CN117177976A

CN117177976A - KRAS inhibitors

Info

Publication number: CN117177976A
Application number: CN202280027443.2A
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: 2023-12-05

Abstract

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

Description

KRAS inhibitors

Cross Reference to Related Applications

The present application claims priority from U.S. provisional application number 63/160,436 filed on day 3, month 12 of 2021 and U.S. provisional application number 63/288,965 filed on day 12, month 13 of 2021, each of which is incorporated by reference in its entirety.

Technical Field

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

Background

The KRAS oncogene is a member of the Ras family of gtpases, which is involved in a variety of cell signaling processes. KR AS mutations are functional acquired mutations that are present in up to 30% of all tumors, including up to 90% of pancreatic cancers. K RAS G12D mutations are present in 28% of pancreatic ductal adenocarcinoma patients, 13% of colorectal cancer patients, 4% of non-small cell lung cancer patients, and 3% of gastric cancer patients (see, e.g., https:// www.mycancergenome.org/content/alternation/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 mainly due to the difficulty in competing KRAS binding pocket with GTP in cells and the lack of known allosteric regulatory sites. Thus, agents that inhibit KRAS G12D are needed.

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 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 Alkoxy, halo C ₁ -C ₃ Alkyl, hydroxy and hydroxy C ₁ -C ₃ One, two, three, four or five substituents of the alkyl group;

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;

n is 0, 1, 2, 3 or 4;

each R ^b Independently selected from C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, halo, and hydroxy; or alternatively, two gem R ^b The groups together with the carbon atom to which they are attached are capable of forming a 3 to 6 membered cycloalkyl ring; 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:

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

a five to ten membered monocyclic, bicyclic or tricyclic 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 Is independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halo C ₁ -C ₃ Alkoxy, halo C ₁ -C ₃ One, two or three groups of alkyl and hydroxy groups are substituted; 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, said ring optionally containing one additional heteroatom selected from nitrogen, oxygen and sulfur, wherein said ring is optionally 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 One, two or three groups of alkyl and oxo groups are substituted; 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 certain aspects, n is zero. In other aspects, n is 1, 2, 3, or 4. In one aspect, n is 1. In another aspect, n is 2. In another aspect, n is 3. And in another aspect, n is 4.

In some aspects, R ⁴ Selected from:

in some aspects, R ⁴ Selected from:

and is also provided with

R ⁶ Is a five to ten membered monocyclic, bicyclic or tricyclic 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 substituted with one or more nitrogen atoms The rings are optionally independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halo C ₁ -C ₃ Alkoxy, halo C ₁ -C ₃ One, two or three groups of alkyl and hydroxy groups are substituted.

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

In some aspects, R ⁵ Selected from:

wherein each ring is optionally independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halo C ₁ -C ₃ 1 or 2 groups of alkyl and hydroxy groups.

In some aspects, R ⁵ Is that

Wherein p is 0, 1 or 2; and wherein each R ^x Independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halo C ₁ -C ₃ Alkyl and hydroxy.

In some aspects, 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.

In some aspects, R ⁵ Is that

Wherein q and r are each independently 0 or 1; 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; and wherein R is ^z Is hydrogen or fluorine.

In some aspects, R ⁵ Is that

Wherein s is 0 or 1; and wherein R is ^x Selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halo C ₁ -C ₃ Alkyl and hydroxy.

In some aspects R ⁵ Is that

In some aspects, 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.

In some aspects, R ⁵ Is that

In some aspects, R ¹ Is naphthyl, wherein said naphthyl is substituted with hydroxy and optionally with a member selected from C ₁ -C ₃ Alkyl, C ₂ -C ₄ One or two additional groups of alkynyl and halo are further substituted.

In some aspects, R ¹ Is that

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 of

Indicating the point of attachment to the parent molecular moiety.

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.

In some 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 the method comprises the steps ofRepresenting an attachment point to the parent molecular moiety;

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; and is also provided with

R ⁵ Selected from:

wherein->Representing the point of attachment to the parent molecular moiety

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

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 R is ^a Is hydrogen or C ₁ -C ₃ An alkyl group; and->Indicating the point of attachment to the parent molecular moiety.

In some aspects, R ⁴ Is thatWherein 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), (II), or (IIa), 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), (II), or (IIa), 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;

n is 0, 1, 2, 3 or 4;

each R ^b Independently selected fromC ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, halo, and hydroxy; or alternatively, two gem R ^b The groups together with the carbon atom to which they are attached are capable of forming a 3 to 6 membered cycloalkyl ring; and is also provided with

Representing an attachment point to the parent molecular moiety;

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

a five to ten membered monocyclic, bicyclic or tricyclic 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 rings are optionally independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halo C ₁ -C ₃ Alkoxy, halo C ₁ -C ₃ One, two or three groups of alkyl and hydroxy groups are substituted; wherein the method comprises the steps of

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 AlkoxycarbonylGroup C ₁ -C ₃ An alkylcarbonyl group. In certain aspects, n is zero. In other aspects, n is 1, 2, 3, or 4. In one aspect, n is 1. In another aspect, n is 2. In another aspect, n is 3. And in another aspect, n is 4.

