCMS來監測。在完成之後，將反應混合物冷卻至0℃並且通過逐滴地添加含水的10%HCl (30 mL)來猝滅。產生的混合物用EtOAc (50 mL×3)萃取。合併的有機層用鹽水(50 mL)洗滌，經無水Na 2SO 4乾燥。在過濾之後，將濾液在減壓下濃縮。獲得的殘餘物通過快速色譜法(用PE/EtOAc，0至20%洗脫)純化，以提供作為無色油的標題化合物(2.40 g，80%收率)。LC-MS [M-(OH -)] += 227.2。 To a stirred solution of methyl 3-bromo-4-ethylbenzoate (3.00 g, 12.3 mmol) in THF (15.0 mL) was added MeMgBr (1.0 M in diethyl ether) dropwise at 0 °C under N atmosphere. medium, 24.6 mL). The mixture was then allowed to warm to ambient temperature and stirred for 3.5 h. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to 0 °C and quenched by dropwise addition of aqueous 10% HCl (30 mL). The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 . 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 afford the title compound (2.40 g, 80% yield) as a colorless oil. LC-MS [M-( OH- )] + = 227.2.

步驟4: 2-[4-乙基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基]丙-2-醇Step 4: 2-[4-Ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol

將2-(3-溴-4-乙基苯基)丙-2-醇(500 mg，2.06 mmol)、B 2Pin 2(574.4 mg, 2.26 mmol)、AcOK (605 mg、6.17 mmol)和Pd(dppf)Cl 2(99.3 mg, 0.136 mmol)在二氧六環中的混合物抽真空，用N 2回填，並且該順序重複三次。將產生的混合物加溫至90℃並且在N 2氣氛下攪拌過夜。反應通過LCMS來監測。允許混合物冷卻下來至rt。將反應混合物濃縮以給出殘餘物，所述殘餘物通過快速色譜法(用PE/MeOH，0至10%洗脫)純化，以提供作為白色固體的標題化合物(560 mg，93%收率)。LC-MS [M-(OH -)] += 273.3。 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 A mixture of (dppf) Cl2 (99.3 mg, 0.136 mmol) in dioxane was evacuated, backfilled with N2 , and the sequence was repeated three times. The resulting mixture was warmed to 90 °C and stirred overnight under N2 atmosphere. The reaction was monitored by LCMS. Allow the mixture to cool down to rt. The reaction mixture was concentrated to give a residue which was purified by flash chromatography (eluting with PE/MeOH, 0 to 10%) to afford the title compound (560 mg, 93% yield) as a white solid . LC-MS [M-( OH- )] + = 273.3.

步驟5: 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶 Step 5: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-chloro-8-fluoro-2-((tetrahydro-1H -pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidine

在rt，向(1R,5S)-3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環並[3.2.1]辛烷-8-羧酸叔丁酯(來自實施例3的步驟2，92.0 mg，0.172 mmol)在ACN (2.0 mL)中的溶液添加1,4-二氧六環中的HCl (0.4 mL,4M)並且攪拌持續1h。反應通過LCMS來監測。在完成之後，將反應混合物濃縮，以給出殘餘物(72 mg)，所述殘餘物在下一步中直接使用。LC-MS[M+H]+ = 436.01。 At rt, to (1R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[ tert-butyl 4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (from step 2 of Example 3, 92.0 mg, 0.172 mmol) in ACN (2.0 mL) was added HCl in 1,4-dioxane (0.4 mL, 4M) and stirred for 1 h. 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.

步驟5: 2-(3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-乙基苯基)丙-2-醇 Step 5: 2-(3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((tetrahydro -1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-4-ethylphenyl)propan-2-ol

將4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶(75.0 mg，0.172 mmol)、2-[4-乙基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基]丙-2-醇(75.1 mg，0.259 mmol)、RuPhos Pd G3 (14.4 mg, 0.0172 mmol)和碳酸鉀(109.8 mg，0.517 mmol)在1,4-二氧六環/H2O (v/v=5:1)中的混合物抽真空，用N 2回填，並且該順序重複三次。將產生的混合物加溫至90℃並且在N 2氣氛下攪拌持續4 h。反應通過LCMS來監測。在完成之後，允許混合物冷卻下來至rt。將反應混合物濃縮以給出殘餘物，所述殘餘物通過製備型-TLC(10% MeOH/DCM)純化，以提供作為白色固體的標題化合物(9.88 mg，10%收率)。LC-MS [M+H] += 563.4。 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.50 (dd, J = 8.0, 2.0 Hz, 1H), 7.40 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 5.03 (s, 1H), 4.40 (d, J = 11.6 Hz, 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 = 7.6 Hz, 3H)。 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrole Azin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidine (75.0 mg, 0.172 mmol), 2-[4-ethyl-3-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol (75.1 mg, 0.259 mmol), RuPhos Pd G3 (14.4 mg, 0.0172 mmol) and A mixture of potassium carbonate (109.8 mg, 0.517 mmol) in 1,4-dioxane/H2O (v/v=5:1) was evacuated, backfilled with N2 , and the sequence was repeated three times. The resulting mixture was warmed to 90 °C and stirred under N2 atmosphere for 4 h. 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 which was purified by prep-TLC (10% MeOH/DCM) to afford the title compound (9.88 mg, 10% yield) as a white solid. LC-MS [M+H] + = 563.4. 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.50 (dd, J = 8.0, 2.0 Hz, 1H), 7.40 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H ), 5.03 (s, 1H), 4.40 (d, J = 11.6 Hz, 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 = 7.6 Hz, 3H).

如上文實施例的類似程式用於合成如申請專利範圍中的申請專利範圍111示出的其他化合物，並且前面提及的示例性化合物如第15頁至第40頁示出。Similar schemes as in the examples above were used to synthesize other compounds as shown in Claim 111 in the Claims, and the exemplary compounds mentioned above are shown on pages 15-40.

生物化學活性和細胞活性biochemical and cellular activity

實施例I. KRAS G12D- SOS1相互作用測定法Example I. KRAS G12D-SOS1 Interaction Assay

SOS1是關鍵的鳥嘌呤交換因數(guanine exchange factor，GEF)，有助於KRAS的活性形式。使用Cisbio KRAS/SOS1結合試劑盒(貨號63ADK000CB21PEH)，通過HTRF測定法測量測試化合物結合至KRAS G12D的能力和損害KRAS G12D- SOS1相互作用的能力。Tag1-KRAS G12D和Tag2-SOS1之間的相互作用通過來自在抗-Tag2上標記的鋱穴狀化合物(Terbium cryptate)(HTRF供體)和在抗-Tag1上標記的XL665 (HTRF受體)的能量轉移來檢測。HTRF信號的減弱指示受損害的KRAS G12D- SOS1相互作用。SOS1 is the key guanine exchange factor (GEF) that contributes 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. 63ADK000CB21PEH). The interaction between Tag1-KRAS G12D and Tag2-SOS1 was mediated by signals from Terbium cryptate (HTRF donor) labeled on anti-Tag2 and XL665 (HTRF acceptor) labeled on anti-Tag1. Energy transfer to detect. Attenuation of HTRF signaling indicates impaired KRAS G12D-SOS1 interaction.

根據製造商的說明書進行程式，Tag1- KRAS G12D、Tag2-SOS1與稀釋的化合物混合，在25℃溫育持續15 min。然後將抗-Tag1-Tb和抗-Tag2-XL665添加至測定板，將混合物另外溫育持續3h。在Envision™酶標儀(Plate Reader)上讀取螢光信號。IC50通過Graphpad Prism8從非線性回歸等式確定。式(I)的示例性化合物的結果在表5中示出。KRAS G12D- SOS1 HTRF測定的範圍是：A = IC50≤ 50 nM；B =IC50 ＞50 nM至250 nM；C = IC50 ＞250 nM至1 μΜ；以及D = IC50 ＞ 1 μΜ. 表5KRAS G12D-SOS1相互作用的抑制 化合物編號 IC 50(nM) MRTX1133 A EX.1 C EX.2 C EX.3 A EX.4 A EX.5 A EX.6 B EX.7 C EX.8 A EX.9 A EX.10 A EX.11 D EX.12 A EX.13 A EX.14 A EX.15 A EX.16 A EX.17 A EX.18 A EX.19 A EX.20 A EX.21 A EX.22 A EX.23 A EX.24 A EX.25 A EX.26 A EX.27  A EX.28 A EX.29 A EX.30 A EX.31 A EX.32 A EX.33 A EX.34 A EX.35 D EX.36 B EX.37    The protocol was performed according to the manufacturer's instructions, Tag1-KRAS G12D, Tag2-SOS1 were mixed with diluted compounds and incubated at 25°C for 15 min. Anti-Tag1-Tb and anti-Tag2-XL665 were then added to the assay plate and the mixture was incubated for an additional 3h. Fluorescent signals were read on an Envision™ microplate reader (Plate Reader). IC50s were determined from nonlinear regression equations by Graphpad Prism8. Results for exemplary compounds of formula (I) are shown in Table 5. The range of KRAS G12D-SOS1 HTRF assay is: A = IC50 ≤ 50 nM; B = IC50 >50 nM to 250 nM; C = IC50 >250 nM to 1 μM; and D = IC50 > 1 μM. Table 5 KRAS G12D-SOS1 Inhibition of interaction Compound number IC 50 (nM) MRTX1133 A EX.1 C EX.2 C EX.3 A EX.4 A EX.5 A EX.6 B EX.7 C EX.8 A EX.9 A EX.10 A EX.11 D. EX.12 A EX.13 A EX.14 A EX.15 A EX.16 A EX.17 A EX.18 A EX.19 A EX.20 A EX.21 A EX.22 A EX.23 A EX.24 A EX.25 A EX.26 A EX.27 A EX.28 A EX.29 A EX.30 A EX.31 A EX.32 A EX.33 A EX.34 A EX.35 D. EX.36 B EX.37

實施例II. 細胞信號傳導活性測定(Cellular signaling activity assay)Example II. Cellular signaling activity assay

本發明的化合物抑制KRAS G12D活性，並且因此抑制下游效應因數pERK (磷酸- ERK(phosphor- ERK))的生成。Compounds of the invention inhibit KRAS G12D activity and thus inhibit the production of the downstream effector factor pERK (phosphor-ERK).

