CN117242074A

CN117242074A - KRAS G12D inhibitors

Info

Publication number: CN117242074A
Application number: CN202280030338.4A
Authority: CN
Inventors: B·E·芬克; R·J·切尔尼; K·恩古; U·维拉帕蒂; W·D·瓦卡罗; 阮哲铭; 秦兰英; P·S·希鲁德; H·拉哈曼
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2021-03-12
Filing date: 2022-03-14
Publication date: 2023-12-15

Abstract

The present disclosure relates to KRAS inhibitors. Methods of using the compounds for treating cancer are also provided.

Description

KRAS G12D inhibitors

Cross Reference to Related Applications

The present application claims U.S. provisional application No. 63/160,431 filed on day 21 of 3 of 2021; U.S. provisional application No. 63/173,021, filed on 4/9 of 2021; U.S. provisional application No. 63/220,386 filed on 7.9 of 2021; and U.S. provisional application No. 63/236,497, filed on 24 at 8 of 2021, each of which is incorporated by reference in its entirety.

Technical Field

The present disclosure provides KRAS inhibitors. Methods of treating cancer using the inhibitors are also provided.

Background

KRAS oncogenes are members of the Ras family of gtpases involved in many cellular signaling processes. KRAS mutations are gain-of-function mutations that are present in up to 30% (including up to 90%) of all tumors. KRAS G12D mutations are present in 28% of all pancreatic ductal adenocarcinoma patients, 13% of all colorectal cancer patients, 4% of all non-small cell lung cancer patients and 3% of all gastric cancer patients (see, e.g., https:// www.mycancergenome.org/content/alteration/KRAS-G12D /). Because of the clinical significance of this protein, many attempts have been made to develop Ras inhibitors, but most of these attempts have been unsuccessful. This is due in large part to the difficulty in competing for KRAS binding pocket in cells over GTP and the lack of known allosteric regulatory sites. Thus, agents that inhibit KRAS G12D are desirable.

Disclosure of Invention

In a first aspect, the present disclosure provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein:

R ¹ is aryl or heteroaryl, wherein said aryl and said heteroaryl are optionally substituted with one, two, three, four or five groups independently selected from C ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkenyl, C ₂ -C ₄ Alkynyl, amino C ₁ -C ₃ Alkyl, C ₃ -C ₄ Cycloalkyl, halo C ₁ -C ₃ Alkyl, hydroxy, and hydroxy C ₁ -C ₃ Substituent substitution of alkyl;

R ² and R is ³ Independently selected from hydrogen, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, cyano, halo C ₁ -C ₃ Alkyl, and hydroxy;

R ⁴ selected from:

wherein the method comprises the steps of

R ^a Is hydrogen or C ₁ -C ₃ An alkyl group; and is also provided with

Representing an attachment point to the parent molecular moiety;

R ⁵ is- (C) ₁ -C ₃ Alkyl) -R ⁶ Or- (C) ₁ -C ₆ Alkyl) NR ^c R ^d Wherein R is ⁶ Selected from the group consisting of

Optionally by NR ^c R ^d (C ₁ -C ₃ Alkyl) -substituted C ₃ -C ₆ Cycloalkyl; and

a five to ten membered monocyclic, bicyclic or tricyclic fully saturated or fully unsaturated ring containing one nitrogen atom and optionally a second heteroatom selected from oxygen or nitrogen, wherein said ring contains zero to three double bonds, and wherein said ring is optionally substituted with one, two or three substituents independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkyl, benzyl, halo C ₁ -C ₃ Alkyl, hydroxy C ₁ -C ₃ Alkyl, and oxo groups; wherein the method comprises the steps of

R ^c And R is ^d Together with the nitrogen atom to which they are attached form a five to ten membered ring monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen and sulfur, wherein the rings are optionally substituted with one, two or three groups independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkyl, benzyl, halo C ₁ -C ₃ Alkyl, hydroxy C ₁ -C ₃ Alkyl and oxo groups; or (b)

R ^c And R is ^d One of them is selected from hydrogen and C ₁ -C ₃ Alkyl, and the other is selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxycarbonyl and C ₁ -C ₃ An alkylcarbonyl group.

In some aspects, R ² And R is ³ Each is a halo group. In some aspects, R ² Is chlorine, and R ³ Is fluorine. In another aspect, R ² Is hydrogen, and R ³ Is fluorine.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁵ Is- (C) ₁ -C ₃ Alkyl) -R ⁶ 。

In some aspects, R ¹ Is substituted, wherein R ¹ One of the substituents on this is halo C ₁ -C ₃ An alkyl group.

In some aspects, R ⁶ Is a five to eight membered monocyclic or bicyclic fully saturated or fully unsaturated ring containing one nitrogen atom and optionally a second heteroatom selected from oxygen or nitrogen, wherein the ring contains zero to three double bonds, and wherein the ring is optionally substituted with one, two or three groups independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halo C ₁ -C ₃ Alkyl and hydroxy groups.

In some aspects, R ⁵ Selected from:

wherein each ring is optionally substituted with 1, 2 or 3 groups independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkyl, benzyl, halo C ₁ -C ₃ Alkyl, hydroxy C ₁ -C ₃ Alkyl and oxo groups; and wherein

Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein- >Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R is

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁶ Is an eight membered bicyclic fully saturated or fully unsaturated ring containing one nitrogen atom, said ring optionally being independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkyl, benzyl, halo C ₁ -C ₃ Alkyl, hydroxy C ₁ -C ₃ Alkyl and oxo groups.

In some aspects, R ⁵ Is that

Wherein:

z is 1, 2 or 3;

each R ⁵⁰ Independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkyl, benzyl, halo C ₁ -C ₃ Alkyl, hydroxy C ₁ -C ₃ Alkyl and oxo; and is also provided with

Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein:

z is 1, 2 or 3;

Indicating the point of attachment to the parent molecular moiety.

In some aspects, z is 1, and R ⁵⁰ Is a halo group. In some aspects, R ⁵⁰ Is fluorine. In some aspects, R ¹ Is naphthyl, wherein said naphthyl is optionally substituted with one selected from C ₁ -C ₃ Alkyl and hydroxy groups.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein the method comprises the steps of

q and r are each independently 0 or 1;

R ^x and R is ^y Independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halo C ₁ -C ₃ Alkyl and hydroxy; and is also provided with

Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein q, r and d are each independently 0 or 1; wherein R is ^x 、R ^y And R is ^p Independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halo C ₁ -C ₃ Alkyl and hydroxy; and is also provided with

Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ¹ Is phenyl, wherein said phenyl is optionally substituted with one or two substituents selected from C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, halo and halo C ₁ -C ₃ The groups of the alkyl groups are substituted.

In some aspects, R ¹ Is naphthyl, wherein the naphthyl is optionally one, two or three independently selected from C ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkynyl, C ₃ Cycloalkyl, halo, and hydroxy groups.

In some aspects, R ¹ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ¹ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ¹ Is that

Wherein->Representing the parent molecular moietyAttachment points.

In some aspects, R ¹ Is that

Wherein q is 1, 2 or 3; each R ^z Independently selected from C ₁ -C ₃ Alkyl and halo; and is also provided withIndicating the point of attachment to the parent molecular moiety.

In some aspects, R ¹ Is that

Wherein the method comprises the steps of

q and r are each independently 0 or 1;

Indicating the point of attachment to the parent molecular moiety.

In some aspects, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

R ² Is hydrogen;

R ³ is fluorine;

R ¹ selected from the group consisting of

And is also provided with

R ⁵ Selected from the group consisting of

Wherein the method comprises the steps ofIndicating the point of attachment to the parent molecular moiety.

R ² Is chlorine;

R ³ is fluorine; r is R ¹ Selected from the group consisting of

And is also provided with

R ⁵ Selected from the group consisting of

In certain aspects, the present disclosure provides a compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ selected from the group consisting of

Wherein->Representing an attachment point to the parent molecular moiety; and is also provided with

R ⁴ Selected from:

wherein the method comprises the steps of

R ^a Is hydrogen or C ₁ -C ₃ An alkyl group; and is also provided with

Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In certain aspects, the present disclosure provides a compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ selected from the group consisting of

Wherein the method comprises the steps ofRepresenting an attachment point to the parent molecular moiety; and is also provided with

R ⁴ Selected from:

wherein the method comprises the steps of

R ^a Is hydrogen or C ₁ -C ₃ An alkyl group; and is also provided with

Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects, the disclosure provides atropisomers of the compounds of any of the preceding aspects. In certain embodiments, the compound is a stable atropisomer as described herein.

In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

In some aspects, the present disclosure provides an oral dosage form comprising a compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

In certain aspects, the present disclosure provides methods of treating a cancer expressing a KRAS G12D mutation in a subject in need thereof, the method comprising administering to the subject a compound of formula (I):

Or a pharmaceutically acceptable salt thereof; wherein:

R ⁴ selected from:

wherein the method comprises the steps of

R ^a Is hydrogen or C ₁ -C ₃ An alkyl group; and, moreover;

indicating the point of attachment to the parent molecular moiety.

R ⁵ Is- (C) ₁ -C ₃ Alkyl) -R ⁶ Or- (C) ₁ -C ₆ Alkyl) NR ^c R ^d Wherein R is ⁶ Selected from:

a five to ten membered monocyclic, bicyclic or tricyclic fully saturated or fully unsaturated ring containing one nitrogen atom and optionally a second heteroatom selected from oxygen or nitrogen,wherein the ring contains zero to three double bonds, and wherein the ring is optionally substituted with one, two or three groups independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkyl, benzyl, halo C ₁ -C ₃ Alkyl, hydroxy C ₁ -C ₃ Alkyl, and oxo groups; wherein the method comprises the steps of

In some aspects of the method, R ² And R is ³ Each is a halo group. In some aspects, R ² Is chlorine, and R ³ Is fluorine. In other aspects, R ² Is hydrogen, and R ³ Is fluorine.

In some aspects of the method, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects of the method, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects of the method, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects of the method, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects of the method, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects of the method, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects of the method, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects of the method, R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects of the method, R ⁵ Is- (C) ₁ -C ₃ Alkyl) -R ⁶ 。

In some aspects of the method, R ¹ Is substituted and wherein R ¹ One of the substituents on this is halo C ₁ -C ₃ An alkyl group.

In some aspects of the method, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects of the method, R ⁶ Is an eight membered bicyclic fully saturated or fully unsaturated ring containing one nitrogen atom, said ring optionally being independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkyl, benzyl, halo C ₁ -C ₃ Alkyl, hydroxy C ₁ -C ₃ Alkyl and oxo groups.

In some aspects of the method, R ⁵ Is that

Wherein: />

z is 1, 2 or 3;

Indicating the point of attachment to the parent molecular moiety.

In some aspects of the method, R ⁵ Is that

Wherein:

z is 1, 2 or 3;

Indicating the point of attachment to the parent molecular moiety.

In some aspects of the method, z is 1, and R ⁵⁰ Is a halo group. In some aspects, R ⁵⁰ Is fluorine.

In some aspects of the method, R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects of the method, R ⁵ Is that

Wherein the method comprises the steps of

q and r are each independently 0 or 1;

Indicating the point of attachment to the parent molecular moiety.

In some aspects of the method, R ⁵ Is that

Indicating the point of attachment to the parent molecular moiety. />

In some aspects of the method, R ⁵ Is that

Wherein the method comprises the steps of

Indicating the point of attachment to the parent molecular moiety.

In some aspects of the method, R ¹ Is naphthyl, wherein the naphthyl is optionally one, two or three independently selected from C ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkynyl, C ₃ Cycloalkyl, halo, and hydroxy groups. In some aspects of the method, R ¹ Is naphthyl, wherein said naphthyl is optionally substituted with one selected from C ₁ -C ₃ Alkyl and hydroxy groups.

In some aspects of the method, R ¹ Is phenyl, wherein said phenyl is optionally substituted with one or two substituents selected from C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, halo and halo C ₁ -C ₃ The groups of the alkyl groups are substituted.

In some aspects of the method, R ¹ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects of the method, R ¹ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects of the method, R ¹ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects of the method, R ¹ Is that

Wherein:

q is 1, 2 or 3;

each R ^z Independently selected from C ₁ -C ₃ Alkyl and halo; and is also provided with

Indicating the point of attachment to the parent molecular moiety.

In some aspects of the method, R ¹ Is that

Wherein the method comprises the steps of

q and r are each independently 0 or 1;

Indicating the point of attachment to the parent molecular moiety.

In some aspects of the method, R ² Is hydrogen; r is R ³ Is fluorine; r is R ¹ Selected from the group consisting of

And is also provided with

R ⁵ Selected from the group consisting of

Wherein->Indicating the point of attachment to the parent molecular moiety.

In some aspects of the method, R ² Is chlorine; r is R ³ Is fluorine; r is R ¹ Selected from the group consisting of

And is also provided with

R ⁵ Selected from the group consisting of

Wherein->Indicating the point of attachment to the parent molecular moiety.

In certain aspects of the methods, the compound is a compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ selected from the group consisting of

R ⁴ Selected from:

wherein the method comprises the steps of

R ^a Is hydrogen or C ₁ -C ₃ An alkyl group; and is also provided with

Indicating the point of attachment to the parent molecular moiety.

In some aspects of the methods, the compound is a compound of formula (II), wherein R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects of the methods, the compound is a compound of formula (II), wherein R ⁴ Is thatWherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects of the methods, the compound is a compound of formula (II), wherein R ⁴ Is thatWherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group. />

In certain aspects of the method the compound is a compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ selected from the group consisting of

R ⁴ Selected from:

wherein the method comprises the steps of

R ^a Is hydrogen or C ₁ -C ₃ An alkyl group; and is also provided with

Indicating the point of attachment to the parent molecular moiety.

In some aspects of the methods, the compound is a compound of formula (III), wherein R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group. />

In some aspects of the method described herein,the compound is of formula (III) wherein R ⁴ Is that

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group. />

Wherein R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group.

In some aspects of the methods, the compound is an atropisomer of a compound of any of the preceding aspects. In certain aspects, the compound is a stable atropisomer as described herein.

In another aspect, the present disclosure provides a method for inhibiting KRAS Gl2D activity in a cell, the method comprising contacting the cell with a compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein. In one aspect, the contacting is in vitro. In one aspect, the contacting is in vivo.

In another aspect, the present disclosure provides a method of inhibiting proliferation of a cell in vitro or in vivo, the method comprising contacting the cell with an effective amount of a compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein.

In another aspect, the present disclosure provides a method of treating a KRAS Gl 2D-associated disease or disorder in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), formula (II), or formula (III) as defined herein, over a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In another aspect, the present disclosure provides a method for treating cancer susceptible to KRAS G12D inhibition in a subject in need thereof, the method comprising administering to the subject a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, gastric cancer, and combinations thereof.

In another aspect, the present disclosure provides a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, for use in inhibiting KRAS G12D.

In another aspect, the present disclosure provides a compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein, for use in the treatment of KRAS G12D-related diseases or disorders.

In another aspect, the present disclosure provides the use of a compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of cancer.

In another aspect, the present disclosure provides the use of a compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for inhibiting KRAS Gl2D activity.

In another aspect, the present disclosure provides the use of a compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRAS G12D-related disease or disorder.

In another aspect, the present disclosure provides a compound selected from the group consisting of:

/>

Or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides a compound selected from the group consisting of:

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 1;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 2;

6- (6-chloro-4- {3, 6-diazabicyclo [3.1.1] hept-6-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-8-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 9-diazabicyclo [3.3.1] non-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 6-diazabicyclo [3.1.1] hept-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {2, 5-diazabicyclo [2.2.1] hept-2-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {2, 5-diazabicyclo [2.2.1] hept-2-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (isomer 1);

6- (6-chloro-4- {2, 5-diazabicyclo [2.2.1] hept-2-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (isomer 2);

6- (6-chloro-4- {2, 5-diazabicyclo [2.2.2] oct-2-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 9-diazabicyclo [3.3.1] non-9-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-8-fluoro-4- { 8-methyl-3, 8-diazabicyclo [3.2.1] oct-3-yl } -2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2R) -1- (piperidin-1-yl) propan-2-yl ] oxy } quinazolin-7-yl) naphthalen-2-ol;

1- [ (2R) -2- [ (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-2-yl) oxy ] propyl ] piperidin-4-ol;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol;

4- { 6-chloro-4- [ (1 r,4 r) -2, 5-diazabicyclo [2.2.1] hept-2-yl ] -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl } naphthalen-2-ol;

4- (6-chloro-4- {3, 6-diazabicyclo [3.1.1] hept-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalene-2-ol;

6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- (5-methyl-1H-indazol-4-yl) -2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazoline;

6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } -7-phenylquinazoline;

6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- (2-fluorophenyl) -2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazoline;

6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- (1H-indazol-4-yl) -2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazoline;

8- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol;

-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- (1-methyl-1H-indazol-7-yl) -2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazoline;

6-chloro-7- (2-cyclopropylphenyl) -4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazoline;

6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- (2-fluoro-6-methylphenyl) -2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazoline;

6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- (3-fluoro-2-methylphenyl) -2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazoline;

4- ((1 r, 5S) -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } -7- [2- (propan-2-yl) phenyl ] quinazoline;

6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- [ 3-fluoro-2- (trifluoromethyl) phenyl ] -2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazoline;

6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } -7- (naphthalen-1-yl) quinazoline;

6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- (2-methylnaphthalen-1-yl) -2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazoline;

6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } -7- [2- (trifluoromethyl) phenyl ] quinazoline;

4- (6-chloro-4- {3, 6-diazabicyclo [3.1.1] hept-6-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalene-2-ol;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-8-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol;

4- (6-chloro-4- {3, 9-diazabicyclo [3.3.1] non-9-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol;

4- (6-chloro-8-fluoro-4- { 8-methyl-3, 8-diazabicyclo [3.2.1] oct-3-yl } -2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol;

4- (6-chloro-4- {2, 5-diazabicyclo [2.2.1] hept-2-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol;

(5S) -5- { [ (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-2-yl) oxy ] methyl } pyrrolidin-2-one;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2R) -4-methylmorpholin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- [2- (1-methyl-1H-imidazol-2-yl) ethoxy ] quinazolin-7-yl) naphthalene-2-ol;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- [ (1H-pyrazol-5-yl) methoxy ] quinazolin-7-yl) naphthalen-2-ol;

(5R) -5- { [ (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-2-yl) oxy ] methyl } pyrrolidin-2-one;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2 s,4 r) -4-methoxy-1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol;

n- {1- [ (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-2-yl) oxy ] -2-methylpropan-2-yl } acetamide;

4- {2- [ (2-benzyl-1-methylpyrrolidin-2-yl) methoxy ] -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl } naphthalen-2-ol;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [2- (methoxymethyl) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol;

6- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 1;

6- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 2;

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol;

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol, isomer 1;

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol, isomer 2;

6- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 1;

6- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 2;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol, isomer 1;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol, isomer 2;

4- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol;

4- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol, isomer 1;

4- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol, isomer 2;

6- (2- { [ (2 s,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

4- (2- { [ (2 s,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol;

4- (2- { [ (2 s,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol, isomer 1;

4- (2- { [ (2 s,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol, isomer 2;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3,8-;

diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-fluoronaphthalene-2-ol;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -2- ({ 1- [ (dimethylamino) methyl ] cyclopropyl } methoxy) -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- [ (1- { [ (3R) -3-fluoropyrrolidin-1-yl ] methyl } cyclopropyl) methoxy ] quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1- [ (piperidin-1-yl) methyl ] cyclopropyl } methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1- [ (morpholin-4-yl) methyl ] cyclopropyl } methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1- [ (3-fluoropiperidin-1-yl) methyl ] cyclopropyl } methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- [ (1- { [4- (trifluoromethyl) piperidin-1-yl ] methyl } cyclopropyl) methoxy ] quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- [ (1- { [ (3R) -3-fluoropyrrolidin-1-yl ] methyl } cyclopropyl) methoxy ] quinazolin-7-yl) -5-fluoronaphthalene-2-ol;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [1- ({ 3-oxa-8-azabicyclo [3.2.1] oct-8-yl } methyl) cyclopropyl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -2- { [1- ({ 6, 6-dimethyl-3-azabicyclo [3.1.0] hex-3-yl } methyl) cyclopropyl ] methoxy } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

(3S) -1- ({ 1- [ ({ 7- [ 6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl ] -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-2-yl } oxy) methyl ] cyclopropyl } methyl) pyrrolidin-3-ol;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- [ (1- { [ (3S) -3-fluoropyrrolidin-1-yl ] methyl } cyclopropyl) methoxy ] quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1- [ (3-fluoroazetidin-1-yl) methyl ] cyclopropyl } methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -2- ({ 1- [ (4, 4-difluoropiperidin-1-yl) methyl ] cyclopropyl } methoxy) -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- [ (1- { [ (3R) -3-methylmorpholin-4-yl ] methyl } cyclopropyl) methoxy ] quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

4- (4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- [ (1- { [ (3R) -3-fluoropyrrolidin-1-yl ] methyl } cyclopropyl) methoxy ] quinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;

4- ({ 1- [ ({ 7- [ 6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl ] -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-2-yl } oxy) methyl ] cyclopropyl } methyl) -1λ6-thiomorpholine-1, 1-dione;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- [ (1- { [3- (trifluoromethyl) piperidin-1-yl ] methyl } cyclopropyl) methoxy ] quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1- [ (3-methoxypiperidin-1-yl) methyl ] cyclopropyl } methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- [ (1- { [ (2 r,5 s) -2,4, 5-trimethylpiperazin-1-yl ] methyl } cyclopropyl) methoxy ] quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -2- [ (1- { [ (2R) -2, 4-dimethylpiperazin-1-yl ] methyl } cyclopropyl) methoxy ] -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -2- ({ 1- [ (3, 3-dimethylpiperidin-1-yl) methyl ] cyclopropyl } methoxy) -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (2- { [ (4 as,7 ar) -1-methyl-octahydro-1H-cyclopenteno [ b ] pyridin-4 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl } methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl } methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 1;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl } methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 2;

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl } methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 3;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl } methoxy) quinazolin-7-yl) naphthalen-2-ol;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl } methoxy) quinazolin-7-yl) naphthalene-2-ol, isomer 1;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl } methoxy) quinazolin-7-yl) naphthalene-2-ol, isomer 2;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl } methoxy) quinazolin-7-yl) naphthalen-2-ol, isomer 3;

4- (2- { [ (4 as,7 ar) -1-methyl-octahydro-1H-cyclopenteno [ b ] pyridin-4 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -5-fluoronaphthalene-2-ol;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -5-fluoronaphthalene-2-ol, isomer 2;

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -5-fluoronaphthalene-2-ol, isomer 1;

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol;

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol, isomer 1;

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol, isomer 2;

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethyl-6-fluoronaphthalene-2-ol;

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethyl-6-fluoronaphthalene-2-ol, isomer 1;

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethyl-6-fluoronaphthalene-2-ol, isomer 2;

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-fluoronaphthalene-2-ol;

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-fluoronaphthalene-2-ol, isomer 1;

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-fluoronaphthalene-2-ol, isomer 2;

6- (2- { [ (7 aR) -2, 2-difluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (2- { [ (7 aR) -2, 2-difluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 1;

6- (2- { [ (7 aR) -2, 2-difluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 2;

6- {2- [ (1S) -1- [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] ethoxy ] -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl } -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- {2- [ (1S) -1- [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] ethoxy ] -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl } -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 1;

6- {2- [ (1S) -1- [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] ethoxy ] -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl } -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 2;

6- (2- { [ (2 r,6r,7 ar) -2-fluoro-6-methyl-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

4- (2- { [ (6 ' r,7' ar) -6' -fluoro-hexahydrospiro [ cyclopropan-1, 2' -pyrrolizine ] -7' a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol;

4- (2- { [ (6 ' r,7' ar) -6' -fluoro-hexahydrospiro [ cyclopropan-1, 2' -pyrrolizine ] -7' a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol, isomer 1;

4- (2- { [ (6 ' r,7' ar) -6' -fluoro-hexahydrospiro [ cyclopropan-1, 2' -pyrrolizine ] -7' a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol, isomer 2;

6- (2- { [ (2 r,6s,7 ar) -2, 6-difluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

4- (2- { [ (2 r,6s,7 ar) -2, 6-difluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol;

4- (2- { [ (2 r,6s,7 ar) -2, 6-difluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol, isomer 1;

4- (2- { [ (2 r,6s,7 ar) -2, 6-difluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol, isomer 2;

6- (2- { [ (6 ' r,7' ar) -3, 6' -trifluoro-hexahydrospiro [ cyclopropan-1, 2' -pyrrolizine ] -7' a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

4- (2- { [ (4 as,7 ar) -1-methyl-octahydro-1H-cyclopenteno [ b ] pyridin-4 a-yl ] methoxy } -4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol;

4- (2- { [ (4 as,7 ar) -1-methyl-octahydro-1H-cyclopenteno [ b ] pyridin-4 a-yl ] methoxy } -4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-fluoronaphthalene-2-ol;

4- (2- { [ (4 as,7 ar) -1-methyl-octahydro-1H-cyclopenteno [ b ] pyridin-4 a-yl ] methoxy } -4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol;

4- (2- { [ (4 as,7 ar) -1-methyl-octahydro-1H-cyclopenteno [ b ] pyridin-4 a-yl ] methoxy } -4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol;

2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -7- (8-ethylnaphthalen-1-yl) -8-fluoroquinazoline;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-fluoronaphthalene-2-ol;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol, isomer 1;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol, isomer 2;

1- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -8-fluoroisoquinolin-3-amine;

3- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-chloro-4-cyclopropylphenol;

6- (2- { [ (2 s,7 as) -2- (difluoromethoxy) -hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 1;

6- (2- { [ (2 s,7 as) -2- (difluoromethoxy) -hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine, isomer 2;

6- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-7- (5-chloro-6-methyl-1H-indazol-4-yl) -4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazoline;

1- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) isoquinolin-3-amine;

1- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -8-fluoroisoquinolin-3-amine; and

4- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-fluoronaphthalene-2-ol;

or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound as described in any of the above aspects, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

In another aspect, the present disclosure provides a method for treating cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of any of the above aspects, or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure provides a method for treating cancer susceptible to KRAS G12D inhibition in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of any of the above aspects, or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure provides a method for treating a cancer that expresses KRAS G12D inhibition in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of any of the above aspects, or a pharmaceutically acceptable salt thereof.

Detailed Description

Unless otherwise indicated, any atom having an unsaturated valence is assumed to have a hydrogen atom sufficient to satisfy the valence.

The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

As used herein, the term "or" is a logical disjunctive (i.e., and/or) and does not indicate a mutually exclusive disjunctive unless expressly indicated by words such as the terms "or," "unless," "alternatively," and the like.

As used herein, the phrase "or a pharmaceutically acceptable salt thereof" refers to at least one compound, or at least one salt of the compound, or a combination thereof. For example, "a compound of formula (I) or a pharmaceutically acceptable salt thereof" includes, but is not limited to, one compound of formula (I), two compounds of formula (I), a pharmaceutically acceptable salt of a compound of formula (I), one or more pharmaceutically acceptable salts of a compound of formula (I) and a compound of formula (I), and two or more pharmaceutically acceptable salts of a compound of formula (I).

As used herein, the term "C ₂ -C ₄ Alkenyl "refers to groups derived from straight or branched chain hydrocarbons containing two to four carbon atoms and one double bond.

As used herein, the term "C ₁ -C ₃ Alkoxy "refers to C attached to the parent molecular moiety through an oxygen atom ₁ -C ₃ An alkyl group.

As used herein, the term "C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl "means by C ₁ -C ₃ C with alkyl groups attached to the parent molecular moiety ₁ -C ₃ An alkoxy group.

As used herein, the term "C ₁ -C ₃ Alkoxycarbonyl "refers to C attached to the parent molecular moiety through a carbonyl group ₁ -C ₃ An alkoxy group.

As used herein, the term "C ₁ -C ₃ Alkyl "refers to a group derived from a straight or branched chain saturated hydrocarbon containing one to three carbon atoms.

As used herein, the term "C ₁ -C ₆ Alkyl "refers to a group derived from a straight or branched chain saturated hydrocarbon containing one to three carbon atoms.

As used herein, the term "C ₁ -C ₃ Alkylcarbonyl "refers to C attached to the parent molecular moiety through a carbonyl group ₁ -C ₃ An alkyl group.

As used herein, the term "C ₂ -C ₄ Alkynyl "refers to a group derived from a straight or branched hydrocarbon containing two to four carbon atoms and one triple bond.

The term "amino" as used herein refers to-NH ₂ 。

The term "amino C", as used herein ₁ -C ₃ Alkyl "means by C ₁ -C ₃ The alkyl is attached to the amino group of the parent molecular moiety.

As used herein, the term "aryl" refers to a phenyl group or a bicyclic fused ring system in which one or both rings are phenyl groups. The bicyclic fused ring system consists of a phenyl group fused to a four to six membered aromatic or non-aromatic carbocyclic ring. The aryl groups of the present disclosure may be attached to the parent molecular moiety through any substitutable carbon atom in the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.

As used herein, the term "cyano" refers to-CN.

As used herein, the term "C ₃ -C ₄ Cycloalkyl "refers to a saturated monocyclic hydrocarbon ring system having three or four carbon atoms and zero heteroatoms.

As used herein, the terms "halo" and "halogen" refer to F, cl, br or I.

The term "halo C", as used herein ₁ -C ₃ Alkyl "means C substituted by one, two or three halogen atoms ₁ -C ₃ An alkyl group.

As used herein, the term "heteroaryl" refers to an aromatic five or six membered ring in which at least one atom is selected from N, O and S, and the remaining atoms are carbon. The term "heteroaryl" also includes bicyclic ring systems in which the heteroaryl ring is fused to a four to six membered aromatic or non-aromatic ring containing zero, one or two additional heteroatoms selected from N, O and S; and a tricyclic system wherein the bicyclic system is fused to a four to six membered aromatic or non-aromatic ring containing zero, one or two additional heteroatoms selected from N, O and S. Heteroaryl groups are attached to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group. Representative examples of heteroaryl groups include, but are not limited to, alloxazine, benzo [1,2-d:4,5-d' ] dithiazolyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, purinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl.

As used herein, the term "hydroxy" refers to-OH.

As used herein, the term "hydroxy C ₁ -C ₃ Alkyl "means by C ₁ -C ₃ An alkyl group is attached to a hydroxy group of the parent molecular moiety.

As used herein, the term "oxo" refers to = O.

Another aspect of the subject matter described herein is the use of the disclosed compounds as radiolabeled ligands for developing ligand binding assays or for monitoring in vivo adsorption, metabolism, distribution, receptor binding or occupancy or compound disposal. For example, the compounds described herein may be prepared using radioisotopes, and the resulting radiolabeled compounds may be used to develop binding assays or for metabolic studies. Alternatively and for the same purpose, the compounds described herein may be converted to radiolabeled form by catalytic tritiation using methods known to those skilled in the art.

Certain compounds of the present disclosure exist as stereoisomers. It should be understood that when stereochemistry is not specified, the present disclosure encompasses all stereochemically isomeric forms or mixtures thereof having the ability to inhibit KRAS G12D. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials containing chiral centers or by preparing mixtures of enantiomeric products followed by separation, such as conversion to mixtures of diastereomers, followed by separation or recrystallization, chromatographic techniques or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of a particular stereochemistry are commercially available or may be prepared and resolved by techniques known in the art.

Certain compounds of the present disclosure may exist as tautomers, which are compounds that result from the phenomenon of proton transfer of a molecule to a different atom within the molecule. The term "tautomer" also refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer to another. All tautomers of the compounds described herein are included within the present disclosure.

Certain compounds of the present disclosure exist as atropisomers. The term "atropisomer" refers to conformational stereoisomers that occur when rotation about a single bond in a molecule is prevented or greatly slowed due to spatial interactions with other parts of the molecule, and substituents at both ends of the single bond are asymmetric (i.e., optically active occurs without the need for asymmetric carbon centers or stereocenters). Separation and isolation of the isomeric species may be allowed where the rotational energy barrier around the single bond is sufficiently high and interconversion between conformations is sufficiently slow. Atropisomers are enantiomers (or epimers) that do not have a single asymmetric atom.

A atropisomer may be considered stable if the interaction energy barrier is high enough to allow the atropisomer to undergo little or no interconversion for at least one week at room temperature. In some aspects, the atropisomers undergo little or no tautomerism at room temperature for at least one year. In some aspects, when the atropisomerised compound is in a substantially pure form (which is typically a solid state), the atropisomerised compound of the disclosure does not undergo more than about 5% tautomerism of its opposite atropisomer during one week at room temperature. In some aspects, a atropisomerised compound of the disclosure does not undergo more than about 5% tautomerism of its opposite atropisomer within one year at room temperature (about 25 ℃). In some aspects, the atropisomerisable compounds of the present disclosure are stable enough to undergo no more than about 5% interconversion in an aqueous pharmaceutical formulation that is stored at 0 ℃ for at least one week. The chemical entities, pharmaceutical compositions and methods of the invention are intended to include all such possible atropisomers (including racemic mixtures, diastereomeric mixtures, epimeric mixtures, single atropisomers in optically pure form, and intermediate mixtures).

The energy barrier for thermal racemization of the atropisomers can be determined by the steric hindrance of free rotation of one or more bonds forming the chiral axis. Certain biaryl compounds exhibit atropisomerism in which rotation about the inter-ring bond lacking C2 symmetry is limited. The free energy barrier for isomerisation (enantiomer) is a measure of the stability of the inter-ring bond with respect to rotation. Light and thermal excitation can promote racemization of such isomers, depending on electronic and steric factors.

Ortho-substituted biaryl compounds may exhibit this type of conformational rotamers. Such biaryl groups are chiral atropisomers of enantiomers in which sp is between aryl rings ² -sp ² The carbon-carbon ring bond has a sufficiently high energy barrier to prevent free rotation, and wherein the substituent W ¹ ≠W ² And W is ³ ≠W ⁴ Making the molecule asymmetric.

W ¹ :W ³ 、W ¹ :W ⁴ And/or W ² :W ⁴ 、W ² :W ³ The spatial interactions between them are large enough to give the planar conformation an energy maximum. When two are in useThe two non-planar axial chiral enantiomers are then present as atropisomers when the interconversions of the two non-planar axial chiral enantiomers are slow enough that they can be freely separated from each other. The bold and dashed lines in the figures shown above indicate those parts or portions of the molecule that are spatially limited due to the rotational energy barrier. The bold line portion exists orthogonally above the page plane and the dotted line portion exists orthogonally below the page plane. The 'flat' portion of the molecule (left ring in each of the two depicted biaryl groups) is in the plane of the page.

The pharmaceutical compositions of the present disclosure may include one or more pharmaceutically acceptable salts. By "pharmaceutically acceptable salt" is meant a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see, e.g., berge, s.m. et al, j.pharm.sci.,66:1-19 (1977)). Salts may be obtained during the final isolation and purification of the compounds described herein, or by reacting the free base functionality of the compounds with a suitable acid or by reacting the acidic groups of the compounds with a suitable base alone. Acid addition salts include salts derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and the like, and from non-toxic organic acids such as aliphatic monocarboxylic and aliphatic dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include salts derived from alkaline earth metals (such as sodium, potassium, magnesium, calcium, etc.) and from non-toxic organic amines (such as N, N' -dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, etc.).

Pharmaceutical composition

In another aspect, the present disclosure provides compositions, e.g., pharmaceutical compositions, comprising one or a combination of compounds described within the present disclosure formulated with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present disclosure may also be administered in combination therapy, i.e., in combination with other agents as described herein.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In some aspects, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound may be coated in a material to protect the compound from acids and other natural conditions that may inactivate the compound.

The pharmaceutical compositions of the present disclosure may be administered via one or more routes of administration using one or more of a variety of methods known in the art. As the skilled artisan will appreciate, the route and/or manner of administration will vary depending upon the desired result. In some aspects, routes of administration of the compounds of the present disclosure include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal, or other parenteral routes of administration, such as by injection or infusion. The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration (typically by injection) and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

The sterile injectable solution may be prepared by the following manner: the active compound is incorporated in the desired amount in an appropriate solvent, optionally with one or a combination of the ingredients listed above, and then microfiltered for sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, some methods of preparation are vacuum drying and freeze-drying (lyophilization) which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils, and injectable organic esters. Proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional medium or agent is incompatible with the active compound, its use in the pharmaceutical compositions of the present disclosure is contemplated. Supplementary active compounds may also be incorporated into the compositions.

Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition may be formulated as a solution or as a liquid with an ordered structure suitable for high drug concentrations. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycols, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. In many cases, it will be desirable to include an isotonic agent, for example, a sugar, a polyalcohol (such as mannitol, sorbitol) or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition agents which delay absorption (e.g., monostearates and gelatins).