In some aspects of the method, R ⁴ Selected from the group consisting of

In some aspects of the method, R ⁴ Selected from:

and is also provided with

R ⁶ Is a five to ten membered monocyclic, bicyclic or tricyclic 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 rings are optionally independently selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halo C ₁ -C ₃ Alkoxy, halo C ₁ -C ₃ One, two or three groups of alkyl and hydroxy groups are substituted.

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

In some aspects of the method, R ⁵ Selected from:

In some aspects of the method, R ⁵ Is that

At the position ofIn some aspects of the method, R ⁵ Is that

In some aspects of the method, R ⁵ Is that

In some aspects of the method, R ¹ Is naphthyl, wherein said naphthyl is substituted with hydroxy and optionally with a member selected from C ₁ -C ₃ Alkyl, C ₂ -C ₄ One or two additional groups of alkynyl and halo are further substituted.

In some aspects of the method, R ¹ Is that

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 the method comprises the steps of

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 the method comprises the steps of

Indicating the point of attachment to the parent molecular moiety.

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

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

In another aspect, the present disclosure provides a compound of formula (I), formula (II), or formula (IIa), 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 (IIa), 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 (IIa), 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 (IIa), 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 (IIa), 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 some aspects, 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

4- (6-chloro-4- {3, 9-diazabicyclo [4.2.1] non-9-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol;

4- (6-chloro-4- {1, 4-diazabicyclo [3.2.2] non-4-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol;

6- (6-chloro-4- {3, 9-diazabicyclo [4.2.1] 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 [3.2.2] non-3-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (2- { [ (4 as,7 ar) -1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-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- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-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- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-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- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- { 6-chloro-4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoro-2- { [ (2S, 4R) -4-methoxy-1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl } -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (2- { [ (2 s,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- (2- { [ (2 s,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine isomer 1;

6- (2- { [ (2 s,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine isomer 2;

4- { 6-chloro-4- [ (1S, 6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl } naphthalen-2-ol;

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) naphthalen-2-ol;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-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 } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-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- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol isomer 2;

4- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol;

4- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol isomer 1;

4- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol isomer 2;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-fluoronaphthalen-2-ol;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-fluoronaphthalen-2-ol isomer 1;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-fluoronaphthalen-2-ol isomer 2;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) naphthalen-2-ol;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) naphthalen-2-ol isomer 1;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) naphthalen-2-ol isomer 2;

4- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) naphthalen-2-ol;

4- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) naphthalen-2-ol isomer 1;

4- (2- { [ (2 s,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) naphthalen-2-ol isomer 2;

4- (2- { [ (4 as,7 ar) -1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl ] methoxy } -4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) naphthalen-2-ol;

4- (2- { [ (4 as,7 ar) -1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl ] methoxy } -4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-fluoronaphthalen-2-ol;

4- (2- { [ (4 as,7 ar) -1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl ] methoxy } -4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol;

4- (2- { [ (4 as,7 ar) -1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl ] methoxy } -4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;

6- { 6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -2- ({ 1- [ (dimethylamino) methyl ] cyclopropyl } methoxy) -8-fluoroquinazolin-7-yl } -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- { 6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-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- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-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- [ (1 s, 6R) -3, 9-diazabicyclo [4.2.1] non-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- (2- { [ (2 s,7 as) -2- (difluoromethoxy) -hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- { 6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-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- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-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- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoro-2- ({ 1- [ (4-fluoropiperidin-1-yl) methyl ] cyclopropyl } methoxy) quinazolin-7-yl } -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

4- {4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -2- ({ 1- [ (dimethylamino) methyl ] cyclopropyl } methoxy) -8-fluoroquinazolin-7-yl } -5-ethynyl-6-fluoronaphthalen-2-ol;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-fluoronaphthalen-2-ol;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -4- [ (1 r,6 s) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-fluoronaphthalen-2-ol;

4- {4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoro-2- { [1- ({ 3-oxa-8-azabicyclo [3.2.1] oct-8-yl } methyl) cyclopropyl ] methoxy } quinazolin-7-yl } -5-ethylnaphthalen-2-ol;

1- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -8-fluoroisoquinolin-3-amine;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-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- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;

4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) naphthalen-2-ol;

2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -7- (8-ethylnaphthalen-1-yl) -8-fluoroquinazoline;

6- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-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 } -4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

6- {4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -2- [ (2, 2-difluoro-hexahydro-1H-pyrrolizin-7 a-yl) methoxy ] -8-fluoroquinazolin-7-yl } -4-methyl-5- (trifluoromethyl) pyridin-2-amine; and

6- (2- { [ (6 ' r,7' ar) -6' -fluoro-hexahydrospiro [ cyclopropan-1, 2' -pyrrolizine ] -7' a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine;

or a pharmaceutically acceptable salt thereof.

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

In another aspect, the present disclosure provides a method of 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 foregoing aspects, or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure provides a method of treating cancer sensitive 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 foregoing aspects, or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure provides a method of 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 foregoing 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 of the term "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 Alkoxycarbonyl "refers to C attached to the parent molecular moiety through the carbonyl 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 "means derived from a straight chain containing one to three carbon atoms Or a group of a branched saturated hydrocarbon.

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 group 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 Alkoxy "refers to a halogenated C attached to the parent molecular moiety through an oxygen atom ₁ -C ₃ An alkyl group.