將GP2D細胞(CBP60010)在包含10%胎牛血清和青黴素/鏈黴素的DMEM培養基中培養，接種在384孔細胞培養板中並且允許黏附(attach)持續12h-14h。將稀釋的化合物添加至細胞培養板並且溫育持續3h。添加4.0%甲醛以固定細胞並且板用PBS洗滌，並且用100%甲醇滲透(permeabilize)。使用非特異性抗體，將板在室溫封閉持續1h。GP2D cells (CBP60010) were cultured in DMEM medium containing 10% fetal bovine serum and penicillin/streptomycin, seeded in 384-well cell culture plates and allowed to attach for 12h-14h. Diluted compounds were added to cell culture plates and incubated for 3h. 4.0% formaldehyde was added to fix cells and plates were washed with PBS and permeabilized with 100% methanol. Plates were blocked for 1 h at room temperature using non-specific antibodies.

使用對於ERK的磷酸化形式特異性的抗體來確定pERK的量，並且與GAPDH的量相比。將一級抗體磷酸ERK (CST，4370S)和GADPH (CST，97166S)添加至板並且在4℃溫育過夜。板用PBST洗滌。將二級抗體IRDye 800CW羊抗-兔IgG (LI-COR，926-32211)和IRDye 680RD羊抗鼠IgG (LI-COR, 926-68070)添加至板，並且在室溫溫育持續1小時。板用PBST洗滌，並且在Odyssey CLx酶標儀上讀取。The amount of pERK was determined using an antibody specific for the phosphorylated form of ERK and compared to the amount of GAPDH. Primary antibodies phospho-ERK (CST, 4370S) and GADPH (CST, 97166S) were added to the plate and incubated overnight at 4°C. Plates were washed with PBST. 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 plate and incubated for 1 hour at room temperature. Plates were washed with PBST and read on an Odyssey CLx plate reader.

對於每個孔，將pERK信號歸一化成GAPDH信號，並且計算DMSO對照孔的值。IC 50值從非線性回歸等式產生：Y=底部+ (頂部-底部) / (1+10^ ((LogIC 50-X)*Hill斜率))。 For each well, the pERK signal was normalized to the GAPDH signal, and the value for DMSO control wells was calculated. IC50 values are generated from the non-linear regression equation: Y=Bottom+(Top-Bottom)/(1+10^(( LogIC50 -X)*Hill Slope)).

示例性化合物的結果在表6中示出。細胞信號傳導活性測定的範圍是：A = IC 50≤ 50 nM；B =IC 50＞50 nM至250 nM；C = IC 50＞250 nM至1 μΜ；以及D = IC 50＞ 1 μΜ. 表6GP2D中的ERK的KRAS G12D介導的磷酸化的抑制 化合物編號 IC 50(nM) MRTX1133 A EX.1 C EX.2 D EX.3 B EX.4 A EX.5 A EX.6 B EX.7 C EX.8 A EX.9 A EX.10 A EX.11 D EX.12 A EX.13 A EX.14 A EX.15 A EX.16 A EX.17 A EX.18 A EX.19 A EX.20 A EX.21 A EX.22 A EX.23 A EX.24 A EX.25 A EX.26 A EX.27 A EX.28 A EX.29 B EX.30 A EX.31 A EX.32 C EX.33 A EX.34 A EX.35 D EX.36 D EX.37 D Results for exemplary compounds are shown in Table 6. The range of cell signaling activity assays is: A = IC50 ≤ 50 nM; B = IC50 > 50 nM to 250 nM; C = IC50 > 250 nM to 1 μΜ; and D = IC50 > 1 μΜ. Table 6GP2D Inhibition of KRAS G12D-mediated phosphorylation of ERK in Compound number IC 50 (nM) MRTX1133 A EX.1 C EX.2 D. EX.3 B EX.4 A EX.5 A EX.6 B EX.7 C EX.8 A EX.9 A EX.10 A EX.11 D. EX.12 A EX.13 A EX.14 A EX.15 A EX.16 A EX.17 A EX.18 A EX.19 A EX.20 A EX.21 A EX.22 A EX.23 A EX.24 A EX.25 A EX.26 A EX.27 A EX.28 A EX.29 B EX.30 A EX.31 A EX.32 C EX.33 A EX.34 A EX.35 D. EX.36 D. EX.37 D.

實施例III.    KRAS- CRAF相互作用測定法：結合至CRAF的KRAS G12D突變體相對於野生型(WT) KRAS的抑制Example III. KRAS-CRAF Interaction Assay: Inhibition of KRAS G12D Mutant Binding to CRAF Relative to Wild-Type (WT) KRAS

CRAF是充分研究的KRAS效應蛋白，並且已知KRAS- CRAF相互作用有助於MAPK信號轉導。本發明的化合物結合至KRAS並且阻斷KRAS和CRAF之間的相互作用。為了確定化合物在KRAS G12D和野生型(WT) KRAS之間的選擇性，通過HTRF測定法測量KRAS G12D- CRAF和KRAS WT- CRAF的抑制。  Tag1-CRAF (內部(in house)純化的GST-CRAF)和Tag2-KRAS G12D/ KRAS WT之間的相互作用通過來自在抗-Tag1上標記的鋱穴狀化合物(HTRF供體)和在抗-Tag2 (Cisbo，63ADK000CB21PEH)上標記的XL665 (HTRF受體)的能量轉移來檢測。HTRF信號的減弱指示受損害的KRAS G12D/ KRAS WT- CRAF相互作用。CRAF is a well-studied KRAS effector protein, and KRAS-CRAF interaction is known to contribute to MAPK signaling. Compounds of the invention bind to KRAS and block the interaction between KRAS and CRAF. To determine the selectivity of compounds between KRAS G12D and wild-type (WT) KRAS, inhibition of KRAS G12D-CRAF and KRAS WT-CRAF was measured by HTRF assay. The interaction between Tag1-CRAF (GST-CRAF purified in house) and Tag2-KRAS G12D/ KRAS WT was regulated by cryptate (HTRF donor) labeled on anti-Tag1 and on anti- The energy transfer of XL665 (HTRF acceptor) labeled on Tag2 (Cisbo, 63ADK000CB21PEH) was detected. Attenuation of HTRF signaling indicates impaired KRAS G12D/KRAS WT-CRAF interaction.

根據製造商的說明書進行程式，Tag1- KRAS G12D/ KRAS WT、Tag2-CRAF與稀釋的化合物混合，在25℃溫育持續15 min。然後將抗-Tag1-Tb和抗-Tag2-XL665添加至測定板，將混合物另外在4℃溫育持續3h。在Envision™酶標儀上讀取螢光信號。IC 50通過Graphpad Prism8從非線性回歸等式確定。式(I)的示例性化合物的結果在表7中示出。 表7KRAS G12D相對於KRAS WT的選擇性抑制 化合物ID    KRAS G12D- CRAF相互作用的抑制 IC 50(nM)    KRAS WT- CRAF相互作用的抑制 IC 50(nM) 選擇性比率 MRTX1133 5.27 14.2 2.7x EX.28 13.9 ＞1000 ＞72x EX.31 5.07 19.6 3.9x The protocol was performed according to the manufacturer's instructions, Tag1-KRAS G12D/KRAS WT, Tag2-CRAF were mixed with diluted compounds and incubated at 25°C for 15 min. Anti-Tag1-Tb and anti-Tag2-XL665 were then added to the assay plate and the mixture was incubated for an additional 3 h at 4°C. Fluorescence signals were read on an Envision™ microplate reader. IC50s were determined from nonlinear regression equations by Graphpad Prism8. Results for exemplary compounds of formula (I) are shown in Table 7. Table 7 Selective inhibition of KRAS G12D relative to KRAS WT Compound ID Inhibition IC 50 (nM) of KRAS G12D-CRAF interaction Inhibition IC 50 (nM) of KRAS WT-CRAF interaction selectivity ratio MRTX1133 5.27 14.2 2.7x EX.28 13.9 >1000 >72x EX.31 5.07 19.6 3.9x

結果闡明，在KRAS G12D和野生型(WT) KRAS相對於參考化合物MRTX1133之間，本發明的示例性化合物具有較高的選擇性，所述參考化合物MRTX1133在專利WO 2021/041671、WO2022/015375或在“Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12DInhibitor”, J. Med.Chem.2022, 65, 3123-3133, doi:10.1021/acs. jmedchem.1c01688中公開。

Figure 02_image217
The results illustrate that the exemplary compounds of the present invention have higher selectivity between KRAS G12D and wild-type (WT) KRAS relative to the reference compound MRTX1133 described in patents WO 2021/041671, WO 2022/015375 or Disclosed in "Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12D Inhibitor", J. Med. Chem.2022, 65, 3123-3133, doi:10.1021/acs.jmedchem.1c01688.
Figure 02_image217

MRTX1133MRTX1133

實施例IV.肝微粒體代謝穩定性Example IV. Liver Microsome Metabolic Stability

本發明公開的代謝穩定性使用肝微粒體穩定性測定法來評估。評估人類肝微粒體、大鼠肝微粒體、小鼠肝微粒體、犬肝微粒體、猴肝微粒體(來自Corning)。將分別至6 µM和0.75 mg/mL的濃度的測試化合物和肝微粒體添加至0.1 M磷酸鉀緩衝液、1.0 mM EDTA，pH 7.4。將轉移到測定板中的30uL的混合物在37℃水浴中預加熱持續5 min。將5 µL的6 mM NADPH溶液添加至每個板以使反應開始，通過添加135 µL的乙腈，在5-min時、15-min時、30-min時和45-min時終止微粒體反應。對於0-min板，同時添加NADPH溶液和乙腈。將板在20℃以5594 g離心持續15 min。收集上清液並且通過HPLC來定量。T 1/2(分鐘)和Clint (mL/min/kg)如下計算： Metabolic stability disclosed herein was assessed using a liver microsomal stability assay. Human liver microsomes, rat liver microsomes, mouse liver microsomes, dog liver microsomes, monkey liver microsomes (from Corning) were evaluated. Test compounds and liver microsomes were added to concentrations of 6 µM and 0.75 mg/mL, respectively, in 0.1 M potassium phosphate buffer, 1.0 mM EDTA, pH 7.4. 30uL of the mixture transferred to the assay plate was pre-warmed in a 37°C water bath for 5 min. 5 µL of 6 mM NADPH solution was added to each plate to initiate the reaction and the microsomal reaction was terminated at 5-min, 15-min, 30-min, and 45-min by adding 135 µL of acetonitrile. For 0-min plates, NADPH solution and acetonitrile were added simultaneously. The plate was centrifuged at 5594 g for 15 min at 20°C. Supernatants were collected and quantified by HPLC. T 1/2 (minutes) and Clint (mL/min/kg) are calculated as follows:

T 1/2= 0.693/K (K是ln [濃度]的點相對於溫育時間的速率常數) T 1/2 = 0.693/K (K is the rate constant of the point ln [concentration] with respect to the incubation time)

Clint = (0.693/T 1/2) × (1/(微粒體蛋白濃度(0.5 mg/mL))) × 比例因數 物種 微粒體蛋白 每千克體重的肝重量 比例因數 a 每克肝臟的肝血流速(mL/min/kg) 小鼠 45 87.5 3937.5 90 大鼠 44.8 40 1792 55.2 犬 77.9 32 2492.8 30.9 猴 45 32.5 1462.5 44 人類 48.8 25.7 1254.2 20.7 a比例因數= (微粒體蛋白/克肝臟) × (肝重/千克體重) Clint = (0.693/T 1/2 ) × (1/(microsomal protein concentration (0.5 mg/mL))) × scaling factor species microsomal protein liver weight per kilogram body weight Scale factor a Hepatic blood flow rate per gram of liver (mL/min/kg) mouse 45 87.5 3937.5 90 the rat 44.8 40 1792 55.2 dog 77.9 32 2492.8 30.9 monkey 45 32.5 1462.5 44 Humanity 48.8 25.7 1254.2 20.7 aScale factor = (microsomal protein/g liver) × (liver weight/kg body weight)

如表8和表9中示出的，相比於參考化合物MRTX1133，本發明的化合物展示出較高的肝微粒體代謝穩定性。 表8肝微粒體代謝穩定性 化合物ID 小鼠 人類 T 1/2(min) CL (mL/min/kg) T 1/2(min) CL (mL/min/kg) MRTX1133 11.1 491 72.9 23.9 Ex.10 15.2 332 116 14.5 EX.21 12.4 441 126 13.8 EX.24 15.7 349 102 17.1 EX.25 17.5 322 189 9.17 EX.25的非氘代物 10.8 546 103 16.9 EX.29 69.5 78.6 202 8.59 EX.29的非氘代物 53.6 102 161 10.8 As shown in Table 8 and Table 9, compared to the reference compound MRTX1133, the compound of the present invention exhibited higher metabolic stability of liver microsomes. Table 8 Metabolic stability of liver microsomes Compound ID mouse Humanity T 1/2 (min) CL (mL/min/kg) T 1/2 (min) CL (mL/min/kg) MRTX1133 11.1 491 72.9 23.9 Ex.10 15.2 332 116 14.5 EX.21 12.4 441 126 13.8 EX.24 15.7 349 102 17.1 EX.25 17.5 322 189 9.17 Non-deuterated substances of EX.25 10.8 546 103 16.9 EX.29 69.5 78.6 202 8.59 Non-deuterated substances of EX.29 53.6 102 161 10.8

表9肝微粒體代謝穩定性 化合物ID 小鼠 大鼠 犬 猴 人類 T 1/2(min) CL (mL/min/kg) T 1/2(min) CL (mL/min/kg) T 1/2(min) CL (mL/min/kg) T 1/2(min) CL (mL/min/kg) T 1/2(min) CL (mL/min/kg) EX.30 17.4 314 75.8 32.8 64.4 53.7 33.1 61.3 129 13.5 EX.30的非氘代物 13.8 397 49.4 50.3 50.6 68.3 32.8 61.8 78.2 22.2 EX.31 226 24.2 700 3.55 321 10.8 59.0 34.3 370 4.70 EX.31的非氘代物 176 31.0 518 4.80 156 22.1 45.6 44.4 227 7.67 Table 9 Metabolic stability of liver microsomes Compound ID mouse the rat dog monkey Humanity T 1/2 (min) CL (mL/min/kg) T 1/2 (min) CL (mL/min/kg) T 1/2 (min) CL (mL/min/kg) T 1/2 (min) CL (mL/min/kg) T 1/2 (min) CL (mL/min/kg) EX.30 17.4 314 75.8 32.8 64.4 53.7 33.1 61.3 129 13.5 Non-deuterated substances of EX.30 13.8 397 49.4 50.3 50.6 68.3 32.8 61.8 78.2 22.2 EX.31 226 24.2 700 3.55 321 10.8 59.0 34.3 370 4.70 Non-deuterated substances of EX.31 176 31.0 518 4.80 156 22.1 45.6 44.4 227 7.67

實施例V-1.本發明氘代化合物相對於未氘代化合物在SD大鼠中的藥代動力學Example V-1. The pharmacokinetics of deuterated compounds of the present invention relative to non-deuterated compounds in SD rats

該研究的目的是使用LC-MS/MS，確定在雄性SD大鼠中單次靜脈(IV)施用後，本發明氘代化合物相對於未氘代化合物的藥代動力學(PK)。The aim of this study was to determine the pharmacokinetics (PK) of deuterated compounds of the invention relative to non-deuterated compounds following a single intravenous (IV) administration in male SD rats using LC-MS/MS.

動物資訊：  SD大鼠，SPF，6-8周齡，雄性，重量300 ~315 g，購自Hunan Slaike Jinda Experimental Animal Co., LTD。Animal information: SD rats, SPF, 6-8 weeks old, male, weighing 300-315 g, were purchased from Hunan Slaike Jinda Experimental Animal Co., LTD.

配方：5%DMSO+5%聚氧乙烯蓖麻油EL+90%鹽水。在製備之後立即使用。Formula: 5% DMSO+5% polyoxyethylene castor oil EL+90% saline. Use immediately after preparation.

施用：靜脈施用；Administration: intravenous administration;

劑量：1 mg/kg；Dose: 1 mg/kg;

給藥濃度：0.5 mg/mL；Dosing concentration: 0.5 mg/mL;

給藥量：2 mL；Dosage: 2 mL;

收集血漿的時間點：施用之後第2min、第5min、第15min、第30min、第1h、第2h、第4h、第6h、第8h、第24h。Time points of plasma collection: 2min, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after administration.

樣品收集(血漿)：收集0.2mL的血液，並且放置在標記的EDTA-2K抗凝血劑管中。在抗凝血劑(EDTA-2K)與血液輕輕地倒置混合之後，將血液立即放置在濕的冰中，並且在血液收集之後的1小時內將血漿離心。將離心條件設定在4℃、6800 g和6分鐘。Sample collection (plasma): 0.2 mL of blood was collected and placed in labeled EDTA-2K anticoagulant tubes. Immediately after mixing the anticoagulant (EDTA-2K) with the blood by inversion by gentle inversion, the blood was placed on wet ice and the plasma was centrifuged within 1 hour of blood collection. Centrifugation conditions were set at 4°C, 6800 g, and 6 minutes.

樣品儲存：在離心之後，將分離的血漿放置在標記的EP管中並且盡可能快地儲存在超低溫冰箱中，直到樣品分析。Sample storage: After centrifugation, separated plasma was placed in labeled EP tubes and stored in an ultra-low temperature freezer as soon as possible until sample analysis.

儀器：LC-MS/MS (API 5000)(LC-MS-005);Instrument: LC-MS/MS (API 5000) (LC-MS-005);

流動相：流動相A：0.3%FA-10mM乙酸銨水；流動相B：70%MeOH-30%ACN。Mobile phase: mobile phase A: 0.3%FA-10mM ammonium acetate water; mobile phase B: 70%MeOH-30%ACN.

流速：0.800 mL/minFlow rate: 0.800 mL/min

柱    Nano chrom core C18 (4.6×530 mm, 3.0 µm)。Column Nano chrom core C18 (4.6×530 mm, 3.0 µm).

資料分析和計算：Data analysis and calculation:

本發明的測試化合物在施用後的不同時間點在大鼠血漿中的濃度通過LC-MS/MS來實現。將資料處理，並且通過非房室模型，使用Phoenix winnonlin 7.0軟體(pharsight，USA)計算施用後大鼠的藥代動力學參數。峰時間T 最大和峰濃度C 最大是測量值； Concentrations of test compounds of the present invention in rat plasma at different time points after administration were achieved by LC-MS/MS. The data were processed, and the pharmacokinetic parameters of rats after administration were calculated by non-compartmental model using Phoenix winnonlin 7.0 software (pharsight, USA). Peak time Tmax and peak concentration Cmax are measured values;

通過梯形法計算曲線下面積的AUC0-t值；Calculate the AUC0-t value of the area under the curve by the trapezoidal method;

AUC0-無窮= AUC 0-t+ C t/k e，C t是血漿中在最後可測量時間點時的可檢測的化合物濃度，k e是消除速率常數； AUC0-infinity = AUC0 -t + Ct / ke , where Ct is the detectable compound concentration in plasma at the last measurable time point, and ke is the elimination rate constant;

消除半衰期t 1/2= 0.693 / k e； Elimination half-life t 1/2 = 0.693/ ke ;

平均保留時間，MRT = AUMC / AU；mean retention time, MRT = AUMC / AU;

清除率，CL = D/AUC 0- 無窮(D是劑量)； Clearance, CL = D/AUC 0- infinity (D is dose);

穩態時的表觀分佈體積，V SS= CL x MRT。 Apparent volume of distribution at steady state, V SS = CL x MRT.

藥代動力學結果(表10)Pharmacokinetic results (table 10)

表10SD大鼠中的PK 化合物ID t 1/2(h) V ss(L/kg) MRT 無窮(h) CL (mL/min/kg) AUC 0-t(h*ng/mL) AUC 0- 無窮(h*ng/mL) MRTX1133 2.13±0.840 7.05±1.45 0.770±0.299 155±11.3 101±8.56 108±7.64 EX.10 2.49±0.457 4.59±1.45 0.430±0.299 89.9±14.6 194±10.7 197±9.25 EX.15 2.56±0.350 4.68±0.156 0.442±0.267 90.2±12.4 201±12.4 203.3±8.24 Table 10 PK in SD rats Compound ID t 1/2 (h) V ss (L/kg) MRT infinite (h) CL (mL/min/kg) AUC 0-t (h*ng/mL) AUC 0- infinity (h*ng/mL) MRTX1133 2.13±0.840 7.05±1.45 0.770±0.299 155±11.3 101±8.56 108±7.64 EX.10 2.49±0.457 4.59±1.45 0.430±0.299 89.9±14.6 194±10.7 197±9.25 EX.15 2.56±0.350 4.68±0.156 0.442±0.267 90.2±12.4 201±12.4 203.3±8.24

實施例V-2.本發明氘代化合物相對於未氘代化合物在ICR小鼠中的藥代動力學Example V-2. Pharmacokinetics of deuterated compounds of the present invention relative to non-deuterated compounds in ICR mice

該研究的目的是使用LC-MS/MS，確定在雄性ICR小鼠中單次靜脈(IV)施用後，本發明氘代化合物相對於未氘代化合物的藥代動力學(PK)。The aim of this study was to determine the pharmacokinetics (PK) of deuterated compounds of the invention relative to non-deuterated compounds following a single intravenous (IV) administration in male ICR mice using LC-MS/MS.