Alternatively, the compounds of the present disclosure may be administered via a non-parenteral route, such as a topical, epidermal, or mucosal route of administration, e.g., intranasal, oral, vaginal, rectal, sublingual, or topical administration.

Any pharmaceutical composition contemplated herein may be delivered orally, e.g., via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups and elixirs. Pharmaceutical compositions intended for oral administration may be prepared according to any method known in the art for manufacturing pharmaceutical compositions intended for oral administration. To provide a pharmaceutically palatable preparation, a pharmaceutical composition according to the present disclosure may contain at least one agent selected from the group consisting of sweetening agents, flavouring agents, colouring agents, demulcents, antioxidants and preserving agents.

Tablets may be prepared, for example, by mixing at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets.

Aqueous suspensions may be prepared, for example, by mixing at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of aqueous suspensions, including, but not limited to, suspending agents such as, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth, and gum arabic; dispersing or wetting agents, such as, for example, naturally occurring phospholipids, such as lecithin; condensation products of alkylene oxides with fatty acids, such as, for example, polyoxyethylene stearates; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example, heptadecane ethylene-oxy cetyl alcohol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. The aqueous suspension may also contain at least one preservative, such as ethyl parahydroxybenzoate and n-propyl parahydroxybenzoate; at least one colorant; at least one flavoring agent; and/or at least one sweetener (including, but not limited to, sucrose, saccharin, and aspartame, for example).

Oily suspensions may be formulated, for example, by suspending at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof in a vegetable oil, for example, such as arachis oil, sesame oil and coconut oil, or in a mineral oil, for example, such as liquid paraffin. Oily suspensions may also contain at least one thickening agent, for example, such as beeswax, hard paraffin or cetyl alcohol. In order to provide a palatable oily suspension, at least one sweetener and/or at least one flavoring agent, which have been described above, may be added to the oily suspension. The oily suspensions may further contain at least one preservative including, but not limited to, for example, antioxidants such as, for example, butylated hydroxyanisole and alpha-tocopherol.

Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof with at least one dispersing and/or wetting agent, at least one suspending agent and/or at least one preservative. Suitable dispersing, wetting and suspending agents have been described above. Exemplary preservatives include, but are not limited to, antioxidants such as ascorbic acid. In addition, the dispersible powders and granules may also contain at least one excipient including, but not limited to, for example, sweeteners, flavoring agents, and coloring agents.

The active compounds can be prepared with carriers that will protect the compound from rapid release, such as controlled release formulations, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid may be used. Many methods for preparing such formulations have been patented or are generally known to those skilled in the art. See, e.g., robinson, j.r. edit, sustained and Controlled Release Drug Delivery Systems, marcel Dekker, inc., new York (1978).

The therapeutic composition may be administered with medical devices known in the art. For example, in one aspect, the therapeutic compositions of the present disclosure may be administered with a needleless subcutaneous injection device (such as the devices disclosed in U.S. Pat. nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556). Examples of well known implants and modules that may be used in the present disclosure include: us patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing a drug at a controlled rate; us patent No. 4,486,194, which discloses a therapeutic device for transdermal administration of a drug; U.S. Pat. No. 4,447,233, which discloses a drug infusion pump for delivering a drug at a precise infusion rate; U.S. Pat. No. 4,447,224, which discloses a variable flow implantable infusion device for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system having multiple compartments; and U.S. patent No. 4,475,196, which discloses an osmotic drug delivery system. These patents are incorporated herein by reference. Many other such implants, delivery systems and modules are known to those skilled in the art.

In certain aspects, compounds of the present disclosure may be administered parenterally (i.e., by injection), including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and/or infusion.

In some aspects, the compounds of the present disclosure may be administered orally (i.e., via gelatin capsules, tablets, hard or soft capsules, or liquid capsules).

Use/treatment of KRAS inhibitors

Administration of the therapeutic agents described herein includes, but is not limited to, administration of a therapeutically effective amount of the therapeutic agent. The term "therapeutically effective amount" as used herein refers to, but is not limited to, an amount of a therapeutic agent that treats a treatable condition by administering a composition comprising a KRAS inhibitor as described herein. The amount is an amount sufficient to exhibit a detectable therapeutic or ameliorating effect. Such effects may include, for example, but are not limited to, treating the disorders listed herein. The precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition being treated, the advice of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration.

For administration of the compounds described herein, the dosage ranges from about 0.0001 to 100mg/kg of host body weight and more typically from 0.01 to 40mg/kg of host body weight. Exemplary treatment regimens require once daily administration, twice weekly, three times weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, once every 3 months, or once every three to 6 months.

The disclosed compounds strongly inhibit anchorage-independent cell growth and thus have the potential to inhibit tumor metastasis. Thus, in another aspect, the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier.

Ras mutations have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and/or lymph nodes), including but not limited to KRAS mutations. Accordingly, certain aspects relate to the administration of the disclosed compounds (e.g., in the form of pharmaceutical compositions) to a patient in need of treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the presently disclosed compounds may be used to treat diseases such as Acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), chronic Lymphocytic Leukemia (CLL), small Lymphocytic Lymphoma (SLL), chronic Myelogenous Leukemia (CML), acute monocytic leukemia (AMoL), and/or other leukemias. In other aspects, the compounds are useful for treating lymphomas (such as hodgkin's lymphoma or all subtypes of non-hodgkin's lymphoma).

Determining whether a tumor or cancer comprises a KRAS mutation may be performed by assessing the nucleotide sequence encoding the KRAS protein, by assessing the amino acid sequence of the KRAS protein, or by assessing the characteristics of putative KRAS mutant proteins. The sequence of wild-type human KRAS proteins is known in the art.

Methods for detecting KRAS mutations are known to those skilled in the art. Such methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, taqMan assays, SNP genotyping assays, high resolution melting assays, and microarray assays. In some aspects, the samples are evaluated for KRAS mutation, including by real-time PCR. In real-time PCR, fluorescent probes specific for KRAS mutations are used. When mutations are present, the probe binds and fluorescence is detected. In some aspects, for example, KRAS mutations are identified using direct sequencing methods of specific regions (e.g., exon 2 and/or exon 3) in the KRAS gene. This technique will identify all possible mutations in the sequencing region.

Methods for detecting mutations in KRAS proteins are known to those of skill in the art. Such methods include, but are not limited to, detection of KRAS mutants using binding agents (e.g., antibodies) specific for the mutant proteins, protein electrophoresis and western blotting, and direct peptide sequencing.

Methods for determining whether a tumor or cancer contains a KRAS mutation can use a variety of samples. In some aspects, the sample is taken from a subject having a tumor or cancer. In some aspects, the sample is taken from a subject having cancer or tumor. In some aspects, the sample is a fresh tumor/cancer sample. In some aspects, the sample is a frozen tumor/cancer sample. In some aspects, the sample is a formalin fixed paraffin embedded sample. In some aspects, the sample is processed into a cell lysate. In some aspects, the sample is processed into DNA or RNA. The present disclosure also relates to methods of treating hyperproliferative disorders in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. In some aspects, the methods relate to the treatment of cancer, such as acute myeloid leukemia, juvenile cancer, childhood adrenocortical cancer, AIDS-related cancer (e.g., lymphoma and kaposi's sarcoma), anal cancer, appendicular cancer, astrocytomas, atypical teratomas, basal cell carcinomas, cholangiocarcinomas, bladder cancers, bone cancers, brain stem gliomas, brain tumors, breast cancers, bronchial tumors, burkitt's lymphoma, carcinoid tumors, atypical teratomas, embryonal tumors, germ cell tumors, primary lymphomas, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngeal neoplasia, cutaneous T-cell lymphomas, in situ extrahepatic Duct Carcinomas (DCIS), embryonal tumors, CNS cancers, endometrial cancer, ependymal tumors, esophageal cancer, nasal glioma Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, bone fibroblastic tumor, gall bladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastoma, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin lymphoma, hypopharynx cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, in situ Lobular Carcinoma (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline bundle cancer (midline tract carcinoma), oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, meckel cell carcinoma, malignant mesothelioma, osteomalignant fibrous histiocytoma and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleural pneumoblastoma, oral cavity cancer, pancreatic cancer, papillomatosis, paranasal sinus and nasal cavity cancer, malignant mesothelioma primary Central Nervous System (CNS) lymphomas, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, skin cancer, gastric cancer (stomach (gastric) cancer), small cell lung cancer, small intestine cancer, soft tissue sarcoma, T cell lymphoma, testicular cancer, throat cancer, thymoma (thymoma) and thymus cancer (thymus cancer), thyroid cancer, renal pelvis and ureter transitional cell carcinoma, trophoblastoma, childhood rare cancer, urinary tract cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer. In some aspects, the methods relate to the treatment of non-cancerous hyperproliferative disorders, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis benign hyperplasia, or benign hyperplasia of the prostate (e.g., benign Prostatic Hypertrophy (BPH)).

In certain aspects, the present disclosure relates to methods for treating lung cancer, comprising administering to a subject in need thereof an effective amount of any of the compounds described above (or pharmaceutical compositions comprising the same). In certain aspects, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In other aspects, the lung cancer is small cell lung cancer. Other lung cancers treatable with the disclosed compounds include, but are not limited to, adeno-and carcinoid tumors and undifferentiated cancers. Subjects that can be treated according to the methods of the present disclosure with a compound of the present disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate, or derivative of the compound include, for example, subjects that have been diagnosed as having: acute myeloid leukemia, juvenile cancer, childhood adrenocortical cancer, AIDS-related cancer (e.g., lymphoma and kaposi's sarcoma), anal carcinoma, appendicular carcinoma, astrocytomas, atypical teratomas, basal cell carcinomas, cholangiocarcinomas, bladder cancers, bone cancers, brain stem gliomas, brain tumors, breast cancers, bronchial tumors, burkitt's lymphoma, carcinoid tumors, atypical teratomas, embryonal tumors, germ cell tumors, primary lymphomas, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngeal tumors, cutaneous T-cell lymphomas, in situ extrahepatic Duct Carcinomas (DCIS), embryonal tumors, CNS cancers, endometrial cancers, ependymomas, esophageal cancers, nasal gliomas, ewing's sarcoma, extracranial germ cell tumors extragonadal germ cell tumors, eye cancers, bone fibroblastic tumors, gall bladder cancers, stomach cancers, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancers, heart cancers, liver cancers, hodgkin's lymphomas, hypopharyngeal cancers, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancers, laryngeal cancers, lip and oral cancers, liver cancers, in situ Lobular Cancers (LCIS), lung cancers, lymphomas, metastatic squamous neck cancers with occult primary, central line beam cancers, mouth cancers, multiple endocrine neoplasias, multiple myeloma/plasmacytoid tumors, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative tumors, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, bone malignant fibrous histiocytoma and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, labial and oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleural and pulmonary blastoma, primary Central Nervous System (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer (stomach (gastric) cancer), small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma (thyoma) and thymus cancer, thyroid cancer, renal pelvis and ureteral transitional cell carcinoma, cell tumor, childhood cancer, vulval cancer, cancer of the vagina, cancer of the stomach, cancer of the induced or ureter. In some aspects, subjects treated with compounds of the present disclosure include subjects that have been diagnosed with a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis benign hyperplasia, or benign hyperplasia of the prostate (e.g., benign Prostatic Hypertrophy (BPH)). The present disclosure further provides methods of modulating mutant KRAS protein activity by contacting a protein with an effective amount of a compound of the present disclosure. Modulation may be inhibition or activation of protein activity. In some aspects, the present disclosure provides methods of inhibiting protein activity by contacting a mutant KRAS protein with an effective amount of a compound of the present disclosure in solution. In some aspects, the disclosure provides methods of inhibiting mutant KRAS protein activity by contacting a cell, tissue, organ expressing a protein of interest. In some aspects, the present disclosure provides methods of inhibiting protein activity in a subject, including but not limited to rodents and mammals (e.g., humans), by administering to the subject an effective amount of a compound of the present disclosure. In some aspects, the percentage of modulation is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the percent inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the present disclosure provides methods of inhibiting the activity of KRAS in a cell by contacting the cell with a compound of the present disclosure in an amount sufficient to inhibit the activity of a KRAS mutant in the cell. In some aspects, the present disclosure provides methods of inhibiting mutant KRAS in a tissue by contacting the tissue with a compound of the present disclosure in an amount sufficient to inhibit the activity of the mutant KRAS in the tissue. In some aspects, the present disclosure provides methods of inhibiting KRAS in an organism by contacting the organism with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS in the organism. In some aspects, the present disclosure provides methods of inhibiting KRAS activity in an animal by contacting the animal with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS in the animal. In some aspects, the present disclosure provides for inhibiting KRAS contained in a mammal by contacting the mammal with an amount of a compound of the present disclosure sufficient to inhibit the activity of KRAS in the mammal. In some aspects, the present disclosure provides methods of inhibiting KRAS activity in a human by contacting the human with a compound of the present disclosure in an amount sufficient to inhibit KRAS activity in the human. The present disclosure provides methods of treating a disease mediated by KRAS activity in a subject in need of such treatment. The present disclosure also provides methods for combination therapies in which agents known to modulate other pathways or other components of the same pathway or even overlapping sets of target enzymes are used in combination with a compound of the present disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate, or derivative thereof. In one aspect, such therapies include, but are not limited to, combinations of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation therapy.

Many chemotherapeutic agents are currently known in the art and may be used in combination with the compounds of the present disclosure. In some aspects, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormonal agents, angiogenesis inhibitors, and anti-androgens. In some aspects, the chemotherapeutic agent is an immune tumor (IO) agent that may enhance, stimulate, or up-regulate the immune system.

The compounds described herein may be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some aspects, one or more compounds of the present disclosure will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered simultaneously or separately with the second agent. Such combined administration may include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the agents described above may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound of the present disclosure and any of the agents described above may be administered simultaneously, wherein the two agents are present in separate formulations. In another alternative, the compounds of the present disclosure may be administered immediately after any of the agents described above, or vice versa. In some aspects of separate administration regimens, the compounds of the disclosure and any agents described above are administered at intervals of minutes, or hours, or days.

The compounds may be prepared by methods known in the art, including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be prepared by methods known in the art using readily available materials. Any variables (e.g., numbered "R" substituents) used to describe the synthesis of a compound are intended only to illustrate how the compound is prepared and should not be confused with variables used in the claims or elsewhere in this specification. The following methods are for illustration purposes and are not intended to limit the scope of the present disclosure.

Synthesis

General scheme

The compounds described herein can be prepared as shown below and as described in methods 1-4.

Method 1: in step 1, a known compound a (CAS 1698028-11-3) is reacted with an amine in a suitable solvent such as THF with a base such as diisopropylethylamine to provide compound B. In step 2, compound B is treated with potassium fluoride in a solvent such as dimethylacetamide to provide compound C. In step 3, compound C is coupled with an aryl boronic acid or ester under Suzuki (Suzuki) conditions to provide compound D. In step 4, compound D is treated with ROH in a solvent (such as THF) in the presence of a base to provide compound E.

Method 2: the amino group of compound E can be converted to a different amino group by the following sequence. In step 5, a base is hydrolyzed to provide compound F. In step 6, the introduction of the amine substituent is accomplished using a coupling agent (such as BOP) in the presence of a base in a solvent (such as dichloromethane) to provide compound E.

Method 3: in step 7, POCl is used in the presence of a base ₃ Treatment of compound H provided compound G. Treatment of compound G with an appropriate amine in the presence of a base in a solvent such as dimethylacetamide provides compound E.

Method 4: in step 9, compound B is treated with an alcohol of formula R-OH in the presence of a base to provide compound H. In step 10, compound H is coupled with an arylboronic acid or ester under suzuki conditions to provide compound E. Protecting groups (such as Boc, PMB, MOM, etc.) may be introduced and removed as desired by those skilled in the art and as described in the examples. Functionalization and processing of aryl, NRR' and OR groups to prepare compounds of general structure E are described in the examples.

Examples

The invention is further defined in the following examples. It should be understood that the examples are given by way of illustration only. From the foregoing discussion and examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Accordingly, the invention is not limited by the illustrative embodiments described below, but is defined by the appended claims.

Abbreviations (abbreviations)

The following abbreviations are used in the examples section below and elsewhere herein:

abbreviations (abbreviations)	Full scale
		Ac	Acetyl group
ACN	Acetonitrile
		aq.	Aqueous based
DCM	Dichloromethane (dichloromethane)
		DMSO	Dimethyl sulfoxide
DMOCP	2-chloro-5, 5-dimethyl-1, 3, 2-dioxaphosphorinane 2-oxide
		EtOAc	Acetic acid ethyl ester
Et ₃ N or TEA	Triethylamine
		EtOH	Ethanol
HPLC	High performance liquid chromatography
		iPr	Isopropyl group
MeOH	Methanol
		RT、R.T.	Room temperature
sat, satd, or sat' d	Saturation
		TBAF	Tetrabutylammonium fluoride
TBS	Tert-butyldimethylsilyl group
		TFA	Trifluoroacetic acid
t _R	Retention time

Examples 1-1 and 1-2

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 1A: 6-bromo-NN-bis (4-methoxybenzyl) -4-methylpyridin-2-amine

To a solution of 6-bromo-4-methylpyridin-2-amine (1 g,5.35 mmol) in DMF (20 mL) was added NaH (0.64 g,16mmol, 60%) at 0deg.C. The mixture was stirred at 0℃for 0.5h. 1- (chloromethyl) -4-methoxybenzene (2.1 g,13.4 mmol) was then added. The mixture was stirred at 0℃for 1.5h. TLC (on silica gel, petroleum ether: ethyl acetate=5:1) showed the reaction was complete. Saturated NH for reaction ₄ Cl (20 mL) and extracted with ethyl acetate (20 mL. Times.3), washed with brine (50 mL), and dried over anhydrous Na ₂ SO ₄ And (5) drying. The mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=5:1) to give 6-bromo-N, N-bis (4-methoxybenzyl) -4-methylpyridin-2-amine (2 g,4.68mmol,87.5% yield) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.16(d,J＝8.8Hz,4H),6.88-6.84(m,4H),6.60(s,1H),6.16(s,1H),4.64(s,4H),3.80(s,6H),2.13(s,3H)。

Preparation of intermediate 1B: (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) boronic acid

To a solution of 6-bromo-N, N-bis (4-methoxybenzyl) -4-methylpyridin-2-amine (1000 mg,2.34 mmol), bis (pinacolato) diboron (832.5 mg,3.28 mmol), (1, 1' -bis (diphenylphosphino) ferrocene) palladium (II) dichloride (171 mg,0.23 mmol) in 1, 4-dioxane (20 mL) was added KOAc (459.32 mg,4.68 mmol). The mixture was stirred at 90℃under N ₂ Stirred for 5h. The reaction mixture was filtered. The filtrate containing the crude product (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) boronic acid (918 mg,2.34mmol, crude) in 1, 4-dioxane (20 mL) was used in the next step without purification. MS (ESI) m/z 393.3[ M+1 ]] ⁺ 。

Preparation of intermediate 1C: 4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

At N ₂ To a solution of 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (1 g,3.03 mmol) and DIPEA (1.32 mL,7.57 mmol) in THF (15 mL) was added tert-butyl piperazine-1-carboxylate (0.56 g,3.03 mmol). The reaction mixture was stirred at 25℃for 2h. The mixture was concentrated. The residue was diluted with ethyl acetate (60 mL), washed with water (30 mL x 2) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, petroleum ether: ethyl acetate=10:1 to 4:1) to give tert-butyl 4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) piperazine-1-carboxylate (1.33 g,2.77mmol,91.5% yield) as a yellow solid. MS (ESI) m/z 481.0[ M+3 ] ] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.77(d,J＝1.6Hz,1H),3.93-3.84(m,4H),3.72-3.61(m,4H),1.50(s,9H)。

Preparation of intermediate 1D: 4- (7-bromo-6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) piperazine-1-carboxylate (1000 mg,2.08 mmol) and potassium fluoride (2420 mg,41.65 mmol) in DMA (10 mL) was reacted at 110℃under N ₂ Stirring was carried out for 12h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 ml x 3) and dried over anhydrous Na ₂ SO ₄ And (5) drying. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, petroleum ether: ethyl acetate=20:1 to 3:1) to give tert-butyl 4- (7-bromo-6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylate (730 mg,1.57mmol,75.6% yield) as a yellow solid. MS (ESI) m/z 463.1[ M+1 ]] ⁺ 。

Preparation of intermediate 1E: 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 4- (7-bromo-6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylate (600 mg,1.29 mmol), (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) boronic acid (756 mg,1.93 mmol), (1, 1' -bis (diphenylphosphino) ferrocene) palladium (II) dichloride (104 mg,0.14 mmol) and potassium phosphate (268 mg,2.59 mmol) in 1, 4-dioxane (20 mL) and water (2 mL) was stirred at 60℃under N ₂ Stirring 12. The mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (silica gel, petroleum ether: ethyl acetate=10:1 to 3:1) to give tert-butyl 4- (7- (4- (bis (4-methoxybenzyl) amino) -6-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylate (600 mg,0.82mmol,63.4% yield) as a yellow oil。MS(ESI)m/z 731.4[M+1] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ7.76(d,J＝1.2Hz,1H),7.18(d,J＝8.8Hz,4H),6.85(d,J＝8.8Hz,4H),6.59(s,1H),6.37(s,1H),4.69(s,4H),3.98-3.87(m,4H),3.80(s,6H),3.69-3.65(m,4H),2.27(s,3H),1.51(s,9H)。

Preparation of intermediate 1F: 4- (7- (6- (bis (4-methoxybenzyl) amino) -3-iodo-4-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

A solution of 4- (7- (4- (bis (4-methoxybenzyl) amino) -6-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (800 mg,1.09 mmol), tosOH (5 mg,0.05 mmol) and NIS (1200 mg,5.33 mmol) in DMF (10 mL) was stirred at 25℃for 12h. The reaction mixture was diluted with water (15 mL) and EtOAc (15 mL). The mixture was extracted with EtOAc (30 ml x 3). The combined organic layers were washed with brine (30 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=10:1 to 3:1) to give tert-butyl 4- (7- (6- (bis (4-methoxybenzyl) amino) -3-iodo-4-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylate (400 mg,0.467mmol,42.7% yield) as a yellow solid. MS (ESI) m/z 857.2[ M+1 ] ] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ7.82(d,J＝1.2Hz,1H),7.17(d,J＝8.4Hz,4H),6.86(d,J＝8.4Hz,4H),6.48(s,1H),4.76-4.65(m,2H),4.62-4.50(m,2H),4.01-3.92(m,4H),3.82(s,6H),3.72-3.63(m,4H),2.38(s,3H),1.52(s,9H)。

Preparation of intermediate 1G: 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

4- (7- (6- (bis (4-methoxybenzyl) benzyl)) A mixture of amino) -3-iodo-4-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl piperazine-1-carboxylic acid tert-butyl ester (400 mg,0.4700 mmol), 2-difluoro-2-fluorosulfonyl-acetic acid methyl ester (1345 mg,7 mmol) and CuI (267 mg,1.4 mmol) in DMA (10 mL) was reacted at 80℃under N ₂ Stirred for 5h. The reaction mixture was then cooled to room temperature, and additional CuI (267 mg,1.4 mmol) and methyl 2, 2-difluoro-2-fluorosulfonyl-acetate (1345 mg,7 mmol) were added to the mixture. The reaction mixture was taken up in N at 80 ℃ ₂ Stirring was carried out for a further 12h. The mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with brine (30 ml x 3) and dried over anhydrous Na ₂ SO ₄ Dried, and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=10:1 to 3:1) to give tert-butyl 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylate (270 mg,0.34mmol,72.4% yield) as a yellow solid. MS (ESI) m/z 799.0[ M+1 ] ] ⁺ 。

Preparation of intermediate 1H: 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of (2S) -1-methylpyrrolidin-2-yl-methanol (97.6 mg,0.85 mmol) in THF (10 mL) was added NaH (81 mg,2.03mmol, 60%) at 0deg.C. The mixture was stirred at 0℃for 0.5h. Tert-butyl 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylate (270 mg,0.34 mmol) in THF (5 mL) was added. The mixture was stirred at 0℃for 1h. The reaction mixture was treated with saturated NH ₄ Cl (20 mL) was quenched and extracted with EtOAc (20 mL. Times.3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na ₂ SO ₄ And (5) drying. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel,DCM: meoh=10:1) to afford tert-butyl 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylate (250 mg,0.28mmol,82.7% yield) as a white solid. MS (ESI) m/z 894.5[ M+1 ]] ⁺ 。

Preparation of intermediate 1I: 7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4 (3H) -one

A mixture of tert-butyl 4- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) piperazine-1-carboxylate (250 mg,0.28 mmol) and NaOH (224 mg,5.59 mmol) in ethanol (30 mL) and water (10 mL) was stirred at 45℃for 3d. The mixture was quenched with 2N HCl to ph=6-7. The mixture was concentrated in vacuo to remove EtOH. The residue was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na ₂ SO ₄ And (5) drying. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4 (3H) -one (200 mg,0.28mmol,98.5% yield) as a pale yellow solid. MS (ESI) m/z 726.3[ M+1 ]] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ8.07(s,1H),7.14(d,J＝8.4Hz,4H),6.85(d,J＝8.4Hz,4H),6.41(s,1H),4.98-4.65(m,4H),4.59-4.49(m,2H),3.80(s,6H),3.55-3.38(m,1H),2.90(d,J＝8.0Hz,3H),2.41(s,3H),2.31-2.21(m,2H),2.14-2.03(m,2H),1.37-1.19(m,2H)。

Preparation of intermediate 1J: 7- (6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4 (3H) -one

A solution of 7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4 (3H) -one (300 mg,0.4100 mmol) in TFA (10 mL,130 mmol) was stirred at 50℃for 4 hours. The reaction mixture was concentrated under reduced pressure to give the crude product 7- (6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4 (3H) -one (247 mg,0.41mmol,99.7% yield) as a brown oil. MS (ESI) m/z:486.1[ M+H ] ] ⁺ 。

Preparation of intermediate 1K: 3- (7- (6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a solution of 7- (6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4 (3H) -one (80 mg,0.13 mmol) in DCM (3 mL) at 25 ℃ was added 3, 8-diazabicyclo [ 3.2.1)]Tert-butyl octane-8-carboxylate (85 mg,0.40 mmol), DIPEA (51 mg,0.39 mmol) and BOP (192 mg,0.43 mmol). The reaction mixture was stirred at 25 ℃ for 12 hours. The reaction mixture was diluted with water (15 mL) and then extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (instrument: ACSWH-GX-N; column: phenomenex Synergi C: 150X25mm 10um; mobile phase: A: H) ₂ O (0.1% tfa), and B is acetonitrile; gradient: linearly B is 38% -68% in 10 min; flow rate: 25mL/min; column temperature: room temperature; wavelength: 220nm and 254 nm) to afford 3- (7- (6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1) as a yellow solid ]Tert-butyl octane-8-carboxylate (25 mg,0.037mmol,27.6% yield) was used directly in the next step. MS (ESI) m/z:680.2[ M+H ]] ⁺ 。

Examples 1-1 and 1-2

To 3- (7- (6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1)]To a solution of tert-butyl octane-8-carboxylate (20 mg,0.03 mmol) in DCM (1.5 mL) was added TFA (0.5 mL,6.53 mmol). The reaction mixture was stirred at 25 ℃ for 3 hours. The reaction mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA as additive, apparatus: GX-p; column: phenomenex Synergi C: 150X25mm,10um; mobile phase: A is H) ₂ O (0.225% FA), and B is acetonitrile; gradient: linearly B3% -33% in 10 min; flow rate: 15mL/min; column temperature: room temperature; wavelength: 220nm,254 nm) to give the desired product. The atropisomer mixture was subjected to chiral SFC (column: cellucoat 50X 4.6mm I.D,3um; mobile phase: phase A is CO) ₂ And phase B is IPA (0.05% DEA); gradient elution: in CO ₂ 40% IPA (0.05% DEA); flow rate: 3mL/min; a detector: a PDA; column temperature: 35 ℃; back pressure: 100 bar) to obtain two product peaks. Peak 1 product: 1-1 (4.88 mg,0.0082mmol,27.9% yield). MS (ESI) m/z 580.0[ M+1 ]] ⁺ ； ¹ H NMR (400 MHz, methanol-d) ₄ ) Delta 7.89 (s, 1H), 6.62 (s, 1H), 4.77 (brdd, j=13.6, 2.8hz, 1H), 4.63-4.52 (m, 3H), 3.95-3.87 (m, 2H), 3.76-3.69 (m, 2H), 3.64-3.48 (m, 2H), 3.16-3.02 (m, 1H), 2.96 (s, 3H), 2.45 (d, j=1.2 hz, 3H), 2.39-2.28 (m, 1H), 2.13-1.93 (m, 7H). Peak 2 product 1-2 (3.79 mg,0.0064mmol,21.7% yield) as brown solid, MS (ESI) m/z 580.0[ M+1 ]] ⁺ ； ¹ H NMR (400 MHz, methanol)-d ₄ )δ7.85(d,J＝1.2Hz,1H),6.61(s,1H),4.62-4.36(m,4H),3.73-3.59(m,4H),3.28-3.21(m,1H),3.15-3.03(m,1H),2.67(s,3H),2.60(br d,J＝9.2Hz,1H),2.45(d,J＝1.2Hz,3H),2.21(s,1H),1.97-1.78(m,7H)。

The examples in table 1 were prepared according to the procedure described in example 1 from intermediate 1J and the appropriate amine.

TABLE 1

/>

Example 2-1

6- (6-chloro-4- {2, 5-diazabicyclo [2.2.2] oct-2-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 2A: 6- (4, 6-dichloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

To 7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) -pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -quinazolin-4 (3H) -one (50 mg,0.07 mmol) in POCl ₃ To a solution of (1.5 mL,16.09 mmol) was added DIEA (0.01 mL,0.07 mmol). The reaction mixture was stirred at 50℃for 3 hours.The reaction mixture was concentrated under reduced pressure and treated with ethyl acetate (10 mL). The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated NaHCO ₃ The solution (20 mL) and brine (20 mL) were washed, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product 6- (4, 6-dichloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (50 mg,0.067mmol,97.5% yield) as a yellow solid. MS (ESI) m/z:744.0[ M+H ]] ⁺ 。

Preparation of intermediate 2B: 5- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 5-diazabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester

To a solution of 6- (4, 6-dichloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -quinazolin-7-yl) -N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (40 mg,0.05 mmol) in DMA (2 mL) was added DIEA (0.02 mL,0.2700 mmol) and 2, 5-diazabicyclo [ 2.2.2.2 ]Tert-butyl octane-2-carboxylate (31.7 mg,0.15 mmol). The mixture was stirred at 50℃for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel plate, dichloromethane: methanol=10:1) to give the product as a colorless oil (40 mg,0.044mmol,80.9% yield). MS (ESI) m/z:920.3[ M+H ]] ⁺ 。

Example 2-1

6- (4, 6-dichloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

5- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -quinazolin-4-yl) -2, 5-diazabicyclo [2.2.2]A solution of tert-butyl octane-2-carboxylate (40 mg,0.040 mmol) in TFA (4 mL,52.24 mmol) was stirred at 50℃for 4 hours. The mixture was then concentrated to dryness. The residue was purified by preparative HPLC (formic acid as additive, apparatus: ACSWH-GX-Q; column: shim-pack C18X 25, 10um; mobile phase: A is H) ₂ O (0.225% FA), and B is acetonitrile; gradient: linearly B2% -35% in 11 min; flow rate: 25mL/m; column temperature: room temperature; wavelength: 220nm.254 nm) to give the desired product as a white solid (11.1 mg,0.019mmol,44.2% yield). MS (ESI) m/z 580.2[ M+H ]] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD)δ8.53(s,0.4H),8.05(s,1H),6.61(s,1H),4.95(br s,1H),4.68-4.49(m,2H),4.35(d,J＝11.6Hz,1H),4.27-4.19(m,1H),3.62-3.33(m,4H),2.86-2.70(m,4H),2.45(d,J＝1.2Hz,3H),2.40-2.18(m,2H),2.16-1.79(m,7H)。

The examples in table 2 were prepared according to the procedure of example 2 from intermediate 2A and the appropriate amine.