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: a bicyclic ring system wherein 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. The heteroaryl is 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.

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 atropisomers. The term "atropisomers" refers to conformational stereoisomers that occur when rotation around a single bond in a molecule is prevented or greatly slowed down by steric interactions with other parts of the molecule and substituents at both ends of the single bond are asymmetric (i.e., an asymmetric carbon center or stereocenter is not required for an increase in optical activity). In case the rotation barrier around a single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of the isomeric species may be allowed. Atropisomers are enantiomers (or epimers) that do not exist in a single asymmetric atom.

An atropisomer may be considered stable if the interconversion barrier is high enough to allow the atropisomer to undergo little or no interconversion at room temperature for at least one week. In some aspects, the atropisomers undergo little or no interconversion at room temperature for at least one year. In some aspects, when the atropisomer compounds of the present disclosure are in a substantially pure form (which is typically a solid state), the atropisomer compounds do not undergo more than about 5% interconversion of their relative atropisomers at room temperature during one week. In some aspects, a atropisomer compound of the present disclosure does not undergo more than about 5% interconversion of its opposite atropisomer at room temperature (about 25 ℃) over a period of one year. In some aspects, the atropisomer compounds of the present disclosure are stable enough to undergo no more than about 5% interconversion in an aqueous pharmaceutical formulation maintained 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, optically pure forms of single atropisomers, and intermediate mixtures.

The thermal racemization energy barrier of the atropisomers may 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. Optical and thermal excitation can promote racemization of such isomers, depending on electronic and spatial factors.

Ortho-substituted biaryl compounds may exhibit this type of conformational rotamers. Such biaryl groups are enantiomers of chiral atropisomers in which sp is between the 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 bring the planar conformation to the energy maximum. When the interconversion of the two non-planar, axial chiral enantiomers is slow enough that they can be freely separated from each other, then they exist as atropisomers. The bold and dashed lines in the diagrams shown above indicate those parts or molecular parts that are spatially constrained due to the rotational energy barrier. The bold line portion exists orthogonally above the page plane and the dashed line portion exists orthogonally below the page plane. The "planar" portion of the molecule (the left ring of the two biaryl groups depicted) 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)). The salts may be obtained during the final isolation and purification of the compounds described herein, either by reacting the free base functionality of the compounds with a suitable acid alone, or by reacting the acid groups of the compounds with a suitable base. Acid addition salts include salts derived from non-toxic inorganic acids (e.g., hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, and the like) and from non-toxic organic acids (e.g., 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 (e.g., sodium, potassium, magnesium, calcium, etc.) and from non-toxic organic amines (e.g., 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 on 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 drying under reduced pressure 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 must generally be sterile and stable under the conditions of manufacture and storage. The composition may be formulated as a solution or as a liquid of 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 is desirable to include isotonic agents, for example, sugars, polyalcohols (e.g., 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 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. editors, 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, the compounds of the present disclosure may be administered parenterally, i.e., by injection, including, without limitation, 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.

Methods of use/treatment of KRAS inhibitors

Administration of the therapeutic agents described herein may include 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, the amount of a therapeutic agent for treating a disorder treatable by administration of 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, more typically 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 significantly 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 administering 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 compounds disclosed herein 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 all subtypes of hodgkin's lymphoma or 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 a putative KRAS mutant protein. The sequence of wild-type human KRAS proteins is known in the art.

Methods for detecting KRAS mutations are well 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 analysis. In some aspects, the samples are evaluated for KRAS mutation, including by real-time PCR. In real-time PCR, a specific fluorescent probe for KRAS mutation is 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 well known to those skilled 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 protein, protein electrophoresis and western blotting, and direct peptide sequencing.

The method of determining whether a tumor or cancer comprises a KRAS mutation may use various 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 treating cancer, such as acute myeloid leukemia, juvenile cancer, childhood adrenocortical cancer, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendicular cancer, astrocytoma, atypical teratoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, burkitt's lymphoma, carcinoid tumor, atypical teratoid tumor, embryonoma, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngeal tumor, skin T cell lymphoma, extrahepatic Duct Carcinoma In Situ (DCIS), embryonoma, central nervous system cancer endometrial cancer, ependymoma, esophageal cancer, nasal glioma, ewing's 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, 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 mouth cancer, liver cancer, lobular Carcinoma In Situ (LCIS), lung cancer, lymphoma, occult primary metastatic squamous neck cancer, central harness cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, bone malignant fibrous histiocytoma and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-hodgkin 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 and pulmonary blastoma, primary Central Nervous System (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T cell lymphoma, testicular cancer, thymoma and thymus cancer, thyroid cancer, renal pelvis and transitional cell carcinoma, cell tumor, childhood cancer, cancer of the vulva, cancer of the uterus, cancer of the vagina, cancer of the uterus, or cancer induced viruses. In some aspects, the methods relate to treating non-cancerous proliferative disorders, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign Prostatic Hypertrophy (BPH)).