動物資訊： ICR小鼠，SPF，雄性，購自Hunan Slaike Jingda Experimental Animal Co., LTD.，證書編號430727221100520536。Animal information: ICR mice, SPF, male, were purchased from Hunan Slaike Jingda Experimental Animal Co., LTD., certificate number 430727221100520536.

配方：5% DMSO + 5 %聚氧乙烯蓖麻油EL + 90 %鹽水。在製備之後立即使用。Formula: 5% DMSO + 5% polyoxyethylene castor oil EL + 90% saline. Use immediately after preparation.

施用：靜脈施用；Administration: intravenous administration;

劑量：1 mg/kg；Dose: 1 mg/kg;

給藥濃度：0.2 mg/mL；Dosing concentration: 0.2 mg/mL;

給藥量：5 mL/kg；Dosage: 5 mL/kg;

收集血漿的時間點：施用之後第5min、第15min、第30min、第1h、第2h、第4h、第8h、第24h。Time points for collecting plasma: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h after administration.

樣品收集(血漿)：收集0.2mL的血液，並且放置在標記的EDTA-2K抗凝血管中。在抗凝血劑(EDTA-2K)與血液輕輕地倒置混合之後，將血液立即放置在濕的冰中，並且在血液收集之後的1小時內將血漿離心。將離心條件設定在4℃、6800 g和6分鐘。Sample collection (plasma): 0.2 mL of blood was collected and placed in labeled EDTA-2K anticoagulated blood vessels. Immediately after mixing the anticoagulant (EDTA-2K) with the blood by inversion by gentle inversion, the blood was placed on wet ice and the plasma was centrifuged within 1 hour of blood collection. Centrifugation conditions were set at 4°C, 6800 g, and 6 minutes.

樣品儲存：在離心之後，將分離的血漿放置在標記的EP管中並且盡可能快地儲存在-20℃冰箱中，直到樣品分析。Sample Storage: After centrifugation, the separated plasma was placed in labeled EP tubes and stored in a -20°C freezer as soon as possible until sample analysis.

儀器：LC-MS/MS (API 5000)(LC-MS-005);Instrument: LC-MS/MS (API 5000) (LC-MS-005);

流動相：流動相A：0.3FA - 10 mM乙酸銨水；流動相B：70% MeOH – 30 % ACN。Mobile phase: Mobile phase A: 0.3FA - 10 mM ammonium acetate in water; Mobile phase B: 70% MeOH - 30% ACN.

流速：0.800 mL/minFlow rate: 0.800 mL/min

柱    Nano chrom core C18 (4.6×530 mm, 3.0 µm)。Column Nano chrom core C18 (4.6×530 mm, 3.0 µm).

資料分析和計算：Data analysis and calculation:

本發明的測試化合物在施用後的不同時間點在大鼠血漿中的濃度通過LC-MS/MS來實現。將資料處理，並且通過非房室模型，使用Phoenix winnonlin 7.0軟體(pharsight，USA)計算施用後大鼠的藥代動力學參數。峰時間T 最大和峰濃度C 最大是測量值； Concentrations of test compounds of the present invention in rat plasma at different time points after administration were achieved by LC-MS/MS. The data were processed, and the pharmacokinetic parameters of rats after administration were calculated by non-compartmental model using Phoenix winnonlin 7.0 software (pharsight, USA). Peak time Tmax and peak concentration Cmax are measured values;

通過梯形法計算曲線下面積的AUC 0-t值； Calculate the AUC 0-t value of the area under the curve by the trapezoidal method;

AUC 0- 無窮= AU C0-t+ C t/k e，C t是血漿中在最後可測量時間點時的可檢測的化合物濃度，k e是消除速率常數； AUC 0- infinity = AU C0-t + C t / ke , where C t is the detectable compound concentration in plasma at the last measurable time point, and ke is the elimination rate constant;

消除半衰期t 1/2= 0.693 / k e； Elimination half-life t 1/2 = 0.693/ ke ;

平均保留時間，MRT = AUMC / AU；mean retention time, MRT = AUMC / AU;

清除率，CL = D/AUC 0- 無窮(D是劑量)； Clearance, CL = D/AUC 0- infinity (D is dose);

穩態時的表觀分佈體積，V SS= CL x MRT Apparent volume of distribution at steady state, V SS = CL x MRT

藥代動力學結果(表11)Pharmacokinetic results (Table 11)

表11ICR小鼠中的PK 化合物ID t 1/2(h) V ss(L/kg) MRT 無窮(h) CL (mL/min/kg) AUC 0-t(h*ng/mL) AUC 0-inf.(h*ng/mL) MRTX1133 13.2±7.35 15.2±4.70 10.1±4.09 27.5±10.3 490±225 543±261 EX.31 4.08±4.25 1.64±1.38 1.34±1.08 19.9±3.95 847±185 862±185 EX.31的非氘代物 7.02±5.30 0.162±0.139 5.57±4.74 30.3±5.49 469±189 494±175 Table 11 PK in ICR mice Compound ID t 1/2 (h) V ss (L/kg) MRT infinite (h) CL (mL/min/kg) AUC 0-t (h*ng/mL) AUC 0-inf. (h*ng/mL) MRTX1133 13.2±7.35 15.2±4.70 10.1±4.09 27.5±10.3 490±225 543±261 EX.31 4.08±4.25 1.64±1.38 1.34±1.08 19.9±3.95 847±185 862±185 Non-deuterated substances of EX.31 7.02±5.30 0.162±0.139 5.57±4.74 30.3±5.49 469±189 494±175

Figure 111122693-A0101-11-0001-3
Figure 111122693-A0101-11-0001-3

無。none.

Claims (47)