TABLE 2

Example 3-1

6- (6-chloro-4- {2, 5-diazabicyclo [2.2.1] hept-2-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 3A: 5- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

To 7-bromo-2, 4, 6-trichloro-8-fluoro-quinazoline (2 g,6.05 mmol) and 2, 5-diazabicyclo [2.2.1]To a mixture of tert-butyl heptane-2-carboxylate (1.2 g,6.05 mmol) in THF (100 mL) was added triethylamine (1.84 g,18.16 mmol) and the mixture was stirred at 25 ℃ for 12h. The mixture was poured into water (200 mL). The mixture was separated and the aqueous phase extracted with ethyl acetate (50 ml x 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and the filtrate concentrated. The residue was triturated in petroleum ether/ethyl acetate (50 mL/5 mL), then filtered, and the filtrate was dried under reduced pressure to provide a yellow solid. ¹ H NMR(400MHz,CDCl ₃ )δ＝7.89-7.85(m,1H),5.41-5.34(m,1H),4.80-4.67(m,1H),4.16-4.10(m,1H),3.98-3.80(m,1H),3.68-3.54(m,2H),2.05-2.03(m,2H),1.47-1.44(m,9H)。

Preparation of intermediate 3B: 5- (7-bromo-6-chloro-2, 8-difluoroquinazolin-4-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

5- (7-bromo-2, 6-dichloro-8-fluoro-quinazolin-4-yl) -2, 5-diazabicyclo [2.2.1]A mixture of tert-butyl heptane-2-carboxylate (1.8 g,3.66 mmol) and KF (4.25 g,73.15 mmol) in DMA (20 mL) was stirred at 140℃for 12h. The mixture was added to water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Drying, filtering and concentrating the filtrate. The residue was purified by column chromatography (SiO ₂ Petroleum ether/ethyl acetate=7/1 to 4/1). Obtaining 5- (7-bromo-6-chloro-2, 8-difluoro-quinazolin-4-yl) -2, 5-diazabicyclo [2.2.1] as a yellow solid]Heptane-2-carboxylic acidTert-butyl ester (1.4 g,2.943mmol,80.5% yield). MS (ESI) m/z 476.9[ M+1 ]] ⁺ 。

Preparation of intermediate 3C: 5- (7- (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

To N, N-bis [ (4-methoxyphenyl) methyl)]-4-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (2.09 g,4.41 mmol), 5- (7-bromo-6-chloro-2, 8-difluoro-quinazolin-4-yl) -2, 5-diazabicyclo [2.2.1 ]Heptane-2-carboxylic acid tert-butyl ester (1.4 g,2.94 mmol), K ₃ PO ₄ (1.25 g,5.89 mmol) Pd (dppf) Cl was added to a mixture of 1, 4-dioxane (20 mL) and water (5 mL) ₂ DCM (240 mg,0.29 mmol) and the mixture was stirred at 60℃under N ₂ Stirring for 4h under an atmosphere. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Drying, filtering and concentrating the filtrate. The residue was purified by column chromatography (SiO ₂ Petroleum ether/ethyl acetate=5/1 to 3/1). Obtaining 5- [7- [6- [ bis [ (4-methoxyphenyl) methyl) as a yellow solid]Amino group]-4-methyl-2-pyridinyl]-6-chloro-2, 8-difluoro-quinazolin-4-yl]-2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (500 mg,0.6727mmol,22.9% yield). MS (ESI) m/z 743.5[ M+1 ]] ⁺ 。

Preparation of intermediate 3D: 5- (7- (6- (bis (4-methoxybenzyl) amino) -3-iodo-4-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

To 5- [7- [6- [ bis [ (4-methoxyphenyl) methyl)]Amino group]-4-methyl-2-pyridinyl]-6-chloro-2, 8-difluoro-quinazolin-4-yl]-2, 5-diazabisRing [2.2.1]To a solution of tert-butyl heptane-2-carboxylate (500 mg,0.6700 mmol) in DMA (6 mL) was added N-iodosuccinimide (151.35 mg,0.6700 mmol). TsOH (10 mg,0.01 eq) was then added and the mixture was stirred at 25 ℃ for 12h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ Drying, filtering and concentrating the filtrate. The residue was purified by column chromatography (SiO ₂ Petroleum ether/ethyl acetate=5/1 to 3/1). Obtaining 5- [7- [6- [ bis [ (4-methoxyphenyl) methyl) as a yellow solid]Amino group]-3-iodo-4-methyl-2-pyridinyl]-6-chloro-2, 8-difluoro-quinazolin-4-yl]-2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (410 mg,0.4717mmol,70.1% yield). MS (ESI) m/z 869.4[ M+1 ]] ⁺ 。

Preparation of intermediate 3E: 5- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

To 5- [7- [6- [ bis [ (4-methoxyphenyl) methyl)]Amino group]-3-iodo-4-methyl-2-pyridinyl]-6-chloro-2, 8-difluoro-quinazolin-4-yl]-2, 5-diazabicyclo [2.2.1]To a mixture of tert-butyl heptane-2-carboxylate (400 mg,0.4600 mmol) and CuI (262 mg,1.38 mmol) in DMA (6 mL) was added methyl 2, 2-difluoro-2-fluorosulfonyl-acetate (1326.21 mg,6.9 mmol) and the mixture was stirred at 75℃for 12h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ Drying, filtering and concentrating the filtrate. The residue was purified by column chromatography (SiO ₂ Petroleum ether/ethyl acetate=4/1 to 3/1). Obtaining 5- [7- [6- [ bis [ (4-methoxyphenyl) methyl) as a yellow solid]Amino group]-4-methyl-3- (trifluoromethyl) -2-pyridinyl]-6-chloro-2, 8-difluoro-quinazolin-4-yl]-2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (240 mg,0.2958mmol,64.3% yield). MS (ESI))m/z 811.5[M+1] ⁺ 。

Preparation of intermediate 3F: 5- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

To (2S) -1-methylpyrrolidin-2-yl at 0 ℃]To a solution of methanol (102.22 mg,0.8900 mmol) in THF (10 mL) was added NaH (59.17 mg,1.48 mmol), and the mixture was stirred at 0deg.C for 20min. Then 5- [7- [6- [ bis [ (4-methoxyphenyl) methyl) is added]Amino group]-4-methyl-3- (trifluoromethyl) -2-pyridinyl]-6-chloro-2, 8-difluoro-quinazolin-4-yl]-2, 5-diazabicyclo [2.2.1]Tert-butyl heptane-2-carboxylate (240 mg,0.30 mmol) and the mixture was stirred at 0℃for 1h. Adding the mixture to cold saturated NH ₄ Cl (30 mL) and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ Drying, filtering and concentrating the filtrate. The residue was purified by preparative TLC (DCM/meoh=10/1). Obtaining 5- [7- [6- [ bis [ (4-methoxyphenyl) methyl) as a yellow solid]Amino group]-4-methyl-3- (trifluoromethyl) -2-pyridinyl]-6-chloro-8-fluoro-2- [ [ rac- (2S) -1-methylpyrrolidin-2-yl ]]Methoxy group]Quinazolin-4-yl]-2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (160 mg,0.1765mmol,59.7% yield). MS (ESI) m/z 906.9[ M+1 ]] ⁺ 。

Example 3-1

5- [7- [6- [ bis [ (4-methoxyphenyl) methyl)]Amino group]-4-methyl-3- (trifluoromethyl) -2-pyridinyl]-6-chloro-8-fluoro-2- [ [ rac- (2S) -1-methylpyrrolidin-2-yl ]]Methoxy group]Quinazolin-4-yl]-2, 5-diazabicyclo [2.2.1]A solution of tert-butyl heptane-2-carboxylate (140 mg,0.1500 mmol) in TFA (5 mL,65.3 mmol) was stirred at 50℃for 4h. The mixture was concentrated under reduced pressure and the crude material was purified by preparative HPLC (formic acid as additive, apparatus: ACS-WH-GX-F; column: phenomenex luna C: 150X25mm,10um; mobile phase: A: H) ₂ O (0.225% FA), and B is acetonitrile; gradient: linearly B is 10% -35% within 10 min; flow rate: 25mL/min; column temperature: room temperature; wavelength: 220nm.254 nm) to give the desired product. 6- [ 6-chloro-4- (2, 5-diazabicyclo [2.2.1 ] as an off-white solid (14.86 mg,0.0256 mmol) was obtained]Hept-2-yl) -8-fluoro-2- [ [ rac- (2S) -1-methylpyrrolidin-2-yl]Methoxy group]Quinazolin-7-yl]-4-methyl-5- (trifluoromethyl) pyridin-2-amine (2.26 mg,0.0039mmol,2.5% yield) ¹ H NMR(400MHz,CDCl ₃ )δ＝8.00(d,J＝1.6Hz,1H),6.61(s,1H),5.41(s,1H),4.83-4.76(m,2H),468-4.60(m,1H),4.53-4.41(m,2H),4.12-4.05(m,1H),3.83-3.72(m,1H),3.69-3.58(m,2H),3.49-3.41(m,1H),3.21-3.12(m,1H),3.02(s,3H),2.44(s,3H),2.41-2.30(m,2H),2.21-1.98(m,4H)。MS(ESI)m/z 566.3[M+1] ⁺ 。

Example 4-1

6- (6-chloro-8-fluoro-4- { 8-methyl-3, 8-diazabicyclo [3.2.1] oct-3-yl } -2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 4A: 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

7- (6- (bis (4-methyl) alpha-hydroxy)Oxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4 (3H) -one (60 mg,0.080 mmol), 3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (51.4 mg,0.2400 mmol), BOP (108 mg,0.2400 mmol) and DIEA (0.04 mL,0.5000 mmol) in DCM (2 mL) was stirred at 25℃for 12 h. The reaction mixture was diluted with water (10 mL) and then extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to preparative HPLC (TFA as additive, apparatus: ACSWH-GX-N; column: phenomenex Synergi C, 150X25mm,10um; mobile phase: A is H) ₂ O (0.1% TFA), and B is acetonitrile; gradient: linearly B55% -85% in 10 min; flow rate: 25mL/min; column temperature: room temperature; wavelength: 220nm,254 nm) to give the product 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a white solid]Tert-butyl octane-8-carboxylate (50 mg,0.054mmol,65.7% yield). MS (ESI) m/z:920.2[ M+H ]] ⁺ 。

Preparation of intermediate 4B: 6- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

To 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a solution of tert-butyl octane-8-carboxylate (45 mg,0.05 mmol) in DCM (6 mL) was added HCl/EtOAc (2 mL,0.05 mmol). The mixture was stirred at 20℃for 2 hours. The reaction mixture was concentrated to give the crude product 6- (4- (3, 8-diazabicyclo [ 3.2.1) as a yellow solid ]Oct-3-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) Quinazolin-7-yl) -N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (41 mg,0.048mmol,97.9% yield, HCl salt). MS (ESI) m/z:820.0[ M+H ]] ⁺ 。

Preparation of intermediate 4C: 6- (6-chloro-8-fluoro-4- (8-methyl-3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

To 6- (4- (3, 8-diazabicyclo [ 3.2.1)]To a solution of oct-3-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (41 mg,0.05 mmol) in methanol (5 mL) was added Et ₃ N (0.01 mL,0.10 mmol). AcOH (0.01 mL,0.1000 mmol), HCHO (0.03 mL,0.1500 mmol) and NaBH were then added ₃ CN (9 mg,0.1400 mmol). The mixture was stirred at 20℃for 12 hours. The reaction mixture was diluted with EtOAc (10 mL) and water (10 mL). The mixture was extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product 6- (6-chloro-8-fluoro-4- (8-methyl-3, 8-diazabicyclo [ 3.2.1) as a colourless solid ]Oct-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (40 mg,0.048mmol,100% yield). MS (ESI) m/z:834.3[ M+H ]] ⁺ 。

Example 4-1

6- (6-chloro-8-fluoro-4- (8-methyl-3),8-diazabicyclo [3.2.1]A solution of oct-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (40 mg,0.05 mmol) in TFA (4 mL,52.24 mmol) was stirred at 50℃for 4 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid as additive, apparatus: GX-p; column: phenomenex luna C18150. 25 mm. 10. Mu.m; mobile phase: A is H) ₂ O (0.225% FA), and B is acetonitrile; gradient: linearly B3% -33% in 10 min; flow rate: 25mL/min; column temperature: room temperature; wavelength: 220nm.254 nm) to give 6- (6-chloro-8-fluoro-4- (8-methyl-3, 8-diazabicyclo [ 3.2.1) as a yellow solid]Oct-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (12.28 mg,0.021mmol,43% yield). MS (ESI) m/z 594.2[ M+H ] ] ⁺ ,1H NMR(400MHz,CD ₃ OD)δ8.46(s,1.9H),7.91(s,1H),6.62(s,1H),4.86-4.79(m,1H),4.70-4.51(m,3H),3.91-3.79(m,3H),3.76(br s,2H),3.72-3.63(m,1H),3.25-3.16(m,1H),3.05(s,3H),2.67(s,3H),2.45(d,J＝1.2Hz,3H),2.41-2.33(m,1H),2.26-2.15(m,3H),2.12-2.02(m,2H),1.98-1.87(m,2H)。

Example 5-1

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2R) -1- (piperidin-1-yl) propan-2-yl ] oxy } quinazolin-7-yl) naphthalen-2-ol

Preparation of intermediate 5A: 3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (3.5 g,10.6 mmol) and 3, 8-diazabicyclo [3.2.1]]To a solution of tert-butyl octane-8-carboxylate (2240 mg,10.55 mmol) in THF (50 mL) was added DIEA (2.48 mL,26.5 mmol). The mixture was stirred at 20 ℃And 12h. LCMS showed the reaction was complete and the desired product was detected. The reaction mixture was diluted with EtOAc (40 mL) and water (40 mL). The mixture was extracted with EtOAc (40 ml x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. The crude product 3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (5.3 g,10.5mmol,98.8% yield) was used in the next step without purification. MS (ESI) m/z 506.9[ M+3 ]] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.75(d,J＝2.0Hz,1H),4.40(s,4H),3.78-3.51(m,2H),2.02-1.90(m,2H),1.77-1.67(m,2H),1.53(s,9H)。

Preparation of intermediate 5B: 3- (7-bromo-6-chloro-2- (((R) -1, 1-dimethoxyprop-2-yl) oxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 at 20 ]]To a solution of tert-butyl octane-8-carboxylate (1000 mg,1.98 mmol) in MeCN (80 mL) was added cesium carbonate (1280 mg,3.93 mmol), l, 4-diazabicyclo [ 2.2.2.2]Octane (40 mg,0.36 mmol) and (R) -1, 1-dimethoxypropan-2-ol (400 mg,3.33 mmol). The mixture was stirred at 45℃for 2h. TLC (petroleum ether: ethyl acetate=4:1) indicated that one major new spot with greater polarity was observed. The reaction was diluted with EtOAc (30 mL) and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether: etoac=20:1 to 4:1, rf=0.3) to give 3- (7-bromo-6-chloro-2- (((R) -1, 1-dimethoxyprop-2-yl) oxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 as a yellow oil]Tert-butyl octane-8-carboxylate (1000 mg,1.70mmol,85.8% yield). MS (ESI) m/z 591.0[ M+3 ]] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.70(d,J＝2.0Hz,1H),5.48-5.37(m,1H),4.51(d,J＝5.6Hz,1H),4.31(d,J＝12.0Hz,4H),3.64-3.52(m,2H),3.49-3.45(m,6H),2.00-1.91(m,2H),1.83-1.73(m,2H),1.52(s,9H),1.40(d,J＝6.4Hz,3H)。

Preparation of intermediate 5C: (2R) -2- ((4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-2-yl) oxy) propanal

To 3- (7-bromo-6-chloro-2- (((R) -1, 1-dimethoxyprop-2-yl) oxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 ]To a solution of tert-butyl octane-8-carboxylate (950 mg,1.61 mmol) and (3-hydroxynaphthalen-1-yl) boronic acid (284 mg,1.52 mmol) in THF (20 mL) and water (2 mL) was added potassium phosphate (703 mg,3.31 mmol) and Xphos-Pd-G3 (133 mg,0.16 mmol). The reaction was carried out at 60℃under N ₂ Stirring was carried out for 12h. LCMS showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate=10:1 to 2:1) to give (2R) -2- ((4- (3, 8-diazabicyclo [ 3.2.1) as a yellow solid]Oct-3-yl) -6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-2-yl) oxy) propanal (0.8 g,1.22mmol,76.0% yield). MS (ESI) m/z 653.1[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.71-7.63(m,2H),7.37-7.30(m,1H),7.26-7.20(m,2H),7.17-7.10(m,1H),7.04(dd,J＝8.8,2.4Hz,1H),5.36-5.23(m,1H),4.48-4.23(m,5H),3.68-3.46(m,2H),3.40-3.34(m,6H),1.94-1.86(m,2H),1.82-1.73(m,2H),1.46(s,9H),1.36-1.30(m,3H)。

Intermediate 5D preparation: 3- (6-chloro-2- (((R) -1, 1-dimethoxyprop-2-yl) oxy) -8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (6-chloro-2- (((R) -1, 1-dimethoxyprop-2-yl) oxy) -8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a solution of tert-butyl octane-8-carboxylate (750 mg,1.15 mmol) in 1, 4-dioxane (20 mL) was added HCl (1.05 mL,12.63 mmol). The mixture is mixedStirring is carried out at 20℃for 12h. LCMS showed the desired product. The residue was concentrated in vacuo. The crude product (2R) -2- ((4- (3, 8-diazabicyclo [ 3.2.1) is reacted as a yellow solid ]Oct-3-yl) -6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-2-yl) oxy) propanal (624 mg,1.15mmol,100% yield) was used in the next step without purification. MS (ESI) m/z:507.2[ M+H ]] ⁺ 。

Preparation of intermediate 5E: 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((R) -1- (piperidin-1-yl) propan-2-yl) oxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To (2R) -2- ((4- (3, 8-diazabicyclo [ 3.2.1)]Octyl-3-yl) -6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-2-yl) oxy) propanal (624 mg,1.15 mmol) to a solution of THF (30 mL) and water (10 mL) was added NaHCO ₃ (0.81 mL,5.94 mmol) and (Boc) ₂ O (0.42 mL,1.83 mmol). The mixture was stirred at 20℃for 2h. LCMS showed the reaction was complete and the desired MS was detected. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The mixture was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=5:1 to 1:1) to give 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((R) -1- (piperidin-1-yl) prop-2-yl) oxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a yellow solid ]Tert-butyl octane-8-carboxylate (470 mg,0.7742mmol,67.3% yield). MS (ESI) m/z:607.2[ M+H ]] ⁺ 。

Preparation of intermediate 5F: 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((R) -1-oxopropan-2-yl) oxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((R) -1-oxopropan-2-yl) oxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a mixture of tert-butyl octane-8-carboxylate (80 mg,0.13 mmol), piperidine (32 mg,0.38 mmol) and AcOH (0.01 mL,0.09 mmol) in methanol (2 mL) was added NaBH ₃ CN (32 mg,0.51 mmol). The mixture was stirred at 20℃for 12 hours. LCMS showed the reaction was complete and the desired product was detected. The reaction mixture was diluted with EtOAc (10 mL) and water (10 mL). The mixture was extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 1/2) to give 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((R) -1- (piperidin-1-yl) prop-2-yl) oxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a yellow solid ]Tert-butyl octane-8-carboxylate (80 mg,0.118mmol,89.8% yield). MS (ESI) m/z:676.2[ M+H ]] ⁺ 。

Example 5-1

To 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((R) -1- (piperidin-1-yl) propan-2-yl) oxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a solution of tert-butyl octane-8-carboxylate (60 mg,0.09 mmol) in DCM (3 mL) was added TFA (0.5 mL,6.53 mmol). The mixture was stirred at 20℃for 12h. LCMS showed the desired product was detected. The reaction mixture was concentrated in vacuo. The residue was subjected to preparative HPLC (formic acid as additive, instrument: GX-c; column: phenomenex luna C: 150X25mm X10 um; mobile phase: A: H) ₂ O (0.225% fa), and B is acetonitrile; gradient: linearly B3% -33% in 10 min; flow rate: 25mL/m; column temperature: room temperature; wavelength: 220nm.254 nm) to give the desired product 4- (4-) -as a yellow solid(3, 8-diazabicyclo [ 3.2.1)]Oct-3-yl) -6-chloro-8-fluoro-2- (((R) -1- (piperidin-1-yl) prop-2-yloxy) quinazolin-7-yl) naphthalen-2-ol (32.9 mg,0.0571mmol,64.4% yield). MS (ESI) m/z 576.3[ M+H ] ] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD)δ8.50(s,1H),8.00(d,J＝1.2Hz,1H),7.76(d,J＝8.0Hz,1H),7.48-7.36(m,1H),7.27(d,J＝2.4Hz,1H),7.25-7.16(m,2H),7.07-7.00(m,1H),5.74-5.62(m,1H),4.67-4.53(m,2H),3.94(s,2H),3.77(dd,J＝13.2,10.0Hz,2H),3.46-3.33(m,2H),3.27-3.08(m,4H),2.00(s,4H),1.85-1.70(m,4H),1.66-1.55(m,2H),1.47(d,J＝5.6Hz,3H)。

Example 5-2

1- [ (2R) -2- [ (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-2-yl) oxy ] propyl ] piperidin-4-ol

Preparation of intermediate 5G: 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((R) -1- (4-hydroxypiperidin-1-yl) propan-2-yl) oxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((R) -1-oxopropan-2-yl) oxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a mixture of tert-butyl octane-8-carboxylate (100 mg,0.160 mmol), piperidin-4-ol (47 mg,0.4600 mmol) and AcOH (0 mL,0.0800 mmol) in methanol (5 mL) was added NaBH ₃ CN (40 mg,0.6400 mmol). The mixture was stirred at 25℃for 12 hours. LCMS showed the reaction was complete and a peak of the desired mass was detected. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (15 mL x 3). Salt for combined organic layersWashed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by preparative TLC (silica gel plate, dichloromethane: methanol=10:1) to afford the desired product 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((R) -1- (4-hydroxypiperidin-1-yl) propan-2-yl) oxy) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1) as an off-white solid ]Tert-butyl octane-8-carboxylate (70 mg,0.10mmol,61.4% yield). MS (ESI) m/z:692.4[ M+H ]] ⁺ 。

Example 5-2

To 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((R) -1- (4-hydroxypiperidin-1-yl) propan-2-yl) oxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a solution of tert-butyl octane-8-carboxylate (70 mg,0.10 mmol) in DCM (3 mL) was added TFA (1 mL,13.06 mmol). The mixture was stirred at 25℃for 2 hours. LCMS showed complete consumption of reactant 1 and detection of one major peak with the desired MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid as additive, apparatus: GX-c; column: phenomenex luna C: 150X25mm X10 um; mobile phase: A is H2O (0.225% FA) and B is acetonitrile; gradient: linearly B3% -33% over 10 min; flow rate: 25mL/m; column temperature: room temperature; wavelength: 220nm.254 nm) to give the desired product 1- ((2R) -2- ((4- (3, 8-diazabicyclo [ 3.2.1) as a yellow solid]Oct-3-yl) -6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-2-yl) oxy) propyl piperidin-4-ol (24.99 mg,0.041mmol,41.0% yield, 1.1FA salt). MS (ESI) m/z 592.2[ M+H ] ] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD)δ8.46(s,1.1H),8.00(s,1H),7.76(d,J＝8.4Hz,1H),7.47-7.39(m,1H),7.28(d,J＝2.4Hz,1H),7.25-7.16(m,2H),7.05-6.99(m,1H),5.78-5.62(m,1H),4.64(t,J＝11.2Hz,2H),4.11(br s,2H),3.84(dd,J＝13.2,6.0Hz,3H),3.53-3.42(m,1H),3.41-3.32(m,2H),3.21(d,J＝12.8Hz,2H),3.09-2.97(m,1H),2.09(br s,4H),2.03-1.88(m,2H),1.79-1.64(m,2H),1.47(d,J＝6.0Hz,3H)。

Example 6-1

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol

Bar of intermediate 6A: 3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a solution of 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (300 mg,3.03 mmol) in dioxane (8 mL) was added DIPEA (0.476 mL,2.72 mmol) and 3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (193 mg, 0.258 mmol). The resulting mixture was stirred at 25℃for 2 hours. LCMS showed the reaction was complete. The mixture was concentrated. The residue was diluted with ethyl acetate (50 mL) and washed with water (30 mL x 2) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (12 g ISCO column, meOH/DCM,0-5%,20 min) to give tert-butyl 4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) piperazine-1-carboxylate (418 mg,0.82mmol,90% yield) as a white solid. MS (ESI) m/z 507.0[ M+1 ]] ⁺ 。 ¹ H NMR(499MHz,DMSO-d ₆ )δ8.10(d,J＝1.9Hz,1H),4.38(br d,J＝10.6Hz,2H),4.25(br s,2H),3.66(m,2H)1.79(m,2H),1.62(m,2H),1.47s,9H)。

Preparation of intermediate 6B: 3- (7-bromo-6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a solution of tert-butyl octane-8-carboxylate (415 mg, 0.630 mmol) in DMSO (6 mL) was added cesium fluoride (187 mg,1.230 mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (236 mg,2.050 mmol). The mixture was heated to 100 ℃ for 2 hours. The residue was diluted with DCM (50 mL) and washed with water (30 mL x 2) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (12 g ISCO column, meOH/DCM,0-15%,30 min) to afford 3- (7-bromo-6-chloro-8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl as a yellow oil]Methoxy } quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (108 mg,0.185mmol,22.5% yield). MS (ESI) m/z 586.1[ M+1 ]] ⁺ 。

Preparation of intermediate 6C: 3- [ 6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-4-yl ] -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

3- (7-bromo-6-chloro-8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl]Methoxy } quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (108 mg,0.185 mmol) and Na ₂ CO ₃ The suspension in 1, 4-dioxane (2954 μl) and water (739 μl) was degassed, and Pd (Ph) was added in one portion ₃ ) ₄ (42.7 mg,0.037 mmol). The mixture was again degassed and heated in a pressure vial at 95 ℃ for 1 hour. The reaction mixture was diluted with water (10 mL) and DCM (10 mL). The mixture was extracted with DCM (10 ml x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude 3- [ 6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- { [ (2S) -1-methylpyrrolidin-2-yl]Methoxy } quinazolin-4-yl]-3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester, MS (ESI) m/z 857.2[ M+1 ]] ⁺ It is directly used in the followingA step.

Example 6-1

To crude 3- [ 6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- { [ (2S) -1-methylpyrrolidin-2-yl at 25 ℃]Methoxy } quinazolin-4-yl]-3, 8-diazabicyclo [3.2.1]To a solution of tert-butyl octane-8-carboxylate in DCM (4 mL) was added TFA (0.8 mL). The reaction mixture was stirred at 25 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure to provide a residue, which was purified via preparative HPLC with the following conditions: column: XBIdge C18, 200mm x 19mm, 5-. Mu.m particles; mobile phase a:5:95 acetonitrile: water (containing 0.05% trifluoroacetic acid); mobile phase B:95:5 acetonitrile: water (containing 0.05% trifluoroacetic acid); gradient: holding at 5% B for 0 min, for 20 min 5% -45% B, then at 100% B for 0 min; flow rate: 20mL/min; column temperature: 25 ℃. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative HPLC with the following conditions: column: XBIdge C18, 200mm x 19mm, 5-. Mu.m particles; mobile phase a:5:95 acetonitrile: water (containing 0.05% trifluoroacetic acid); mobile phase B:95:5 acetonitrile: water (containing 0.05% trifluoroacetic acid); gradient: hold at 4% B for 0 min, over 20 min 4% -44% B, then hold at 100% B for 0 min; flow rate: 20mL/min; column temperature: 25 ℃. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the desired product as a white solid (22.3 mg,0.039 mmol). MS (ESI) m/z 547.93[ M+1 ] ] ⁺ ； ¹ H NMR(500MHz,DMSO-d ₆ )δ8.02(s,1H),7.82(br d,J＝8.2Hz,1H),7.46(br t,J＝7.5Hz,1H),7.36-7.15(m,3H),7.24(m,1H),4.63(br d,1H),4.60(m,3H),4.21(br s,2H),3.83(m,2H),2.97(m,2H),2.55(m,4H),2.28(s,1H),2.08(m,2H),1.97(m,5H)。

The examples in Table 3 were prepared according to the procedure described in example 6-1 from the appropriate amine and/or the appropriate borate/acid.

TABLE 3 Table 3

/>

Example 7-1

4- (6-chloro-4- {3, 6-diazabicyclo [3.1.1] hept-6-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol

Preparation of intermediate 7A: 4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

At N ₂ Next, 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (1 g,3.03 mmol) and DIPEA (1.32 mL,7.57 mmol) were combined in THF (15 mL) To the solution in (1) piperazine-1-carboxylic acid tert-butyl ester (0.56 g,3.03 mmol) was added. The reaction was stirred for 2h at 25 ℃. LCMS showed the reaction was complete. The mixture was concentrated. The residue was diluted with ethyl acetate (60 mL) and washed with water (30 mL x 2) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, petroleum ether: ethyl acetate=10:1 to 4:1) to give tert-butyl 4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) piperazine-1-carboxylate (1.33 g,2.77mmol,91.5% yield) as a yellow solid. MS (ESI) m/z 481.0[ M+1 ]] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.77(d,J＝1.6Hz,1H),3.93-3.84(m,4H),3.72-3.61(m,4H),1.50(s,9H)。

Preparation of intermediate 7B: (S) -4- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) piperazine-1-carboxylate (540 mg,1.125 mmol) in DMSO (6 mL) was added cesium fluoride (349mg, 2.249 mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (324 mg,2.81 mmol). The mixture was heated to 100 ℃ for 2h. After cooling the mixture to room temperature, saturated NaHCO was added ₃ (50 mL). The aqueous phase was extracted with DCM (50 mL. Times.2). The combined DCM phases were washed with brine and dried (Na ₂ SO ₄ ) And then concentrated. The residue was purified on a 40g silica gel column eluting with 0-10% meoh in DCM (w/0.5% TEA) to provide tert-butyl (S) -4- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (0.43 g,0.769mmol,68.4% yield) as a yellow solid. MS (ESI) m/z 558.2/560.2[ M+1 ]] ⁺ 。

Preparation of intermediate 7C: 4- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

Tert-butyl (S) -4- (7-bromo-6-chloro-8-fluoro-2- ((1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (430 mg,0.769 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-2-ol (249 mg,0.923 mmol), na ₂ CO ₃ (248 mg,2.308 mmol) in 1, 4-dioxane (10 mL) and water (2 mL) with N ₂ Deaeration was carried out for 5min, and tetrakis (triphenylphosphine) palladium (0) (178 mg,0.154 mmol) was then added in one portion. Subjecting the resulting mixture to N ₂ Deaeration and then heating in a microwave oven at 95℃for 1h. The reaction was cooled to room temperature, filtered and the filter cake was washed with dioxane (2 ml x 3). The filtrate and washings were combined and concentrated. The residue was purified on 24g silica eluting with 0-10% MeOH in DCM (w 0.5% TEA) to provide tert-butyl 4- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (174 mg,0.280mmol,36.4% yield) as a yellow solid. MS (ESI) m/z 622.4[ M+1 ]] ⁺ 。

Preparation of intermediate 7D: 6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4 (3H) -one

A solution of tert-butyl 4- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazine-1-carboxylate (400 mg,0.643 mmol) in EtOH (5 mL) and water (0.5 mL) was treated with sodium hydroxide (1.284 mL, 1.284 mmol). The reaction was stirred at 50℃for 16h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 0-10% MeOH in DCM (w 0.5% TEA) to give the desired compound (174 mg,0.383mmol,59.6% yield) as a white solid. MS (ESI) m/z:454.1[ M+H ] ] ⁺ 。

Preparation of intermediate 7E: 6- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-3-carboxylic acid tert-butyl ester

To 6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-ol (10 mg,0.022 mmol), 3, 6-diazabicyclo [3.1.1]]To a mixture of tert-butyl heptane-3-carboxylate (5.24 mg,0.026 mmol) and DIEA (11.54 μl,0.066 mmol) in dichloromethane (2 mL) was added BOP (12.18 mg,0.028 mmol) and the reaction stirred at room temperature for 16h until complete. The reaction was run with 4mL of NaHCO ₃ The aqueous solution was quenched and extracted with DCM (5 mL. Times.3). The combined organics were washed with brine, dried over Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was dissolved in 2mL of THF, and TBAF (88. Mu.L, 0.088 mmol) was added. The mixture was stirred at room temperature for 15min. The reaction was concentrated and the residue was purified on 4g silica eluting with 0-10% meoh/DCM (w 0.5% TEA) to provide the desired compound (10 mg,0.016mmol,71.6% yield). MS (ESI) m/z:634.1[ M+H ]] ⁺ 。

Preparation of example 7-1: 4- (6-chloro-4- {3, 6-diazabicyclo [3.1.1] hept-6-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol

6- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 6-diazabicyclo [ 3.1.1.1]Tert-butyl heptane-3-carboxylate (10 mg,0.016 mmol) was treated with 1mL of 30% TFA/DCM at room temperature for 30min. The reaction mixture was then concentrated. The residue was purified via preparative LC/MS with the following conditions: column: XBIdge C18, 200mm x 19mm,5-Particles; mobile phase a:5:95 acetonitrile: water (containing 0.05% trifluoroacetic acid);mobile phase B:95:5 acetonitrile: water (containing 0.05% trifluoroacetic acid); gradient: hold at 7% B for 0min, over 20 min 7% -47% B, then hold at 100% B for 0 min; flow rate: 20mL/min; column temperature: 25 ℃. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the final compound example 7-1 (4.6 mg,6mmol,37.7% yield). MS (ESI) m/z 534.4[ M+1 ]] ⁺ ； ¹ H NMR(500MHz,DMSO-d ₆ )δ7.93(s,1H),7.82(br d,J＝8.5Hz,1H),7.45(br t,J＝7.3Hz,1H),7.31(d,J＝1.9Hz,1H),7.24(br t,J＝7.3Hz,1H),7.19-7.13(m,1H),7.10-7.03(m,1H),5.28-5.06(m,1H),4.78-4.67(m,1H),4.66-4.51(m,1H),3.89-3.76(m,1H),3.75-3.31(m,5H),3.15-2.75(m,5H),2.32-2.20(m,1H),2.11-1.99(m,2H),2.00-1.77(m,3H)

The examples in Table 4 were prepared according to the procedure described in example 7-1 from intermediate 7D and the appropriate amine.

TABLE 4 Table 4

/>

Example 8-1

(5S) -5- { [ (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-2-yl) oxy ] methyl } pyrrolidin-2-one

To 3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a degassed solution of tert-butyl octane-8-carboxylate (1 g,3.03 mmol) in DMA (80 mL) was added cesium fluoride (5.25 g,34.6 mmol). It was degassed with nitrogen for 10min and heated in a sealed tube at 88 ℃ for 5h. Water (200 mL) and ethyl acetate (150 mL) were added and stirred for 15min. The separated aqueous layer was purified with ethyl acetate (2X100 mL) and the combined organic layers were extracted over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated. The resulting residue was purified by flash column chromatography (using 15% -25% ethyl acetate in petroleum ether as eluent) to afford 3- (7-bromo-6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a pale yellow solid]Tert-butyl octane-8-carboxylate (4.7 g,8.77mmol,63.4% yield). MS (ESI) m/z 489.0[ M+1 ]] ⁺ 。

Preparation of intermediate 8B: 3- (7-bromo-6-chloro-8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (7-bromo-6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a solution of tert-butyl octane-8-carboxylate (0.2 g,0.408 mmol) in acetonitrile (5.0 mL) was added (S) -5- (hydroxymethyl) pyrrolidin-2-one (0.071 g,0.613 mmol) and DABCO (0.055 g,0.490 mmol). The reaction mixture was stirred at 80℃for 16h. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine solution, and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated. The resulting residue was purified by column chromatography over neutral alumina (Grace, 25g snap, dry bag) (by elution with 50% -100% ethyl acetate in petroleum ether) to afford tert-butyl 3- (7-bromo-6-chloro-8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1) as a gum solid]Tert-butyl octane-8-carboxylate (0.150 g,0.180mmol,44.1% yield). MS (ESI) m/z 584.0/586.0[ M+1 ]] ⁺ 。

Intermediate 8C preparation: 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((S) -5-oxopyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (7-bromo-6-chloro-8-fluoro-2- (((S) -5-oxopyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a degassed solution of tert-butyl octane-8-carboxylate (0.150 g,0.256 mmol) in 1, 4-dioxane (3.0 mL) and water (0.5 mL) was added 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalene-2-ol (0.173 g,0.641 mmol), dipotassium hydrogen phosphate (0.089 g,0.513 mmol) and PdCl ₂ (dppf) (0.019 g,0.026 mmol). The reaction mixture was stirred at 80℃for 16h. After cooling, the reaction was diluted with ethyl acetate and passed through celite The bed was filtered and concentrated to give 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((S) -5-oxopyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a brown solid]Tert-butyl octane-8-carboxylate (0.2 g,0.173mmol,67.4% yield). MS (ESI) m/z 648.2/649.2[ M+1]] ⁺ 。

Example 8-1

To a stirred solution of tert-butyl 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((S) -5-oxopyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.2 g,0.309 mmol) in DCM (5.0 mL) was added 4.0M hydrogen chloride solution in dioxane (2.0 mL,8.00 mmol) at 0 ℃. The reaction mixture was stirred at ambient temperature for 16h. The reaction mixture was concentrated under reduced pressure to provide a residue, which was purified via preparative HPLC with the following conditions: YMC Triart C18 (250 x 20) mm,5- μm particles; mobile phase a = 10mM ammonium acetate in water, mobile phase B = acetonitrile, flow: 15mL/min, mobile phase-A=grade-80% -40%, mobile phase-B grade-20% -60% within 15 min. Fractions containing the desired product were lyophilized to give (5S) -5- (((4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-2-yl) oxy) methyl) pyrrolidin-2-one, acOH (50 mg,0.079mmol,25.5% yield) as an off-white solid. MS (ESI) m/z 548.2[ M+1] +;1H NMR (500 MHz, DMSO-d 6) delta 10.06 (s, 1H), 7.96 (s, 1H), 7.80-7.85 (m, 2H), 7.42-7.48 (m, 1H), 7.29 (d, J=2.40 Hz, 1H), 7.23-7.25 (m, 2H), 7.22-7.20 (m, 1H), 4.24-4.37 (m, 4H), 3.90-3.93 (m, 1H), 3.48-3.58 (m, 4H), 2.11-2.22 (m, 4H), 1.90-1.91 (m, 1H), 1.86-1.88 (m, 1H), 1.66-1.76 (m, 4H).

The examples in Table 5 were prepared according to the procedure described in example 8-1 from intermediate 8A and the appropriate alcohol.