In certain aspects, the disclosure relates to methods of treating lung cancer, comprising administering to a subject in need thereof an effective amount of any of the foregoing compounds (or pharmaceutical compositions comprising the compounds). 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 some aspects, the lung cancer is small cell lung cancer. Other lung cancers treatable by the disclosed compounds include, but are not limited to, adenocarcinomas, carcinoids, and undifferentiated carcinomas. 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 diagnosed with: an acute leukemia of the myeloid family, adolescent cancer, childhood adrenocortical cancer, AIDS-related cancers (e.g., lymphoma and kaposi's sarcoma), anal cancer, appendicular cancer, astrocytomas, atypical teratoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchogenic tumor, burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic Lymphoblastic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngeal tumor, skin T cell lymphoma, extrahepatic Duct Carcinoma (DCIS), embryonal tumor, central nervous system cancer, endometrial cancer, ependymal tumor, esophageal cancer, primary lymphoma, cervical cancer, cardiac tumor, chronic Lymphocytic Leukemia (CLL) nasal glioma, ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, bone fibrocytoma, gall bladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, trophoblastoma, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin's lymphoma, hypopharynx cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and mouth cancer, liver cancer, lobular Carcinoma In Situ (LCIS), lung cancer, lymphoma, occult primary metastatic squamous neck cancer, midline bundle cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, 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 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) (gastch) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymus cancer, thyroid cancer, renal pelvis and ureter cancer, trophoblastoma, childhood cancer, uterine sarcoma, vaginal cancer, vulval cancer or virus-induced cancer. In some aspects, subjects treated with compounds of the present disclosure include subjects diagnosed with: noncancerous proliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign Prostatic Hypertrophy (BPH)). The present disclosure further provides methods of modulating the activity of a mutant KRAS protein by contacting the 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 in solution with an effective amount of a compound of the present disclosure. In some aspects, the disclosure provides methods of inhibiting the activity of a mutant KRAS protein by contacting a cell, tissue, organ expressing the 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 exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the percentage of inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the disclosure provides methods of inhibiting KRAS activity in a cell by contacting the cell with a compound of the disclosure in an amount sufficient to inhibit KRAS mutant activity 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 mutant KRAS activity 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 KRAS activity 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 KRAS activity in the animal. In some aspects, the present disclosure provides methods of inhibiting KRAS included in a mammal by contacting the mammal with a compound of the present disclosure in an amount sufficient to inhibit KRAS activity 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 of the compound. 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.

A variety of 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: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors and anti-androgens. In some aspects, the chemotherapeutic agent is an Immunooncology (IO) agent that may enhance, stimulate, or up-regulate the immune system.

Depending on the condition being treated, the compounds described herein may be used in combination with the agents disclosed herein or other suitable agents. 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 may be formulated together with any of the agents described above into the same dosage form and administered simultaneously. Alternatively, the compounds of the present disclosure may be administered simultaneously with any of the agents described above, wherein both agents are present in separate formulations. In another alternative, any of the agents described above may be administered immediately after administration of the compounds of the present disclosure, and vice versa. In some aspects of the separate administration regimen, the administration of the compounds of the present disclosure and any of the agents described above is separated by a few minutes, or by a few hours, or by a few days.

The compounds may be prepared by methods known in the art, including those described below and including variations within the skill in 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, compound A (CAS 1698028-11-3) is known to react with an amine in a suitable solvent (e.g., THF) with a base (e.g., diisopropylethylamine) to provide compound B. In step 2, compound B is treated with potassium fluoride in a solvent (e.g., dimethylacetamide) to provide compound C. In step 3, compound C is coupled with an arylboronic acid or ester under suzuki conditions to provide compound D. In step 4, compound D is treated with ROH in a solvent (e.g., 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 in a solvent (e.g., methylene chloride) using a coupling agent (e.g., BOP) in the presence of a base 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 and the like can be introduced and removed as desired by one skilled in the art and are described in the examples. Functionalization and elaboration 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:

example 1-1

4- (6-chloro-4- {3, 9-diazabicyclo [4.2.1] non-9-yl } -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl) naphthalen-2-ol

Preparation of intermediate 1A: 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 was stirred at 25℃for 2h. The mixture was then 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 1B: (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 inorganic phase was extracted with DCM (50 mL. Times.2). The combined DCM extracts were washed with brineWashed and dried (Na ₂ SO ₄ ) Filtered and then concentrated. The residue was purified on a 40g silica gel column eluting with 0-10% meoh in DCM (containing 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 1C: 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 microwaves 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 of silica eluting with 0-10% meoh in DCM (containing 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 1D: 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 vacuum. The residue was purified by flash chromatography on silica gel eluting with 0-10% meoh/DCM (containing 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 1E: 9- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] nonane-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, 9-diazabicyclo [ 4.2.1)]To a mixture of nonane-3-carboxylic acid tert-butyl ester (5.98 mg,0.026 mmol) and DIEA (11.54. Mu.L, 0.066 mmol) in DCM (2 mL) was added BOP (12.18 mg,0.028 mmol) and the reaction was stirred at room temperature for 16h. The reaction was treated with 4mL of NaHCO ₃ The aqueous solution was quenched and extracted with DCM (5 ml x 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried, filtered 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 mixture was concentrated and the residue was purified on 4g of silica eluting with 0-10% meoh/DCM (containing 0.5% tea) to provide 1E (12 mg,0.018mmol,82% yield). MS (ESI) m/z 662.7[ M+H ]] ⁺ 。