一種包含式(I)的部分的化合物或一種包含式(I)的部分的PROTAC化合物，
Figure 03_image005
或其藥學上可接受的鹽、前驅藥、溶劑化物、水合物、互變異構體和異構體， 其中： X 0是H、氘、鹵素、OH、NH 2、CN、C 1-6烷基、C 1-6羥基烷基或C1-6烷氧基；並且其中的每個能夠獨立地任選地是未被取代的或獨立地任選地被3元至7元雜環取代，所述3元至7元雜環具有一個或更多個獨立地選自N、O或S的雜原子，並且所述雜原子中的至少一個是N，所述雜原子被直接連接至所述C 1-6烷基或C 1-6羥基烷基的C原子中的一個；所述3元至7元雜環另外任選地被-CH 3或-N(CH 3) 2取代； R 1和R 2中的每個獨立地選自H、氘、鹵素、-NH 2、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、鹵素、-NH 2、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基取代； R 3和R 4中的每個獨立地選自H、氘、鹵素、-NH 2、-CN、-OH、-C 1-4烷基或-C 1-4烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、鹵素、-NH 2、-CN、-OH、-NHC(O)NHC 1-6烷基、-NHC(O)N(C 1-6烷基) 2、-OH、-OC(O)NHC 1-6烷基、-OC(O)N(C 1-6烷基) 2、
Figure 03_image036
、-C 1-6烷基或-C 1-6烷氧基取代； R 5和R 6中的每個獨立地選自H、氘、鹵素、-NH 2、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、鹵素、-NH 2、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基取代； 並且R 1、R 2、R 3、R 4、R 5和R 6中的至少一個是氘； R獨立地是：
Figure 03_image009
、
Figure 03_image011
、
Figure 03_image223
或
Figure 03_image015
其中： n是0、1、2或3； q是0、1、2或3； X 1是H、-CH 2CN、C 1-6烷基或C 1-6烷氧基； X 2是6元至10元芳基或5元至10元雜芳基；並且所述6元至10元芳基或所述5元至10元雜芳基中的每個獨立地任選地是未被取代的或獨立地任選地被一個或更多個R 2x取代； R 2x中的每個獨立地選自鹵素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6羥基烷基、C 1-6烷氧基、C 1-6鹵代烷基、C 2-6烯基、C 2-6炔基、C 2-6氘代炔基、氰基、(C 1-6烷氧基)C 1-6烷基、(C 1-6烷氧基)C 1-6烷氧基、(C 1-6羥基烷氧基)C 1-6烷氧基、3元至7元環烷基或3元至7元雜環烷基；並且其中的每個獨立地任選地是未被取代的或獨立地任選地被一個或更多個-NH 2、鹵素、氘、-CN、-OH、-C 1-6烷基或-C 1-6烷氧基取代； X 3獨立地選自H、鹵素、C 1-6烷基或C 1-6烷氧基； “
Figure 03_image017
”是單鍵或雙鍵； 5X是N或CR 7，其中 當 5X是N或 5X是CR 7時，“
Figure 03_image017
”是雙鍵； 當 5X是C(R 7) 2或 5X是NR 7時，“
Figure 03_image017
”是單鍵。 R 7中的每個獨立地是H、鹵素、-C 1-6烷基或被一個或更多個鹵素、氘、-OH或NH 2取代的-C 1-6烷基；或 兩個R 7連同兩個R 7兩者均被附接至的C原子形成氧代(=O)，所述氧代連同所述X 2被附接至的N原子形成內醯胺，或 R 7和R 7連同它們各自被附接至的C原子形成3元至6元環烷基、3元至6元雜環；或 W是O或NR w，並且R w是H、氘或C 1-6烷基。 a compound comprising a moiety of formula (I) or a PROTAC compound comprising a moiety of formula (I),
Figure 03_image005
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 alkane group, C 1-6 hydroxyalkyl or C 1-6 alkoxy; and each of which can be independently optionally unsubstituted or independently optionally substituted by a 3- to 7-membered heterocyclic ring, so The 3- to 7-membered heterocyclic ring has one or more heteroatoms independently selected from N, O or S, and at least one of the heteroatoms is N, and the heteroatoms are directly connected to the C One of the C atoms of 1-6 alkyl or C 1-6 hydroxyalkyl; the 3-membered to 7-membered heterocyclic ring is additionally optionally substituted by -CH 3 or -N(CH 3 ) 2 ; R 1 and Each of R 2 is independently selected from H, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkyl or -C 1-6 alkoxy, and each of them is independently optionally unsubstituted or independently optionally substituted by deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkyl or -C 1-6 alkoxy; R 3 and Each of R 4 is independently selected from H, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-4 alkyl or -C 1-4 alkoxy, and each of them is independently Optionally unsubstituted or independently optionally replaced by deuterium, halogen, -NH 2 , -CN, -OH, -NHC(O)NHC 1-6 alkyl, -NHC(O)N(C 1 -6 alkyl) 2 , -OH, -OC(O)NHC 1-6 alkyl, -OC(O)N(C 1-6 alkyl) 2 ,
Figure 03_image036
, -C 1-6 alkyl or -C 1-6 alkoxy; each of R 5 and R 6 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 replaced by deuterium, halogen, -NH 2 , -CN, -OH , -C 1-6 alkyl or -C 1-6 alkoxy substituted; and at least one of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is deuterium; R is independently:
Figure 03_image009
,
Figure 03_image011
,
Figure 03_image223
or
Figure 03_image015
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 alkoxy; X 2 is 6-membered to 10-membered aryl or 5-membered to 10-membered heteroaryl; and each of said 6- to 10-membered aryl or said 5- to 10-membered heteroaryl is independently optionally unsubstituted Substituted or independently optionally substituted by one or more R 2x ; each of R 2x 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 3-7 membered heterocycloalkyl; and each of which is independently optionally unsubstituted or independently optionally replaced by one or more -NH 2 , halogen, deuterium , -CN, -OH, -C 1-6 alkyl or -C 1-6 alkoxy substituted; X 3 is independently selected from H, halogen, C 1-6 alkyl or C 1-6 alkoxy; "
Figure 03_image017
"is a single bond or a double bond; 5 X is N or CR 7 , wherein when 5 X is N or 5 X is CR 7 , "
Figure 03_image017
"is a double bond; when 5 X is C(R 7 ) 2 or 5 X is NR 7 , "
Figure 03_image017
" is a single bond. Each of R is independently H, halogen, -C 1-6 alkyl, or -C 1-6 alkyl substituted by one or more halogen, deuterium, -OH or NH or two R 7 together with the C atom to which both R 7 are attached form an oxo (=0), said oxo together with the N atom to which said X 2 is attached form a lactam, or R 7 and R 7 , together with the C atoms to which they are each attached, form a 3- to 6-membered cycloalkyl, a 3- to 6-membered heterocycle; or W is O or NR , and R is H, deuterium or C 1-6 alkyl. 如請求項1所述的化合物或其藥學上可接受的鹽，其中X 0是H、氘、F、Cl、OH、NH 2、CN、甲基或甲氧基。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X 0 is H, deuterium, F, Cl, OH, NH 2 , CN, methyl or methoxy. 如請求項1所述的化合物或其藥學上可接受的鹽，其中X 0是H。 The compound or a pharmaceutically acceptable salt thereof as claimed in item 1, wherein X is H. 如請求項1或請求項3中任一項所述的化合物或其藥學上可接受的鹽，其中R 1和R 2中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基取代。 A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claim 1 or claim 3, wherein each of R and R 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 replaced by deuterium, F, Cl, -NH 2 , -CN, - OH, methyl or methoxy substitution. 如請求項1至請求項4中任一項所述的化合物或其藥學上可接受的鹽，其中R 1和R 2中的每個獨立地選自H或氘。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 4, wherein each of R and R is independently selected from H or deuterium. 如請求項1至請求項5中任一項所述的化合物或其藥學上可接受的鹽，其中R 3和R 4中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、-NHC(O)NHC 1-3烷基、-NHC(O)N(C 1-3烷基) 2、-OC(O)NHC 1-3烷基、-OC(O)N(C 1-3烷基) 2、
Figure 03_image036
、-C 1-3烷基或-C 1-3烷氧基取代。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 5, wherein each of R and R 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 replaced by deuterium, F, Cl, -NH 2 , -CN, -OH, -NHC(O)NHC 1-3 alkyl, -NHC(O)N(C 1-3 alkyl) 2 , -OC(O)NHC 1-3 alkyl group, -OC(O)N(C 1-3 alkyl) 2 ,
Figure 03_image036
, -C 1-3 alkyl or -C 1-3 alkoxy. 如請求項1至請求項5中任一項所述的化合物或其藥學上可接受的鹽，其中R 3和R 4中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、甲基或甲氧基取代。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 5, wherein each of R and R 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 replaced by deuterium, F, Cl, -NH 2 , -CN, - OH, methyl or methoxy substitution. 如請求項1至請求項10中任一項所述的化合物或其藥學上可接受的鹽，其中R 5和R 6中的每個獨立地選自H、氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基，並且其中的每個獨立地任選地是未被取代的或獨立地任選地被氘、F、Cl、-NH 2、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基取代。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 10, wherein each of R and R 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 replaced by deuterium, F, Substituted by Cl, -NH 2 , -CN, -OH, -C 1-3 alkyl or -C 1-3 alkoxy. 如請求項1至請求項8中任一項所述的化合物或其藥學上可接受的鹽，其中R 1、R 2、R 3、R 4、R 5和R 6中的至少兩個是氘；並且R 1和R 2兩者均是氘。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 8, wherein at least two of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are deuterium and R and R are both deuterium. 如請求項1至請求項8中任一項所述的化合物或其藥學上可接受的鹽，其中R 1、R 2、R 3、R 4、R 5和R 6中的至少兩個是氘；並且R 3和R 4兩者均是氘。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 8, wherein at least two of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are deuterium and R3 and R4 are both deuterium. 如請求項1至請求項10中任一項所述的化合物或其藥學上可接受的鹽，其中R 1、R 2、R 3、R 4、R 5和R 6中的至少三個是氘；並且R 1和R 2兩者均是氘，並且R 5是氘或R 6是氘。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 10, wherein at least three of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are deuterium and R 1 and R 2 are both deuterium, and R 5 is deuterium or R 6 is deuterium. 如請求項1至請求項10中任一項所述的化合物或其藥學上可接受的鹽，其中R 1、R 2、R 3、R 4、R 5和R 6中的至少三個是氘；並且R 3和R 4是氘，並且R 5是氘或R 6是氘。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 10, wherein at least three of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are deuterium and R 3 and R 4 are deuterium, and R 5 is deuterium or R 6 is deuterium. 如請求項1至請求項12中任一項所述的化合物或其藥學上可接受的鹽，其中R 1、R 2、R 3、R 4、R 5和R 6中的至少五個是氘；並且R 1和R 2兩者均是氘，並且R 3和R 4兩者均是氘，並且R 5是氘或R 6是氘。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 12, wherein at least five of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are deuterium and R 1 and R 2 are both deuterium, and R 3 and R 4 are both deuterium, and R 5 is deuterium or R 6 is deuterium. 如請求項1至請求項13中任一項所述的化合物或其藥學上可接受的鹽，其中R獨立地是：
Figure 03_image009
。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 13, wherein R is independently:
Figure 03_image009
. 如請求項1至請求項13中任一項所述的化合物或其藥學上可接受的鹽，其中R獨立地是：
Figure 03_image011
。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 13, wherein R is independently:
Figure 03_image011
. 如請求項1至請求項13中任一項所述的化合物或其藥學上可接受的鹽，其中R獨立地是：
Figure 03_image040
。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 13, wherein R is independently:
Figure 03_image040
. 如請求項1至請求項10中任一項所述的化合物或其藥學上可接受的鹽，其中R獨立地是：
Figure 03_image015
。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 10, wherein R is independently:
Figure 03_image015
. 如請求項1至請求項14中任一項或請求項16所述的化合物或其藥學上可接受的鹽，其中n是2。The compound or a pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 14 or claim 16, wherein n is 2. 如請求項1至請求項18中任一項所述的化合物或其藥學上可接受的鹽，其中X 1是H、-CH 2CN、甲基或甲氧基。 The compound or the pharmaceutically acceptable salt thereof according to any one of claim 1 to claim 18, wherein X 1 is H, -CH 2 CN, methyl or methoxy. 如請求項1至請求項19中任一項所述的化合物或其藥學上可接受的鹽，其中X 2是苯基或萘基，並且苯基或萘基中的每個獨立地任選地是未被取代的或獨立地任選地被3個R 2x取代。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim item 1 to claim item 19, wherein X 2 is phenyl or naphthyl, and each of phenyl or naphthyl is independently optionally are unsubstituted or independently optionally substituted with 3 R 2x . 如請求項1至請求項20中任一項所述的化合物或其藥學上可接受的鹽，其中X 2是萘基，並且所述萘基獨立地任選地是未被取代的或獨立地任選地被3個R 2x取代。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim item 1 to claim item 20, wherein X 2 is naphthyl, and said naphthyl is independently optionally unsubstituted or independently Optionally substituted with 3 R 2x . 如請求項1至請求項21中任一項所述的化合物或其藥學上可接受的鹽，其中R 2x中的每個獨立地選自F、Cl、-OH、-NH 2、-CN、C 1-3烷基、C 1-3羥基烷基、C 1-3烷氧基、C 1-3鹵代烷基、C 2-4烯基、C 2-4炔基、C 2-4氘代炔基、氰基、(C 1-3烷氧基)C 1-3烷基、(C 1-3烷氧基)C 1-3烷氧基、(C 1-3羥基烷氧基)C 1-3烷氧基、3元環烷基或4元環烷基、或3元雜環烷基或4元雜環烷基；並且其中的每個獨立地任選地是未被取代的或獨立地任選地被1個、2個或3個-NH 2、F、Cl、氘、-CN、-OH、-C 1-3烷基或-C 1-3烷氧基取代。 The compound or pharmaceutically acceptable salt thereof as described in any one of Claim 1 to Claim 21, wherein each of R 2x 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-membered cycloalkyl or 4-membered cycloalkyl, or 3-membered heterocycloalkyl 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. 如請求項1至請求項22中任一項所述的化合物或其藥學上可接受的鹽，其中R 2x中的每個獨立地選自F、Cl、-OH、-NH 2、-CN、甲基、乙基、甲氧基、被3個F取代的甲基、被3個Cl取代的甲基、被3個F取代的乙基、乙烯基、乙炔基、被氘取代的乙炔基、3元環烷基、3元雜環烷基或氰基；並且其中的每個獨立地任選地是未被取代的或獨立地任選地被1個、2個或3個-NH 2、F、Cl、氘、-CN、-OH、甲基或甲氧基取代。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 22, wherein each of R 2x is independently selected from F, Cl, -OH, -NH 2 , -CN, Methyl, ethyl, methoxy, methyl substituted by 3 F, methyl substituted by 3 Cl, ethyl substituted by 3 F, vinyl, ethynyl, ethynyl substituted by deuterium, 3-membered cycloalkyl, 3-membered heterocycloalkyl or cyano; and each of which is independently optionally unsubstituted or independently optionally replaced by 1, 2 or 3 -NH 2 , F, Cl, deuterium, -CN, -OH, methyl or methoxy substitution. 如請求項1至請求項23中任一項所述的化合物或其藥學上可接受的鹽，其中R 2x中的每個獨立地選自F、Cl、-OH、甲基、被3個F取代的甲基、乙烯基、乙炔基或環丙基；並且其中的每個獨立地任選地是未被取代的或獨立地任選地被3個F、3個氘或甲基取代。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim item 1 to claim item 23, wherein each of R 2x is independently selected from F, Cl, -OH, methyl, 3 F substituted methyl, vinyl, ethynyl, or cyclopropyl; and each of which is independently optionally unsubstituted or independently optionally substituted with 3 F, 3 deuterium, or methyl. 如請求項1至請求項24中任一項所述的化合物或其藥學上可接受的鹽，其中X 3獨立地選自H、F、Cl、甲基或甲氧基。 The compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 24, wherein X 3 is independently selected from H, F, Cl, methyl or methoxy. 如請求項1至請求項25中任一項所述的化合物或其藥學上可接受的鹽，其中W是NR w，並且R w是H、氘、甲基或甲氧基。 The compound according to any one of claim 1 to claim 25 or a pharmaceutically acceptable salt thereof, wherein W is NR w , and R w is H, deuterium, methyl or methoxy. 如請求項1至請求項26中任一項所述的化合物或其藥學上可接受的鹽，其中W是NR w，並且R w是H。 The compound according to any one of claim 1 to claim 26, or a pharmaceutically acceptable salt thereof, wherein W is NR w , and R w is H. 如請求項1至請求項25中任一項所述的化合物或其藥學上可接受的鹽，其中W是O。The compound or a pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 25, wherein W is O. 所述化合物或其藥學上可接受的鹽選自： 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-(甲基-d 3)-吡咯烷-2-基)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-8-氧雜-3-氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(3,6-二氮雜雙環並[3.2.1]庚烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-(三氟甲基)苯酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-8-氟吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-7-基)-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-7-基)-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-7-基)-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙基-7-氟-3-羥基萘-1-基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙基-7-氟-3-羥基萘-1-基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-7(8H)-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-yl)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙基-7-氟-3-羥基萘-1-基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙基-7-氟-3-羥基萘-1-基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙基-7-氟-3-羥基萘-1-基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)吡啶並[3,4-d]嘧啶-7(8H)-基)-5-乙基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙基-6-氟萘-2-酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5,6-二氟萘-2-酚； 4-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-5,8-二氫吡啶並[3,4-d]嘧啶-7(6H)-基)-5-乙炔基-6-氟萘-2-酚； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2-d)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((S)-1-(甲基-d 3)吡咯烷-2-基)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d 3)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-5,5-d 2)甲氧基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(吡咯烷-1-基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙基-7-氟-3-羥基萘-1-基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-2-((1-((二甲基氨基)甲基)環丙基)甲氧基-d 2)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(嗎啉基甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 3-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚； 4-(4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-((1-(((R)-3-氟吡咯烷-1-基)甲基-d 2)環丙基)甲氧基-d 2)吡啶並[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)-6-(三氟甲基)吡啶並[3,4-d]嘧啶-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(((R)-3-氟吡咯烷-1-基)甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙基-7-氟-3-羥基萘-1-基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(3-氯-5-羥基-2-(三氟甲基)苯基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 4-((1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-2-((1-(嗎啉基甲基)環丙基)甲氧基-d 2)嘧啶並[4,5-d]噠嗪-8(7H)-酮； 3-(4-(1R,5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-環丙基苯酚； 3-(4-(1R，5S)-3,8-二氮雜雙環並[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-環丙基-5-氟苯酚； 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-5-氯-4-環丙基苯酚；或 3-(4-(2,5-二氮雜雙環並[2.2.2]辛烷-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基-2,5,5-d3)甲氧基)吡啶並[4,3-d]嘧啶-7-基)-4-環丙基-5-氟苯酚。 