TABLE 5

/>

Examples 9-1 and 9-2

6- (2- { [ (2R, 7 aR) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

/>

Preparation of intermediate 9A: (3-bromopropoxy) (tert-butyl) dimethylsilane

To a stirred solution of 3-bromopropan-1-ol (10.00 g,71.9 mmol) in anhydrous dichloromethane (50 mL) at 0deg.C under nitrogen was added imidazole (4.90 g,71.9 mmol) followed by tert-butyldimethylsilyl chloride (14.10 g,94 mmol). The reaction mixture was slowly warmed to room temperature and stirred at the same temperature for 12h. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and diluted with water (50 mL). The suspension was extracted with dichloromethane (3×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue of the product. The residue was purified by silica gel column chromatography using 0-5% ethyl acetate in petroleum ether to give (3-bromopropyloxy) (tert-butyl) dimethylsilane (8.00 g,31.6mmol,43.9% yield) as a colorless oil. ¹ H NMR(400MHz,CD ₃ OD):δ3.69(t,J＝4.0Hz,2H),3.57(t,J＝6.4Hz,2H),1.99-1.93(m,2H),0.87(s,9H),0.06(s,6H)ppm。

Preparation of intermediate 9B: 1- (tert-butyl) 2-methyl (2R, 4R) -2- (3- ((tert-butyldimethylsilyl) oxy) propyl) -4-)

Fluoropyrrolidine-1, 2-dicarboxylic acid ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2S, 4R) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (5.00 g,20.22 mmol) in anhydrous THF (30 mL) at-25℃under nitrogen atmosphere was added LiHMDS (1M in THF, 30.3mL,30.3 mmol) dropwise. The reaction mixture was stirred at the same temperature for 30min, after which (3-bromopropyloxy) (tert-butyl) dimethylsilane (7.68 g,30.3 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 30min and then slowly warmed to room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and then diluted with water (50 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. Will be disabledThe residue was purified by silica gel column chromatography using 20% -30% ethyl acetate in petroleum ether to give 1- (tert-butyl) 2-methyl (2 r,4 r) -2- (3- ((tert-butyldimethylsilyl) oxy) propyl) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (7.23 g,17.24mmol,85.0% yield) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ ):δ5.18-5.03(m,1H),4.10-3.98(m,1H),3.78(s,3H),3.74-3.52(m,3H),2.48-2.23(m,3H),2.19-1.98(m,1H),1.65(s,9H),1.48-1.44(m,2H),0.90(s,9H),0.60(s,6H)ppm。 ¹⁹ F(376MHz,CD ₃ OD): delta-172.47 to-172.96 (m) ppm. LCMS-ELSD (ESI) m/z 320.2[ M+H-Boc ]] ⁺ 。

Preparation of intermediate 9C: 1- (tert-butyl) 2-methyl (2R, 4R) -4-fluoro-2- (3-hydroxypropyl) pyrrolidine-1, 2-dicarboxylic acid ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2 r,4 r) -2- (3- ((tert-butyldimethylsilyl) oxy) propyl) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (7.00 g,16.68 mmol) was added dropwise TBAF (1M in THF, 16.68ml,16.68 mmol) at 25 ℃ and stirred at the same temperature for 4h. The reaction mixture was quenched with saturated aqueous ammonium chloride (90 mL) and diluted with ethyl acetate (100 mL). The mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue as a colorless oil. The crude product was purified by silica gel column chromatography (using 50% ethyl acetate in petroleum ether) to give 1- (tert-butyl) 2-methyl (2 r,4 r) -4-fluoro-2- (3-hydroxypropyl) pyrrolidine-1, 2-dicarboxylic acid ester (4.97 g,15.64mmol,94.0% yield) as a colorless oil. LCMS-ELSD (ESI) m/z 206.2[ M+H-Boc ]] ⁺ 。

Preparation of intermediate 9D: 1- (tert-butyl) 2-methyl (2R, 4R) -4-fluoro-2- (3-iodopropyl) pyrrolidine-1, 2-dicarboxylic acid ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2R, 4R) -4-fluoro-2- (3-hydroxypropyl) pyrrolidine-1, 2-dicarboxylic acid ester (9.00 g,29.5 mmol) in dichloromethane (100 mL) was added triphenylphosphine (15.50 g,58.9 mmol), imidazole (6.02 g,88 mmol) at 0deg.C, and the reaction mixture was stirred at the same temperature for 10min, followed by iodine (29.9 g,118 mmol). The reaction mixture was stirred at room temperature for 12h. The reaction mixture was then quenched with saturated aqueous sodium thiosulfate (30 mL) and the suspension extracted with dichloromethane (2 x200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. This crude product was purified by silica gel column chromatography (using 10% -20% ethyl acetate in petroleum ether) to give 1- (tert-butyl) 2-methyl (2 r,4 r) -4-fluoro-2- (3-iodopropyl) pyrrolidine-1, 2-dicarboxylic acid ester (10.10 g,24.32mmol,83.0% yield) as a colorless oil. LCMS-ELSD (ESI) m/z 361.2[ M+H-Boc ]] ⁺ 。

Preparation of intermediate 9E: 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((R) -1- (piperidin-1-yl) propan-2-yl) oxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2 r,4 r) -4-fluoro-2- (3-iodopropyl) pyrrolidine-1, 2-dicarboxylic acid ester (10.0 g,24.08 mmol) in dichloromethane (20 mL) was added HCl in dioxane (8.03 mL,24.08 mmol) at 25 ℃ and the reaction mixture was stirred at the same temperature for 6h. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure at room temperature to obtain the crude residue (2 r,4 r) -4-fluoro-2- (3-iodopropyl) pyrrolidine-2-carboxylic acid methyl ester HCl salt (6.5 g,20.63mmol,86.0% yield) which was used as such in the next step without any further purification. LCMS-ELSD (ESI) m/z 188.2[ M+H ] ] ⁺ 。

Preparation of intermediate 9F: (2R, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester

To a stirred solution of methyl (2 r,4 r) -4-fluoro-2- (3-iodopropyl) pyrrolidine-2-carboxylate (6.5 g,20.63 mmol) in anhydrous acetonitrile (30 mL) was added triethylamine (10 mL) at room temperature. The reaction mixture was stirred at 45℃for 12h. The reaction mixture was concentrated under reduced pressure to obtain a crude residue. The residue was purified by column chromatography (neutral alumina) (using 40% -50% ethyl acetate in petroleum ether) to give methyl (2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (3.20 g,83.0% yield) as a pale yellow oil. ¹ H NMR(400MHz,DMSO-d ₆ ):δ5.76-5.19(m,1H),3.59(s,3H),3.25-3.16(m,1H),2.97-2.95(m,1H),2.86 -2.76(m,1H),2.68-2.51(m,2H),2.02-1.91(m,2H),1.85-1.72(m,3H)ppm。LCMS-ELSD(ESI)m/z:188.3[M+H] ⁺ 。

Preparation of intermediate 9G: ((2R, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol

LiAlH was added dropwise to a stirred solution of (2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester (3.20 g,17.09 mmol) under nitrogen at 0℃over 10min ₄ (2M in THF, 17.09mL,34.2 mmol). After the addition, the reaction mixture was warmed to room temperature over 30 min. The mixture was stirred at this temperature for 1h, then quenched with saturated aqueous ammonium chloride (5 mL) at 0 ℃. Once effervescence was stopped, anhydrous sodium sulfate was added to the reaction mixture followed by dichloromethane (20 mL). The reaction mixture was stirred for 20min and filtered. The filtrate was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue ((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (2.20 g,13.68mmol,80.0% yield) as a pale brown oil. ¹ H NMR(400MHz,CD ₃ OD):δ5.34-5.10(m,1H),3.51-3.29(m,3H),3.25-3.10(m,1H),3.04-2.93(m,1H),2.90-2.73(m,1H),2.71-2.59(m,1H),2.28-2.12(m,,1H),1.95-1.73(m,4H),1.68-1.66(m,1H)ppm。 ¹⁹ F(376MHz,CD ₃ OD): delta-175.69 to-176.04 (m) ppm. LCMS-ELSD (ESI) m/z 160.0[ M+H ]] ⁺ 。

Preparation of intermediate 9H: 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazoline

-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a degassed solution of example 8A (2.00 g,4.08 mmol) in anhydrous 1, 4-dioxane (20 mL) was added potassium phosphate (1.73 g,8.17 mmol), N-bis (4-methoxybenzyl) -4-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (5.8 g,12.25 mmol), pdCl ₂ (dppf) (149 mg,0.204 mmol). The mixture was degassed again and heated at 80 ℃ for 48h. The progress of the reaction was monitored by LCMS. The reaction vessel was allowed to cool to ambient temperature, diluted with ethyl acetate (40 mL), filtered through a celite bed, and concentrated in vacuo to give the crude product. The residue was purified by silica gel column chromatography (using 30% ethyl acetate in petroleum ether) to give 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (1.5 g,1.74mmol,42% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.76(d,J＝1.6Hz,1H),7.20-7.18(d,J＝8.8Hz,4H),6.86(dt,J＝9.6Hz,4H),6.60(s,1H),6.38(s,1H),4.60(s,3H),4.39-4.21(m,4H),3.63(s,6H),2.29(s,3H),1.98-1.96(m,6H),1.76-1.63(m,2H),1.49(s,9H)ppm。LCMS(ESI)m/z:757.2[M+H] ⁺ 。

Preparation of intermediate 9I: 3- (7- (6- (bis (4-methoxybenzyl) amino) -3-iodo-4-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

At 0 ℃ underTo 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 under nitrogen]To a stirred solution of tert-butyl octane-8-carboxylate (1.40 g,1.849 mmol) in anhydrous acetonitrile (15 mL) was added N-iodosuccinimide (0.42 g,1.849 mmol) and trifluoroacetic acid (0.028 mL,0.370 mmol). The reaction mixture was allowed to reach room temperature over one hour. The reaction mixture was then quenched with saturated aqueous sodium thiosulfate (5 mL) and saturated aqueous sodium bicarbonate (4 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by silica gel column chromatography (using 30% ethyl acetate in petroleum ether) to give 3- (7- (6- (bis (4-methoxybenzyl) amino) -3-iodo-4-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 as a pale yellow fluffy solid]Tert-butyl octane-8-carboxylate (1.42 g,1.560mmol,84% yield). LCMS (ESI) m/z 883.3[ M+H ]] ⁺ 。

Preparation of intermediate 9J: 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

3- (7- (6- (bis (4-methoxybenzyl) amino) -3-iodo-4-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 in a sealed tube under a nitrogen atmosphere]To a stirred solution of tert-butyl octane-8-carboxylate (1.40 g,1.585 mmol) in anhydrous DMA (10 mL) was added cuprous iodide (I) (0.60 g,3.17 mmol). The reaction mixture was degassed for 10min, then methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (0.91 g,4.76 mmol) was added and the reaction mixture was heated to 90 ℃ for 12h. The progress of the reaction was monitored by LCMS. The reaction mixture was diluted with diethyl ether (20 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a mixtureA crude residue was obtained. The crude product was purified by silica gel column chromatography (using 30% ethyl acetate in petroleum ether) to give 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 ] as a pale yellow solid]Tert-butyl octane-8-carboxylate (0.85 g,0.630mmol,40% yield). ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.77 (s, 1H), 7.16 (d, J=8.8 Hz, 4H), 6.87 (dt, J=9.6 and 2.8Hz, 4H), 6.43 (s, 1H), 4.76-4.72 (m, 2H), 4.59-4.55 (m, 2H), 3.81 (s, 6H), 2.43 (s, 3H), 1.97-1.82 (m, 4H), 1.97-1.82 (m, 4H), 1.53 (s, 9H) ppm. LCMS (ESI) m/z 825.2[ M+H ] ] ⁺ 。

Preparation of intermediate 9K: 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of ((2 r,7 ar) -2-fluorotetrahydro-H-pyrrolazin-7 a (5H) -yl) methanol (0.23 g,1.454 mmol) in anhydrous THF (2.1 mL) at 0 ℃ was added sodium hydride (43.6 mg,1.091 mmol) and the reaction mixture was stirred at the same temperature for 30min. After 30min, 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] dissolved in anhydrous THF (10 mL)]Tert-butyl octane-8-carboxylate (0.60 g,0.727 mmol) was added dropwise to the reaction mixture while maintaining the temperature at 0 ℃. The reaction mixture was stirred for the next 2h while the reaction mixture was warmed to room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride (1 mL) and diluted with ethyl acetate (5 mL). The mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue of the product. The crude residue was purified by neutral alumina (using 30% ethyl acetate in petroleum ether) to give 3- (7- (6- (bis (4-methoxybenzyl)) as a pale yellow solid Group) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (657 mg,0.703mmol,97.0% yield). LCMS (ESI) m/z 964.3[ M+H ]] ⁺ 。

Examples 9-1 and 9-2

To a stirred solution of TFA (200. Mu.l, 2.59 mmol) and triethylsilane (83. Mu.l, 0.518 mmol) at room temperature was added 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-8-carboxylic acid tert-butyl ester (0.50 g,0.518 mmol). The reaction mixture was then stirred at 35℃for 12h. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was concentrated at less than 35 ℃ under reduced pressure to remove most of TFA. The residue was co-evaporated with methanol (3 x1 mL) to remove any residual TFA. The residue was neutralized with DIPEA and concentrated under reduced pressure to obtain the free base. The crude product was then purified by column chromatography on silica gel (previously neutralized with DIPEA) using a mixture of MeOH, dichloromethane and DIPEA (15:80:2.5) to give 6- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ]Methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1]Oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine. The atropisomers were subjected to chiral SFC (column: OD 25X 5mm I.D.,5um; mobile phase: phase A is CO) ₂ And phase B is MeOH (0.1% NH ₄ OH); gradient elution: in CO ₂ 40% MeOH (0.1% NH) ₄ OH); flow rate: 350mL/min; a detector: UV 220nm; column temperature: 30 ℃; back pressure: 100 bar) to obtain two product peaks: peak 1 (example 9-1) and peak 2 (example 9-2).

Peak 1, isomer 1: example 9-1 (66 mg,33% yield). MS (ESI) m/z 624.3[ M+1 ]]+。 ¹ H NMR(499MHz,DMSO-d ₆ )δ7.88-7.76(m,1H),6.94-6.75(m,2H),6.57-6.42(m,1H),5.49-5.24(m,1H),4.36-4.27(m,1H),4.22-4.16(m,1H),4.11(s,1H),4.07-4.01(m,1H),3.58-3.49(m,3H),3.48-3.42(m,1H),3.01-2.92(m,1H),2.89-2.74(m,1H),2.58-2.54(m,1H),2.40-2.36(m,3H),2.35-2.26(m,1H),1.87-1.87(m,1H),1.96-1.78(m,3H),1.71-1.57(m,5H)。

Peak 2, isomer 2: example 9-2 (58.8 mg,29% yield). MS (ESI) m/z 624.3[ M+1 ]]+。 ¹ H NMR(499MHz,DMSO-d ₆ )δ7.92-7.72(m,1H),6.96-6.76(m,2H),6.60-6.41(m,1H),5.52-5.23(m,1H),4.40-4.31(m,1H),4.27-4.18(m,1H),4.15-4.04(m,2H),3.68-3.61(m,2H),3.60-3.54(m,1H),3.53-3.46(m,1H),3.00-2.92(m,1H),2.90-2.75(m,1H),2.60-2.53(m,1H),2.37(d,J＝1.4Hz,3H),2.36-2.27(m,1H),1.96-1.77(m,4H),1.74-1.61(m,5H)。

Examples 10-1 and 10-2

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalen-2-ol

Preparation of intermediate 10A: 3- (7-bromo-6-chloro-8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of ((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolazin-7 a (5H) -yl) methanol (0.390 g,2.450 mmol) in THF (20 mL) at 0 ℃ was added NaH (60% in mineral oil, 0.074g,3.06 mmol) and the reaction mixture was stirred for 30min. 3- (7-bromo-6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] in THF (20 mL) at 0deg.C ]Octane-8-carboxylic acid tert-butyl esterEster (1.0 g,2.042 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16h. The progress of the reaction was monitored by LCMS to confirm the formation of the desired product. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water and saturated brine solution, and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The crude product obtained was purified by column chromatography over neutral alumina (Grace, 50g snap, dry bag) (by elution with 50% -100% ethyl acetate in petroleum ether). The desired fractions were pooled and concentrated under reduced pressure to give 3- (7-bromo-6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a pale brown solid]Tert-butyl octane-8-carboxylate (650 mg,1.002mmol,49.1% yield). LCMS (ESI) m/z 629.0[ M+H ]] ⁺ 。

Preparation of intermediate 10B: 3- (6-chloro-8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) yl) methoxy) -7- (3-hydroxynaphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (7-bromo-6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a degassed solution of tert-butyl octane-8-carboxylate (650 mg,1.033 mmol) in water (0.5 mL), DMF (1.5 mL) and 1, 4-dioxane (5.0 mL) was added 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalene-2-ol (698 mg,2.58 mmol), sodium carbonate (274 mg,2.58 mmol) and bis (triphenylphosphine) palladium (II) dichloride (76 mg,0.103 mmol). The mixture was again degassed and heated in a pressure vial at 100 ℃ for 16h. The reaction was monitored by LCMS; analysis showed the formation of the desired product. The reaction vessel was allowed to cool to ambient temperature, diluted with ethyl acetate, filtered through a celite bed and concentrated in vacuo to give the crude product. The residue was purified by prep HPLC (bAmmonium acid as additive, instrument: agilent; column: XBridge C8250 x 19 x 5um; mobile phase: a (10 Mm ammonium acetate in water) and B: acetonitrile; gradient: linearly B4% -80% within 15 min; flow rate: 15mL/min; wavelength: 220nm.254 nm) to afford the desired product 3- (6-chloro-8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (3-hydroxynaphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1) as an off-white solid ]Tert-butyl octane-8-carboxylate (0.15 g,0.204mmol, 19.70%). LCMS (ESI) m/z 692.2[ M+H ]] ⁺ 。

Examples 10-1 and 10-2

To 3- (6-chloro-8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (3-hydroxynaphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1) at 0deg.C]To a stirred solution of tert-butyl octane-8-carboxylate (0.15 mg, 0.217. Mu. Mol) in dichloromethane (10 mL) was added hydrogen chloride in dioxane (4M, 0.054. Mu.l, 0.217. Mu. Mol). The reaction mixture was stirred at 25℃for 5h. The progress of the reaction was monitored by LCMS to confirm the formation of the desired product. The reaction mixture was concentrated under reduced pressure to give the desired product 4- (2- { [ (2R, 7 aR) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl]Methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1]Oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalen-2-ol. HCl as a yellow solid (0.12 g,0.202mmol, 88.2%). LCMS (ESI) m/z 592.1[ M+H ]] ⁺ 。1H NMR(400MHz,CD ₃ OD) delta 8.22 (s, 1H), 7.80 (d, j=8.4 hz, 1H), 7.46 (t, j=6.8 hz, 1H), 7.33-7.22 (m, 3H), 7.10 (d, j=2.4 hz, 1H), 5.62-5.50 (m, 1H), 5.11-4.93 (m, 3H), 4.35-4.14 (m, 3H), 3.76-3.74 (m, 2H), 3.71-3.61 (m, 1H), 3.49-3.36 (m, 1H), 3.32-3.24 (m, 1H), 2.56 (t, j=5.6 hz, 1H), 2.34-2.32 (m, 1H), 2.24-2.19 (m, 2H), 2.19-2.01 (m, 4.37 ppm (m, 1.37 ppm-4.37H). The atropisomers were passed through chiral SFC (column: cellulose-4X 25X 3 mm i.d.,5um; mobile phase: phase A is CO ₂ And phase B is MeOH (0.2% NH ₄ OH); eluting: in CO ₂ 40% MeOH (0.2% NH) ₄ OH); flow rate: 180mL/min; a detector: UV 220nm; column temperature: 28 ℃; back pressure: 100 bar) to obtain two product peaks: peak 1 (example 10-1) and Peak 2 (example 10-2).

Peak 1, isomer 1: example 10-1 (29 mg). MS (ESI) m/z 592.5[ M+1 ]]+。 ¹ H NMR (499 MHz, methanol-d) ₄ )δ8.02-7.93(m,1H),7.81-7.74(m,1H),7.47-7.38(m,1H),7.30-7.24(m,2H),7.24-7.18(m,1H),7.08-7.01(m,1H),5.54-5.20(m,1H),4.65-4.51(m,2H),4.49-4.43(m,1H),4.40-4.29(m,1H),3.79-3.61(m,4H),3.54-3.41(m,1H),3.21-3.07(m,1H),3.04-2.88(m,1H),2.85-2.72(m,1H),2.64-2.44(m,1H),2.23-2.12(m,1H),2.09-1.93(m,4H),1.88(br s,4H),1.45-1.14(m,2H)。

Peak 2, isomer 2: example 10-2 (29 mg). MS (ESI) m/z 592.5[ M+1 ]]+。 ¹ H NMR (499 MHz, methanol-d) ₄ )δ8.01-7.94(m,1H),7.81-7.73(m,1H),7.47-7.39(m,1H),7.30-7.18(m,3H),7.08-7.01(m,1H),5.49-5.23(m,1H),4.65-4.51(m,2H),4.49-4.41(m,1H),4.40-4.31(m,1H),3.80-3.63(m,5H),3.55-3.42(m,1H),3.20-3.10(m,1H),3.04-2.88(m,1H),2.85-2.72(m,1H),2.63-2.46(m,1H),2.22-2.11(m,1H),2.09-1.93(m,4H),1.92-1.81(m,5H)。

Examples 11-1 and 11-2

6- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 11A: 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolazin-7 a (5H) -yl) methanol (251 mg,1.575 mmol) in THF (5 mL) at 0 ℃ was added NaH (28.4 mg,1.181 mmol) and the mixture was stirred for an additional 30 min. Then, 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 is added ]A solution of tert-butyl octane-8-carboxylate (650 mg,0.788 mmol) in THF (2 mL) was allowed to warm gradually to room temperature over a period of 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, and then Na ₂ SO ₄ Dried and concentrated under reduced pressure to provide a crude residue, which was purified by silica gel column chromatography using CombiFlash instrument (40 gColumn, 50% to 60% EtOAc-petroleum ether) to afford 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1) as a brown solid]Tert-butyl octane-8-carboxylate (470 mg,0.492mmol,62.5% yield). MS (ESI) M/z 964.2 (M+H) ⁺ 。

Examples 11-1 and 11-2

A stirred solution of TFA (190. Mu.L, 2.462 mmol) and triethylsilane (79. Mu.L, 0.492 mmol) was added to tert-butyl 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (475 mg,0.492 mmol) at room temperature and the resulting reaction mixture was heated to 35℃for 24H. The reaction mixture was then concentrated under reduced pressure, co-distilled with toluene (twice), neutralized with DIPEA, and concentrated under reduced pressure to afford a crude residue that was purified by achiral SFC, then by chiral SFC to afford 6- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (11-1, isomer 1) (9 mg,0.014mmol,2.93% yield) and (11-2, isomer 2) (8 mg,0.013mmol,2.60% yield).

11-1 (isomer 1): MS (ESI) M/z 624.2, [ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δ＝7.82(s,1H),6.84(s,2H),6.49(s,1H),5.27(d,J＝45.2Hz,1H),4.35(d,J＝9.4Hz,1H),4.27(d,J＝9.4Hz,1H),4.08(ABq,J＝8.4Hz,2H),3.76-3.68(m,2H),3.59(d,J＝10.1Hz,1H),3.51(d,J＝10.1Hz,1H),3.10-3.00(m,3H),2.87-2.80(m,1H),2.35(s,3H),2.14-2.10(m,1H),2.05-2.03(m,1H),2.02-1.95(m,1H),1.80-1.70(m,7H)。

11-2 (isomer 2): MS (ESI) M/z 624.2, [ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δ＝7.80(s,1H),6.84(s,2H),6.49(s,1H),5.27(d,J＝45.2Hz,1H),4.29(d,J＝9.4Hz,1H),4.16(d,J＝9.4Hz,1H),4.01(ABq,J＝8.4Hz,2H),3.66-3.49(m,3H),3.42(d,J＝10.1Hz,1H),3.10-3.00(m,3H),2.87-2.80(m,1H),2.35(s,3H),2.13-2.10(m,1H),2.05-2.03(m,1H),2.02-1.98(m,1H),1.88-1.70(m,3H),1.65-1.55(m,4H)。

Preparation type achiral SFC condition: column/size: princeton SFC Diol (250X 4.6) mm,5u; CO ₂ Percent: 30%; cosolvent%: 70% (0.2% NH in methanol) ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the Flow rate: 3mL/min; back pressure: 100 bar; retention time = 6.129min.

Preparation chiral SFC conditions: column/size: chiralcel ODH (250X 4.6) mm,5u; CO ₂ Percent: 30%; cosolvent%: 70% (5 mM NH in CAN: methanol (1:1)) ₄ OAc); flow rate: 4mL/min; back pressure: 100 bar; retention time of peak-01 = 3.234min and retention time of peak-02 = 6.862min.

Examples 12-1 and 12-2

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalen-2-ol

Preparation of intermediate 12A: 3- (7-bromo-6-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolazin-7 a (5H) -yl) methanol (195 mg,1.225 mmol) in THF (8 mL) at 0deg.C was added NaH (61.3 mg,1.531 mmol) and the resulting reaction mixture was stirred for an additional 30 minutes. Then, a solution of example 8A (500 mg,1.021 mmol) in THF (2 mL) was added and gradually warmed to room temperature over a period of 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, and over Na ₂ SO ₄ Dried and concentrated to provide a crude residue, which was purified by silica gel column chromatography using CombiFlash instrument (40 gColumn, 70% to 80% EtOAc-petroleum ether) to give 3- (7-bromo-6-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (400 mg,0.636mmol,62.3% yield). MS (ESI) m/z 628.2[ M+H ]] ⁺ 。

Preparation of intermediate 12B: 3- (6-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (3-hydroxynaphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (7-bromo-6-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 at room temperature]To a stirred solution of tert-butyl octane-8-carboxylate (320 mg,0.509 mmol) in 1, 4-dioxane (5 mL) was added 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalene-2-ol (165 mg,0.611 mmol) and K ₂ CO ₃ (aqueous solution) (0.509 mL,1.526 mmol). The reaction mixture was purged with nitrogen for 5 minutes and charged with Pd (Ph ₃ P) ₄ (58.8 mg,0.051 mmol). The reaction mixture was again purged with nitrogen for 3 minutes and heated at 85 ℃ for 16h. The reaction mixture was then cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude compound, which was purified by silica gel column chromatography using CombiFlash instrument (24 g A column; petroleum ether-ethyl acetate as eluent). The desired product was eluted with 60% -70% ethyl acetate in petroleum ether. The pure fractions were evaporated under reduced pressure to give 3- (6-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -7- (3-hydroxynaphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a pale yellow solid]Tert-butyl octane-8-carboxylate (170 mg,0.246mmol,48.3% yield). MS (ESI) m/z 692.7[ M+H ]] ⁺ 。

Examples 12-1 and 12-2

To 3- (6-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (3-hydroxynaphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1) at 0deg.C]To a stirred solution of tert-butyl octane-8-carboxylate (150 mg,0.217 mmol) in DCM (1 mL) was added TFA (0.083 mL,1.083 mmol) and the resulting reaction mixture was stirred at room temperature for 1h. The reaction mixture was then concentrated at 30 ℃ under reduced pressure and co-distilled with 1, 4-dioxane using Et ₃ N-neutralization, co-distillation with 1, 4-dioxane and MeOH again to give the crude compound as a pale yellow solid, which was purified by chiral SFC to give 4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ]Methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1]Oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalen-2-ol (12-1, isomer 1) (13 mg,0.022mmol,9.93% yield) and (12-2, isomer 2) (20 mg,0.032mmol,14.81% yield).

12-1 (isomer 1): MS (ESI) m/z 592.2. ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.98-9.55(brs,1H),7.93(s,1H),7.80(d,J＝8.3Hz,1H),7.47-7.40(m,1H),7.28(d,J＝2.3Hz,1H),7.22(d,J＝3.9Hz,2H),7.06(d,J＝2.3Hz,1H),5.27(d,J＝45.2Hz,1H),4.37-4.28(m,2H),3.95(ABq,J＝9.6Hz,2H),3.57-3.49(m,4H),3.12-3.05(m,2H),3.03-2.98(m,1H),2.87-2.78(m,1H),2.16-2.11(m,1H),2.07-2.03(m,1H),2.03-1.98(m,1H),1.90-1.72(m,3H),1.70-1.60(m,4H)。

12-2 (isomer 2): MS (ESI) m/z 592.2. ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.98-9.55(brs,1H),7.93(s,1H),7.79(d,J＝8.4Hz,1H),7.47-7.41(m,1H),7.27(d,J＝2.3Hz,1H),7.21(d,J＝3.8Hz,2H),7.07-7.04(m,1H),5.27(d,J＝45.2Hz,1H),4.36-4.28(m,2H),3.98(ABq,J＝9.6Hz,2H),3.57-3.49(m,4H),3.12-3.06(m,2H),3.02-2.99(m,1H),2.87-2.77(m,1H),2.15-2.10(m,1H),2.07-2.03(m,1H),2.02-1.97(m,1H),1.88-1.72(m,3H),1.68-1.62(m,4H)。

Preparation chiral SFC conditions: column/size: column name: lux cell C2 (250 x 4.6) mm 5 μ; co-solvent name: 5mM ammonium acetate in ACN: methanol (1:1); flow rate: 4mL/min; the percentage of cosolvent: 50%; back pressure: 100 bar. Retention time of peak-01 = 4.380min and retention time of peak-02 = 7.016min.

Examples 13-1 and 13-2

4- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalen-2-ol

Preparation of intermediate 13A: 3- (2- { [ (2S, 7 aR) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -7-bromo-6-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of example 8A (200 mg,0.408 mmol) and ((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol HCl salt (120 mg, 0.611 mmol) in 1, 4-dioxane (2 mL) was added Cs ₂ CO ₃ (534 mg,1.634 mmol) and the resulting reaction mixture was heated at 80℃for 16h. The reaction mixture was filtered and concentrated to provide a crude residue which was purified by silica gel column chromatography using CombiFlash instrument (24 gColumn, 100% EtOAc-petroleum ether) to give 3- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl]Methoxy } -7-bromo-6-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (140 mg,0.223mmol,54.5% yield). MS (ESI) m/z 628.5[ M+H ]] ⁺ 。

Preparation of intermediate 13B: 3- (2- { [ (2S, 7 aR) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of example 13A (320 mg,0.509 mmol) in 1, 4-dioxane (2 mL) and water (0.2 mL) was added 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalene-2-ol (72.2 mg,0.267 mmol) and K at room temperature ₂ CO ₃ (92 mg,0.668 mmol). The reaction mixture was purged with nitrogen for 5 minutes and charged with Pd (Ph ₃ P) ₄ (12.86 mg,0.01 mmol). The reaction mixture was again purged with nitrogen for 3 minutes and heated at 85 ℃ for 16h. The reaction mixture was then cooled to room temperature, filtered through celite and the filtrate concentrated under reduced pressure to give crude 3- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl as a brown solid ]Methoxy } -6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (140 mg) was used in the next step without further purification. MS (ESI) m/z 692.3[ M+H ]] ⁺ 。

Examples 13-1 and 13-2

To 3- (2- { [ (2S, 7 aR) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl at 0 ℃]Methoxy } -6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a stirred solution of tert-butyl octane-8-carboxylate (120 mg,0.173 mmol) in DCM (2 mL) was added TFA (1 mL,12.98 mmol) and the resulting reaction mixture was stirred at room temperature for 1h. The reaction mixture was then concentrated at 30 ℃ under reduced pressure and co-distilled with 1, 4-dioxane using Et ₃ N-neutralization, co-distillation with 1, 4-dioxane and MeOH again to give crude compound as pale yellow solid, purification of the crude compound by preparative HPLC followed by chiral SFC purification to give 4- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl]Methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1 ]Oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalen-2-ol (13-1, isomer 1) (5 mg, 8.44. Mu. Mol,4.87% yield) and (13-2, isomer 2) (3.7 mg, 6.12. Mu. Mol,3.53% yield).

13-1 (isomer 1): MS (ESI) m/z 592.2. ¹ H NMR(400MHz,DMSO-d6)δ＝10.04(br s,1H),7.94(s,1H),7.81(d,J＝8.4Hz,1H),7.44(ddd,J＝2.8,5.2,8.3Hz,1H),7.29(d,J＝2.3Hz,1H),7.26-7.17(m,2H),7.06(d,J＝2.4Hz,1H),5.25(d,J＝53.6Hz,1H),4.42-4.27(m,2H),4.05(ABq,J＝10.3Hz,2H),3.64-2.84(m,7H),2.16-2.11(m,2H),2.07-1.97(m,2H),1.86-1.71(m,7H)。

13-2 (isomer 2): MS (ESI) m/z 592.2. ¹ H NMR(400MHz,DMSO-d6)δ＝10.04(br s,1H),7.96(s,1H),7.81(d,J＝8.4Hz,1H),7.45(ddd,J＝1.8,6.2,8.2Hz,1H),7.29(d,J＝2.3Hz,1H),7.25-7.16(m,2H),7.06(d,J＝2.4Hz,1H),5.28(d,J＝54.3Hz,1H),4.45-4.40(m,2H),4.08(ABq,J＝10.7Hz,2H),3.90(br s,2H),3.70-3.00(m,5H),2.87-2.81(m,1H),2.17-2.11(m,1H),2.07-1.96(m,2H),1.89-1.85(m,3H),1.81-1.70(m,4H)。

Preparative HPLC conditions: column/size: column name: kineex EVO (250mm x 21.2mm ID,5 μ); mobile phase a = 10mM ammonium bicarbonate in water pH 9.5, mobile phase B = acetonitrile: meOH (1:1), flow rate: 19mL/min; retention time = 11.66min. Preparation chiral SFC conditions: column/size: column name: lux cell C4 (250 x 4.6) mm,5 μ; co-solvent name: 5mM ammonium acetate in ACN: methanol (1:1); flow rate: 4mL/min; the percentage of cosolvent: 50%; back pressure: 100 bar. Retention time of peak-01 = 5.11min and retention time of peak-02 = 6.86min.

Example 14

6- (2- { [ (2S, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3- ] Heterophyll

Phenyl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 14A: 1- (tert-butyl) 2-methyl (2S, 4S) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2S, 4R) -4-hydroxypyrrolidine-1, 2-dicarboxylic acid ester (60.0 g, 248 mmol) in dichloromethane (900 mL) was added diethylaminosulfur trifluoride (64.6 mL, 4819 mmol) at 0deg.C. The reaction mixture was stirred at room temperature for 16h. The reaction mixture was quenched with ice and extracted with dichloromethane (3×500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide a pale yellow oil. The residue was purified by silica gel column chromatography with 0-20% ethyl acetate in petroleum ether to give 1- (tert-butyl) 2-methyl (2 s,4 s) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (53.0 g,206mmol,84% yield) as a pale yellow oil. LCMS-ELSD (ESI) m/z 148.2[ M+H-Boc ] ⁺ 。

Preparation of intermediate 14B: 1- (tert-butyl) 2-methyl (2S, 4S) -2- (3- ((tert-butyldimethylsilyl) oxy) propyl) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2S, 4S) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (20.0 g,81 mmol) in anhydrous THF (200 mL) at-25℃under nitrogen atmosphere was added LiHMDS (1M in THF, 121.0mL,121 mmol) dropwise. The reaction mixture was stirred at the same temperature for 30 minutes, and then (3-bromopropyloxy) (tert-butyl) dimethylsilane (24.6 g,97 mmol) was added dropwise. After stirring at-25 ℃ for 30 minutes, the reaction mixture was slowly warmed to room temperature. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and then diluted with water (100 mL). The mixture was extracted with ethyl acetate (2×500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 20% -30% ethyl acetate in petroleum ether to give 1- (tert-butyl) 2-methyl (2 s,4 s) -2- (3- ((tert-butyldimethylsilyl) oxy) as a colorless oil) Propyl) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (28.0 g,66.1mmol,82% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ5.18-5.03(m,1H),4.10-3.98(m,1H),3.78(s,3H),3.74-3.52(m,3H),2.48-2.23(m,3H),2.19-1.98(m,1H),1.65(s,9H),1.48-1.44(m,2H),0.90(s,9H),0.06(s,6H)ppm。 ¹⁹ F(376MHz,CD ₃ OD): delta-172.47 to-172.96 (m) ppm. LCMS-ELSD (ESI) m/z 320.2[ M+H-Boc ]] ⁺ 。

Preparation of intermediate 14C: 1- (tert-butyl) 2-methyl (2S, 4S) -4-fluoro-2- (3-hydroxypropyl) pyrrolidine-1, 2-dicarboxylic acid ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2 s,4 s) -2- (3- ((tert-butyldimethylsilyl) oxy) propyl) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (28 g,66.7 mmol) was added dropwise TBAF (1M in THF, 100ml,100 mmol) at 25 ℃ and the mixture was stirred at the same temperature for 4h. The reaction was then quenched with saturated aqueous ammonium chloride (200 mL) and diluted with ethyl acetate (300 mL). The mixture was extracted with ethyl acetate (3×600 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain a crude residue as a colorless oil. The crude material was purified by silica gel column chromatography using 50% ethyl acetate in petroleum ether to give 1- (tert-butyl) 2-methyl (2 s,4 s) -4-fluoro-2- (3-hydroxypropyl) pyrrolidine-1, 2-dicarboxylic acid ester (15 g,49.0mmol,74% yield) as a colorless oil. LCMS-ELSD (ESI) m/z 206.2[ M+H-Boc ]] ⁺ 。

Preparation of intermediate 14D: 1- (tert-butyl) 2-methyl (2S, 4S) -4-fluoro-2- (3-iodopropyl) pyrrolidine-1, 2-dicarboxylic acid ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2S, 4S) -4-fluoro-2- (3-hydroxypropyl) pyrrolidine-1, 2-dicarboxylic acid ester (22.0 g,72.0 mmol) in dichloromethane (500 mL) at 0deg.C was addedTriphenylphosphine (76.0 g,288 mmol) and imidazole (9.81 g,144 mmol) and the mixture was stirred for 10min. Iodine (73.1 g,288 mmol) was added and the mixture was warmed to room temperature and stirred for 12h. The reaction was then quenched with saturated aqueous sodium thiosulfate (70 mL) and the suspension extracted with dichloromethane (3 x200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. The crude product was purified by silica gel column chromatography using 10% -20% ethyl acetate in petroleum ether to give 1- (tert-butyl) 2-methyl (2 s,4 s) -4-fluoro-2- (3-iodopropyl) pyrrolidine-1, 2-dicarboxylic acid ester (16.5 g,39.5mmol,55% yield) as a pale yellow oil. LCMS-ELSD (ESI) m/z 361.0[ M+H-Boc ]] ⁺ 。

Preparation of intermediate 14E: (2S, 4S) -4-fluoro-2- (3-iodopropyl) pyrrolidine-2-carboxylic acid methyl ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2 s,4 s) -4-fluoro-2- (3-iodopropyl) pyrrolidine-1, 2-dicarboxylic acid ester (16.5 g,39.7 mmol) in dichloromethane (200 mL) was added HCl in dioxane (4 m,160mL,640 mmol) at 25 ℃ and the reaction mixture was stirred for 6h. The reaction mixture was then concentrated at room temperature under reduced pressure to obtain a crude residue of (2 s,4 s) -4-fluoro-2- (3-iodopropyl) pyrrolidine-2-carboxylic acid methyl ester HCl salt (12 g,33.7mmol,85% yield) which was used in the next step without any further purification. LCMS-ELSD (ESI) m/z 188.2[ M+H ] ] ⁺ 。

Preparation of intermediate 14F: (2S, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester

To a stirred solution of (2S, 4S) -4-fluoro-2- (3-iodopropyl) pyrrolidine-2-carboxylic acid methyl ester (12.0 g,38.1 mmol) in anhydrous acetonitrile (120 mL) was added triethylamine (26.5 mL,190 mmol) at room temperature. The reaction mixture was stirred at 45℃for 12h. Then the reaction is carried outThe mixture was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (neutral alumina) using 40% -50% ethyl acetate in petroleum ether to give methyl (2 s,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (6.2 g,15.57mmol,41% yield) as a pale brown oil. 1H NMR (400 MHz, CDCl) ₃ ):δ5.32-5.19(m,1H),3.78(s,3H),3.64-3.55(m,1H),3.31-3.29(m,1H),2.97-2.73(m,1H),2.89-2.81(m,1H),2.73-2.71(m,1H),2.19-2.16(m,1H),1.96-1.77(m,4H)ppm。LCMS-ELSD(ESI)m/z:188.3[M+H] ⁺ 。

Preparation of intermediate 14G: ((2S, 7 aS) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol

LiAlH was added dropwise to a stirred solution of methyl (2S, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (7.00 g,37.4 mmol) in anhydrous THF (100 mL) at 0deg.C under nitrogen over 10 min ₄ (2M in THF, 37.4mL,74.8 mmol). After the addition was complete, the reaction mixture was warmed to room temperature over 30 minutes. The mixture was stirred at this temperature for 1h and then quenched with saturated aqueous ammonium chloride (5 mL) at 0 ℃. Anhydrous sodium sulfate was added to the reaction mixture, followed by dichloromethane (50 mL). The reaction mixture was stirred for 20 minutes and filtered. The filtrate was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give ((2 s,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (4.7 g,29.2mmol,78% yield) as a colorless oil. ¹ HNMR(400MHz,DMSO-d6):δ5.32-5.38(m,1H),5.18-5.25(m,1H),4.48-4.55(m,2H),3.60-3.65(m,1H),3.13-3.21(m,6H),2.83-2.87(m,4H),2.50(s,1H),2.16-2.25(m,2H),1.76-1.87(m,2H),1.67-1.73(m,7H),1.36-1.46(m,2H)。 ¹⁹ F(376MHz,CD ₃ OD): delta-175.69 to-176.04 (m) ppm. LCMS-ELSD (ESI) m/z 160.2[ M+H ]] ⁺ 。

Intermediates 14H and 14I:3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Example 9J (5.0 g,6.06 mmol) was subjected to SFC separation (column: chiralpak IH (250 mm. Times.4.6x5u), mobile phase-0.25% isopropyl alcohol), wherein peak-1 eluted at 5.85RT (2.4 g,2.90mmol,40% yield) and peak-2 eluted at 9.53 retention time (2.4 g,2.90mmol,40% yield).