Preparation of example 1-1: 4- (4- (3, 9-diazabicyclo [4.2.1] non-9-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) naphthalen-2-ol

9- (6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1 ] with 1mL of 30% TFA/DCM at room temperature]Tert-butyl nonane-3-carboxylate (12 mg,0.018 mmol) was treated for 30min. The reaction mixture was then concentrated. The crude material was purified via preparative HPLC with the following conditions: column: XBIdge C18, 200mm x 19mm,5 μm particles; mobile phase a:5:95 acetonitrile: water (containing ammonium acetate); mobile phase B:95:5 acetonitrile: water (containing ammonium acetate); gradient: hold at 14% b for 0min, over 20 min 14-54% b, then at 100% b for 0 min; flow rate: 20mL/min; column temperature: 25C. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was purified via preparative HPLC using the following conditions: column: XBIdge C18, 200mm x 19mm,5 μm particles; mobile phase a:5:95 acetonitrile: water (containing 0.05% trifluoroacetic acid); mobile phase B:95:5 acetonitrile in water (containing 0.05% trifluoroacetic acid); gradient: hold at 2% b for 0min, over 20 min 2-42% b, then at 100% b for 0 min; flow rate: 20mL/min; column temperature: 25C. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford example 1-1 (1.3 mg,1.6 μmol,9.1% yield). MS (ESI) m/z 562.2[ M+1 ] ] ⁺ ； ¹ H NMR(500MHz,DMSO-d ₆ )δ8.28-7.93(m,1H),7.83-7.61(m,1H),7.54-7.35(m,1H),7.27-7.18(m,2H),7.11-6.93(m,2H),5.49-5.11(m,1H),4.79-4.47(m,2H),4.29-4.06(m,1H),3.23-3.09(m,1H),2.98-2.76(m,2H),2.72(s,3H),2.65-2.56(m,1H),2.33-2.08(m,2H),2.01-0.67(m,11H)。

The examples in Table 1 were prepared from the appropriate starting materials according to the procedure described in example 1-1.

TABLE 1

Example 2-1

6- (6-chloro-4- {3, 9-diazabicyclo [4.2.1] non-3-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-bromo-N, N-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. The reaction was treated with saturated NH ₄ Cl (20 mL) was quenched and extracted with ethyl acetate (20 mL. Times.3). The combined organic layers were 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 2B: (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) boronic acid

To 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) and (1, 1' -bis (diphenylphosphino) ferrocene) dichlorideTo a solution of palladium (II) (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 (268 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 2C: 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 then 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 2D: 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 chloride (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 2E: 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 was carried out for 12h. 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 2F: 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 2G: 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

A mixture of 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 (400 mg,0.4700 mmol), methyl 2, 2-difluoro-2-fluorosulfonyl-acetate (1345 mg,7 mmol) and CuI (267 mg,1.4 mmol) in DMA (10 mL) was reacted at 80℃at 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 ₂ Stirring was carried out at 80℃for a further 12 hours. The mixture was diluted with EtOAc (50 mL) and filtered. Filtering the filtrateWashed 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 2H: 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 then 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 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 (250 mg,0.28mmol,82.7% yield) as a white solid. MS (ESI) m/z 894.5[ M+1 ]] ⁺ . Preparation of intermediate 2I: 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. 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 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 2J: 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, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

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,0.0700 mmol) and 3, 9-diazabicyclo [ 4.2.1) ]To a solution of tert-butyl nonane-9-carboxylate (75 mg,0.3300 mmol) in DCM (1 mL) was added DIEA (0.07 mL,0.7800 mmol) and BOP (105 mg,0.4100 mmol). The mixture was stirred at 25℃for 12 hours. The reaction mixture was diluted with water (20 mL) and then with dichloroMethane extraction (15 ml x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA as additive, apparatus: ACSWH-GX-N; column: phenomenex Synergi C: 150x 25mm x10 um; mobile phase: A is H) ₂ O (0.1% tfa) and B is acetonitrile; gradient: b56% -86% changing linearly within 10 min; flow rate: 25mL/min; column temperature: room temperature; wavelength: 220nm.254 nm) to give the desired 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, 9-diazabicyclo [4.2.1] as a yellow solid]Nonane-9-carboxylic acid tert-butyl ester (40 mg,0.043 mmol). MS (ESI) m/z 934.7[ M+H ]] ⁺ 。

Example 2-1

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, 6-diazabicyclo [3.2.2]A solution of tert-butyl nonane-6-carboxylate (45 mg,0.05 mmol) in TFA (4.mL, 52.24 mmol) was stirred at 50℃for 4 hours. 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, 150x 25mm,10um; mobile phase: A is H) ₂ O (0.225% FA) and B is acetonitrile; gradient: b3% -33% changing linearly within 10 min; flow rate: 25mL/m; column temperature: room temperature; wavelength: 220nm.254 nm) to give the desired product 6- (4- (3, 6-diazabicyclo [ 3.2.2) as a yellow solid]Non-3-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (17.98 mg,0.028 mmol). MS (ESI) m/z 594.2[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD)δ8.51(s,2H),7.93(s,1H),6.62(s,1H),4.76-4.69(m,1H),4.66-4.58(m,1H),4.54-4.42(m,1H),4.13-3.98(m,2H),3.97-3.88(m,1H),3.65-3.50(m,4H),3.49-3.43(m,1H),3.05-2.97(m,1H),2.92(s,3H),2.55-2.48(m,1H),2.45(s,3H),2.36-2.27(m,1H),2.13-2.05(m,3H),2.04-1.97(m,2H),1.94-1.81(m,2H)。

The examples in Table 2 were prepared from the appropriate starting materials according to the procedure described in example 2-1.