The compound or a pharmaceutically acceptable salt thereof is selected from: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8- Fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol; 3-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy -d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo [3.2.1] Octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo [3.2.1] Octane-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy -d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy -d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol; 3-(4-((1R,5S)-3,8-diazepine Bicyclo[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-diazepine Bicyclo[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-difluoronaphthalene-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-fluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[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-fluoronaphthalene-2-ol; 3-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[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-difluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo [3.2.1] Octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methyl Oxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo [3.2.1] Octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methyl Oxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[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-fluoronaphthalene-2-ol; 3-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d )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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl -2-d)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-(((S)-1-(methyl-d 3 )pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S )-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R ,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine -7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-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-fluoronaphthalene-2-ol; 3-(4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azin-7a(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-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5 -d 2 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo [3.2.1] Octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5 -d 2 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol; 3-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5 ,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5 ,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5 ,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo [3.2.1] Octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5 -d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 3-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5 ,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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl -2,5,5-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl -2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-two Azabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2 ,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-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-fluoronaphthalene-2-ol; 3-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-d 3 )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)phenol; 3-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-diazepine Bicyclo[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-difluoronaphthalene-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-fluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[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-fluoronaphthalene-2-ol; 3-(4-((1R,5S)-3,8-diazepine Bicyclo[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-difluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-two Azabicyclo[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-fluoronaphthalene-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-fluoronaphthalene-2-ol; 3-(4-((1R,5S)-8-oxo Hetero-3-azabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(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-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 3-(4-(2,5-diazabicyclo[2.2.2 ]octane-2-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2,5-diazabicyclo[2.2.2]octane Alkyl-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2,5-diazabicyclo[2.2.2]octane Alkyl-2-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)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-((tetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-difluoronaphthalene-2-ol; 4-(4-(2,5-diazabicyclo[2.2.2]octane Alkyl-2-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)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-(((S)-1-methylpyrrolidin-2-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)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-(((S)-1-(methyl-d 3 )pyrrolidin-2-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2,5-diazabicyclo[2.2.2]octane Alkyl-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2,5-diazabicyclo[2.2.2]octane Alkyl-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)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-(((S)-1-(methyl-d 3 )pyrrolidin-2-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyridine And[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol; 4-(4-(2,5-diazabicyclo[2.2.2]octano Alkyl-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)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-(((S)-1-(methyl-d 3 )pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2,5- Diazabicyclo[2.2.2]octane-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl- 2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-(2,5-diazabicyclo And[2.2.2]octane-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-fluoronaphthalene-2-ol; 3-(4-(2, 5-diazabicyclo[2.2.2]octane-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)- base-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2,5-diazabicyclo[2.2.2]octane Alkyl-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2,5-diazabicyclo[2.2.2]octane Alkyl-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 3-(4-(2,5-diazabicyclo[2.2.2 ]octane-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5 -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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5 -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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy)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-(((S)-1-(methyl-d 3 )pyrrolidin-2-yl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 3-(4-(2,5-diazabicyclo[2.2.2 ]octane-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-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-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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]octane- 2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrido[4, 3-d]pyrimidin-7-yl)-4-(trifluoromethyl)phenol; 3-(4-(2,5-diazabicyclo[2.2.2]octan-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-difluoronaphthalene-2-ol; 4-(4-(2,5-diazabicyclo[2.2.2]octane Alkyl-2-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)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-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)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)-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-fluoronaphthalene-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-fluoronaphthalene-2-ol; 4-((1R,5S)-3,8-diazepine Heterobicyclo[3.2.1]octane-3-yl)-7-(3-chloro-5-hydroxyl-2-(trifluoromethyl)phenyl)-2-((tetrahydro-1H-pyrrolizine -7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (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-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) Methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl) Methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]octan-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]octan-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]octan-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]octan-3-yl)- 7-(3-Chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl -2-d) Methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl- 2-d) Methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]octan-3-yl)- 7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2- d) Methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl- 2-d) Methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(3-Chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine -7a(5H)-yl-2-d)methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazepine Bicyclo[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-((1R,5S)-3,8-diazabicyclo[3.2 .1] Octane-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole oxazin-7a(5H)-yl-2-d)methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazepine Heterobicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolidin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrole Azin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl- 2,5,5-d 3 )methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(3-Chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl -2,5,5-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H )-base-2,5,5-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,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- base-2,5,5-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H )-base-2,5,5-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,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- base-5,5-d 2 )methoxy-d 2 )pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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]octan-3-yl)- 7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H )-base-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-hydroxyl-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a( 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]octan-3-yl)- 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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]octan-3-yl)- 7-(3-Chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H )-base-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-hydroxyl-2-(trifluoromethyl)phenyl)-2-((tetrahydro-1H-pyrrolazin-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-hydroxyl-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-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-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)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-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-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-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolazin-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-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azin-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-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-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-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azin-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-hydroxyl-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 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-(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-hydroxyl-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(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-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azin-7a(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-((1R,5S)-3,8-diazabicyclo[3.2.1 ]octane-3-yl)-7-(3-chloro-5-hydroxyl-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl-2-d)methoxy)-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R ,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-two 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]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine-8(7H) - Ketone; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene -1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-6-(trifluoromethyl )pyrido[3,4-d]pyrimidin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azin-7a(5H)-yl-2,5,5-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-hydroxyl-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl-2,5,5-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-hydroxynaphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro -1H-Pyrrolazin-7a(5H)-yl-2,5,5-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-hydroxynaphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H -Pyrrolazin-7a(5H)-yl-2,5,5-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-hydroxynaphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro -1H-Pyrrolazin-7a(5H)-yl-2,5,5-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-hydroxynaphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H -Pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(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-hydroxyl-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrolazin-7a(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-hydroxyl-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(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-hydroxynaphthalene-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]octan-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]octan-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]octan-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]octan-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]octan-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-hydroxyl-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]octan-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-hydroxyl-2-(trifluoromethyl)phenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl base) 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)methyl