Peak-1 (14H): ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.78 (s, 1H), 7.16 (d, J=8.8 Hz, 4H), 6.87 (dt, J=9.6 and 2.8Hz, 4H), 6.43 (s, 1H), 4.76-4.72 (m, 2H), 4.59-4.55 (m, 2H), 3.81 (s, 6H), 2.43 (s, 3H), 1.97-1.82 (m, 4H), 1.97-1.82 (m, 4H), 1.53 (s, 9H) ppm. LCMS (ESI) m/z 825.2[ M+H ]] ⁺ 。LCMS(ESI)m/z:825.2[M+H] ⁺ 。[α] ^23.5 (MeOH＝0.10)＝+96.00

Peak-2: (14I) ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.78 (s, 1H), 7.16 (d, J=8.8 Hz, 4H), 6.87 (dt, J=9.6 Hz and 2.8Hz, 4H), 6.43 (s, 1H), 4.76-4.72 (m, 2H), 4.59-4.55 (m, 2H), 3.81 (s, 6H), 2.43 (s, 3H), 1.97-1.82 (m, 4H), 1.97-1.82 (m, 4H), 1.53 (s, 9H) ppm. LCMS (ESI) m/z 825.2[ M+H ]] ⁺ 。[α] ^23.3 (MeOH＝0.10)＝-110.00。

Preparation of intermediate 14J: 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((2S, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of ((2 s,7 as) -2-fluorotetrahydro-1H-pyrrolazin-7 a (5H) -yl) methanol (109 mg,0.685 mmol) in anhydrous THF (2.1 mL) at 0 ℃ was added sodium hydride (60% in mineral oil, 43.6mg,1.091 mmol) and the reaction mixture was stirred for 30 min. A solution of intermediate 14I (300 mg, 0.264 mmol) in anhydrous THF (10 mL) was added dropwise to the reaction mixture while maintaining the temperature at 0deg.C.The reaction mixture was allowed to reach room temperature over 2 h. The reaction was then quenched with saturated aqueous ammonium chloride (1 mL) and diluted with ethyl acetate (5 mL). The mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude residue was purified by column chromatography over neutral alumina (using 30% ethyl acetate in petroleum ether) to give 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((2 s,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 ] as a pale yellow solid]Tert-butyl octane-8-carboxylate (250 mg,0.251mmol,69% yield). LCMS (ESI) m/z 964.2[ M+H ] ] ⁺ 。

Example 14

6- (2- { [ (2S, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

To a stirred solution of TFA (2 mL,26.0 mmol) and triethylsilane (0.2 mL,1.252 mmol) at room temperature was added 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((2S, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1)]Tert-butyl octane-8-carboxylate (250 mg, 0.299 mmol). The reaction mixture was then stirred at 35℃for 12h. The reaction mixture was then concentrated under reduced pressure at a temperature below 35 ℃ to remove most of the TFA. The residue was then co-evaporated with methanol (3 x2 mL) to remove residual TFA. The residue was then neutralized with DIPEA and concentrated under reduced pressure to obtain the free base. The crude product was then purified by column chromatography on silica gel (previously neutralized with DIPEA) using a mixture of MeOH, dichloromethane and DIPEA (15:80:2.5) to give 6- (4- (3, 8-diazabicyclo [ 3.2.1) as a white solid]Oct-3-yl) -6-chloro-8-fluoro-2- (((2 s,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (56 mg,0.089mmol,34% yield). MS (ESI) m/z 624.3[ M+H ]]+。 ¹ H NMR(400MHz,DMSO-d ₆ )δ77.85(s,1H),6.62(s,1H),5.28(m,1H),4.54-4.41(m,3H),4.31(d,J＝10.40Hz,1H),3.85-3.61(m,4H),3.49-3.46(m,1H),3.15-3.11(m,1H),2.77(t,J＝5.20Hz,1H),2.54(m,3H),2.16-2.11(m,3H),1.37-1.31(m,2H)ppm。

Example 15

6- (2- { [ (2S, 7 aR) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 15A: 3- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -7- (6- { bis [ (4-methoxyphenyl) methyl ] amino } -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a solution of ((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanolic HCl salt (427 mg,2.181 mmol) in DCM (10 mL) was added approximately 1g of Na ₂ CO ₃ And the reaction mixture was stirred at room temperature for 30 minutes. The solid was filtered and the filtrate evaporated at 20 ℃ under minimal vacuum to obtain the free amine. The free base was dissolved in THF (10 mL) and cooled to 0 ℃. Then NaH (87 mg,2.181 mmol) was added and stirred for another 30 minutes. Then, a solution of intermediate 14I (900 mg,1.091 mmol) in THF (2 mL) was added, and the mixture was gradually warmed to room temperature over a period of 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water and brine and then Na ₂ SO ₄ And (5) drying. The mixture was filtered and concentrated under reduced pressure to provide a crude product, which was isolatedThe product was purified by silica gel column chromatography (using CombiFlash instrument (40 gColumn, 50% to 60% etoac-petroleum ether)) to give 3- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl as a pale brown solid]Methoxy } -7- (6- { bis [ (4-methoxyphenyl) methyl)]Amino } -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (1 g,1.037mmol,95% yield). MS (ESI) M/z 964.3 (M+H) ⁺ 。

Example 15

A stirred solution of TFA (5 mL,64.9 mmol) and triethylsilane (2 mL,12.52 mmol) was added to 3- (2- { [ (2S, 7 aR) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl at room temperature]Methoxy } -7- (6- { bis [ (4-methoxyphenyl) methyl)]Amino } -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (1 g,1.037 mmol) and the resulting reaction mixture was heated to 35 ℃ for 24h. The reaction mixture was then concentrated under reduced pressure, co-distilled with toluene (twice), neutralized with DIPEA and concentrated under reduced pressure to afford a crude residue that was purified by achiral SFC to give 6- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ]Methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1]Oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (320 mg,0.513mmol,49.5% yield). MS (ESI) M/z 624.2, [ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δ＝7.81(s,1H),6.83(s,2H),6.48(s,1H),5.26(d,J＝52Hz,1H),4.30(d,J＝12Hz,1H),4.17(d,J＝12Hz,1H),4.02(ABq,J＝10.4Hz,2H),3.54-3.40(m,3H),3.44(d,J＝12Hz,1H),3.08-2.98(m,3H),2.88-2.78(m,1H),2.36(s,3H),2.12-2.0(m,3H),1.84-1.76(m,3H),1.62-1.60(m,4H)。

Preparation type achiral SFC condition: column/size: princeton SFC Diol (250X 4.6) mm,5u; CO ₂ Percent: 70% of the total weight of the steel sheet; cosolvent%: 30% (0.2% NH in methanol) ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the Flow rate: 3mL/min; back pressure: 100 bar; retention time = 6.289min.

Examples 16-1 and 16-2

4- (2- { [ (2 s,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalen-2-ol

Preparation of intermediate 16A: 3- (6-chloro-2, 8-difluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a degassed solution of example 8A (1000 mg,2.042 mmol) in 1, 4-dioxane (60 mL) was added 2- (3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (1283 mg,4.08 mmol), pd ₂ (dba) ₃ (93 mg,0.102 mmol) and pentacenyl (di-t-butylphosphine) ferrocene (72.5 mg,0.102mmol, QPhos, cas number 312959-24-3). The mixture was again degassed and heated in a pressure vial at 70 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude residue. The crude material was purified by silica gel column chromatography (using 30% ethyl acetate in petroleum ether) to give 3- (6-chloro-2, 8-difluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a pale brown solid ]Tert-butyl octane-8-carboxylate (1.0 g,1.591mmol,78% yield). LCMS (ESI) m/z 597.2[ M+H ]] ⁺ 。

Preparation of intermediate 16B: 3- (6-chloro-8-fluoro-2- (((2S, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of ((2 s,7 as) -2-fluorotetrahydro-1H-pyrrolazin-7 a (5H) -yl) methanol (192 mg,1.206 mmol) in THF (20 mL) at 0 ℃ was added NaH (40.2 mg,1.005 mmol) and the suspension was stirred for 30 min. 3- (6-chloro-2, 8-difluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] in THF (20 mL) at 0deg.C]Tert-butyl octane-8-carboxylate (400 mg, 0.640 mmol) was added to the reaction mixture. The reaction mixture was then stirred at ambient temperature for 16h. The reaction was then quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (2 x20 mL). The combined organic layers were washed with water (20 mL) and brine solution (10 mL), and then over anhydrous Na ₂ SO ₄ The mixture was dried, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography over neutral alumina (by eluting with 50% -100% ethyl acetate in petroleum ether). The desired fractions were pooled and concentrated under reduced pressure to give 3- (6-chloro-8-fluoro-2- (((2 s,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a pale brown solid ]Tert-butyl octane-8-carboxylate (406 mg,0.540mmol,81% yield). LCMS (ESI) m/z 629.0[ M+H ]] ⁺ 。

Examples 16-1 and 16-2

At 0 ℃, 3- (6-chloro-8-fluoro-2- (((2S, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7-3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a stirred solution of tert-butyl octane-8-carboxylate (350 mg,0.475 mmol) in methanol (2 mL) was added hydrogen chloride in dioxane (4 m,2.377mL,9.51 mmol). The reaction mixture was stirred at 25℃for 8h. The reaction mixture was then concentrated under reduced pressure to give a crude product, which was purified by column chromatography (Biotage, siO ₂ Purification by elution with 3% -5% methanol in dichloromethane to give 4- (4- (3, 8-diazabicyclo [ 3.2.1)]Oct-3-yl) -6-chloro-8-fluoro-2- (((2 s,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) naphthalene-2-ol (130 mg,0.24mmol,25% yield). The desired compound was subjected to SFC separation (column: cellulose-4 (250 mm. Times.4.6X5u), mobile phase-0.5% isopropyl amine in MeOH) to give 4- (2- { [ (2S, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl) ]Methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1]Two isomers of oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol (16-1, isomer 1, 50mg,0.079mmol,17% yield) and (16-2, isomer 2, 54mg,0.085mmol,19% yield).

16-1, isomer 1: ¹ H NMR(400MHz,DMSO-d ₆ )δ7.97(d,J＝1.60Hz,1H),7.76(d,J＝8.40Hz,1H),7.44-7.42(m,1H),7.27-7.21(m,3H),7.05(d,J＝2.40Hz,1H),5.28-5.41(m,1H),4.55(t,J＝14.80Hz,2H),4.43(d,J＝10.00Hz,1H),4.31(d,J＝10.00Hz,1H),3.69-3.64(m,3H),3.45-3.43(m,1H),3.12-3.10(m,1H),2.90(dd,J＝,Hz,1H),2.76-2.73(m,1H),2.50(m,1H),2.15-2.10(m,1H),2.00(m,3H),1.97-1.86(m,5H),1.22(d,J＝6.40Hz,2H)ppm。LCMS(ESI)m/z:592.2[M+H] ⁺ 。

16-2, isomer 2: ¹ H NMR(400MHz,DMSO-d ₆ )δ7.97(d,J＝1.60Hz,1H),7.76(d,J＝8.40Hz,1H),7.44-7.42(m,1H),7.27-7.21(m,3H),7.05(d,J＝2.40Hz,1H),5.28-5.41(m,1H),4.55(t,J＝14.80Hz,2H),4.43(d,J＝10.00Hz,1H),4.31(d,J＝10.00Hz,1H),3.69-3.64(m,3H),3.45-3.43(m,1H),3.12-3.10(m,1H),2.90(dd,J＝,Hz,1H),2.76-2.73(m,1H),2.50(m,1H),2.15-2.10(m,1H),2.00(m,3H),1.97-1.86(m,5H),1.22(d,J＝6.40Hz,2H)ppm。LCMS(ESI)m/z:592.2[M+H] ⁺ 。

example 17-1

Preparation of intermediate 17A: 7-bromo-8-fluoroquinazoline-2, 4-diol

A mixture of 2-amino-4-bromo-3-fluorobenzoic acid (1.5 g,6.41 mmol) and urea (11.55 g,192 mmol) was stirred at 200℃for 2h. The reaction mixture was cooled to 80 ℃ and water (30 mL) was added with stirring and continued for 1h at the same temperature. After filtration, the solid was collected and washed with hot water (30 ml x 2), dried under reduced pressure and co-evaporated with toluene (50 ml x 2) to give 7-bromo-8-fluoroquinazoline-2, 4-diol (1.338 g,5.17mmol,81% yield). MS (ESI) M/z 258.9, [ M+H ]] ⁺ 。

Preparation of intermediate 17B: 7-bromo-2, 4-dichloro-8-fluoroquinazoline

To 7-bromo-8-fluoroquinazoline-2, 4-diol (1.4 g,5.40 mmol) in POCl ₃ To a stirred suspension in (10.1 mL,108 mmol) was added DMF (0.021 mL,0.270 mmol) and the reaction mixture was refluxed (115 ℃) for 16h. Volatiles were removed from the reaction mixture under reduced pressure to give a crude solid residue, which was dissolved in anhydrous dichloromethane (100 mL) and filtered. The filtrate was concentrated under reduced pressure to give 7-bromo-2, 4-dichloro-8-fluoroquinazoline (1.213 g,4.10mmol,76% yield). MS (ESI) M/z 294.9, [ M+H ] ] ⁺ 。

Preparation of intermediate 17C: 3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of 7-bromo-2, 4-dichloro-8-fluoroquinazoline (1.0 g,3.38 mmol) in 1, 4-dioxane (15 mL) was added DIPEA (1.77 mL,10.14 mmol) and 8-Boc-3, 8-diaza-bicyclo [3.2.1] at room temperature]Octane (1.076 g,5.07 mmol). The reaction mixture was stirred at room temperature for 2h. Volatiles were evaporated from the reaction mixture under reduced pressure, and the crude residue was dissolved in ethyl acetate (100 mL). The organic layer was washed with water. The aqueous layer was back-extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford the crude product. The crude compound was purified by ISCO (pretreatment with 5% triethylamine in petroleum ether using a 40g silica gel column; 50% to 100% ethyl acetate/petroleum ether) to give 3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (1.105 g, 2.345 mmol,69.3% yield). MS (ESI) M/z 473.1, [ M+H ]] ⁺ 。

Preparation of intermediate 17D: 3- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -7-bromo-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolazin-7 a (5H) -yl) methanol (0.157 g,0.988 mmol) in tetrahydrofuran (10 mL) was added sodium hydride, 60% dispersion in mineral oil (0.079 g,1.977 mmol) at 0 ℃ and the reaction was stirred at room temperature for 30min. The reaction mixture was cooled back to 0 ℃ and 3- (7-bromo-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 ] was added]Tert-butyl octane-8-carboxylate (0.3 g,0.659 mmol) (in 0.5mL THF). The reaction mixture was stirred at the same temperature for 2h. Several pieces of ice were then added to the reaction mixture to quench the excess NaH. Volatiles were removed from the reaction mixture under reduced pressure, and the crude residue was taken upDissolved in ethyl acetate (50 mL). The organic layer was washed with water. The aqueous layer was back-extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford the crude product. The crude compound was purified by ISCO (pretreatment with 5% triethylamine in petroleum ether using a 40g silica gel column; 3% to 5% dcm/methanol) to give 3- (7-bromo-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1) ]Tert-butyl octane-8-carboxylate (312 mg,0.525mmol,80% yield). MS (ESI) M/z 596.3, [ M+H ]] ⁺ 。

Preparation of intermediate 17E: 3- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -8-fluoro-7- [3- (methoxymethoxy) naphthalen-1-yl ] quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (7-bromo-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a stirred solution of tert-butyl octane-8-carboxylate (0.4 g,0.673 mmol) in 1, 4-dioxane (5 mL) was added 2- (3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (0.254 g, 0.803 mmol), aqueous sodium carbonate (1.0 mL,2.018 mmol) followed by bis (triphenylphosphine) palladium (II) dichloride (0.047 g,0.067 mmol). The reaction mixture was taken up in N ₂ Purging for 5min and heating at 100℃for 16h. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was dissolved in ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure to give a crude product which was purified by ISCO (using 40g silica gel column, pretreatment with 5% triethylamine in petroleum ether; using 50% to 100% ethyl acetate/petroleum ether) to give 3- (8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1) ]Octane-8-carboxylic acid tert-butyl ester (355 mg,0.506mmol, 75)% yield). MS (ESI) M/z 702.3, [ M+H ]] ⁺ 。

Example 17-1

To 3- (8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] at 0deg.C]To a stirred solution of tert-butyl octane-8-carboxylate (0.06 g,0.085 mmol) was added 4N HCl (0.214 mL,0.855mmol in 1, 4-dioxane) and the reaction mixture was stirred at room temperature for 5h. Volatiles from the reaction mixture were removed under reduced pressure (about 30 ℃ C. At lower temperature) and the crude residue was co-evaporated with 1, 4-dioxane. The crude residue was then dissolved in 1, 4-dioxane and triethylamine was added and evaporated under reduced pressure to afford an off-white solid. The crude compound was purified by preparative HPLC [ HPLC method: preparation type column: YMC EXRS (250 x20x 5), mobile phase a: 10mM ammonium bicarbonate in water-9.5; mobile phase B: acetonitrile, methanol; gradient = 60% -80% B over 13 minutes; temperature: 27 ℃; flow rate: 20.0mL/min; and (3) detection: UV at 220 nm. ]Purification to give 4- (3, 8-diazabicyclo [ 3.2.1)]Oct-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) naphthalen-2-ol (7.0 mg,0.012mmol,14.4% yield) MS (ESI) M/z 558.4, [ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δppm 9.99-9.94(m,1H),7.87(d,J＝8.3Hz,1H),7.80(d,J＝8.5Hz,1H),7.47-7.38(m,2H),7.28-7.21(m,3H),7.10-7.08(m,1H),5.38-5.19(m,1H),4.37-4.25(m,2H),4.13-3.98(m,2H),3.51-3.50(m,4H),3.44-3.43(m,1H),3.14-3.07(m,2H),3.02-3.00(m,1H),2.88-2.79(m,1H),2.17-2.12(m,1H),2.07-2.00(m,2H),1.86-1.75(m,3H),1.71-1.64(m,4H)。

The examples in Table 6 were prepared in accordance with the procedure described in example 17-1 from the appropriate starting materials.

TABLE 6

/>

Example 18-1

6- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -2- ({ 1- [ (dimethylamino) methyl ] cyclopropyl } methoxy) -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 18A: 1- (dimethylcarbamoyl) cyclopropane-1-carboxylic acid methyl ester

To a solution of 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid (10 g,69.4 mmol), dimethylamine hydrochloride (11.32 g,139 mmol) and DIPEA (48.5 mL,278 mmol) in DCM (100 mL) was added HOBt (15.94 g,104 mmol) and EDC (19.95 g,104 mmol) at 0 ℃ and the reaction mixture was stirred at room temperature for 16h. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with water, brine, and dried over Na ₂ SO ₄ Dried and concentrated under reduced pressure to provide a crude residue, which was purified by silica gel column chromatography (using CombiFlash instrument (80 g Column, 60% to 80% EtOAc-petroleum ether, uv inactive, slight KMnO ₄ Active)) to give methyl 1- (dimethylcarbamoyl) cyclopropane-1-carboxylate (8 g,46.7mmol,67.4% yield) as a pale yellow liquid. ¹ H NMR (300 MHz, chloroform-d) δppm=3.73 (s, 3H),3.04(s,3H),2.99(s,3H),1.54-1.47(m,2H),1.38-1.31(m,2H)。

Preparation of intermediate 18B: {1- [ (dimethylamino) methyl ] cyclopropyl } methanol

To a solution of methyl 1- (dimethylcarbamoyl) cyclopropane-1-carboxylate (8 g,46.7 mmol) in THF (150 mL) at 0deg.C was slowly added LiAlH ₄ (2.4M solution in THF) (38.9 mL,93 mmol) and the reaction mixture was stirred at room temperature for 4h. The reaction was cooled and quenched with water (20 mL), 10% NaOH solution (40 mL) and water (40 mL) and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over Na ₂ SO ₄ Dried and concentrated to provide {1- [ (dimethylamino) methyl ] as a yellow liquid]Cyclopropyl } methanol (3.7 g,28.6mmol,61.3% yield). ¹ H NMR (300 MHz, chloroform-d) δppm=5.30-4.15 (m, 1H), 3.55 (s, 2H), 2.41 (s, 2H), 2.31 (s, 6H), 0.54-0.47 (m, 2H), 0.39-0.32 (m, 2H).

Preparation of intermediate 18C: 3- [7- (6- { bis [ (4-methoxyphenyl) methyl ] amino } -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2- ({ 1- [ (dimethylamino) methyl ] cyclopropyl } methoxy) -8-fluoroquinazolin-4-yl ] -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

At 0 ℃, {1- [ (dimethylamino) methyl group]To a solution of cyclopropyl } methanol in THF (2 mL) was added NaH (29.1 mg,0.727 mmol) and stirred for an additional 30min. Then, intermediate 14I was added and gradually warmed to room temperature over a period of 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na ₂ SO ₄ Dried and concentrated under reduced pressure to provide a crude residue, which was purified by silica gel column chromatography (using CombiFlash instrument (40 gColumn, 50% to 60% etoac-petroleum ether)) to give 3- [7- (6- { bis [ (4-methoxyphenyl) -methyl) as a pale yellow solid]Amino } -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2- ({ 1- [ (dimethylamino) methyl group]Cyclopropyl } -methoxy) -8-fluoroquinazolin-4-yl]-3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (250 mg,0.268mmol,73.6% yield). MS (ESI) M/z 934.3 (M+H) ⁺ 。

Example 18-1

A stirred solution of TFA (3 mL,38.9 mmol) and triethylsilane (1 mL,6.26 mmol) was added to 3- [7- (6- { bis [ (4-methoxyphenyl) methyl) at room temperature ]Amino } -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2- ({ 1- [ (dimethylamino) methyl group]Cyclopropyl } methoxy) -8-fluoroquinazolin-4-yl]-3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (280 mg,0.300 mmol) and the resulting reaction mixture was heated to 40℃over a period of 24 h. The reaction mixture was then concentrated under reduced pressure, co-distilled with toluene (twice), neutralized with DIPEA, and concentrated under reduced pressure to provide a crude residue that was purified by preparative HPLC to give 6- (6-chloro-4- {3, 8-diazabicyclo [ 3.2.1)]Oct-3-yl } -2- ({ 1- [ (dimethylamino) methyl group]Cyclopropyl } methoxy) -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (45 mg,0.076mmol,25.3% yield). MS (ESI) M/z 594.4, [ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ ) δppm=7.80 (s, 1H), 6.84 (s, 2H), 6.49 (s, 1H), 4.30 (br d, j=11.9 hz, 1H), 4.24-4.12 (m, 3H), 3.58-3.39 (m, 5H), 2.37 (br d, j=1.4 hz, 3H), 2.22 (s, 2H), 2.15 (s, 6H), 1.70-1.56 (m, 4H), 0.66-0.59 (m, 2H), 0.44-0.37 (m, 2H). Preparative HPLC conditions: column/size: kinetex EVO (250X 4.6) mm,5u; mobile phase a: 10mM ammonium bicarbonate in water-9.5 pH, mobile phase B: ACN: meOH (1:1), flow rate: 19mL/min; retention time = 13.184min.

The examples in Table 7 were prepared in accordance with the procedure described in example 18-1 from the appropriate starting materials.

TABLE 7

/>

Example 19-1

6- (2- { [ (4 as,7 ar) -1-methyl-octahydro-1H-cyclopenteno [ b ] pyridin-4 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 19A: octahydro-4 aH-cyclopenteno [ b ] pyridine-4 a-carboxylic acid ethyl ester

Intermediate 19A was prepared according to the procedure in molecular 2017,22:827, compound 25 a.

Preparation of intermediates 19B1, 19B2, 19B3, 19B 4: 1-benzyl 4 a-ethyl (4 aS,7 aR) -hexahydro-1H-cyclopenteno [ b ] pyridine-1, 4a (2H) -dicarboxylic acid ester (peak 2)

Octahydro-4 aH-cyclopenteno [ b ]]To a solution of pyridine-4 a-carboxylic acid ethyl ester (1.7 g,8.62 mmol) and TEA (2.402 mL,17.23 mmol) in THF (10 mL) was added N- (benzyloxycarbonyl) succinimide (1.428 g,6.89 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc (15 mL) and washed with saturated aqueous sodium bicarbonate (2×15 mL). The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel/DCM-20% MeOH/DCM 100:0 to 50:50 gradient) to give 1-benzyl 4 a-ethylhexahydro-1H-cyclopenteno [ b ]Pyridine-1, 4a (2H) -dicarboxylic acid ester (2.20 g,6.64mmol,77% yield). 1-benzyl-4 a-ethyl hexahydro-1H-cyclopenta [ b ]]Pyridine-1, 4a (2H) -dicarboxylic acid ester (2.20 g) was subjected to SFC chiral separation. [ column: cellulose-4 (5×25cm,5 μm) method=CO ₂ IPA: heptane (1:3) with 0.1% ammonium hydroxide, 320mL/min.]To obtain:

peak 1 (19B 1): 1-benzyl 4 a-ethyl hexahydro-1H-cyclopenta [ b ]]Pyridine-1, 4a (2H) -dicarboxylic acid ester (625 mg,1.792mmol,20.79% yield). LCMS (ESI) m/z 332.3[ M+H ]] ⁺ LC retention time: 1.05min (Waters Acquity UPLC BEH C, 2.1X50mm,1.7 μm particles; mobile phase A: water (0.05% TFA; mobile phase B: ACN (0.05% TFA)), gradient: 2% -98% B over 1 min and then 0.5 min at 98% B; flow rate: 0.8mL/min; detection: MSAnd UV (220 nm)). ¹ H NMR (499 MHz, chloroform-d) delta 7.41-7.28 (m, 5H), 5.17 (br s, 2H), 4.13 (br d, J=6.4 Hz, 2H), 2.86 (br s, 1H), 2.15 (br d, J=10.8 Hz, 1H), 2.03-1.90 (m, 1H), 1.90-1.74 (m, 4H), 1.73-1.63 (m, 1H), 1.58-1.42 (m, 3H), 1.27-1.14 (m, 4H), 0.98-0.68 (m, 1H).

Peak 2 (19B 2): 1-benzyl 4 a-ethyl (4 aS,7 aR) -hexahydro-1H-cyclopenteno [ b ]]Pyridine-1, 4a (2H) -dicarboxylic acid ester (640 mg,1.835mmol,21.29% yield). LCMS (ESI) m/z 332.3[ M+H ] ] ⁺ LC retention time: 1.05min (Waters Acquity UPLC BEH C, 2.1X50mm,1.7 μm particles; mobile phase A: water (0.05% TFA; mobile phase B: ACN (0.05% TFA)), gradient: 2% -98% B over 1 min and then 0.5 min at 98% B; flow rate: 0.8mL/min; detection: MS and UV (220 nm)). ¹ H NMR (499 MHz, chloroform-d) delta 7.41-7.28 (m, 5H), 5.17 (br s, 2H), 4.13 (br d, J=6.4 Hz, 2H), 2.86 (br s, 1H), 2.15 (br d, J=10.8 Hz, 1H), 2.03-1.90 (m, 1H), 1.90-1.74 (m, 4H), 1.73-1.63 (m, 1H), 1.58-1.42 (m, 3H), 1.27-1.14 (m, 4H), 0.98-0.68 (m, 1H)

Peak 3 (19B 3): 1-benzyl 4 a-ethyl hexahydro-1H-cyclopenta [ b ]]Pyridine-1, 4a (2H) -dicarboxylic acid ester (130 mg,0.373mmol,4.32% yield). LCMS (ESI) m/z 332.3[ M+H ]] ⁺ LC retention time: 1.05min (Waters Acquity UPLC BEH C, 2.1X50mm,1.7 μm particles; mobile phase A: water (0.05% TFA; mobile phase B: ACN (0.05% TFA)), gradient: 2% -98% B over 1 min and then 0.5 min at 98% B; flow rate: 0.8mL/min; detection: MS and UV (220 nm)). ¹ H NMR (499 MHz, chloroform-d) delta 7.40-7.28 (m, 5H), 5.18-5.10 (m, 2H), 4.38 (ddd, j=13.4, 2.5,1.4hz, 1H), 4.13-4.05 (m, 2H), 2.88 (dd, j=12.8, 7.0hz, 1H), 2.79-2.67 (m, 2H), 2.42 (dt, j=13.1, 2.7hz, 1H), 2.28-2.14 (m, 2H), 1.76-1.55 (m, 4H), 1.46-1.26 (m, 2H), 1.20 (t, j=7.2 hz, 3H).

Peak 4 (19B 4): 1-benzyl 4 a-ethyl hexahydro-1H-cyclopenta [ b ]]Pyridine-1, 4a (2H) -dicarboxylic acid ester (141 mg,0.404mmol,4.69% yield). LCMS (ESI) m/z 332.3[ M+H ]] ⁺ LC retention time: 1.05min (Waters Acquity UPLC BEH C, 2.1X50mm,1.7 μm particles; mobile phase A: water (0.05% TFA; mobile phase B: ACN (0.05% TFA); gradient: 2% -98% B over 1 min, then 98%Holding for 0.5 min under B; flow rate: 0.8mL/min; and (3) detection: MS and UV (220 nm)). ¹ H NMR (499 MHz, chloroform-d) delta 7.40-7.28 (m, 5H), 5.18-5.10 (m, 2H), 4.38 (ddd, j=13.4, 2.5,1.4hz, 1H), 4.13-4.05 (m, 2H), 2.88 (dd, j=12.8, 7.0hz, 1H), 2.79-2.67 (m, 2H), 2.42 (dt, j=13.1, 2.7hz, 1H), 2.28-2.14 (m, 2H), 1.76-1.55 (m, 4H), 1.46-1.26 (m, 2H), 1.20 (t, j=7.2 hz, 3H).

Preparation of intermediate 19C-: (4 aS,7 aR) -octahydro-4 aH-cyclopenteno [ b ] pyridine-4 a-carboxylic acid ethyl ester

1-benzyl 4 a-ethyl (4 aS,7 aR) -hexahydro-1H-cyclopenteno [ b ]]A mixture of pyridine-1, 4a (2H) -dicarboxylic acid ester-intermediate 19B2 (640 mg,1.931 mmol) and 10% Pd-C (103 mg,0.097 mmol) in MeOH (10 mL) was hydrogenated under 1atm of hydrogen for 18 hours. Pd/C was filtered off and the filtrate was concentrated to give crude (4 aS,7 aR) -octahydro-4 aH-cyclopenta [ b ] as a clear oil ]Pyridine-4 a-carboxylic acid ethyl ester (385 mg,1.854mmol,96% yield). ¹ H NMR (499 MHz, chloroform-d) delta 4.17 (dtt, j=10.6, 7.1,3.6hz, 2H), 3.57 (t, j=6.1 hz, 1H), 2.90 (ddd, j=13.0, 7.7,3.7hz, 1H), 2.71 (ddd, j=13.0, 7.0,3.6hz, 1H), 2.01-1.92 (m, 2H), 1.84-1.62 (m, 7H), 1.60-1.40 (m, 2H), 1.28 (t, j=7.1 hz, 3H).

Preparation of intermediate 19D: (4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenteno [ b ] pyridine-4 a-carboxylic acid ethyl ester

To (4 aS,7 aR) -octahydro-4 aH-cyclopenteno [ b ]]Pyridine-4 a-carboxylic acid ethyl ester (385 mg,1.952 mmol) and 37wt.% in H ₂ A solution of formaldehyde in O (176 mg,5.85 mmol) in MeOH (5.0 mL) was added sodium cyanoborohydride (123 mg,1.952 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was then concentrated. The mixture was diluted with EtOAc (5 mL) and washed with saturated aqueous sodium carbonate (2×5 mL). The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated to giveTo crude (4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenteno [ b ]]Pyridine-4 a-carboxylic acid ethyl ester (380 mg,1.798mmol,92% yield). ¹ H NMR (499 MHz, chloroform-d) delta 4.24-4.12 (m, 2H), 3.29 (t, J=6.4 Hz, 1H), 2.60-2.51 (m, 1H), 2.36-2.28 (m, 3H), 2.00-1.88 (m, 2H), 1.83-1.60 (m, 8H), 1.56-1.40 (m, 1H), 1.32-1.26 (m, 3H).

Preparation of intermediate 19E: ((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenteno [ b ] pyridin-4 a-yl) methanol

To (4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenteno [ b ]]To a solution of pyridine-4 a-carboxylic acid ethyl ester (380 mg,1.798 mmol) in anhydrous THF (2.0 mL) was added a 1.0M solution of lithium aluminum hydride in THF (4496 μl,4.50 mmol), and the mixture was stirred at room temperature for 18 hours. Brine (0.3 mL) was added dropwise to the mixture. EtOAc (5.0 mL) was added to the mixture. The precipitate was filtered off and the filtrate was concentrated to give the crude ((4 as,7 ar) -1-methyl octahydro-4 aH-cyclopenta [ b ]]Pyridin-4 a-yl) methanol (327 mg,1.739mmol,97% yield). ¹ H NMR (499 MHz, chloroform-d) delta 3.69-3.62 (m, 2H), 2.87 (t, J=7.6 Hz, 1H), 2.51 (td, J=11.1, 3.4Hz, 1H), 2.43-2.35 (m, 1H), 2.30 (s, 3H), 2.01-1.85 (m, 2H), 1.82-1.74 (m, 1H), 1.68-1.52 (m, 6H), 1.47-1.42 (m, 1H), 1.39-1.33 (m, 1H).