TABLE 2

Example 3

6- (2- { [ (4 aS,7 aR) -1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl ] methoxy } -6-chloro-4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 3A: octahydro-4 aH-cyclopenta [ b ] pyridine-4 a-carboxylic acid ethyl ester

Intermediate 3A was prepared according to the procedure in compound 25a of Molecules 2017,22,827.

Preparation of intermediate 3B: 1-benzyl 4 a-ethyl (4 aS,7 aR) -hexahydro-1H-cyclopenta [ b ] pyridine-1, 4a (2H) -dicarboxylic acid ester

To octahydro-4 aH-cyclopenta [ b ]]To a solution of pyridine-4 a-carboxylic acid ethyl ester (1.7 g,8.62 mmol) and TEA (2.40 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 temperatureMix for 18 hours. The mixture was then 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-cyclopenta [ 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) underwent SFC chiral separation [ column: cellulose-4 (5×25cm,5 μm), method=CO ₂ IPA heptane (1:3), containing 0.1% ammonium hydroxide, 320mL/min]To give 1-benzyl-4 a-ethyl (4 aS,7 aR) -hexahydro-1H-cyclopenta [ 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, 2.1X50 mm,1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 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)

Preparation of intermediate 8C: (4 aS,7 aR) -octahydro-4 aH-cyclopenta [ b ] pyridine-4 a-carboxylic acid ethyl ester

1-benzyl 4 a-ethyl (4 aS,7 aR) -hexahydro-1H-cyclopenta [ b ]]A mixture of pyridine-1, 4a (2H) -dicarboxylic acid ester (640 mg,1.931 mmol) and 10% Pd-C (103 mg,0.097 mmol) in MeOH (10 mL) was hydrogenated at 1 atmosphere 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(499MHz,CDCl ₃ )δ4.17(dtt,J＝10.6,7.1,3.6Hz,2H),3.57(t,J＝6.1Hz,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＝7.1Hz,3H)。

Preparation of intermediate 3D: (4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenta [ b ] pyridine-4 a-carboxylic acid ethyl ester

To (4 aS,7 aR) -octahydro-4 aH-cyclopenta [ b ]]Pyridine-4 a-carboxylic acid ethyl ester (385 mg,1.952 mmol) and 37wt.% formaldehyde H ₂ To a solution of 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 h. The mixture was then concentrated. The residue 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 give crude (4 as,7 ar) -1-methyl octahydro-4 aH-cyclopenta [ b ]]Pyridine-4 a-carboxylic acid ethyl ester (380 mg,1.798mmol,92% yield). ¹ H NMR(499MHz,CDCl ₃ )δ4.24-4.12(m,2H),3.29(t,J＝6.4Hz,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 3E: ((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenta [ b ] pyridin-4 a-yl) methanol

To (4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenta [ 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 solution of lithium aluminum hydride (1.0M 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 then added to the mixture. The reaction mixture was filtered and the filtrate was concentrated to give 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)。

preparation of intermediate 3F: 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. The mixture was then 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 3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] as a white solid]Tert-butyl octane-8-carboxylate (418 mg,0.82mmol,90% yield). 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 3G: 3- (7-bromo-6-chloro-2, 8-difluoroquinazolin-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 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). The mixture 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 the mixture was stirred for 15min. Water to be separatedThe layers were extracted with ethyl acetate (2X 100 mL) and the combined organic layers were dried 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 provide 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 3H: 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 3G in anhydrous 1, 4-dioxane (20 mL) (2.00G, 4.08 mmol) was added potassium phosphate (1.73G, 8.17 mmol), N-bis (4-methoxybenzyl) -4-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (5.8G, 12.25 mmol) and PdCl ₂ (dppf) (149 mg,0.204 mmol). The mixture was degassed again and heated at 80 ℃ for 48h. The reaction vessel was then allowed to cool to ambient temperature, diluted with ethyl acetate (40 mL), and passed throughThe bed was filtered 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 3I: 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

To 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) -6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] at 0℃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 solid ]Tert-butyl octane-8-carboxylate (1.42 g,1.560mmol,84% yield). LCMS (ESI) m/z 883.3[ M+H ]] ⁺ 。

Preparation of intermediate 3J: 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

To 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]A stirred solution of tert-butyl octane-8-carboxylate (1.40 g,1.585 mmol) in anhydrous DMA (10 mL)Copper (I) iodide (0.60 g,3.17 mmol) was added thereto. The reaction mixture was degassed for 10 min, 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 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 obtain a crude residue. The crude material 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 ):δ7.77(s,1H),7.16(d,J＝8.8Hz,4H),6.87(dt,J＝9.6and 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] ⁺ 。

Intermediate 3K and 3L:3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2, 8-

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

Example 3J (5.0 g,6.06 mmol) was separated by SFC (column: chiralpak IH (250 mm x 4.6x 5 u), mobile phase-0.25% isopropyl alcohol) into the single atropisomer, with peak 1 eluting at retention time = 5.85 minutes (2.4 g,2.90mmol,40% yield) and peak 2 eluting at retention time = 9.53 minutes (2.4 g,2.90mmol,40% yield).