Oxy-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-((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]octan-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)methyl Oxy-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-7a(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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(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-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl )methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-2-((tetrahydro-1H-pyrrolazin-7a(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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(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-pyrrolazin-7a(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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(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-difluoronaphthalene-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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(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-difluoronaphthalene-2-ol; 4-(4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl -2-d) Methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -yl-2-d)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,7aS)-2-fluorotetrahydro -1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethane Base-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)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6- Difluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-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)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalene-2- Phenol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl -2,5,5-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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -base-2,5,5-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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H)-yl-2,5,5-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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H)-yl-2,5,5-d 3 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a( 5H)-yl-2,5,5-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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H)-yl-5,5-d 2 )methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S) -3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -base-5,5-d 2 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a( 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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -base-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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -base-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]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(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)methyl Oxy-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-difluoronaphthalene-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-difluoronaphthalene-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-hydroxyl-2-(trifluoromethyl)phenyl)-2-((tetrafluoromethyl) Hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(3-Chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- base) methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol Oxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl )methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl )methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]octan-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]octan-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]octan-3-yl) -7-(3-Chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- Base-2-d)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl -2-d) Methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]octan-3-yl) -7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2 -d) Methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl -2-d) Methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(3-Chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- Base-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-hydroxynaphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8- Diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((S)-1-(methyl base-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,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(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-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R ,5S)-3,8-diazabicyclo[3.2.1]octan-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,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl -2,5,5-d 3 )methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(3-Chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- base-2,5,5-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a( 5H)-yl-2,5,5-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,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -base-2,5,5-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a( 5H)-yl-2,5,5-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,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -base-5,5-d 2 )methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(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]octan-3-yl) -7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a( 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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (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]octan-3-yl) -7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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]octan-3-yl) -7-(3-Chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- base-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,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a( 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]octan-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]octan-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]octan-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]octan-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-hydroxyl-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]octan-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]octan-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-two Azabicyclo[2.2.2]octane-2-yl)-7-(3-chloro-5-hydroxyl-2-(trifluoromethyl)phenyl)-2-((tetrahydro-1H-pyrrole Azin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-ethyne Base-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(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-ethyne Base-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-ethane Base-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(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-ethane Base-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-ethyne Base-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-ethane Base-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methanol Oxy-d 2 ) pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane-2-yl)-7-(8-ethane Base-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy base-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-ethyne Base-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy base-d 2 ) pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane-2-yl)-7-(8-ethane Base-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]octane-2-yl)-7-(3-chloro -5-Hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methanol Oxy)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8 -Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d) Methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-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]octane- 2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(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-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -base-2,5,5-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-ethyne Base-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5- 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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5 -d 3 )methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7- (8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2, 5,5-d 3 )methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7- (7,8-Difluoro-3-hydroxynaphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5, 5-d 3 )methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2, 5,5-d 3 )methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7- (7,8-Difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-ethyne Base-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5, 5-d 2 )methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7- (3-Chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-ethane Base-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7- (8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5, 5-d 2 )methoxy)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7- (3-Chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane-2- Base)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H )-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane-2- Base)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane-2- Base)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl )methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane-2- Base)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane-2- Base)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane-2- Base) -7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane-2- Base)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -yl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane-2- Base) -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- Base) -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- Base) -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- Base)-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- Base)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(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- Base)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(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- Base)-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- Base)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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- Base)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(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- Base)-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]octane-2- Base)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H )-yl-2-d)methoxy)-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo And[2.2.2]octane-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4 -(2,5-diazabicyclo[2.2.2]octan-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 And[2.2.2]octane-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolazin-7a(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-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methoxy)-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine- 8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-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 And[2.2.2]octane-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane-2- Base)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -base-2,5,5-d 3 )methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane-2- Base)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H )-base-2,5,5-d 3 )methoxy)-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane Alkyl-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H)-yl-2,5,5-d 3 )methoxy)-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane Alkyl-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a( 5H)-yl-2,5,5-d 3 )methoxy)-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane Alk-2-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H)-yl-2,5,5-d 3 )methoxy)-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane Alkyl-2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a( 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- Base)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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 Alk-2-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine -7a(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- Base)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H )-base-5,5-d 2 )methoxy)-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane Alkyl-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl Oxy-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-ethyne Base-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-diazepine Heterobicyclo[2.2.2]octane-2-yl)-7-(3-chloro-5-hydroxyl-2-(trifluoromethyl)phenyl)-2-((1-((dimethyl Amino)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-diazepine Heterobicyclo[2.2.2]octan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((1-(pyrrolidin-1- methyl)cyclopropyl)methoxy-d 2 )-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octane-2- Base)-7-(3-chloro-5-hydroxyl-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- Base)-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- Base) -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- Base)-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]octan-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- Base)-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- Base)-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]octan-2-yl)-2-((tetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2,5-two Azabicyclo[2.2.2]octane-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2,5-two Azabicyclo[2.2.2]octane-2-yl)-2-((tetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy -d 2 )pyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-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-difluoronaphthalene-2-ol; 4-(4-(2,5-two Azabicyclo[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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-difluoronaphthalene-2-ol; 4-(4-(2,5-two Azabicyclo[2.2.2]octane-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methanol Oxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2,5-two Azabicyclo[2.2.2]octane-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methanol Oxy-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]octane-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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]octane-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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]octan-2-yl)-2-(((S)-1-(methyl-d 3 )pyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl-2-d)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2- Phenol; 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine -7a(5H)-yl-2-d)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoro Naphthalene-2-ol; 