Example 19-1

To 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 under nitrogen at room temperature ]Octane-8-carboxylic acid tert-butyl ester (intermediate 14I,20mg,0.024 mmol) and ((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenteno [ b ]]To a solution of pyridin-4 a-yl) methanol (intermediate 19E,4.10mg,0.024 mmol) in anhydrous THF (1.0 mL) was added a 1.0M solution of LiHMDS in THF (36.4 μl,0.036 mmol) and the mixture was stirred for 18 hours. The mixture was then diluted with DMF (1 mL) and the crude product was purified by preparative HPLC (Phenomenex, luna 5 microns 30x250mm, flow rate = 30mL/min, gradient = 20% a to 100% B in 30min, a = H ₂ O/ACN/TFA(90:10:0.1)，B＝H ₂ O/ACN/TFA (10:90:0.1)) to afford 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenta [ b ])]Pyridin-4 a-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester. 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenta [ b)]Pyridin-4 a-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]A mixture of tert-butyl octane-8-carboxylate, water (1 drop), triethylsilane (1 drop) and TFA (1.5 mL) was stirred at 40℃for 18 hours. The mixture was concentrated. The crude product was purified by preparative HPLC (Phenomenex, luna 5 microns 30x250mm, flow = 30mL/min, gradient = 20% a to 100% B in 30min, a = H ₂ O/ACN/TFA(90:10:0.1)，B＝H ₂ O/ACN/TFA (10:90:0.1)). The pure fractions were loaded onto Oasis MCX cation mixed mode polymer cartridges (150 mg), the cartridges were washed with methanol (30 mL), and the product eluted with 0.1N ammonia (5.0 mL) in methanol. The ammonia eluate is concentrated. The pure product was treated with ACN/H ₂ O (1:1, 5 mL) was lyophilized to give 6- (2- { [ (4 aS,7 aR) -1-methyl-octahydro-1H-cyclopenta [ b ] as a white powder]Pyridin-4 a-yl]Methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1]Oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (8.67 mg,0.013mmol,53.6% yield). LCMS (ESI) m/z 635[ M+H ]] ⁺ LC retention time: 0.74min (Waters Acquity UPLC BEH C, 2.1X50mm,1.7 μm particles; mobile phase A: water (0.05% TFA; mobile phase B: ACN (0.05% TFA)), gradient: 2% -98% B over 1 min and then 0.5 min at 98% B; flow: 0.8mL/min; detection: MS and UV (220 nm)). ¹ H NMR (499 MHz, methanol-d) ₄ )δ7.85(d,J＝1.5Hz,1H),6.62(s,1H),4.55-4.43(m,3H),4.24(d,J＝10.7Hz,1H),3.69-3.58(m,4H),2.89(br d,J＝4.9Hz,1H),2.71-2.63(m,1H),2.47(d,J＝1.3Hz,3H),2.43-2.37(m,1H),2.33(s,3H),2.01-1.88(m,1H),1.88-1.67(m,12H),1.63-1.52(m,1H)。

The compounds found in table 8 can be prepared from intermediate 19B according to the procedure found in example 19-1.

TABLE 8

/>

Example 20-1

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- ({ 1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl } methoxy) quinazolin-7-yl) naphthalen-2-ol

Preparation of intermediates 20A (isomer 1) and 20B (isomer 2): 3- (6-chloro-2, 8-difluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Intermediate 16A was subjected to SFC purification to separate the atropisomers (column: chiralpak ADH (250 mm x4.6x5 μ), mobile phase-30% isopropanol), with peak-1 (intermediate 20A) eluting at 2.72min (230 mg, 46%); LCMS (ESI) m/z 597.2[ M+H ]] ⁺ And peak-2 (intermediate 20B) eluted at 5.47min (205 mg, 41%); LCMS (ESI) m/z 597.2[ M+H ]] ⁺ 。

Example 20-1

To 3- (6-chloro-2, 8-difluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] under nitrogen at room temperature]Octane-8-carboxylic acid tert-butyl ester (intermediate 20A,20mg,0.033 mmol) and ((4 aR,7 aS) -1-methyl octahydro-4 aH-cyclopenteno [ b ]]To a solution of pyridin-4 a-yl) methanol (intermediate 19b1,5.67mg,0.033 mmol) in anhydrous THF (1.0 mL) was added a 1.0M solution of LiHMDS in THF (50.2 μl,0.050 mmol) and the mixture was stirred for 18 hours. The mixture was then diluted with DMF (1 mL) and the crude product was purified by preparative HPLC (Phenomenex, luna 5 microns 30x250mm, flow = 30mL/min, gradient = 20% a to 100% B in 30min, a = H ₂ O/ACN/TFA(90:10:0.1)，B＝H ₂ O/ACN/TFA (10:90:0.1)) to give the desired product. The mixture of compounds prepared above, water (1 drop), triethylsilane (1 drop) and TFA (1.5 mL) were stirred at room temperature for 1 hour. The crude product was purified by preparative HPLC (Phenomenex, luna 5 microns 30x250mm, flow = 30mL/min, gradient = 20% a to 100% B in 30min, a = H ₂ O/ACN/TFA(90:10:0.1)，B＝H ₂ O/ACN/TFA (10:90:0.1)). The pure fractions were loaded onto Oasis MCX cation mixed mode polymer cartridges (150 mg), the cartridges were washed with methanol (30 mL), and the product eluted with 0.1N ammonia (5.0 mL) in methanol. The ammonia eluate is concentrated. Pure product from ACN/H ₂ O (1:1, 5 mL) was lyophilized to give 4- (6-chloro-4- {3, 8-diazabicyclo [ 3.2.1) as a white powder]Oct-3-yl } -8-fluoro-2- ({ 1-methyl-octahydro-1H-cyclopenteno [ b ]]Pyridin-4 a-yl } methoxy) quinazolin-7-yl) naphthalen-2-ol (3.33 mg,5.25 μmol,15.68% yield). LCMS (ESI) m/z 603[ M+H ]] ⁺ LC retention time: 0.75min (Waters Acquity UPLC BEH C, 2.1X50mm,1.7 μm particles; mobile phase A: water (0.05% TFA; mobile phase B: ACN (0.05% TFA; gradient: 2% -98% B over 1 min)Then held at 98% B for 0.5 min; flow rate: 0.8mL/min; and (3) detection: MS and UV (220 nm)). ¹ H NMR (499 MHz, methanol-d) ₄ )δ7.97(d,J＝1.5Hz,1H),7.77(d,J＝8.3Hz,1H),7.43(ddd,J＝8.2,6.6,1.4Hz,1H),7.31-7.20(m,3H),7.05(d,J＝2.4Hz,1H),4.58-4.49(m,3H),4.30(br d,J＝11.0Hz,1H),3.72-3.63(m,4H),3.08-2.32(m,5H),2.04-1.56(m,14H),0.12(s,1H)。

The compounds in table 9 were prepared according to the procedure given for example 20-1 and the corresponding intermediate from 19B.

TABLE 9

/>

Examples 21-1 and 21-2

4- (6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -5-fluoronaphthalen-2-ol

Preparation of intermediate 21A: n- (5-bromonaphthalen-1-yl) -1, 1-trimethyl-N- (trimethylsilyl) silaneamine

at-78deg.C under N ₂ LiHMDS (1M solution in THF, 390 mL, 390 mmol) was added dropwise over 30min to a stirred solution of 5-bromonaphthalen-1-amine (40 g,180 mmol) in anhydrous THF (650 mL) under an atmosphere. The reaction mixture was slowly warmed to 20 ℃ over 30min, and thenAfter which it was cooled back to-78 ℃. A solution of TMSCl (48.3 mL,378 mmol) in anhydrous THF was added dropwise to the reaction mixture at-78deg.C, and it was slowly warmed to 20deg.C over 1 h. The reaction mixture was concentrated under reduced pressure to obtain a crude residue. The crude residue was dissolved in hexane (100 mL) and filtered through celite, and the filtrate was concentrated under reduced pressure to give the crude product as a red oil, which was purified by flash column (silica gel 100-200) chromatography (using petroleum ether as eluent). The pure fractions were concentrated under reduced pressure to afford N- (5-bromonaphthalen-1-yl) -1, 1-trimethyl-N- (trimethylsilyl) silanylamine (61 g,166mmol,92% yield) as a brown liquid. LCMS (ESI) m/z 366.45[ M+H ] ] ⁺ 。

Preparation of intermediate 21B: 5-fluoronaphthalen-1-amine

at-78deg.C under N ₂ N-butyllithium (164 mL, 309 mmol) was added dropwise over 30min to a stirred solution of N- (5-bromonaphthalen-1-yl) -1, 1-trimethyl-N- (trimethylsilyl) silane (100 g, 279 mmol) in anhydrous THF (1400 mL) under an atmosphere. After the addition was complete, the reaction mixture was stirred for 10min, and then a solution of N-fluorobenzenesulfonimide (138 g, 433 mmol) in anhydrous THF (400 mL) was added dropwise over 20min at-78 ℃. The resulting reaction mixture was slowly warmed to 20 ℃ for 1h, diluted with ice-cold water (1000 mL) and extracted with ethyl acetate (3 x800 mL). The extracted organic layers were combined, taken over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. The residue was purified by flash column (silica gel 100-200) chromatography using 10% -20% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to obtain semi-pure compounds, which were further purified by reverse phase column chromatography (using 80% acetonitrile in 0.01% ammonium formate in water). The pure fractions were concentrated under reduced pressure to give 5-fluoronaphthalen-1-amine (20 g,115mmol,42.3% yield) as a brown solid. LCMS (ESI) m/z 162.19[ M+H ] ] ⁺ 。

Preparation of intermediate 21C: 2, 4-dibromo-5-fluoronaphthalen-1-amine

Bromine (25.9 mL,502 mmol) was carefully added to a stirred solution of 5-fluoronaphthalen-1-amine (40 g,228 mmol) in acetic acid (800 mL) at 0 ℃ over 30min and the resulting reaction mixture was stirred at 70 ℃ for 1h. The reaction mixture was filtered and the filter cake was washed with acetic acid (2 x200 mL). The residue was suspended in 10% NaOH solution (600 mL) and filtered. The filter cake was washed with water (200 mL) and dried under reduced pressure to give crude 2, 4-dibromo-5-fluoronaphthalen-1-amine (66 g,170mmol,74.3% yield) as a pale yellow solid. The crude compound was used in the next step without any further purification. LCMS (ESI) m/z 319.98[ M+H ]] ⁺ 。

Preparation of intermediate 21D: 5-bromo-6-fluoronaphtho [1,2-d ] [1,2,3] oxadiazole

To a stirred solution of 2, 4-dibromo-5-fluoronaphthalen-1-amine (66 g,170 mmol) in acetic acid (1000 mL) at 0deg.C was added propionic acid (136 mL,1815 mmol). After 10min, sodium nitrite (17.56 g,255 mmol) was added in portions to the reaction mixture at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30min and warmed to 25 ℃ over 1h. The reaction mixture was diluted with cold water (2000 mL), stirred for 10min, and filtered. The solid was washed with water (2X 500 mL) and dried under reduced pressure to give crude 5-bromo-6-fluoronaphtho [1,2-d ] as a brown solid ][1,2,3]Oxadiazole (40 g,118mmol,69% yield) was used in the next step without any purification. LCMS (ESI) m/z 265.9[ M+H ]] ⁺ 。

Preparation of intermediate 21E: 4-bromo-5-fluoronaphthalen-2-ol

To 5-bromo-6-fluoronaphtho [1,2-d ] at 0deg.C under nitrogen for 30min][1,2,3]To a stirred solution of oxadiazole (40 g,118 mmol) in ethanol (500 mL) and tetrahydrofuran (250 mL) was added NaBH in portions ₄ (8.91 g,235 mmol). The reaction was stirred at the same temperature for 30min and then warmed to 25 ℃. The reaction mixture was carefully quenched with aqueous ammonium chloride (20 mL) and concentrated under reduced pressure to remove EtOH. The suspension was extracted with ethyl acetate (3X 500 mL) and the combined organics were taken up in anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give 4-bromo-5-fluoronaphthalene-2-ol (30 g,86mmol,73% yield), which was used in the next step without further purification. LCMS (ESI) m/z 241.08[ M+H ]] ⁺ 。

Preparation of intermediate 21F: 1-bromo-8-fluoro-3- (methoxymethoxy) naphthalene

To a stirred solution of 4-bromo-5-fluoronaphthalene-2-ol (30 g,86 mmol) and DIPEA (22.50 mL,129 mmol) in anhydrous dichloromethane (300 mL) was added MOM-Cl (7.83 mL,103 mmol) dropwise over 10min under nitrogen atmosphere at 0 ℃. The resulting reaction mixture was allowed to warm to room temperature and stirred for 1h. The reaction mixture was diluted with cold water (500 mL) and extracted with DCM (2 x500 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. The crude compound was purified by flash column (silica gel 100-200) chromatography using 5% -10% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to give 1-bromo-8-fluoro-3- (methoxymethoxy) naphthalene (20.5 g,68.3mmol,80% yield) as a brown solid. LCMS (ESI) m/z 285.01[ M+H ]] ⁺ 。

Preparation of intermediate 21G: 1-bromo-8-fluoro-3- (methoxymethoxy) naphthalene

To a degassed solution of 1-bromo-8-fluoro-3- (methoxymethoxy) naphthalene (15 g,50.0 mmol), bis-pinacolato-diboron (25.4 g,100 mmol) and potassium acetate (14.72 g,150 mmol) in anhydrous toluene (300 mL) at room temperature under an inert atmosphere was added PdCl ₂ (dppf) (3.66 g,5.00 mmol). The resulting reaction mixture was stirred at 110℃for 3h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x250 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography (by using 2% -4% ethyl acetate in petroleum ether as eluent). The pure fractions were concentrated under reduced pressure to give a brown gum, which was further purified by reverse phase column chromatography (using 80% acetonitrile in 0.01% ammonium formate in water as eluent). The pure fractions were concentrated under reduced pressure to give 2- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (9 g,26.6mmol,53.2% yield) as an off-white solid. LCMS (ESI) m/z 332.1[ M+H ] ] ⁺ 。1H-NMR(400MHz,DMSO-d ₆ ):δ7.52(d,J＝0.80Hz,1H),7.42-7.44(m,1H),7.36-7.38(m,1H),7.33-7.35(m,1H),7.03(dd,J＝1.20,7.60Hz,1H),5.31(s,2H),3.52(s,3H),1.46(s,12H)ppm。

Preparation of intermediate 21H: 3- (6-chloro-8-fluoro-7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (7-bromo-6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (intermediate 6B,588mg,1.005 mmol) in 1, 4-dioxane (20 mL) and H ₂ To a degassed solution in O (1 mL) was added 2- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (668 mg, 2.0111 mmol), cesium carbonate (650 mg, 2.0111 mmol)) And SPhos Pd-G3 (15.69 mg, 0.020mmol). The mixture was again degassed and heated in a pressure vial at 70 ℃ for 16 hours. The reaction vessel was allowed to cool to ambient temperature, diluted with ethyl acetate, filtered through a celite bed, and the filtrate was concentrated in vacuo to give the crude product. The residue was purified by neutral alumina column chromatography in EtOAc to give the desired product 3- (6-chloro-8-fluoro-7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- (((S) -methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a pale yellow oil ]Octane-8-carboxylic acid tert-butyl ester (321 mg, 41%). LCMS (ESI) m/z 710.2[ M+H ]] ⁺ 。

Examples 21-1 and 21-2

To 3- (6-chloro-8-fluoro-7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 at room temperature]To a stirred solution of tert-butyl octane-8-carboxylate (293 mg,0.413 mmol) in MeOH (3 mL) was added HCl in 1, 4-dioxane (1.031 mL,4.13 mmol). The reaction mixture was stirred at the same temperature for the next 2 hours, and then concentrated under reduced pressure to obtain a crude residue. The residue was purified by column chromatography (Biotage, sfar KP-amino), eluting with 100% ethyl acetate in petroleum ether, to give 4- (4- (3, 8-diazabicyclo [ 3.2.1)]Oct-3-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -5-fluoronaphthalene-2-ol (110 mg). The compound was subjected to SFC separation (column: cellulose-4 (250 mm X4.6X5u), mobile phase-0.2% ammonia in methanol-40-5. Lcd, run time: 25.00, flow rate: 3.0000mL/min, co-solvent: 40.0%), wherein peak-1 (21-1) eluted (13.0 mg,0.02mmol,5.12% yield) LCMS (ESI) m/z:566.2[ M+H ] when retention time = 10.683min ] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD):δ7.88(d,J＝16hz, 1H), 7.58 (d, j=8.0 hz, 1H), 7.40-7.35 (m, 1H), 7.30 (t, j=2.4 hz, 1H), 6.98 (d, j=1.6 hz, 1H), 6.90 (dd, j=13.2 and 7.6hz, 1H), 4.52-4.42 (m, 4H), 3.64-3.50 (m, 4H), 3.50-3.48 (m, 1H), 3.16-3.10 (m, 1H), 2.86-2.81 (m, 1H), 2.54 (s, 3H), 2.40-2.37 (m, 1H), 2.14-2.06 (m, 1H), 1.87-1.31 (m, 6H) ppm. Peak-2 (21-2) eluted (12 mg,0.02mmol, 4.78%) at room temperature= 11.79 with LCMS (ESI) m/z 566.2[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD) [ delta ] 7.88 (d, j=1.6 hz, 1H), 7.58 (d, j=8.0 hz, 1H), 7.40-7.35 (m, 1H), 7.30 (t, j=2.4 hz, 1H), 6.98 (d, j=1.6 hz, 1H), 6.90 (dd, j=13.2 and 7.6hz, 1H), 4.52-4.42 (m, 4H), 3.64-3.50 (m, 4H), 3.50-3.48 (m, 1H), 3.16-3.10 (m, 1H), 2.86-2.81 (m, 1H), 2.54 (s, 3H), 2.40-2.37 (m, 1H), 2.14-2.06 (m, 1H), 1.87-1.31 (m, 6H) ppm.

Examples 22-1 and 22-2

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol

Preparation of intermediate 22A: 8- ((triisopropylsilyl) ethynyl) naphthalene-1, 3-diol

To a stirred solution of naphthalene-1, 3-diol (20 g,125 mmol), (bromoethynyl) triisopropylsilane (34.3 g,131 mmol) and potassium acetate (24.51 g,250 mmol) in anhydrous 1, 4-dioxane (200 mL) was added dichloro (p-cymene) ruthenium (II) dimer (7.65 g,12.49 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 110℃for 12h. The reaction mixture was cooled to ambient temperature and filtered through celite. The celite bed was washed with EtOAc (2×100 mL), the filtrates were combined and concentrated under reduced pressure to give a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 12% -15% ethyl acetate in petroleum ether as eluent. Concentrating the pure fraction under reduced pressure To obtain 8- ((triisopropylsilyl) ethynyl) naphthalene-1, 3-diol (30 g,85mmol,67.7% yield). LCMS (ESI) m/z 341.55[ M+H ]] ⁺ 。

Preparation of intermediate 22B: 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-ol

To a stirred solution of 8- ((triisopropylsilyl) ethynyl) naphthalene-1, 3-diol (25 g,73.4 mmol) in anhydrous DCM (300 mL) under nitrogen at-10deg.C was added DIPEA (38.5 mL,220 mmol). After 10min, MOM-Cl (6.13 mL,81 mmol) was added dropwise to the reaction mixture over 20min under nitrogen. The resulting mixture was stirred at the same temperature for 2h. The reaction mixture was diluted with 100mL of DCM and washed with 200mL of brine. The combined organics were treated with anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 5% -10% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to give 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-ol (21 g,53.5mmol,72.9% yield) as a yellow oil. LCMS (ESI) m/z 385.60[ M+H ]] ⁺ 。

Preparation of intermediate 22C: 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate

To a stirred solution of 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalene-1-ol (20 g,52.0 mmol), TEA (21.75 mL,156 mmol), DMAP (1.271g, 10.40 mmol) in anhydrous DCM (200 mL) at-10℃under nitrogen was added dropwise pivaloyl chloride (12.80 mL,104 mmol) for 10min. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2h. The reaction mixture was then diluted with 200mL of DCM and taken upBrine (200 mL) was washed. The organic matter is treated by anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. The crude product was purified by flash column (silica 100-200 mesh) chromatography using 10% -15% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to give 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate as a yellow oil (23 g,49.1mmol,94% yield). LCMS (ESI) m/z 469.2[ M+H ]] ⁺ 。

Preparation of intermediate 22D: 8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl pivalate

To a stirred solution of 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate (12 g,25.6 mmol) in anhydrous DMF (130 mL) at room temperature under nitrogen was added anhydrous CsF (27.2 g, 178 mmol). The reaction mixture was stirred for 2h. The reaction mixture was diluted with DCM (200 mL) and washed with brine (200 mL). The organic matter is treated by anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. The crude product was purified by flash column (silica 100-200 mesh) chromatography using 5% -8% ethyl acetate in petroleum ether as eluent. The pure fraction was concentrated under reduced pressure to obtain 8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl pivalate (7 g,20.62mmol,81% yield). LCMS (ESI) m/z 313.3[ M+H ]] ⁺ 。

Preparation of intermediate 22E: 8-ethyl-3-methoxymethoxy-naphthalen-1-yl pivalate

To a stirred solution of 8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl pivalate (7 g,22.41 mmol) in anhydrous methanol (70 mL) at 25℃was added Pd/C (1.4 g,13.16 mmol). The suspension was degassed under reduced pressure and purified with H ₂ Purging tableAnd twice. The mixture was stirred at 25℃under H ₂ Stirring is carried out for 5 hours under an atmosphere (1 atm). The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 15% -20% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to afford 8-ethyl-3-methoxymethoxy naphthalen-1-yl pivalate (6.56 g,17.83mmol,80% yield) as a pale yellow oil. LCMS (ESI) m/z 316.1[ M+H ] ] ⁺ 。

Preparation of intermediate 22F: 8-ethyl-3-methoxymethoxy) naphthalen-1-ol

To a stirred solution of 8-ethyl-3- (methoxymethoxy) naphthalen-1-yl pivalate (10 g,31.6 mmol) in THF: water: meOH (5:1:5) at room temperature under nitrogen was added anhydrous LiOH (1.135 g,47.4 mmol). The resulting mixture was stirred at the same temperature for 3h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The reaction mixture was diluted with EtOAc (150 mL) and washed with brine (200 mL). The organic matter is treated by anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 25% -30% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to give 8-ethyl-3-methoxymethoxy-naphthalen-1-ol (6 g,25.8mmol,82% yield). LCMS (ESI) m/z 233.2[ M+H ]] ⁺ 。

Preparation of intermediate 22G: trifluoromethanesulfonic acid 8-ethyl-3- (methoxymethoxy) naphthalen-1-yl ester

To a stirred solution of 8-ethyl-3- (methoxymethoxy) naphthalene-1-ol (3 g,12.92 mmol) and DIPEA (22.50 mL,129 mmol) in anhydrous dichloromethane (50 mL) at-40 ℃ under nitrogen was added Tf dropwise ₂ O (2.182 mL,12.92 mmol). The resulting reaction mixture was allowed to warm to room temperature and stirred for 1h. The reaction mixture was diluted with cold water (500 mL) and extracted with DCM (2 x 500 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure to obtain a crude residue. The crude compound was purified by flash column (silica gel 100-200) chromatography using 5% -10% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to give 8-ethyl-3- (methoxymethoxy) naphthalen-1-yl triflate (3.5 g,9.03mmol,69.9% yield) as a yellow oil. LCMS (ESI) m/z 365.3[ M+H ]] ⁺ 。

Preparation of intermediate 22H: 2- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxapentaborane

To a stirred solution of trifluoromethanesulfonic acid 8-ethyl-3- (methoxymethoxy) naphthalen-1-yl ester (7.4 g,20.31 mmol) in 1, 4-dioxane (80 mL) was added bippinacol borane (12.89 g,50.8 mmol) and potassium acetate (5.98 g,60.9 mmol). The mixture was degassed and purged with nitrogen for 5min, and PdCl was added ₂ (dppf) (1.659 g,2.031 mmol). The resulting mixture was stirred under nitrogen at a temperature of 100 ℃ for 3h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure to obtain a crude residue. The crude product was purified by flash column (silica 100-200 mesh) chromatography (by using 2% -4% ethyl acetate in petroleum ether as eluent). The pure fractions were concentrated under reduced pressure to give a brown gum which was purified again by reverse phase column chromatography (using 80% acetonitrile in 0.01% ammonium formate in water as eluent). The pure fractions were concentrated under reduced pressure to give 2- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (4.5 g,13.10mmol,64.5% yield) )。LCMS(ESI)m/z:344.2[M+H] ⁺ 。 ¹ H-NMR(400MHz,CDCl ₃ ):δ7.62(dd,J＝0.80,8.00Hz,1H),7.36-7.44(m,3H),7.27(t,J＝0.40Hz,1H),5.31(s,2H),3.53(s,3H),3.21(q,J＝7.20Hz,2H),1.46(s,12H),1.38(t,J＝7.60Hz,3H)ppm。

Preparation of intermediate 22I: 3- (7-bromo-6-chloro-8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of ((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolazin-7 a (5H) -yl) methanol (500 mg,3.14 mmol) in anhydrous THF (20 mL) under nitrogen at 0 ℃ was added sodium hydride (60% dispersion in mineral oil, 75mg,3.14 mmol) and the reaction mixture was stirred at the same temperature for 30min. After 30min at 0deg.C, 3- (7-bromo-6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (intermediate 8A,1.0g,2.09 mmol) in THF (2 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at ambient temperature for 3h. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water and saturated brine solution, and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography over neutral alumina (Grace, 50g snap, dry bag) (50% -100% ethyl acetate in petroleum ether). The desired fractions were pooled and concentrated under reduced pressure to give 3- (7-bromo-6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a pale yellow solid ]Tert-butyl octane-8-carboxylate (1200 mg,1.91mmol,91.0% yield). LCMS (ESI) m/z 629.5[ M+H ]] ⁺ 。

Preparation of intermediate 22J: 3- (6-chloro-7- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (7-bromo-6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (400 mg,0.636 mmol) in 1, 4-dioxane (7 mL) and H ₂ To a degassed solution in O (0.5 mL) was added 2- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (435 mg,1.272 mmol), cesium carbonate (414 mg,1.272 mmol) and S-phos-pd-g3 (24.81 mg,0.032 mmol). The mixture was again degassed and heated in a pressure vial at 70 ℃ for 16 hours. The reaction vessel was allowed to cool to ambient temperature, diluted with ethyl acetate, filtered and concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by reverse phase HPLC [ column: xselect C18 (150 x 19) mm,5 microns, mobile phase A: 10mM ammonium acetate in water, mobile phase B: acetonitrile ]And (5) purifying. Fractions from reverse phase HPLC were pooled together and lyophilized to give the desired product 3- (6-chloro-7- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1) as an off-white solid]Tert-butyl octane-8-carboxylate (100 mg,0.118mmol,18.52% yield). LCMS (ESI) m/z 764.3[ M+H ]] ⁺ 。

Examples 22-1 and 22-2

To 3- (6-chloro-7- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] at ice-cold temperature]Octane-To a stirred solution of tert-butyl 8-carboxylate (100 mg,0.131 mmol) was added HCl (4.0M in dioxane, 0.352mL,1.406 mmol). The reaction was allowed to warm to room temperature and then stirred for 2h. The reaction mixture was concentrated under reduced pressure to obtain a crude residue. The residue was purified by column chromatography (Biotage, sfar KP-amino), eluting with 100% ethyl acetate in petroleum ether to give 3- (6-chloro-7- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 ]Octane-8-carboxylic acid tert-butyl ester (123 mg). The compound obtained was subjected to SFC separation (column: cellulose-4 (250 mm. Times. 4.6X5u), mobile phase-0.2% ammonia in methanol-40-5. Lcd, run time: 25.00, flow rate: 3.0000mL/min, co-solvent: 40.0%), wherein peak-1 (22-1) eluted at retention time = 12.16 min. (45 mg,52.8% yield); LCMS (ESI) m/z 621.2[ M+H ]] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD, 298K) δ 8.03-7.96 (m, 1H), 7.65 (d, j=7.6 hz, 1H), 7.41-7.34 (m, 1H), 7.30 (d, j=2.6 hz, 1H), 7.16 (d, j=6.9 hz, 1H), 6.87 (d, j=2.6 hz, 1H), 5.65-5.41 (m, 1H), 4.83-4.67 (m, 4H), 4.28 (br d, j=10.1 hz, 2H), 4.12-4.00 (m, 1H), 3.99-3.83 (m, 2H), 3.76-3.65 (m, 1H), 3.60-3.45 (m, 2H), 2.74 (br s, 1H), 2.56-2.38 (m, 4H), 2.29 (td, j=4.8, 9.1 hz, 2H), 4.12-4.00 (m, 1H), 3.99-3.83 (m, 2H), 3.7-3.7 hz (m, 2H). Peak-2 (22-2) eluted at retention time = 17.95min (40 mg, 57%); LCMS (ESI) m/z 621.2[ M+H ]] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD,298K)δ:8.03-7.96(m,1H),7.65(d,J＝7.6Hz,1H),7.41-7.34(m,1H),7.30(d,J＝2.6Hz,1H),7.16(d,J＝6.9Hz,1H),6.87(d,J＝2.6Hz,1H),5.65-5.41(m,1H),4.83-4.67(m,4H),4.28(br d,J＝10.1Hz,2H),4.12-4.00(m,1H),3.99-3.83(m,2H),3.76-3.65(m,1H),3.60-3.45(m,2H),2.74(br s,1H),2.56-2.38(m,4H),2.29(td,J＝4.8,9.0Hz,2H),2.23-2.08(m,3H),0.94(t,J＝7.4Hz,3H)ppm。

Examples 23-1 and 23-2

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-ethyl-6-fluoronaphthalene-2-ol

Preparation of intermediate 23A: 7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalene-1, 3-diol

To a stirred solution of 7-fluoronaphthalene-1, 3-diol (20 g,112 mol), (bromoethynyl) triisopropylsilane (30.8 g,118 mmol) and potassium acetate (22.03 g,225 mmol) in anhydrous dioxane (200 mL) was added dichloro (p-cymene) ruthenium (II) dimer (6.87 g,11.23 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110℃under a nitrogen atmosphere for 12h. The resulting reaction mixture was filtered through celite, and the celite bed was washed with EtOAc (2×50 mL). The filtrate was collected and concentrated in vacuo to give a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 5% -10% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to give 7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalene-1, 3-diol (32 g,88mmol,79% yield) as a yellow oil. LCMS (ESI) m/z 359.1[ M+H ] ] ⁺ 。

Preparation of intermediate 23B: 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalene-1-ol.

To a stirred solution of 7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalene-1, 3-diol (10 g,27.9 mmol) in anhydrous DCM (100 mL) at 0deg.C under nitrogen was added DIEA (14.61 mL,84 mmol). The reaction mixture was stirred at the same temperature for 10min, and then MOM-Cl (2.54 mL,33.5 mmol) was added dropwise to the reaction mixture. The resulting mixture was stirred at room temperature under nitrogen for 1h. The reaction mixture was diluted with cold water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure to obtain a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 5% -10% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to give 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-ol (10 g,24.84mmol,89% yield). LCMS (ESI) m/z 403.1[ M+H ]] ⁺ 。

Preparation of intermediate 23C: 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate

To a stirred solution of 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalene-1-ol (17 g,42.2 mmol) in anhydrous DCM (170 mL) at 0deg.C under nitrogen was added TEA (17.66 mL,127 mmol) and DMAP (1.032 g,8.45 mmol). The reaction mixture was stirred at the same temperature for 10min, and then pivaloyl chloride (6.23 mL,50.7 mmol) was added dropwise. The resulting reaction mixture was stirred at room temperature for 2h. The reaction mixture was diluted with cold water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure to obtain a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 20% -25% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to give 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate (19 g,35.1mmol,83% yield). LCMS (ESI) m/z 487.2[ M+H ]] ⁺ . Preparation of intermediate 23D: 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate

7-fluoro pivalate at room temperature under nitrogen atmosphere To a stirred solution of 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl ester (20 g,41.1 mmol) in anhydrous DMF (150 mL) was added CsF (43.7 g,288 mmol). The resulting mixture was stirred at room temperature for 5h. The reaction mixture was diluted with DCM (200 mL) and washed with brine (200 mL). The organic matter is treated by anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 5% -8% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to give 8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl pivalate as a yellow oil (12 g,32.7mmol,80% yield). LCMS (ESI) m/z 331.2[ M+H ]] ⁺ 。

Preparation of intermediate 23E: 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl pivalate.