Peak 1 (3K): 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: (3L) 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 ]] ⁺ 。[α] ^23.3 (MeOH＝0.10)＝-110.00。

Preparation of intermediate 3M: 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

To intermediate 3L and ((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenta [ b ] at room temperature under nitrogen]To a solution of pyridin-4 a-yl) methanol (41.0 mg,0.242 mmol) in anhydrous THF (1.0 mL) was added a solution of 1.0M LiHMDS in THF (364 μl,0.364 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with DMF (1 mL) and the crude product was purified by preparative HPLC (Phenomenex, luna 5 microns, 30x 250mm, flow rate = 30mL/min, gradient = 20% a to 100% b within 30min ₂ O/ACN/TFA(90:10:0.1)，B＝H ₂ O/ACN/TFA (10:90:0.1)) to give 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 (267 mg,0.233mmol,96% yield). LCMS (ESI) m/z 974.5[ M+H ]] ⁺ LC retention time: 1.13min (Waters Acquity UPLC BEH C, 2.1X50 mm,1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 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)).

Preparation of intermediate 3N: 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-ol

1.0M sodium hydroxide (2453. Mu.l, 2.453 mmol) and 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 (267 mg,0.245 mmol) in EtOH (20 mL) was stirred at 65deg.C for 3 days. The mixture was then concentrated to remove EtOH. The mixture was extracted with EtOAc (2×15 ml) and the ethyl acetate layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (Phenomenex, luna 5 microns 30x 250mm, flow = 30mL/min, gradient = 20% a to 100% b within 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 combined and concentrated. The pure product was then diluted with EtOAc (15 mL) and washed with saturated aqueous sodium carbonate (2×15 mL). The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated to give 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) as a tan solid ]Pyridin-4 a-yl) methoxy) quinazolin-4-ol (60 mg,0.077mmol,31.4% yield). LCMS (ESI) m/z 780.3[ M+H ]] ⁺ LC retention time: 1.04min (Waters Acquity UPLC BEH C, 2.1X50 mm,1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 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)).

Preparation of example 3: 6- (2- { [ (4 aS,7 aR) -1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl ] methoxy } -6-chloro-4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -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- (((4 as,7 ar) -1-methyl octahydro-4 aH-cyclopenta [ b)]Pyridin-4 a-yl) methoxy) quinazolin-4-ol (25 mg,0.032 mmol), (1S, 6R) -3, 9-diazabicyclo [4.2.1]To a solution of nonane-9-carboxylic acid tert-butyl ester (10.88 mg,0.048 mmol) and BOP (21.26 mg,0.048 mmol) in DCM (1.0 mL) was added DIEA (16.79 μl,0.096 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 microns 30x 250mm, flow = 30mL/min, gradient = 20% a to 100% b within 30min, a = H ₂ O/ACN/TFA(90:10:0.1)，B＝H ₂ O/ACN/TFA (10:90:0.1)) to afford (1S, 6R) -3- (7- (6-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, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester. (1S, 6R) -3- (7- (6-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, 9-diazabicyclo [4.2.1]A mixture of nonane-9-carboxylic acid tert-butyl ester in water (1 drop), triethylsilane (1 drop) and TFA (1.5 mL) was stirred at 40℃for 18 hours. The mixture was then concentrated. The crude product was purified by preparative HPLC (Phenomenex, luna 5 microns 30x 250mm, flow = 30mL/min, gradient = 20% a to 100% b within 30min, a = H ₂ O/ACN/TFA(90:10:0.1)，B＝H ₂ O/ACN/TFA (10:90:0.1)). The pure fraction was loaded onto an Oasis MCX cation mixed mode polymer cartridge (150 mg) and the cartridge was washed with methanol (30 mL) and the product eluted with 0.1N ammonia in methanol (5.0 mL). The ammonia eluent was concentrated. The obtained product is treated with ACN/H ₂ O (1:1, 5 mL) was lyophilized to give 4 6- (4- ((1S, 6R) -3, 9-diazabicyclo [ 4.2.1) as a white powder ]Non-3-yl) -6-chloro-8-fluoro-2-((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenta [ b ]]Pyridin-4 a-yl) methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (10.96 mg,0.016mmol,50.1% yield). LCMS (ESI) m/z 648.2[ M+H ]] ⁺ LC retention time: 1.27min ((Waters Acquity UPLC BEH C, 2.1X 50mm,1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 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, methanol-d) ₄ )δ7.96(d,J＝1.5Hz,1H),6.62(s,1H),4.55-4.47(m,2H),4.27(d,J＝10.7Hz,1H),4.05-3.91(m,2H),3.84-3.77(m,2H),3.68(dd,J＝13.5,3.9Hz,1H),2.87(br s,1H),2.73-2.64(m,1H),2.47(d,J＝1.2Hz,3H),2.44-2.35(m,1H),2.33(s,3H),2.29-2.18(m,1H),2.13-1.92(m,4H),1.91-1.82(m,2H),1.81-1.64(m,8H),1.63-1.54(m,1H)。