4-(4-(2,5-diazabicyclo[2.2.2]octan-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- Phenol; 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine -7a(5H)-yl-2,5,5-d 3 )methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2,5-two Azabicyclo[2.2.2]octane-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5 -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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5 ,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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl -2,5,5-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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl -2,5,5-d 3 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2 ,5-diazabicyclo[2.2.2]octane-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2 ,5,5-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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl -5,5-d 2 )methoxy-d 2 )-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2,5-two Azabicyclo[2.2.2]octane-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5 -d 2 )methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-(2 ,5-Diazabicyclo[2.2.2]octane-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-difluoronaphthalene-2-ol; 4-(4-(2,5-two Azabicyclo[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-difluoronaphthalene-2-ol; 4-(4-(2,5-two Azabicyclo[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-diazo Heterobicyclo[2.2.2]octane-2-yl)-7-(3-chloro-5-hydroxyl-2-(trifluoromethyl)phenyl)-2-((tetrahydro-1H-pyrrolizine -7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methanol Oxy-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d)methanol Oxy-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]octane-2-yl)-7-(3- Chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2-d) Methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7- (8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2- d) Methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-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]octane -2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(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-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (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]octane -2-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H )-base-2,5,5-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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5 -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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5, 5-d 3 )methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7 -(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2 ,5,5-d 3 )methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7 -(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5 ,5-d 3 )methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7 -(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2 ,5,5-d 3 )methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7 -(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5-d 2 )methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7 -(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5 ,5-d 2 )methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7 -(3-Chloro-5-hydroxyl-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5,5- d 2 )methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7 -(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-5 ,5-d 2 )methoxy)pyrimido[4,5-d]pyridazin-8(7H)-one; 4-(2,5-diazabicyclo[2.2.2]octan-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-two Azabicyclo[2.2.2]octane-2-yl)-7-(3-chloro-5-hydroxyl-2-(trifluoromethyl)phenyl)-2-((1-((dimethyl Amino)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]octan-3-yl)-8-fluoro-2-((1-(((R)-3-fluoropyrrolidine-1- Base) methyl) cyclopropyl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy base-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-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-fluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy base-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol; 3-(4-((1R,5S)-3,8-diazepine Bicyclo[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-diazepine Bicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo [3.2.1] Octane-3-yl)-8-fluoro-2-((1-(morpholinylmethyl)cyclopropyl)methoxy-d 2 )pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[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-fluoronaphthalene-2-ol; 3-(4-((1R,5S)-3,8-diazepine Bicyclo[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-diazepine Bicyclo[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-difluoronaphthalene-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-fluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazepine Bicyclo[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-fluoronaphthalene-2-ol; 3-(4-((1R,5S)-3,8-diazepine 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-chloro-4-(trifluoromethyl)phenol; 4-(4-((1R,5S)-3,8-diazepine 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)-5,6-difluoronaphthalene-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-fluoronaphthalene-2-ol; 4-(4-((1R,5S)-3,8-diazepine 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-ethyl-6-fluoronaphthalene-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-fluoropyrrole Alkyl-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-hydroxyl-2-(trifluoromethyl)phenyl)-2-((1-(((R)-3-fluoropyrrolidine- 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-fluoropyrrolidine-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-hydroxynaphthalene-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)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-hydroxyl-2-(trifluoromethyl)phenyl)-2-((1-(morpholinomethyl)cyclopropyl)methyl Oxy-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-hydroxynaphthalene-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)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-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((1-(((R)-3-fluoropyrrolidine-1 -yl)methyl)cyclopropyl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl) -7-(3-Chloro-5-hydroxyl-2-(trifluoromethyl)phenyl)-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl) ring Propyl)methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]octan-3-yl) -7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropane base) methoxy-d 2 )pyrimido[4,5-d]pyridazin-8(7H)-one; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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]octan-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]octan-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]octan-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- Base)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy)pyrido[ 4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol; 3-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octane Alkyl-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy) pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol; or 3-(4-(2,5-diazabicyclo[2.2.2]octane -2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl-2,5,5-d3)methoxy) pyrido[4,3-d]pyrimidin-7-yl)-4-cyclopropyl-5-fluorophenol. 一種藥物組合物，包含治療有效量的至少一種請求項29所述的化合物或其藥學上可接受的鹽，以及藥學上可接受的賦形劑。A pharmaceutical composition, comprising a therapeutically effective amount of at least one compound described in claim 29 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 一種藥物組合物，包含治療有效量的至少一種請求項1至請求項28中任一項所述的化合物或其藥學上可接受的鹽，以及藥學上可接受的賦形劑。A pharmaceutical composition, comprising a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof as described in any one of claim 1 to claim 28, and a pharmaceutically acceptable excipient. 一種抑制細胞中KRAS G12D活性的方法，所述方法包括使其中期望抑制KRAS G12D活性的所述細胞與治療有效量的至少一種根據請求項29所述的化合物或其藥學上可接受的鹽。A method for inhibiting KRAS G12D activity in a cell, the method comprising subjecting the cell in which inhibition of KRAS G12D activity is desired to a therapeutically effective amount of at least one compound according to claim 29 or a pharmaceutically acceptable salt thereof. 一種抑制細胞中KRAS G12D活性的方法，所述方法包括使其中期望抑制KRAS G12D活性的所述細胞與治療有效量的至少一種請求項1至請求項29中任一項所述的化合物或其藥學上可接受的鹽。A method for inhibiting KRAS G12D activity in cells, the method comprising making the cells in which it is desired to inhibit KRAS G12D activity and a therapeutically effective amount of at least one compound described in any one of claim 1 to claim 29 or its pharmaceutical preparation acceptable salt. 一種治療KRAS G12D相關癌症的方法，所述方法包括向需要其的患者施用治療有效量的至少一種根據請求項29所述的化合物或其藥學上可接受的鹽。A method of treating KRAS G12D-related cancer, the method comprising administering a therapeutically effective amount of at least one compound according to claim 29 or a pharmaceutically acceptable salt thereof to a patient in need thereof. 一種治療KRAS G12D相關癌症的方法，所述方法包括向需要其的患者施用治療有效量的至少一種根據請求項1至請求項29中任一項所述的化合物或其藥學上可接受的鹽。A method for treating KRAS G12D-related cancer, the method comprising administering a therapeutically effective amount of at least one compound according to any one of claim 1 to claim 29 or a pharmaceutically acceptable salt thereof to a patient in need thereof. 如請求項32至請求項35中任一項所述的方法，其中所述治療有效量的所述化合物是在約0.01 mg/kg/天至100 mg/kg/天之間。The method of any one of claim 32 to claim 35, wherein the therapeutically effective amount of the compound is between about 0.01 mg/kg/day to 100 mg/kg/day. 如請求項32至請求項35中任一項所述方法，其中所述治療有效量的所述化合物是在約0.1 mg/kg/天至50 mg/kg/天之間。The method according to any one of claim 32 to claim 35, wherein the therapeutically effective amount of the compound is between about 0.1 mg/kg/day to 50 mg/kg/day. 如請求項34至請求項35中任一項所述的方法，其中所述KRAS G12D相關癌症選自由以下組成的組：心臟：肉瘤(血管肉瘤、纖維肉瘤、橫紋肌肉瘤、脂肪肉瘤)、黏液瘤、橫紋肌瘤、纖維瘤、脂肪瘤和畸胎瘤；肺：支氣管原癌 (鱗狀細胞、未分化的小細胞、未分化的大細胞、腺癌)、肺泡(細支氣管)癌、支氣管腺瘤、肉瘤、淋巴瘤、肺軟骨瘤性錯構瘤、間皮瘤；腸胃：食道癌(鱗狀細胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃癌(癌、淋巴瘤、平滑肌肉瘤)、胰腺癌(導管腺瘤、胰島瘤、胰高血糖素瘤、胃泌素瘤、類癌腫瘤、血管活性腸肽瘤)、小腸(腺癌、淋巴瘤、類癌腫瘤、卡波西氏肉瘤、平滑肌肉瘤)；泌尿生殖道：腎(腺癌、威爾姆氏瘤 (腎母細胞瘤)、淋巴瘤、白血病)、膀胱和尿道(鱗狀細胞癌、移行細胞癌、腺癌)、***(腺癌、肉瘤)、睾丸(精原細胞瘤、畸胎瘤、胚胎性癌、畸胎癌、絨毛膜癌、肉瘤、間質細胞癌、纖維瘤、纖維腺瘤、腺瘤樣腫瘤、淋巴瘤)；肝細胞瘤(肝細胞癌)、膽管瘤、肝母細胞瘤、血管肉瘤、肝細胞腺瘤、血管瘤；膽管：膽囊癌、壺腹癌、膽管癌；骨：骨原性肉瘤(骨肉瘤)、纖維肉瘤、惡性纖維組織細胞瘤、軟骨肉瘤、尤文氏肉瘤、惡性淋巴瘤(網狀細胞肉瘤)、多發性骨髓瘤、惡性巨大細胞瘤、脊索瘤、骨軟骨瘤(骨軟骨性外生骨疣)、良性軟骨瘤、軟骨母細胞瘤、軟骨肌瘤樣纖維瘤、骨樣骨瘤以及巨大細胞瘤；神經系統：顱骨(骨瘤、血管瘤、肉芽瘤、黃色瘤、畸形性骨炎)、腦膜(腦膜瘤、腦膜肉瘤、神經膠質瘤)、腦(星形細胞瘤、髓母細胞瘤、神經膠質瘤、室管膜瘤、生殖細胞瘤(松果體瘤)、多形性膠質母細胞瘤、少突神經膠質瘤、施萬細胞瘤、視網膜母細胞瘤、先天性腫瘤)、脊髓神經纖維瘤、腦膜瘤、神經膠質瘤、肉瘤；婦科：子宮(子宮內膜癌、(漿液性囊腺癌、黏液性囊腺癌、未分類的癌)、粒層鞘細胞腫瘤、Sertoli-Leydig細胞瘤、無性細胞瘤、惡性畸胎瘤)、外陰(鱗狀細胞癌、上皮內癌、腺癌、纖維肉瘤、黑色素瘤)、***(透明細胞癌、鱗狀細胞癌、葡萄樣肉瘤、(胚胎型橫紋肌肉瘤)、輸卵管(癌))；血液：血(骨髓樣白血病(急性的和慢性的)、急性淋巴母細胞白血病、慢性淋巴細胞白血病、骨髓增生性疾病、多發性骨髓瘤、骨髓增生異常綜合征)、霍奇金氏疾病、非霍奇金氏淋巴瘤(惡性淋巴瘤)；皮膚：惡性黑色素瘤、基底細胞癌、鱗狀細胞癌、卡波西氏肉瘤、痣、發育不良痣、淋巴瘤、血管瘤、皮膚纖維瘤、瘢痕瘤、銀屑病；以及腎上腺：神經母細胞瘤。The method according to any one of claim 34 to claim 35, wherein the KRAS G12D-associated cancer is selected from the group consisting of: heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma , rhabdomyoma, fibroid, lipoma, and teratoma; lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole) carcinoma, bronchial adenoma , sarcoma, lymphoma, pulmonary chondromatous hamartoma, mesothelioma; stomach: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreas Carcinoma (ductal adenoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small bowel (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, smooth muscle sarcoma); genitourinary tract: kidney (adenocarcinoma, Wilms tumor (Wilms tumor), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma Carcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lymphoma) ; hepatocellular carcinoma (liver cell carcinoma), cholangioma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; bone: osteogenic sarcoma (osteosarcoma ), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral exogenous osteoma), benign chondroma, chondroblastoma, chondromyomatous fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans ), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineeal tumor), glia multiforme Blastoma, oligodendroglioma, Schwann's cell tumor, retinoblastoma, congenital tumor), neurofibroma of the spinal cord, meningioma, glioma, sarcoma; Gynecology: uterus (endometrial carcinoma, (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa sheath cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma , adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, (embryonal rhabdomyosarcoma), fallopian tube (carcinoma)); blood: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorder, 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, nevus, dysplastic nevus, lymphoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal: neuroblastoma cell tumor. 如請求項38所述的方法，其中所述癌症是非小細胞肺癌、小細胞肺癌、結直腸癌、直腸癌或胰腺癌。The method of claim 38, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer. 一種用於治療需要其的患者中的癌症的方法，所述方法包括(a)確定所述癌症與KRAS G12D突變相關(例如，KRAS G12D相關癌症)；以及(b)向所述患者施用治療有效量的至少一種根據請求項1或請求項29所述的化合物。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., a KRAS G12D-associated cancer); and (b) administering to the patient a treatment effective amount of at least one compound according to claim 1 or claim 29. 一種用於治療需要其的患者中的癌症的方法，所述方法包括(a)確定所述癌症與KRAS G12D突變相關(例如，KRAS G12D相關癌症)；以及(b)向所述患者施用治療有效量的至少一種根據請求項29所述的化合物。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., a KRAS G12D-associated cancer); and (b) administering to the patient a treatment effective amount of at least one compound according to claim 29. 如請求項40至請求項41中任一項所述的方法，其中所述施用經由選自由以下組成的組的途徑來進行：腸胃外施用、腹腔施用、經皮施用、心內施用、心室內施用、顱內施用、腦脊髓內施用、滑膜內施用、鞘內施用、肌肉內注射、玻璃體內注射、靜脈注射、動脈內注射、口服施用、鼻內施用、含服、舌下施用、經皮施用、局部施用、氣管內施用、直腸內施用、皮下施用以及局部施用。The method of any one of claim 40 to claim 41, wherein the administering is via a route selected from the group consisting of: parenteral administration, intraperitoneal administration, transdermal administration, intracardiac administration, intraventricular administration Administration, intracranial administration, intracerebrospinal administration, intrasynovial administration, intrathecal administration, intramuscular injection, intravitreal injection, intravenous injection, intraarterial injection, oral administration, intranasal administration, buccal, sublingual administration, via Transdermal, topical, intratracheal, intrarectal, subcutaneous and topical administration. 如請求項42所述的方法，其中所述施用經由靜脈注射來進行。The method of claim 42, wherein said administering is via intravenous injection. 如請求項42所述的方法，其中所述施用經由肌肉內注射來進行。The method of claim 42, wherein said administering is via intramuscular injection. 如請求項42所述的方法，其中所述施用經由口服來進行。The method of claim 42, wherein said administering is performed orally. 如請求項42所述的方法，其中所述施用包括利用遞送裝置。The method of claim 42, wherein said administering comprises using a delivery device. 如請求項42所述的方法，其中所述施用經由醫院設施來進行。The method of claim 42, wherein the administering is via a hospital facility.
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