To a stirred solution of 8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl pivalate (15 g,45.4 mmol) in ethanol (150 mL) at 25℃was added 10% Pd/C (3 g,28.2 mmol). The suspension was degassed under reduced pressure and purified with H ₂ Purging several times. The mixture was stirred at 25℃under H ₂ Stirring was carried out under an atmosphere (1 Atm) for 5 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude residue. The crude product was purified by flash column (silica 100-200 mesh) chromatography using 15% -20% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to afford 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl pivalate (14 g,34.3mmol,76% yield) as a yellow oil. LCMS (ESI) m/z 335.1[ M+H ] ] ⁺ 。

Preparation of intermediate 23F: 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-ol

To a stirred solution of 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl pivalate (5 g,14.95 mmol) in MeOH (50 mL) at room temperature under nitrogen was added anhydrous LiOH (0.537 g,22.43 mmol). The resulting mixture was stirred at the same temperature for 1h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The reaction mixture was diluted with EtOAc (150 mL) and washed with brine (200 mL). The organic matter is treated by anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 25% -30% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to give 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-ol (3.5 g,12.59mmol,84% yield). LCMS (ESI) m/z 251.2[ M+H ]] ⁺ 。

Preparation of intermediate 23G: trifluoromethanesulfonic acid 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl ester

To a stirred solution of 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalene-1-ol (1.5 g,5.99 mmol) and DIEA (3.66 mL,20.98 mmol) in anhydrous dichloromethane (50 mL) at-10 ℃ was added Tf dropwise ₂ O (1.215 mL,7.19 mmol). The resulting reaction mixture was allowed to warm to room temperature and stirred for 1h. The reaction mixture was diluted with cold water (500 mL) and then extracted with DCM (2 x 500 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. The crude compound was purified by flash column (silica gel 100-200) chromatography using 5% -10% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to give 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl triflate (1.8 g,4.66mmol,78% yield) as a yellow oil. LCMS (ESI) m/z 383.0[ M+H ]] ⁺ 。

Preparation of intermediate 23H: 2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan

To a stirred solution of trifluoromethanesulfonic acid 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl ester (2.5 g,6.54 mmol) in anhydrous 1, 4-dioxane (80 mL) was added bippinacol diborane (4.15 g,16.35 mmol) and potassium acetate (1.925 g,19.62 mmol), and the resulting mixture was degassed and purged with nitrogen for 5min. Then, pdCl is added ₂ (dppf) (0.534 g, 0.504 mmol) was added to the reaction mixture. The resulting mixture was stirred at 100 ℃ under nitrogen atmosphere for 2h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. The crude material was purified by flash column (silica 100-200 mesh) chromatography using 2% -4% ethyl acetate in petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to give a brown gum which was purified again by reverse phase column chromatography (using 80% acetonitrile in 0.01% ammonium formate in water as eluent). The pure fractions were concentrated under reduced pressure to give 22- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (1.8 g,4.99mmol,76% yield). LCMS (ESI) m/z 329[ M-OCH ] ₃ ] ⁺ 。 ¹ H-NMR(400MHz,CDCl3):δ7.77(t,J＝8.40Hz,1H),7.54(s,1H),7.37(t,J＝9.60Hz,1H),7.28(s,1H),5.31(s,2H),3.42(s,3H),3.03(d,J＝6.80Hz,2H),1.39(s,12H),1.19(t,J＝7.20Hz,3H)ppm。

Preparation of intermediate 23I: 3- (6-chloro-7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (7-bromo-6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a degassed solution of tert-butyl octane-8-carboxylate (400 mg,0.636 mmol) was added 2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (458 mg,1.272 mmol) and SPhosPd-G3 (24.81 mg,0.032 mmol). The mixture was again degassed and heated in a pressure vial at 70 ℃ for 16 hours. The reaction vessel was allowed to cool to ambient temperature, diluted with ethyl acetate, filtered and concentrated in vacuo to give a crude residue. The crude residue was purified by reverse phase HPLC [ column: xselect C18 (150 x 19) mm,5 microns, mobile phase A: 10mM ammonium acetate in water, mobile phase B: acetonitrile ]. Fractions from reverse phase HPLC were pooled together and lyophilized to give the desired product 3- (6-chloro-7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as an off-white solid]Tert-butyl octane-8-carboxylate (100 mg,0.128mmol,20.10% yield). LCMS (ESI) m/z 782.2[ M+H ]] ⁺ 。

Examples 23-1 and 23-2

To 3- (6-chloro-7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] at ice-cold temperature]To a stirred solution of tert-butyl octane-8-carboxylate (110 mg,0.141 mmol) in MeOH (5 mL) was added HCl (4.0M in dioxane, 0.352mL,1.406 mmol). The reaction was allowed to warm to room temperature and then stirred for 2h. The reaction mixture was concentrated under reduced pressure to obtain a crude residue. The residue was purified by column chromatography (Biotage, sfar KP-amino), 100% ethyl acetate in petroleum ether Elution of esters to obtain 4- (4- ((3, 8-diazabicyclo [ 3.2.1)]Oct-3-yl) -6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethyl-6-fluoronaphthalene-2-ol (110 mg). The compound obtained was subjected to SFC separation (column: cellulose-4 (250 mm X4.6X5u), mobile phase-0.2% ammonia in methanol, run time: 25.00, flow rate: 3.0000mL/min, co-solvent: 40.0%), wherein peak-1 (23-1) eluted (40 mg,42% yield) LCMS (ESI) m/z:639.2[ M+H ] at retention time= 9.216min] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD, 298K) delta 8.05-7.97 (m, 1H), 7.71 (dd, j=5.9, 9.1hz, 1H), 7.36-7.19 (m, 2H), 6.92 (d, j=2.6 hz, 1H), 5.61-5.39 (m, 1H), 4.82-4.63 (m, 3H), 4.35-4.17 (m, 2H), 4.00-3.83 (m, 3H), 3.73-3.60 (m, 1H), 3.55-3.40 (m, 2H), 3.15 (td, j=1.6, 3.2hz, 1H), 2.77-2.62 (m, 2H), 2.51-2.35 (m, 2H), 2.33-2.23 (m, 3H), 2.21-2.06 (m, 5H), 0.81 (t, j=7.4 hz. Peak-2 (23-2) eluted at retention time = 14.51min (41, 43.4% yield); LCMS (ESI) m/z 639.2[ M+H ]] ⁺ ； ¹ H NMR(400MHz,CD3OD,298K)δ:8.05-7.97(m,1H),7.71(dd,J＝5.9,9.1Hz,1H),7.36-7.19(m,2H),6.92(d,J＝2.6Hz,1H),5.61-5.39(m,1H),4.82-4.63(m,3H),4.35-4.17(m,2H),4.00-3.83(m,3H),3.73-3.60(m,1H),3.55-3.40(m,2H),3.15(td,J＝1.6,3.2Hz,1H),2.77-2.62(m,2H),2.51-2.35(m,2H),2.33-2.23(m,3H),2.21-2.06(m,5H),0.81(t,J＝7.4Hz,3H)ppm。

Examples 24-1 and 24-2

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -5-fluoronaphthalen-2-ol

Preparation of intermediate 24A: 3- (6-chloro-8-fluoro-7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- (((2 r,7 ar) -2-fluorotetrahydro)

-1H-Pyrrolidin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (7-bromo-6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a degassed solution of tert-butyl octane-8-carboxylate (400 mg, 0.630 mmol) in 1, 4-dioxane (7 mL) was added 2- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (423 mg,1.272 mmol), cesium carbonate (414 mg,1.272 mmol) and SPhosPd-G3 (49.6 mg,0.064 mmol). The mixture was again degassed and heated in a pressure vial at 70 ℃ for 16 hours. The reaction vessel was allowed to cool to ambient temperature, diluted with ethyl acetate, filtered and concentrated in vacuo to give a crude residue. The crude residue was purified by reverse phase HPLC [ column: YMC 18 phenyl (250 x 21) mM,5 microns, mobile phase a = 10mM ammonium acetate in water, mobile phase B = acetonitrile, flow: 15min, mobile phase-A=grade-70% -30%, mobile phase-B grade-30% -70%20min]. Fractions from reverse phase HPLC were pooled together and lyophilized to give 3- (6-chloro-8-fluoro-7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a pale brown solid ]Tert-butyl octane-8-carboxylate (120 mg,0.107mmol,16.84% yield). LCMS (ESI) m/z 754.2[ M+H ]] ⁺ 。

Examples 25-1 and 25-2

6- (2- { [ (7 aR) -2, 2-difluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 25A: 1- (tert-butyl) 2-methyl- (S) -4, 4-difluoropyrrolidine-1, 2-dicarboxylic acid ester

DAST (81 mL, 611 mmol) was added to a stirred solution of 1- (tert-butyl) 2-methyl (S) -4-oxopyrrolidine-1, 2-dicarboxylic acid ester (30.0 g,123 mmol) in DCM (20.0 mL) at 0deg.C. The reaction mixture was stirred at ambient temperature for 16h. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with water and saturated brine solution, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure to give the crude product. The crude product obtained was purified by column chromatography (Grace, 340g snap, dry bag) over silica (elution with 20% -50% ethyl acetate in petroleum ether). The desired fractions were pooled and concentrated under reduced pressure to give 1- (tert-butyl) 2-methyl (S) -4, 4-difluoropyrrolidine-1, 2-dicarboxylic acid ester (28 g,90mmol,73.4% yield) as a pale brown liquid. LCMS-ELSD (ESI) m/z 166.2[ M+H-Boc ] ] ⁺ 。

Preparation of intermediate 25B: 1- (tert-butyl) 2-methyl-2- (3- ((tert-butyldimethylsilyl) oxy) propyl) -4, 4-difluoropyrrolidine-1, 2-dicarboxylic acid ester

To a stirred solution of 1- (tert-butyl) -2-methyl (S) -4, 4-difluoropyrrolidine-1, 2-dicarboxylic acid ester (28 g,106 mmol) in THF (300.0 mL) at-45℃was added LiHMDS (158 mL,158 mmol) dropwise. The reaction mixture was stirred at the same temperature for 30min, after which 3-bromopropoxy) (t-butyl) dimethylsilane (40.1 g,158 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 30min and then slowly warmed to room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and then diluted with water (50 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 20% -30% ethyl acetate in petroleum ether to give 1- (tert-butyl) 2-methyl-2- (3- ((tert-butyldimethylsilyl) oxy) propyl) -4, 4-difluoropyrrolidine-1, 2-dicarboxylic acid ester (35 g) as a pale brown liquid80mmol,76% yield). LCMS-ELSD (ESI) m/z 388.2[ M+H-Boc ]] ⁺ 。

Preparation of intermediate 25C: 1- (tert-butyl) 2-methyl-4, 4-difluoro-2- (3-hydroxypropyl) pyrrolidine-1, 2-dicarboxylic acid ester

To a stirred solution of 1- (tert-butyl) 2-methyl-2- (3- ((tert-butyldimethylsilyl) oxy) propyl) -4, 4-difluoropyrrolidine-1, 2-dicarboxylic acid ester (35.0 g,80 mmol) in THF (50 mL) at 25 ℃ was added TBAF (1M in THF, 80mL,80 mmol) dropwise and stirred at the same temperature for 4h. The reaction mixture was quenched with saturated aqueous ammonium chloride (90 mL) and diluted with ethyl acetate (100 mL). The mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue as a colorless oil. The crude product was purified by silica gel column chromatography (using 50% ethyl acetate in petroleum ether) to give 1- (tert-butyl) 2-methyl-4, 4-difluoro-2- (3-hydroxypropyl) pyrrolidine-1, 2-dicarboxylic acid ester (20 g,57.9mmol,72.4% yield) as a pale brown liquid. LCMS-ELSD (ESI) m/z 224.2[ M+H-Boc ]] ⁺ 。

Preparation of intermediate 25D: 1- (tert-butyl) 2-methyl-4, 4-difluoro-2- (3-iodopropyl) pyrrolidine-1, 2-dicarboxylic acid ester

/>

To a stirred solution of 1- (tert-butyl) 2-methyl-4, 4-difluoro-2- (3-hydroxypropyl) pyrrolidine-1, 2-dicarboxylic acid ester (20 g,61.9 mmol) in DCM (100 mL) was added triphenylphosphine (48.7 g,186 mmol) and imidazole (8.42 g,124 mmol) at 0deg.C, and the reaction mixture was stirred for 10min, then iodine (62.8 g,247 mmol) was added. The reaction mixture was stirred at room temperature for 12h and then quenched with saturated aqueous sodium thiosulfate (30 mL). The suspension was extracted with dichloromethane (2×200 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered And concentrated under reduced pressure to obtain a crude residue. This crude product was purified by silica gel column chromatography (using 10% -20% ethyl acetate in petroleum ether) to give 1- (tert-butyl) 2-methyl-4, 4-difluoro-2- (3-iodopropyl) pyrrolidine-1, 2-dicarboxylic acid ester (20 g,46.1mmol,75% yield) as a colorless oil. LCMS-ELSD (ESI) m/z 333.0[ M+H-Boc ]] ⁺ 。

Preparation of intermediate 25E: 4, 4-difluoro-2- (3-iodopropyl) pyrrolidine-2-carboxylic acid methyl ester

To a stirred solution of 1- (tert-butyl) 2-methyl-4, 4-difluoro-2- (3-iodopropyl) pyrrolidine-1, 2-dicarboxylic acid ester (15 g,34.6 mmol) in DCM (100 mL) was added HCl (4 m,8.66mL,34.6 mmol) in 1, 4-dioxane at 0 ℃. The reaction mixture was stirred at ambient temperature for 16h. The reaction mixture was then concentrated under reduced pressure at room temperature to give the crude residue, methyl (S) -4, 4-difluoro-2- (3-iodopropyl) pyrrolidine-2-carboxylate HCl salt (11.5 g,31.1mmol,90% yield), which was used in the next step without any further purification. LCMS-ELSD (ESI) m/z 334.1[ M+H ]] ⁺ 。

Preparation of intermediate 25F: 2, 2-Difluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester

To a stirred solution of methyl 4, 4-difluoro-2- (3-hydroxypropyl) pyrrolidine-2-carboxylate HCl salt (11.5 g,51.5 mmol) in THF (120.0 mL) at 0deg.C was added TEA (35.9 mL,258 mmol) followed by heating at 45deg.C for 16h. The reaction mixture was concentrated under reduced pressure to obtain a crude residue as a brown liquid, which was purified by column chromatography (neutral alumina) (using 40% -50% ethyl acetate in petroleum ether) to obtain methyl 2, 2-difluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (6 g,43.5mmol,81% yield).

Preparation of intermediate 25G: (2, 2-Difluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol

LiAlH was added dropwise to a stirred solution of methyl 2, 2-difluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (12.0 g,58.5 mmol) in anhydrous THF (20.0 mL) at 0deg.C under nitrogen over 10min ₄ (117 mL,117 mmol). The mixture was stirred at this temperature for 1h and then quenched with saturated aqueous ammonium chloride (5 mL) at 0 ℃. Once effervescence was stopped, anhydrous sodium sulfate was added to the reaction mixture followed by dichloromethane (20 mL). The reaction mixture was stirred for 20min and filtered. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (2, 2-difluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (4.1 g,23.02mmol,39.4% yield) as a pale yellow liquid. LCMS-ELSD (ESI) m/z 178.1[ M+H ]] ⁺ 。

Preparation of intermediate 25H: 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2- ((2, 2-difluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of (2, 2-difluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (racemic) (129 mg,0.727 mmol) in THF (10 mL) at 0 ℃ was added NaH (60% dispersion in mineral oil, 29.1mg,0.727 mmol) and the reaction mixture was stirred for 30min. And then 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] dissolved in THF is added dropwise ]Tert-butyl octane-8-carboxylate (intermediate 14I,300mg, 0.264 mmol). The reaction mixture was stirred at ambient temperature for 3h. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and then extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water and saturated brine solutionAnhydrous Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography over neutral alumina (Grace, 50g snap, dry bag) (50% -100% ethyl acetate in petroleum ether). The desired fractions were pooled and concentrated under reduced pressure to give 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2- ((2, 2-difluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a pale yellow solid]Tert-butyl octane-8-carboxylate (300 mg,0.305mmol,84% yield). LCMS (ESI) m/z 982.2[ M+H ]] ⁺ 。

Examples 25-1 and 25-2

To 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2- ((2, 2-difluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 ]To a stirred solution of tert-butyl octane-8-carboxylate (300 mg,0.305 mmol) in TFA (1.5 mL) was added water (0.05 mL,2.78 mmol) and triethylsilane (0.979. Mu.l, 6.13. Mu. Mol). The reaction was allowed to stir at 40 ℃ for 16h. The reaction mixture was then concentrated under reduced pressure to give a crude residue which was purified by column chromatography (Biotage, sfar KP-amino), eluting with 100% ethyl acetate in petroleum ether to afford 6- (4- (3, 8-diazabicyclo [ 3.2.1)]Oct-3-yl) -6-chloro-2- ((2, 2-difluoro-tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-fluoro-quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (110 mg). The product obtained was subjected to SFC separation (Cellulose-4 (250 mm X4.6x5u) _0.2% ammonia in methanol, run time: 20.00, flow rate: 3.0000 mL/min), wherein peak-1 eluted at retention time = 14.352min (28 mg,0.040mmol,13.00% yield); LCMS (liquid Crystal Module)(ESI)m/z:642.1[M+H] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD) δ 7.85 (d, j=1.6 hz, 1H), 6.69 (s, 1H), 4.50-4.43 (m, 2H), 4.27 (s, 2H), 3.65-3.60 (m, 4H), 3.50-3.59 (m, 2H), 3.33-3.32 (m, 2H), 3.18-3.12 (m, 1H), 2.87 (q, j=7.6 hz, 1H), 2.46 (s, 3H), 2.35 (q, j=7.9 hz, 1H), 2.35-2.32 (m, 1H), 1.92-1.79 (m, 7H) ppm. Peak-2 eluted at retention time = 16.033min (27 mg,0.039mmol,12.81% yield); LCMS (ESI) m/z 642.1[ M+H ] ] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD)δ:7.85(d,J＝1.6Hz,1H),6.69(s,1H),4.50-4.43(m,2H),4.27(s,2H),3.65-3.60(m,4H),3.50-3.59(m,2H),3.33-3.32(m,2H),3.18-3.12(m,1H),2.87(q,J＝7.6HZ,1H),2.46(s,3H),2.35(q,J＝7.9Hz,1H),2.35-2.32(m,1H),1.92-1.79(m,7H)ppm。

Examples 26-1 and 26-2

6- {2- [ (1S) -1- [ (2R, 7 aR) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] ethoxy ] -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl } -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 26A: 1- (tert-butyl) 2-methyl (2R, 4R) -2- (3- ((tert-butyldimethylsilyl) oxy) propyl) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2S, 4R) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (5.00 g,20.22 mmol) in anhydrous THF (30 mL) at-25℃under nitrogen atmosphere was added LiHMDS (1M in THF, 30.3mL,30.3 mmol) dropwise. The reaction mixture was stirred at the same temperature for the next 30min, after which (3-bromopropyloxy) (tert-butyl) dimethylsilane (7.68 g,30.3 mmol) was added dropwise. The mixture was then stirred at the same temperature for 30min and then warmed slowly to room temperature. The reaction was quenched with saturated aqueous ammonium chloride (15 mL) and then diluted with water (50 mL). The suspension was washed with ethyl acetate (3 x 1)00 mL) of the extract. The combined organic layers were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 20% -30% ethyl acetate in petroleum ether to give 1- (tert-butyl) 2-methyl (2 r,4 r) -2- (3- ((tert-butyldimethylsilyl) oxy) propyl) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (7.23 g,17.24mmol,85% yield) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ ):δ5.18-5.03(m,1H),4.10-3.98(m,1H),3.78(s,3H),3.74-3.52(m,3H),2.48-2.23(m,3H),2.19-1.98(m,1H),1.65(s,9H),1.48-1.44(m,2H),0.90(s,9H),0.60(s,6H)ppm。 ¹⁹ F(376MHz,CD ₃ OD): delta-172.47 to-172.96 (m) ppm. LCMS-ELSD (ESI) m/z 320.2[ M+H-Boc ]] ⁺ 。

Preparation of intermediate 26B: 1- (tert-butyl) 2-methyl (2R, 4R) -4-fluoro-2- (3-hydroxypropyl) pyrrolidine-1, 2-dicarboxylic acid ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2 r,4 r) -2- (3- ((tert-butyldimethylsilyl) oxy) propyl) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (7.00 g,16.68 mmol) was added dropwise TBAF (1M in THF, 16.68ml,16.68 mmol) at 25 ℃ and stirred at the same temperature for 4h. The reaction mixture was quenched with saturated aqueous ammonium chloride (90 mL) and diluted with ethyl acetate (100 mL). The mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue as a colorless oil. The crude product was purified by silica gel column chromatography (using 50% ethyl acetate in petroleum ether) to give 1- (tert-butyl) 2-methyl (2 r,4 r) -4-fluoro-2- (3-hydroxypropyl) pyrrolidine-1, 2-dicarboxylic acid ester (4.97 g,15.64mmol,94% yield) as a colorless oil. LCMS-ELSD (ESI) m/z 206.2[ M+H-Boc ]] ⁺ 。

Preparation of intermediate 26C: 1- (tert-butyl) 2-methyl (2R, 4R) -4-fluoro-2- (3-iodopropyl) pyrrolidine-1, 2-dicarboxylic acid ester

Triphenylphosphine (15.50 g,58.9 mmol) and imidazole (6.02 g,88 mmol) were added to a stirred solution of 1- (tert-butyl) 2-methyl (2R, 4R) -4-fluoro-2- (3-hydroxypropyl) pyrrolidine-1, 2-dicarboxylic acid ester (9.00 g,29.5 mmol) at 0℃and the reaction mixture was stirred at the same temperature for 10min, followed by iodine (29.9 g,118 mmol). After stirring at room temperature for 12h, the reaction mixture was quenched with saturated aqueous sodium thiosulfate (30 mL) and the suspension was extracted with dichloromethane (2 x200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. This crude product was purified by silica gel column chromatography (using 10% -20% ethyl acetate in petroleum ether) to give 1- (tert-butyl) 2-methyl (2 r,4 r) -4-fluoro-2- (3-iodopropyl) pyrrolidine-1, 2-dicarboxylic acid ester (10.10 g,24.32mmol,83% yield) as a colorless oil. LCMS-ELSD (ESI) m/z 361.2[ M+H-Boc ]] ⁺ . Preparation of intermediate 26D: 3- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((R) -1- (piperidin-1-yl) propan-2-yl) oxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2 r,4 r) -4-fluoro-2- (3-iodopropyl) pyrrolidine-1, 2-dicarboxylic acid ester (10.0 g,24.08 mmol) in dichloromethane (20 mL) was added HCl in dioxane (8.03 mL,24.08 mmol) at 25 ℃ and the reaction mixture was stirred at the same temperature for 6h. The reaction mixture was concentrated under reduced pressure at room temperature to obtain crude residue (2 r,4 r) -4-fluoro-2- (3-iodopropyl) pyrrolidine-2-carboxylic acid methyl ester HCl salt (6.5 g,20.63mmol,86% yield) which was used in the next step without any further purification. LCMS-ELSD (ESI) m/z 188.2[ M+H ] ] ⁺ 。

Preparation of intermediate 26E: (2R, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester

To a stirred solution of methyl (2 r,4 r) -4-fluoro-2- (3-iodopropyl) pyrrolidine-2-carboxylate (6.5 g,20.63 mmol) in anhydrous acetonitrile (30 mL) was added triethylamine (10 mL) at room temperature. After stirring at 45 ℃ for 12h, the reaction mixture was concentrated under reduced pressure to obtain a crude residue. The residue was purified by column chromatography (neutral alumina) (using 40% -50% ethyl acetate in petroleum ether) to give methyl (2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (3.20 g,83% yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d 6): delta 5.76-5.19 (m, 1H), 3.59 (s, 3H), 3.25-3.16 (m, 1H), 2.97-2.95 (m, 1H), 2.86-2.76 (m, 1H), 2.68-2.51 (m, 2H), 2.02-1.91 (m, 2H), 1.85-1.72 (m, 3H) ppm. LCMS-ELSD (ESI) m/z 188.3[ M+H ]] ⁺ 。

Preparation of intermediate 26F: ((2R, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol

LiAlH was added dropwise to a stirred solution of methyl (2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (3.20 g,17.09 mmol) under nitrogen at 0deg.C for 10min ₄ (2M in THF, 17.09mL,34.2 mmol). After the addition, the reaction mixture was warmed to room temperature over 30 min. The mixture was stirred at this temperature for 1h and then quenched with saturated aqueous ammonium chloride (5 mL) at 0 ℃. Once effervescence was stopped, anhydrous sodium sulfate was added to the reaction mixture followed by dichloromethane (20 mL). The reaction mixture was stirred for 20min and filtered. The filtrate was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue ((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (2.20 g,13.68mmol,80% yield) as a pale brown oil. ¹ H NMR(400MHz,CD ₃ OD):δ5.34-5.10(m,1H),3.51-3.29(m,3H),3.25-3.10(m,1H),3.04-2.93(m,1H),2.90-2.73(m,1H),2.71-2.59(m,1H),2.28-2.12(m,,1H),1.95-1.73(m,4H),1.68-1.66(m,1H)ppm。 ¹⁹ F(376MHz,CD ₃ OD):δ-175.69 to-176.04 (m) ppm. LCMS-ELSD (ESI) m/z 160.0[ M+H ]] ⁺ 。

Preparation of intermediate 26G: (2R, 7 aR) -2-Fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carbaldehyde

To a stirred solution of ((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (100 mg, 0.6278 mmol) in anhydrous DCM (3 mL) was added Dess-martin hypervalent iodine compound (Dess-Martin periodinane) (53 mg,1.256 mmol) and the reaction mixture was stirred at room temperature for 6H. After 6h, the reaction mixture was carefully treated with saturated NaHCO ₃ Aqueous solution and solid Na ₂ S ₂ O ₃ Quench and then dilute with DCM (30 mL. Times.3). The combined organic layers were washed with brine, over MgSO ₄ Dried, filtered, and concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by neutral alumina column chromatography (eluting with 100% ethyl acetate in petroleum ether) to give the desired product (2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carbaldehyde (50 mg,0.318mmol,51% yield) as a pale yellow oil.

Preparation of intermediate 26H: 1- ((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) ethan-1-ol

To a stirred solution of (2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carbaldehyde (250 mg, 1.560 mmol) in anhydrous THF (10 mL) at 0deg.C was added dropwise methyl magnesium bromide (2M in THF, 2.3836 mL,4.77 mmol). The reaction mixture was stirred at the same temperature for 30min and then at room temperature overnight. The reaction mixture was carefully quenched with aqueous ammonium chloride (1 mL) and diluted with DCM (20 mL). Anhydrous sodium sulfate was added to the reaction mixture and stirred for 10min. The suspension was filtered and concentrated under reduced pressure to give crude residue 1- ((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) ethan-1-ol (256 mg, 1.178 mmol,93% yield) which was used as such in the next step without any further purification.

Preparation of intermediate 26I: 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (1- ((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) ethoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of 1- ((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) ethan-1-ol (31.5 mg,0.182 mmol) in THF (5 mL) at 0 ℃ was added NaH (60% dispersion in mineral oil, 7.27mg,0.182 mmol) and the reaction mixture was stirred for 30min. And then 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] dissolved in THF (2 mL) was added dropwise]Tert-butyl octane-8-carboxylate (intermediate 14I,100mg,0.121 mmol). The reaction mixture was stirred at ambient temperature for 3h. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and then extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water and saturated brine solution, and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography over neutral alumina (Grace, 50g snap, dry bag) (50% -100% ethyl acetate in petroleum ether). The desired fractions were pooled and concentrated under reduced pressure to give 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (1- ((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) ethoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a pale yellow solid ]Tert-butyl octane-8-carboxylate (65 mg,0.066mmol,55% yield). LCMS (ESI) m/z 978.0[ M+H ]] ⁺ 。

Examples 26-1 and 26-2

To 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (1- (-2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) ethoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a stirred solution of tert-butyl octane-8-carboxylate (76 mg,0.078 mmol) in TFA (59.8. Mu.l, 0.777 mmol) was added water (0.05 mL,2.78 mmol) and triethylsilane (35.4 mg,0.311 mmol). The reaction was allowed to stir at 40 ℃ for 16h. The reaction mixture was then concentrated under reduced pressure to give a crude residue which was purified by column chromatography (Biotage, sfar KP-amino), eluting with 100% ethyl acetate in petroleum ether to afford 6- (4- (3, 8-diazabicyclo [ 3.2.1)]Oct-3-yl) -6-chloro-8-fluoro-2- (-1- ((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) ethoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (87 mg). The product obtained was subjected to SFC separation (Cellulose-4 (250 mm X4.6X5u) _0.2% ammonia in methanol, run time: 20.00, flow rate: 3.0000 mL/min), wherein peak-1 (26-1) eluted at retention time = 16.00min (12 mg,0.015mmol,20% yield); LCMS (ESI) m/z 638.1[ M+H ] ] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD) delta 8.01-7.80 (m, 1H), 6.65 (s, 1H), 5.65-5.33 (m, 2H), 4.77-4.52 (m, 3H), 4.26 (br s, 2H), 4.06-3.95 (m, 1H), 3.93-3.81 (m, 2H), 3.64 (dt, j=6.1, 11.9hz, 1H), 3.57-3.40 (m, 2H), 3.15 (td, j=1.6, 3.3hz, 1H), 2.90-2.77 (m, 1H), 2.68 (s, 3H), 2.65-2.57 (m, 1H), 2.47 (d, j=1.3 hz, 2H), 2.39-2.23 (m, 3H), 2.22-2.06 (m, 3H), 1.59 (d, j=6.3 hz, 3.3 ppm. Peak-2 (26-2) eluted at retention time = 9.262min (10 mg,0.012mmol,15.58% yield); LCMS (ESI) m/z 638.1[ M+H ]] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD,296K)δ:8.01-7.80(m,1H),6.65(s,1H),5.65-5.33(m,2H),4.77-4.52(m,3H),4.26(br s,2H),4.06-3.95(m,1H),3.93-3.81(m,2H),3.64(dt,J＝6.1,11.9Hz,1H),3.57-3.40(m,2H),3.15(td,J＝1.6,3.3Hz,1H),2.90-2.77(m,1H),2.68(s,3H),2.65-2.57(m,1H),2.47(d,J＝1.3Hz,2H),2.39-2.23(m,3H),2.22-2.06(m,3H),1.59(d,J＝6.1Hz,3H)ppm。

Example 27

6- (2- { [ (2R, 6R,7 aR) -2-fluoro-6-methyl-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 27A: 1- (tert-butyl) 2-methyl (2R, 4R) -2- (2- (chloromethyl) allyl) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester

LiHMDS (1M solution in THF, 303mL,303 mmol) was added dropwise over 30min to a stirred solution of 1- (tert-butyl) 2-methyl (2S, 4R) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (50 g,202 mmol) in anhydrous THF (300.0 mL) under nitrogen atmosphere at-45℃while maintaining the temperature at-45 ℃. After stirring at this temperature for 1h, 3-chloro-2- (chloromethyl) prop-1-ene (30.3 g,243 mmol) in anhydrous THF (300.0 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature over 2h and stirred for 16h. The reaction mixture was carefully quenched with saturated ammonium chloride solution (40 mL) and extracted with ethyl acetate (2 x200 mL). The combined organic layers were washed with water and saturated brine solution, and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The crude residue was purified by column chromatography (Grace, 350g snap, dry bag) over silica gel (230-400 mesh) (by elution with 10% -30% ethyl acetate in petroleum ether). The desired fractions were pooled and concentrated under reduced pressure to give 1- (tert-butyl) 2-methyl (2 r,4 r) -2- (2- (chloromethyl) allyl) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (64 g,91mmol,45% yield) as a colorless liquid. LCMS (ESI) m/z 336.1[ M+H ]] ⁺ 。

Preparation of intermediate 27B: (2R, 4R) -2- (2- (chloromethyl) allyl) -4-fluoropyrrolidine-2-carboxylic acid methyl ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2 r,4 r) -2- (2- (chloromethyl) allyl) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (64 g,191 mmol) in anhydrous DCM (600 mL) at 0 ℃ under nitrogen atmosphere was added HCl solution (4.0M in dioxane 119mL, 470 mmol). The reaction mixture was stirred at ambient temperature for 6h and then concentrated under reduced pressure to give (2 r,4 r) -2- (2- (chloromethyl) allyl) -4-fluoropyrrolidine-2-carboxylic acid methyl ester HCl salt (50 g,180mmol,94% yield) as a pale brown solid. LCMS (ESI) m/z 236.2[ M+H ]] ⁺ 。

Preparation of intermediate 27C: (2R, 7 aR) -2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester

A stirred solution of (2R, 4R) -2- (2- (chloromethyl) allyl) -4-fluoropyrrolidine-2-carboxylic acid methyl ester (50 g,212 mmol) in anhydrous acetonitrile (500 mL) was added. The reaction mixture was stirred at ambient temperature for 16h. The reaction mixture was diluted with water (50 mL) and then basified with aqueous bicarbonate solution (70 mL). The resulting solution was extracted with DCM (2X 300 mL); the combined organic layers were washed with saturated brine solution (50 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give (2 r,7 ar) -2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester (35 g,176mmol,83% yield) as a brown liquid. LCMS (ESI) m/z 200.1[ M+H ]] ⁺ 。

Preparation of intermediate 27E: (2R, 7 aR) -2-fluoro-6-methyltetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester

To (2R, 7 aR) -2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester (2.0 g,10.04mm at 25 DEG Col) Pd/C (1.068 g,10.04 mmol) was added to a stirred solution in methanol (10 mL). The suspension was degassed under reduced pressure and purified with H ₂ Purging several times. The mixture was then subjected to H at 25 ℃ ₂ (1 Atm) for 5 hours. The suspension was filtered through celite bed and washed with EtOAc (2×20 mL). The combined filtrates were concentrated under reduced pressure to give (2 r,7 ar) -2-fluoro-6-methyltetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester (2.0 g,9.65mmol,96% yield) as a colorless liquid. LCMS (ESI) m/z 202.2[ M+H ] ] ⁺ 。

Preparation of intermediate 27F: ((2R, 7 aR) -2-fluoro-6-methyltetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol

LiAlH was added dropwise to a stirred solution of ((2R, 7 aR) -2-fluoro-6-methyltetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester (2.0 g,9.65 mmol) in anhydrous THF (20 mL) at 0deg.C under nitrogen atmosphere over 10min ₄ (2M in THF, 5.09mL,11.95 mmol). After the addition, the reaction mixture was warmed to room temperature over 30 min. The mixture was stirred at this temperature for 1h and then quenched with saturated aqueous ammonium chloride (5 mL) at 0 ℃. Once effervescence was stopped, anhydrous sodium sulfate was added to the reaction mixture followed by dichloromethane (20 mL). The suspension was stirred for 20min and filtered. The filtrate was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue ((2 r,7 ar) -2-fluoro-6-methyltetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (1.3 g,7.34mmol,76% yield) as a pale brown oil. ¹ H NMR(400MHz,CD ₃ OD):δ5.33-5.10(m,1H),3.51-3.29(m,3H),3.25-3.10(m,1H),3.04-2.93(m,1H),.90-2.73(m,1H),2.71-2.59(m,1H),2.28-2.12(m,,1H),1.93-1.71(m,3H),1.68-1.66(m,1H)。0.92(d,J＝6.4Hz,3H)ppm。LCMS-ELSD(ESI)m/z:174.1[M+H] ⁺ 。

Preparation of intermediate 27G: 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluoro-6-methyltetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of ((2 r,7 ar) -2-fluoro-6-methyltetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (63.0 mg, 0.284 mmol) in anhydrous THF (2.1 mL) at 0 ℃ was added sodium hydride (6.54 mg,0.273 mmol) and the reaction mixture was stirred at the same temperature for 30min. After 30min, 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 ] in anhydrous THF (10 mL) was dissolved]Tert-butyl octane-8-carboxylate (150 mg,0.182 mmol) was added dropwise to the reaction mixture while maintaining the temperature at 0 ℃. The reaction mixture was stirred for the next 2h while the reaction mixture was warmed to room temperature. The reaction mixture was then quenched with saturated aqueous ammonium chloride (1 mL) and then diluted with ethyl acetate (5 mL). The mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography over neutral alumina (Grace, 50g snap, dry bag) (50% -100% ethyl acetate in petroleum ether). The desired fractions were pooled and concentrated under reduced pressure to give 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluoro-6-methyltetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 ] as a pale yellow solid ]Tert-butyl octane-8-carboxylate (126 mg,0.115mmol,63% yield). LCMS (ESI) m/z 978.5[ M+H ]] ⁺ 。

Example 27

To a stirred solution of TFA (15.75 μl,0.204 mmol) and triethylsilane (23.76 mg,0.204 mmol) at room temperature was added 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((2R, 7 aR) -2-fluoro-6-methyltetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [ 3.2.1)]Octane-8-carboxylic acid tert-butyl ester (200 mg,0.204 mmol). The reaction mixture was then stirred at 35℃for 12h. The reaction mixture was concentrated at less than 35 ℃ under reduced pressure to remove most of TFA. The residue was co-evaporated with methanol (3 x1 mL) to remove any residual TFA. The residue was neutralized with DIPEA and concentrated under reduced pressure to obtain the free base. The crude product was then purified by column chromatography on silica gel (previously neutralized with DIPEA) using a mixture of MeOH, dichloromethane and DIPEA (15:80:2.5) to give 6- (4- (3, 8-diazabicyclo [ 3.2.1) as an off-white solid ]Oct-3-yl) -6-chloro-8-fluoro-2- (((2 r,6r,7 ar) -2-fluoro-6-methyltetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (60 mg,0.089mmol,44% yield). LCMS ESI m/z=638.2 [ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD,297K)δ:8.27-8.06(m,1H),6.65(s,1H),5.62-5.47(m,1H),4.77-4.69(m,3H),4.53-4.30(m,4H),4.18-3.91(m,1H),3.74-3.63(m,1H),3.61-3.43(m,5H),2.86-2.68(m,1H),2.61-2.39(m,5H),2.37-2.25(m,3H),2.21-2.14(m,1H),2.12-2.03(m,2H),2.02-1.93(m,1H),1.91-1.78(m,1H)ppm。

Examples 28-1 and 28-2

4- (2- { [ (6 ' r,7' ar) -6' -fluoro-hexahydrospiro [ cyclopropan-1, 2' -pyrrolizine ] -7' a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol

Preparation of intermediate 28A: (6 'R,7a' R) -6 '-fluoro dihydro-1' H,3'H spiro [ cyclopropane-1, 2' -pyrrolizine ] -7a '(5' H) -carboxylic acid methyl ester

To a stirred solution of methyl (2 r,7 ar) -2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (2.0 g,10.04 mmol) in anhydrous toluene (20 mL) under nitrogen atmosphere at 0 ℃ was added diiodomethane (3.64 mL,45.2 mmol). The reaction mixture was stirred at 0deg.C for 30min, then diethyl zinc (50.2 mL,50.2 mmol) was added dropwise (1M solution in hexanes). The reaction mixture was warmed to room temperature and stirred for 16h, then saturated NH ₄ Aqueous Cl (5 mL) was quenched. The suspension was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (neutral alumina) (using 40% -50% ethyl acetate in petroleum ether) to give (6 'r,7a' r) -6 '-fluoro dihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine) as a colorless liquid ]7a '(5' H) -methyl formate (2.0 g,8.05mmol,80% yield). LCMS-ELSD (ESI) m/z 204.1[ M+H ]] ⁺ 。

Preparation of intermediate 28B: ((6 'R,7a' R) -6 '-fluoro dihydro-1' H,3 'H-spiro [ cyclopropane-1, 2' -pyrrolizine ] -7a '(5' H) -yl) methanol

To (6 'R,7a' R) -6 '-fluorodihydro-1' H,3 'H-spiro [ cyclopropane-1, 2' -pyrrolizine ] at 0 DEG C]To a stirred solution of methyl-7 a '(5' H) -carboxylate (2.0 g,9.38 mmol) in THF (20 mL) was added LiAlH ₄ (4.69 mL,9.38mmol,2M in THF). The reaction mixture was stirred at ambient temperature for 3h, then quenched with saturated aqueous ammonium chloride at 0 ℃, and once effervescence ceased, anhydrous sodium sulfate was added to the reaction mixture, followed by DCM (20 mL). The reaction mixture was stirred for 20 minutes and then filtered. The filtrate was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give ((6 'r,7a' r) -6 '-fluorodihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine) as a colorless liquid]7a '(5' H) -yl) methanol (110 mg,0.592mmol,6% yield). LCMS-ELSD (ESI) m/z 186.2[ M+H ]] ⁺ 。

Preparation of intermediate 28C: 3- (6-chloro-8-fluoro-2- (((6 'R,7a' R) -6 '-fluoro dihydro-1' H,3 'H-spiro [ cyclopropane-1, 2' -pyrrolizine ] -7a '(5' H) -yl) methoxy) -7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]

Octane-8-carboxylic acid tert-butyl ester.

To ((6 'R,7a' R) -6 '-fluorodihydro-1' H,3 'H-spiro [ cyclopropane-1, 2' -pyrrolizine) at 0 DEG C]To a stirred solution of 7a '(5' H) -yl) methanol (140 mg,0.754 mmol) in anhydrous THF (2.1 mL) was added NaH (60% dispersion in mineral oil, 30.1mg,0.754 mmol) and the reaction mixture was stirred at the same temperature for 30min. 3- (6-chloro-2, 8-difluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (intermediate 16A,300mg,0.502 mmol) in anhydrous THF (10 mL) was added dropwise to the reaction mixture while maintaining the temperature below 0deg.C. The reaction mixture was warmed to room temperature over 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (1 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography over neutral alumina (Grace, 50g snap, dry bag) (50% -100% ethyl acetate in petroleum ether). The desired fractions were pooled and concentrated under reduced pressure to give 3- (6-chloro-8-fluoro-2- (((6 'r,7a' r) -6 '-fluoro dihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine) as a pale yellow solid ]-7a '(5' h) -yl) methoxy) -7- (3 (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (289 mg,0.379mmol,75% yield). LCMS (ESI) m/z 763.2[ M+H ]] ⁺ 。

Examples 28-1 and 28-2

To 3- (6-chloro-8-fluoro-2- (((6 'R,7a' R) -6 '-fluoro dihydro-1' H,3 'H-spiro [ cyclopropane-1, 2' -pyrrolizine) at ice cold temperature]-7a '(5' h) -yl) methoxy) -7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a stirred solution of tert-butyl octane-8-carboxylate (250 mg,0.328 mmol) in MeOH (5 mL) was added HCl (4.0M in dioxane, 0.410mL,1.640 mmol). The reaction was allowed to warm to room temperature and then stirred for 2h. The reaction mixture was concentrated under reduced pressure to obtain a crude residue. The residue was purified by column chromatography (Biotage, sfar KP-amino), eluting with 100% ethyl acetate in petroleum ether to give 4- (4- (3, 8-diazabicyclo [ 3.2.1)]Oct-3-yl) -6-chloro-8-fluoro-2- (((6 'r,7a' r) -6 '-fluoro dihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine) ]-7a '(5' h) -yl) methoxy) quinazolin-7-yl-naphthalen-2-ol (130 mg). The compound obtained was subjected to reverse phase HPLC (column: X SELECT C18 (4.6X 150 mm) 3.5um, mobile phase a: 0.05% TFA in water: CAN, mobile phase B: ACN: MEOH (50: 50), flow rate: 1.0 mL/min), wherein peak-1 (28-1) eluted (17 mg,0.022mmol,7% yield) at retention time = 6.396 min; LCMS (ESI) m/z 618.2[ M+H ]] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD, 298K) delta 8.14-8.01 (m, 1H), 7.79 (d, j=8.5 hz, 1H), 7.45 (ddd, j=2.3, 5.8,8.2hz, 1H), 7.36-7.30 (m, 1H), 7.24-7.20 (m, 2H), 7.06 (d, j=2.4 hz, 1H), 5.70-5.39 (m, 1H), 4.35-4.15 (m, 2H), 4.05-3.82 (m, 3H), 3.76-3.62 (m, 1H), 2.91-2.59 (m, 3H), 3.22-2.57 (m, 3H), 2.21-2.13 (m, 4H), 1.98-1.66 (m, 3H), 1.02-0.73 (m, 3H), 0.82-0.50 (m, 3H) ppm. Peak-2 (28-2) eluted at retention time = 6.529min (20 mg,0.026mmol,8% yield); LCMS (ESI) m/z 618.2[ M+H ]] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD,298K)δ:8.10-7.99(m,1H),7.79(d,J＝8.4Hz,1H),7.45(ddd,J＝1.9,6.1,8.2Hz,1H),7.31-7.28(m,1H),7.23(d,J＝0.9Hz,1H),7.06(d,J＝2.4Hz,1H),5.75-5.42(m,1H),4.38-4.17(m,2H),4.19-3.97(m,2H),3.97-3.83(m,3H),3.82-3.64(m,1H),3.59-3.44(m,1H),3.18-2.99(m,1H),2.85-2.53(m,3H),1.90(d,J＝13.6Hz,1H),1.58-1.32(m,3H),1.04-0.85(m,3H),0.82-0.66(m,3H)ppm。

Example 30

6- (2- { [ (2R, 6S,7 ar) -2, 6-difluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 30A: (2R, 7 aR) -2-fluoro-6-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester

Ozone gas was bubbled through a solution of methyl (2R, 7 aR) -2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (10 g,50.2 mmol) in 4:1v/v DCM and MeOH (50 mL) at-78deg.C for 45min. Dimethyl sulfide (18.6 mL,251 mmol) was added to the solution described above at-78℃and the reaction mixture was allowed to warm to room temperature over a period of 2 h. All volatiles were removed under reduced pressure and the crude residue was purified by silica gel column chromatography (by eluting with 2:1 petroleum ether and EtOAc) to give (2 r,7 ar) -2-fluoro-6-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester (9.0 g, 78%) as a colorless oil. M/z [ M+H ]202.2.

Preparation of intermediate 30B: (2R, 7 aR) -2-fluoro-6-hydroxytetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester

To a stirred solution of (2 r,7 ar) -2-fluoro-6-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester (800 mg,3.98 mmol) in MeOH (8 mL) at 0 ℃ was added sodium borohydride (150 mg,3.98 mmol) in one portion and the resulting mixture was stirred at room temperature for 4H. The reaction mixture was cooled to 0 ℃ and HCl (1.5M aqueous solution) was added until the gas evolution subsided. Mixing the reactionThe material was evaporated under reduced pressure and the crude residue was taken up with 10:1v/v DCM and MeOH and NaHCO ₃ Diluting the aqueous solution. Separating the two layers, and subjecting the organic layer to Na ₂ SO ₄ Dried, filtered and concentrated to give (2 r,7 ar) -2-fluoro-6-hydroxytetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (450 mg, 28%) as a 4:1 mixture of non-enantiomers. M/z [ M+H ]]204.1。

Preparation of intermediate 30C: (2R, 7 aR) -2, 6-Difluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester

To a stirred solution of (2 r,7 ar) -2-fluoro-6-hydroxytetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (50 mg,0.25 mmol) in DCM (3 mL) at 0 ℃ at room temperature was added (diethylamino) sulfur trifluoride (79 mg,0.49 mmol), and the reaction mixture was stirred at room temperature for 4H. Addition of saturated NaHCO ₃ Aqueous solution (2 mL), and the reaction mixture was extracted with DCM (3×10 mL). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered and concentrated to provide (2 r,7 ar) -2, 6-difluoro-tetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester (50 mg, crude) as a mixture of non-enantiomers. The compound was used in the next step without further purification. M/z [ M+H ]]206.1。

Preparation of intermediate 30D: ((2R, 7 aR) -2, 6-Difluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol

To (2R, 7 aR) -2, 6-difluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (50 mg,0.25 mmol) in THF (3 mL) was added drop-wise LiAlH at 0deg.C ₄ (0.36 mL,0.36mmol,1M in THF) and the resulting mixture was stirred at room temperature for 2h. The reaction mixture was cooled to 0 ℃ and saturated NH was added dropwise ₄ Aqueous Cl until the gas evolved subsides. The reaction mixture was diluted with DCM (5 mL) and Na was added ₂ SO ₄ . The reaction mixture is reactedFiltered through a cotton plug, and the filtrate was evaporated under reduced pressure to give ((2 r,7 ar) -2, 6-difluoro-tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (30 mg, 45%) as a brown oil. This compound was used in the next step without further purification. M/z [ M+H ]]178.1。

Preparation of intermediate 30E: 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2- (((2R) -2, 6-difluoro-tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of (((2R, 7 aR) -2, 6-difluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (32.2 mg,0.182 mmol) (63.0 mg, 0.264 mmol) in anhydrous THF (2.1 mL) at 0deg.C was added sodium hydride (60% dispersion in mineral oil, 6.54mg, 0.2793 mmol) and the reaction mixture was stirred at the same temperature for 30min dropwise 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] is added dropwise ]A solution of tert-butyl octane-8-carboxylate (intermediate 14I,100mg,0.121 mmol) in THF (2 mL) was maintained at 0deg.C. The reaction mixture was warmed to room temperature over 2 h. The reaction mixture was then quenched with saturated aqueous ammonium chloride (1 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography over neutral alumina (Grace, 50g snap, dry bag) (50% -100% ethyl acetate in petroleum ether). The desired fractions were pooled and concentrated under reduced pressure to give 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2- (((2R) -2, 6-difluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a pale yellow solid]Tert-butyl octane-8-carboxylate (145 mg,0.120mmol,99% yield). LCMS ESI m/z=982.2 [ M+H ]] ⁺ 。

Example 30

To a stirred solution of 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2- (((2R) -2, 6-difluoro-tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (120 mg,0.122 mmol) in TFA (94 μl,1.221 mmol) was added triethylsilane (0.244 mmol) and H2O (0.05 ml,2.78 mmol) at room temperature. The reaction mixture was then stirred at 35℃for 12h. After completion, the reaction mixture was concentrated at less than 35 ℃ under reduced pressure to remove most of TFA. The residue was co-evaporated with methanol (3 x1 mL) to remove any residual TFA. The residue was neutralized with DIPEA and concentrated under reduced pressure to obtain the free base. The crude product was then purified by column chromatography on silica gel (previously neutralized with DIPEA) using a mixture of MeOH, dichloromethane and DIPEA (15:80:2.5) to give 6- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-chloro-2- (((2 r,6s,7 ar) -2, 6-difluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (10 mg,0.014mmol,12% yield) (10 mg,0.015mmol,11.25% yield) as a pale yellow solid. LCMS, ESI m/z=642.3 [ m+h ] +.1H NMR (400 MHz, CD3OD, 298K) delta 7.99-7.66 (m, 1H), 6.62 (s, 1H), 5.50-5.15 (m, 2H), 4.50 (br d, J=12.8 Hz, 2H), 4.42-4.28 (m, 2H), 3.78-3.61 (m, 4H), 3.59-3.49 (m, 1H), 3.31-3.10 (m, 5H), 2.57-2.53 (m, 1H), 2.51 (br d, J=4.6 Hz, 1H), 2.45-2.39 (m, 1H), 2.37-2.33 (m, 1H), 2.34-2.28 (m, 1H), 2.26-2.17 (m, 1H), 1.94-1.85 (m, 4H) ppm.

Examples 31-1 and 31-2

4- (2- { [ (2 r,6s,7 ar) -2, 6-difluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalen-2-ol

Preparation of intermediate 31A: 3- (6-chloro-2- (((2R) -2, 6-difluoro-tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-fluoro-7- (3- (methoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a stirred solution of ((2 r,7 ar) -2, 6-difluoro-tetrahydro-1H-pyrrolazin-7 a (5H) -yl) methanol (134 mg,0.754 mmol) in anhydrous THF (2.1 mL) at 0 ℃ was added NaH (60% dispersion in mineral oil, 30.1mg,0.754 mmol) and the reaction mixture was stirred at the same temperature for 30min. 3- (6-chloro-2, 8-difluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (intermediate 16A,300mg,0.502 mmol) in anhydrous THF (10 mL) was added dropwise to the reaction mixture while maintaining the temperature at 0deg.C. The reaction mixture was warmed to room temperature over 2 h. The reaction mixture was then quenched with saturated aqueous ammonium chloride (1 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography over neutral alumina (Grace, 50g snap, dry bag) (50% -100% ethyl acetate in petroleum ether). The desired fractions were pooled and concentrated under reduced pressure to give 3- (6-chloro-2- (((2R) -2, 6-difluoro-tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-fluoro-7- (3- (methoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a pale yellow solid ]Tert-butyl octane-8-carboxylate (145 mg,0.108mmol,21% yield). LCMS (ESI) m/z 754.8[ M+H ]] ⁺ 。

Examples 31-1 and 31-2

To 3- (6-chloro-2- (((2R) -2, 6-difluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-fluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] at ice-cold temperature]To a stirred solution of tert-butyl octane-8-carboxylate (140 mg,0.186 mmol) was added HCl (4M in dioxane, 0.056ml, 1.850 mmol). The reaction was allowed to warm to room temperature and stirred for 2h. The reaction mixture was concentrated under reduced pressure to obtain a crude residue. The residue was purified by column chromatography (Biotage, sfar KP-amino) (eluting with 100% ethyl acetate in petroleum ether) to give 4- (4- (3, 8-diazabicyclo [ 3.2.1)]Oct-3-yl) -6-chloro-2- (((2 r,6s,7 ar) -2, 6-difluoro-tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-fluoro-quinazolin-7-yl) naphthalene-2-ol (80 mg). The compound obtained is subjected to SFC (column: cellulose-4 (250 mm. Times.4.6X5u), mobile phase: 0.1% NH in methanol) for separating atropisomers ₄ OH, flow rate: 3.0 mL/min), wherein peak-1 (31-1), eluted (14 mg,11% yield) LCMS (ESI) m/z 610.0[ M+H ] at retention time= 7.253min] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD, 298K) δ 7.79 (s, 1H), 7.75 (d, j=8.0 hz, 1H), 7.42 (dt, j=6.8 and 1.6hz, 1H), 7.28-7.04 (m, 3H), 7.04 (d, j=1.6 hz, 1H), 5.42-5.26 (m, 2H), 4.62-4.55 (m, 2H), 4.39 (q, j=10.4 hz, 2H), 3.82-3.69 (m, 5H), 3.68-3.55 (m, 1H), 3.32-3.29 (m, 2H), 2.67-2.30 (m, 5H), 1.94 (s, 4H) ppm. Peak-2 (31-2) eluted (9 mg,7% yield) LCMS (ESI) m/z 610.0[ M+H ] at retention time= 9.931min] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD, 298K) δ 7.97 (s, 1H), 7.75 (d, j=8.0 hz, 1H), 7.42 (dt, j=6.8 and 1.6hz, 1H), 7.28-7.04 (m, 3H), 7.04 (d, j=1.6 hz, 1H), 5.42-5.26 (m, 2H), 4.62-4.55 (m, 2H), 4.39 (q, j=10.4 hz, 2H), 3.82-3.69 (m, 5H), 3.68-3.55 (m, 1H), 3.32-3.29 (m, 2H), 2.67-2.30 (m, 5H), 1.94 (s, 4H) ppm.

Example 32

6- (2- { [ (6 ' R,7' aR) -3, 6' -trifluoro-hexahydrospiro [ cyclopropan-1, 2' -pyrrolizine ] -7' a-yl ] methoxy } -6-chloro-4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 32A: (6 'R,7a' R) -2, 6 '-trifluoro-dihydro-1' H,3 'H-spiro [ cyclopropane-1, 2' -pyrrolizine ] -7a '(5' H) -carboxylic acid methyl ester

Trimethyl (trifluoromethyl) silane (1.112 mL,7.53 mmol) and sodium iodide (226 mg,1.506 mmol) were added in one portion to a solution containing methyl (2R, 7 aR) -2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (600 mg,3.01 mmol) in dry THF (5 mL). After refluxing for 4h, the reaction mixture was concentrated in vacuo to give a crude residue. The residue was purified by column chromatography (Biotage, neutral alumina) (using 25% ethyl acetate in petroleum ether) to afford (6 'r,7a' r) -2, 6 '-trifluoro-dihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine ]-7a '(5' h) -methyl formate (237 mg,0.190mmol,6% yield). LCMS (ESI) m/z 250.1[ M+H ]] ⁺ 。

Preparation of intermediate 32B: ((6 'R,7a' R) -2, 6 '-trifluoro-dihydro-1' H,3 'H-spiro [ cyclopropane-1, 2' -pyrrolizine ] -7a '(5' H) -yl) methanol

To (6 'R,7a' R) -2, 6 '-trifluoro-dihydro-1' H,3 'H-spiro [ cyclopropane-1, 2' -pyrrolizine ] at 0deg.C under nitrogen for 10min]-7a '(5' H) -methyl formate (200 mg, 0.803 mmol) in dry THF (5 mL) was added drop wise LiALH ₄ (2M in THF, 0.8mL,1.605 mmol). After the addition the reaction mixture was warmed to room temperature over 30 min. The mixture was stirred at this temperature for 1h and then quenched with saturated aqueous ammonium chloride (5 mL) at 0 ℃. Once effervescence was stopped, anhydrous sodium sulfate was added to the reaction mixture followed by dichloromethane (20 mL). The reaction mixture was stirred for 20min and filtered. The filtrate was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue ((6 'r,7a' r) -2, 6 '-trifluoro-dihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine) as a pale brown oil]-7a '(5' h) -yl) methanol (267 mg,0.507mmol,63% yield). LCMS (ESI) m/z 222.1[ M+H ]] ⁺ . Preparation of intermediate 32C: 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((6 'r,7a' r) -2, 6 '-trifluoro-dihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine) ]-7a '(5' H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester

To ((6 'R,7a' R) -2, 6 '-trifluoro-dihydro-1' H,3 'H-spiro [ cyclopropane-1, 2' -pyrrolizine) at 0deg.C]To a stirred solution of 7a '(5' H) -yl) methanol (121 mg,0.545 mmol) in anhydrous THF (2.0 mL) was added sodium hydride (60% dispersion in mineral oil, 21.81mg,0.545 mmol) and the reaction mixture was stirred for 30min. 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 is added dropwise]A solution of tert-butyl octane-8-carboxylate (intermediate 14I,150mg,0.182 mmol) in THF (2 mL). While maintaining the temperature at 0 ℃. The reaction mixture was warmed to room temperature over 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (1 mL) and then extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography over neutral alumina (Grace, 50g snap, dry bag) (50% -100% ethyl acetate in petroleum ether). The desired fractions were pooled and concentrated under reduced pressure to give 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((6 'r,7a' r) -2, 6 '-trifluoro-dihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine) as a pale yellow solid ]-7a '(5' h) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (150 mg,0.098mmol,54% yield). LCMS (ESI) m/z 1025.384[ M+H ]] ⁺ 。

Example 32

To 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((6 'r,7a' r) -2, 6 '-trifluoro-dihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine) at room temperature]-7a '(5' H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a stirred solution of tert-butyl octane-8-carboxylate (130 mg,0.127 mmol) in TFA (98. Mu.l, 1.266 mmol) was added triethylsilane (29.5 mg, 0.255 mmol) and water (0.05 mL,2.78 mmol). After stirring at 35 ℃ for 12h, the reaction mixture was concentrated under reduced pressure to obtain a crude residue. The residue was purified by reverse phase prep HPLC [ column: x bridge C18 (150X 19) mm,5 microns; mobile phase a: 5mM ammonium formate in water; mobile phase B: acetonitrile; retention time (min): 7.5]And (5) purifying. HPLC fractions were pooled together and lyophilized to give 6- (4- (3, 8-diazabicyclo [ 3.2.1) as an off-white solid ]Oct-3-yl) -6-chloro-8-fluoro-2- (((6 'r,7a' r) -2, 6 '-trifluoro-dihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine)]-7a '(5' h) -yl) methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (24 mg,0.033mmol,26% yield). LCMS (ESI) m/z 686.2[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD,303K)δ:8.56-8.35(m,1H),7.87(s,1H),6.63(s,1H),5.51-5.16(m,2H),4.61(br dd,J＝6.5,14.0Hz,1H),4.49(q,J＝1.0Hz,1H),4.13(br s,2H),3.79(t,J＝1.0Hz,4H),3.51-3.36(m,2H),2.98(t,J＝1.0Hz,1H),2.91-2.81(m,1H),2.56-2.53(m,1H),2.51-2.43(m,3H),2.39(dd,J＝6.3,13.8Hz,1H),2.20-2.00(m,3H),2.21-2.00(m,1H),1.58-1.41(m,4H)ppm。

Example 33-1

4- (2- { [ (4 as,7 ar) -1-methyl-octahydro-1H-cyclopenteno [ b ] pyridin-4 a-yl ] methoxy } -4- {3, 8-diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalen-2-ol

Preparation of intermediate 33A: 3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a solution of 7-bromo-2, 4-dichloro-8-fluoroquinazoline (1.0 g,3.38 mmol) and DIEA (0.560 mL,3.38 mmol) in THF (30 mL) at 0 ℃ under nitrogen was added 8-Boc-3, 8-diaza-bicyclo [3.2.1]Octane (0.789 g,3.72 mmol), and the mixture was stirred at 0 ℃ for 1 hour and at room temperature for 18 hours. The mixture was then concentrated. The mixture was diluted with EtOAc (35 mL) and washed with saturated aqueous sodium bicarbonate (2×35 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel/hexanes-EtOAc 100:0 to 60:40 gradient) to give 3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a pale yellow solid ]Tert-butyl octane-8-carboxylate (1.393 mg, 2.81. Mu. Mol,0.083% yield). LCMS (ESI) m/z 472[ M+H ]] ⁺ LC retention time: 1.14min (method 3:Waters Acquity UPLC BEH C18,2.1x50mm,1.7 μm particles; mobile phase A: water (0.05% TFA; mobile phase B: ACN (0.05% TFA), gradient: 2% -98% B over 1 min and then 0.5 min at 98% B; flow rate: 0.8mL/min; detection: MS and UV (220 nm)). ¹ H NMR (499 MHz, chloroform-d) delta 7.51 (s, 2H), 4.51-4.30 (m, 4H), 3.78-3.51 (m, 2H), 2.02-1.91 (m, 2H), 1.75 (br s, 2H), 1.56-1.52 (m, 9H).

Preparation of intermediate 33B: 3- (7-bromo-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (1.14 g,2.417 mmol) and potassium fluoride (0.281g, 4.83 mmol) in DMSO (12 mL) was stirred at 100deg.C for 2 days. The mixture was diluted with EtOAc (45 mL) and washed with saturated aqueous sodium bicarbonate (2×45 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel/hexanes-EtOAc 100:0 to 70:30 gradient) to give 3- (7-bromo-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as an off-white solid ]Tert-butyl octane-8-carboxylate (987 mg,2.059mmol,85% yield). LCMS (ESI) m/z 456[ M+H ]] ⁺ LC retention time: 1.8min (Waters Acquity UPLC BEH C, 2.1X50mm,1.7 μm particles; mobile phase A: water (0.05% TFA; mobile phase B: ACN (0.05% TFA)), gradient: 2% -98% B over 1 min and then 0.5 min at 98% B; flow rate: 0.8mL/min; detection: MS and UV (220 nm). ¹ H NMR (499 MHz, chloroform-d) delta 7.56-7.47 (m, 2H), 4.53-4.31 (m, 4H), 3.78-3.56 (m, 2H), 2.02-1.92 (m, 2H), 1.76 (br s, 2H), 1.56-1.53 (m, 9H).

Preparation of intermediate 33C: 3- (7-bromo-8-fluoro-2- (((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenteno [ b ] pyridin-4 a-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 3- (7-bromo-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 under nitrogen at 0deg.C]Octane-8-carboxylic acid tert-butyl ester (185 mg,0.406 mmol), ((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenteno [ b ]]To a solution of pyridin-4 a-yl) methanol (68.8 mg,0.406 mmol) in anhydrous THF (2.0 mL) was added a solution of lithium bis (trimethylsilyl) amide in THF (609 μl,0.609 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was then concentrated. The crude product was purified by preparative HPLC (Phenomenex, luna 5 micron 30x250mm, flow = 30mL/min, gradient = within 12min 2 0% a to 100% B, a=h ₂ O/ACN/TFA(90:10:0.1)，B＝H ₂ O/ACN/TFA (10:90:0.1)) to yield 3- (7-bromo-8-fluoro-2- (((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenta [ b)) as a white foam]Pyridin-4 a-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (172 mg,0.270mmol,66.5% yield). LCMS (ESI) m/z 605[ M+H ]] ⁺ LC retention time: 0.89min (Waters Acquity UPLC BEH C, 2.1X50mm,1.7 μm particles; mobile phase A: water (0.05% TFA; mobile phase B: ACN (0.05% TFA)), gradient: 2% -98% B over 1 min and then 0.5 min at 98% B; flow: 0.8mL/min; detection: MS and UV (220 nm)). ¹ H NMR (499 MHz, chloroform-d) delta 7.49-7.40 (m, 1H), 7.33-7.28 (m, 1H), 4.50-4.20 (m, 6H), 3.69-3.42 (m, 3H), 2.77-2.54 (m, 2H), 2.35-2.22 (m, 4H), 2.03-1.47 (m, 22H).

Example 33-1

3- (7-bromo-8-fluoro-2- (((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenteno [ b)]Pyridin-4 a-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (20 mg,0.033 mmol), 2- (3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (10.91 mg,0.035 mmol), [1,1' -bis (di-tert-butylphosphino) ferrocene ]A mixture of palladium (II) dichloride (1.078 mg, 1.654. Mu. Mol) and 2.0M tripotassium phosphate (49.6. Mu.l, 0.099 mmol) in dioxane (1 mL) was stirred at 50℃under nitrogen for 18 hours. EtOAc (5 mL) was then added to the mixture, and the ethyl acetate layer was dried over sodium sulfate, filtered and concentrated to provide crude 3- (8-fluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) -2- (((4 as,7 ar) -1-methyl octahydro-4 aH-cyclopenta [ b ])]Pyridin-4 a-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester. LCMS (ESI) m/z 712[ M+H ]] ⁺ LC retention time:0.95min (Waters Acquity UPLC BEH C, 2.1X50mm,1.7 μm particles; mobile phase A: water (0.05% TFA; mobile phase B: ACN (0.05% TFA)), gradient: 2% -98% B over 1 min and then 0.5m min at 98% B; flow rate: 0.8mL/min; detection: MS and UV (220 nm)). 3- (8-fluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) -2- (((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenta [ b)]Pyridin-4 a-yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate in DCM (0.6 mL), TES (1 drop) and TFA (0.4 mL) was stirred at room temperature for 30min. The mixture was then concentrated. The crude product was purified by preparative HPLC (Phenomenex, luna 5 microns 30x250mm, flow = 30mL/min, gradient = 20% a to 100% B over 12min, a = H2O/ACN/TFA (90:10:0.1), B = H2O/ACN/TFA (10:90:0.1)). The pure fractions were loaded onto Oasis MCX cation mixed mode polymer cartridges (150 mg), the cartridges were washed with methanol (30 mL), and the product eluted with 0.1N ammonia (5.0 mL) in methanol. The ammonia eluate is concentrated. The pure product was treated with ACN/H ₂ O (1:1, 5 mL) was lyophilized to give 4- (2- { [ (4 aS,7 aR) -1-methyl-octahydro-1H-cyclopenta [ b ] as a white powder]Pyridin-4 a-yl]Methoxy } -4- {3, 8-diazabicyclo [3.2.1]Oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalen-2-ol (10.83 mg,0.019mmol,55.9% yield). LCMS (ESI) m/z 568[ M+H ]] ⁺ LC retention time: 0.74min (Waters Acquity UPLC BEH C, 2.1X50mm,1.7 μm particles; mobile phase A: water (0.05% TFA; mobile phase B: ACN (0.05% TFA)), gradient: 2% -98% B over 1 min and then 0.5 min at 98% B; flow: 0.8mL/min; detection: MS and UV (220 nm)). ¹ H NMR (499 MHz, methanol-d) ₄ )δ7.87(d,J＝8.5Hz,1H),7.75(d,J＝8.3Hz,1H),7.48(d,J＝8.4Hz,1H),7.42(t,J＝7.7Hz,1H),7.28-7.21(m,3H),7.11(d,J＝2.5Hz,1H),4.61-4.50(m,3H),4.29-4.24(m,1H),3.68-3.58(m,4H),2.90(br t,J＝6.2Hz,1H),2.68(ddd,J＝11.6,7.9,4.1Hz,1H),2.43-2.36(m,1H),2.34(s,3H),2.00-1.93(m,1H),1.91-1.68(m,12H),1.58(td,J＝8.9,3.9Hz,1H)。

The examples in table 10 were prepared according to the procedure of example 33 using the appropriate starting materials.

Table 10

/>

Preparation of intermediate 34-1: trifluoromethanesulfonic acid 7-fluoro-3- (methoxymethoxy) -8- {2- [ tris (prop-2-yl) silyl ] ethynyl } naphthalen-1-yl ester

To 7-fluoro-3- (methoxymethoxy) -8- {2- [ tri (prop-2-yl) silyl at-40 ℃C]To a solution of ethynyl } naphthalene-1-ol (intermediate 16-2) (8.6 g,22.25 mmol) and DIPEA (11.66 mL,66.7 mmol) in DCM (35 mL) was added dropwise trifluoromethanesulfonic anhydride (5.64 mL,33.4 mmol) and the reaction mixture was stirred for 30min. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure to provide a crude residue, which was purified by silica gel column chromatography (using CombiFlash instrument (80 gColumn, 5% to 10% EtOAc in petroleum ether) to give 7-fluoro-3- (methoxymethoxy) -8- {2- [ tris (prop-2-yl) silyl triflate as a yellow oil]Ethynyl } naphthalen-1-yl ester (8.5 g,16.39mmol,73.7% yield). ¹ H NMR(400MHz,DMSO-d ₆ )δppm 8.12(dd,J＝9.3,5.8Hz,1H),7.78(d,J＝2.5Hz,1H),7.65(t,J＝9.0Hz,1H),7.51(d,J＝2.0Hz,1H),5.37(s,2H),3.43(s,3H),1.31-1.08(m,21H)。

Preparation of intermediate 34-2: {2- [ 2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl ] ethynyl } tris (prop-2-yl) silane

To trifluoromethanesulfonic acid 7-fluoro-3- (methoxymethoxy) -8- {2- [ tri (prop-2-yl) silyl]Ethynyl } naphthalen-1-yl ester (4.0 g,7.48 mmol), potassium acetate (2.203 g,22.45 mmol) and bis (pinacolato) diboron (3.80 g,14.96 mmol) in toluene (40 mL) to a degassed solution was added 1, 1-bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (0.547 g,0.748 mmol) and the reaction mixture was heated at 120℃for 3h. T the reaction mixture was cooled, filtered through celite bed and washed with ethyl acetate. The filtrate was washed with water, brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to provide a crude residue, which was purified by silica gel column chromatography (using CombiFlash instrument (40 g Column, 10% EtOAc in petroleum ether) to give {2- [ 2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl as a pale yellow solid]Ethynyl } tris (prop-2-yl) silane (2.4 g,4.68mmol,62.6% yield). MS (ESI) m/z 513.4[ M+1 ]] ⁺ 。

The examples in table 11 were prepared according to the procedure described above from the appropriate starting materials.

TABLE 11

/>

Biological activity

KRAS ^G12D RAF failure assay

At room temperature in assay buffer (50mM Tris pH 7.5, 100mM NaCl,1mM MgCl ₂ 1mM DTT,100ug/mL BSA), KRAS G12D (5 nM) loaded with recombinant GMPPNP was treated with compound for 20 min. Recombinant GST-RAF1 RBD (9 nM) was added followed by SA-Tb (0.25 nM) and the reaction mixture incubated for 3 hours. HTRF signal (PerkinElmer Envision) is measured, and signal ratio (lambda) is calculated _em 520/λ _em 495 IC50 values were calculated from the dose-response curve).

KRAS ^G12D Nucleotide exchange assay

At room temperature in assay buffer (10mM Hepes pH 7.4, 150mM NaCl,5mM MgCl ₂ KRAS G12D (20 nM) loaded with recombinant GDP was treated with compound for 20 min in 0.0025% Igepal-CA630,0.05% BSA,1mM DTT,0.5nM SA-Tb). BIODIPY-labeled GDP (400 nM) and recombinant SOS (10 nM) were added and the reaction incubated for 30 min. HTRF signal (PerkinElmer Envision) is measured, and signal ratio (lambda) is calculated _em 520/λ _em 495 IC50 values were calculated from the dose-response curve).

The IC50 values for the compounds described herein are shown in table 12.

Table 12

/>

It should be appreciated that the detailed description section, and not the summary and abstract sections, is intended to be used to interpret the claims. The summary and abstract sections may set forth one or more, but not all exemplary aspects of the disclosure as contemplated by the inventors, and are therefore not intended to limit the disclosure and the appended claims in any way.

The present disclosure has been described above with the aid of functional building blocks illustrating the implementation of specific functions and their relationship. Boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries may be defined so long as the specified functions and relationships thereof are appropriately performed.

The foregoing description of the specific aspects will so fully reveal the general nature of the disclosure that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific aspects without undue experimentation without departing from the generic concept of the present disclosure. Accordingly, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed aspects, based on the teaching and guidance presented herein. It is to be understood that the phraseology and terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein:

R ⁴ selected from:

wherein the method comprises the steps of

R ^a Is hydrogen or C ₁ -C ₃ An alkyl group; and is also provided with

Representing an attachment point to the parent molecular moiety;

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ² And R is ³ Each is a halo group.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is- (C) ₁ -C ₃ Alkyl) -R ⁶ 。

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is substituted and wherein R ¹ One of the substituents on this is halo C ₁ -C ₃ An alkyl group.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Selected from:

wherein each ring is optionally substituted with 1, 2 or 3 groups independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkyl, benzyl, halo C ₁ -C ₃ Alkyl, hydroxy C ₁ -C ₃ Alkyl and oxo groups.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

9. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

10. A compound according to claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

Wherein->Indicating the point of attachment to the parent molecular moiety.

11. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

12. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

13. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

14. The compound according to any one of claims 1, 2 or 5, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

15. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R ⁶ Is an eight membered bicyclic fully saturated or fully unsaturated ring containing one nitrogen atom, said ring optionally being independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkyl, benzyl, halo C ₁ -C ₃ Alkyl, hydroxy C ₁ -C ₃ Alkyl and oxo groups.

16. The compound of any one of claims 1-4 or 15, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

Wherein:

z is 1, 2 or 3;

each R ⁵⁰ Independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkyl, benzyl, halo C ₁ -C ₃ Alkoxy, halo C ₁ -C ₃ Alkyl, hydroxy C ₁ -C ₃ Alkyl and oxo; and is also provided with

Indicating the point of attachment to the parent molecular moiety.

17. The compound of any one of claims 1-4, 15, or 16, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

Wherein:

z is 1, 2 or 3;

Indicating the point of attachment to the parent molecular moiety.

18. The compound according to claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein z is 1, and R ⁵⁰ Is a halo group.

19. The compound according to claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein R ⁵⁰ Is fluorine.

20. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

21. The compound according to any one of claims 1 to 4 or 15, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

Wherein q and r are each independently 0 or 1; and wherein R is ^x And R is ^y Independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halo C ₁ -C ₃ Alkyl and hydroxy.

22. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

Wherein q, r and d are each independently 0 or 1; and wherein R is ^x 、R ^y And R is ^p Independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halo C ₁ -C ₃ Alkyl and hydroxy.

23. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is naphthyl, wherein the naphthyl is optionally one, two or three independently selected from C ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkynyl, C ₃ Cycloalkyl, halo, and hydroxy groups.

25. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is a phenyl group, and is preferably a phenyl group,wherein the phenyl groups are optionally substituted with one or two groups selected from C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, halo and halo C ₁ -C ₃ The groups of the alkyl groups are substituted.

26. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is that

27. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is that

28. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is that

Wherein the method comprises the steps of

q is 1, 2 or 3;

Indicating the point of attachment to the parent molecular moiety.

29. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is that

Wherein the method comprises the steps of

q and r are each independently 0 or 1;

Indicating the point of attachment to the parent molecular moiety.

30. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

R ² Is hydrogen;

R ³ is fluorine;

R ¹ selected from the group consisting of

And is also provided with

R ⁵ Selected from the group consisting of

Wherein the method comprises the steps of

Indicating the point of attachment to the parent molecular moiety.

31. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

R ² Is chlorine;

R ³ is fluorine;

R ¹ selected from the group consisting of

And is also provided with

R ⁵ Selected from the group consisting of

Wherein the method comprises the steps of

Indicating the point of attachment to the parent molecular moiety.

32. The compound of claim 1, having formula (II):

Or a pharmaceutically acceptable salt thereof, wherein:

R ¹ selected from the group consisting of

R ⁴ Selected from:

wherein the method comprises the steps of

R ^a Is hydrogen or C ₁ -C ₃ An alkyl group; and is also provided with

Indicating the point of attachment to the parent molecular moiety.

33. The compound of claim 1, having formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ selected from the group consisting of

R ⁴ Selected from:

wherein the method comprises the steps of

R ^a Is hydrogen or C ₁ -C ₃ Alkyl groupThe method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

Indicating the point of attachment to the parent molecular moiety.

34. A compound selected from the group consisting of:

/>

or a pharmaceutically acceptable salt thereof.

35. A compound selected from the group consisting of:

diazabicyclo [3.2.1] oct-3-yl } -8-fluoroquinazolin-7-yl) naphthalene-2-ol;

Or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

37. A method for treating cancer susceptible to KRAS G12D inhibition in a subject in need thereof, the method comprising administering to the subject the compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

38. A method of treating a KRAS G12D mutated-expressing cancer in a subject in need thereof, the method comprising administering to the subject the compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof.

39. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer, colorectal cancer, lung cancer, and/or gastric cancer.