Example 4-1

6- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1]

Non-3-yl ] -8-fluoroquinazolin-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- (((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-pyrrolizin-7 a (5H) -yl) methanol and HCl (81 mg,0.509 mmol) in DCM was added sodium carbonate (231 mg,2.181 mmol) and the reaction mixture was sonicated for 10min then stirred at room temperature for 30min. The solvent was decanted and concentrated under reduced pressure to obtain ((2R) as the free base 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol. The crude residue obtained was dissolved in anhydrous THF (5 mL) and cooled to 0 ℃, followed by the addition of sodium hydride (60% in mineral oil, 12.21mg,0.509 mmol). The reaction mixture was stirred at the same temperature for 30min, then intermediate 3L (280 mg,0.339 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (2 x 20 mL) using ice-cooling. The combined organic layers were washed with water, then brine solution, over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (Grace50g snap, dry fill) was purified on neutral alumina using 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 s,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 (240 mg,0.241mmol,71% yield). LCMS (ESI) m/z 965.8[ M+H ] ] ⁺ 。

Preparation of intermediate 4B: 7- (5- (bis (4-methoxybenzyl) amino) -3-methyl-2- (trifluoromethyl) phenyl) -6-chloro-8-fluoro

-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-ol.

To 3- (7- (5- (bis (4-methoxybenzyl) amino) -3-methyl-2- (trifluoromethyl) phenyl) -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]To a stirred solution of tert-butyl octane-8-carboxylate (240 mg, 0.247 mmol) in ethanol (5 mL) was added NaOH (1M aqueous solution, 199mg,0.498 mmol) and the mixture was heated at 70 ℃48h. The reaction mixture was then concentrated under reduced pressure to obtain a crude residue, which was purified by column chromatography (Biotage, neutral alumina) using 30-40% ethyl acetate in petroleum ether to obtain 7- (5- (bis (4-methoxybenzyl) amino) -3-methyl-2- (trifluoromethyl) phenyl) -6-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-ol (60 mg,0.077mmol,31% yield) as an off-white solid. LCMS (ESI) m/z 771.2[ M+H ]] ⁺ 。

Preparation of intermediate 4C: (1S, 6R) -3- (4-methoxybenzyl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

To 3, 9-diazabicyclo [4.2.1 ]]To a stirred solution of nonane-9-carboxylic acid tert-butyl ester (4.5 g,19.88 mmol) and 4-methoxybenzaldehyde (3.25 g,23.86 mmol) in DCE (50 mL) was added DIPEA (17.36 mL,99 mmol) and the reaction mixture was stirred at 25℃for 15min, after which the reaction was cooled to 0 ℃. After 15min, sodium triacetoxyborohydride (12.64 g,59.7 mmol) was added in portions to the reaction while maintaining the temperature below 5 ℃. After addition, the reaction mixture was gradually warmed to 25 ℃ and stirred overnight. The reaction mixture was then quenched with saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with water and saturated brine solution, then with anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The crude compound was purified by chromatography on silica gel (60-120 mesh) eluting with 10-15% ethyl acetate/petroleum ether to give 3- (4-methoxybenzyl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester. The pure fraction was subjected to chiral SFC separation [ column: chiralpak ADH (250 x 4.6) mm 5 μ, method = 0.5% isopropylamine in meoh_10, run time = 5.00min.]To give (1R, 6S) -3- (4-methoxybenzyl) -3, 9-diazabicyclo [4.2.1 ] as a light brown oil ]Nonane-9-carboxylic acid tert-butyl ester (1.9 g,5.48mmol,28% yield) and (1S, 6R) -3- (4-methoxybenzyl) -3, 9-diaza as a light brown oilBicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (2 g,5.77mmol,29% yield). LCMS (ESI) m/z 347.2[ M+H] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ ,298K)δ7.31-7.19(m,2H),6.88(d,J＝8.6Hz,2H),5.78-5.71(m,1H),4.15-3.89(m,2H),3.73(s,3H),3.49(s,2H),2.78-2.60(m,1H),2.48-2.42(m,1H),2.40(d,J＝2.8Hz,1H),2.20-1.99(m,2H),1.96-1.55(m,4H),1.40(d,J＝1.6Hz,9H)ppm。

Preparation of intermediate 4D: (1S, 6R) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

To (1S, 6R) -3- (4-methoxybenzyl) -3, 9-diazabicyclo [4.2.1 at 25 ]]To a stirred solution of tert-butyl nonane-9-carboxylate (1500 mg,4.33 mmol) in EtOH (20 mL) was added Pd/C (921 mg,8.66 mmol). The resulting mixture was stirred at 25℃under a hydrogen atmosphere (1 atm) for 3h. The reaction mixture was then filtered through a celite pad and washed with ethanol, and the filtrate was concentrated under reduced pressure to obtain the crude compound. Purification of the crude residue by column chromatography (Biotage, neutral alumina) using MeOH in dichloromethane (10%) to give (1 s,6 r) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (700 mg and 71%). LCMS (ESI) m/z 227.1[ M+H ]] ⁺ 。

Preparation of intermediate 4E: (1 s,6 r) -3- (7- (5- (bis (4-methoxybenzyl) amino) -3-methyl-2- (trifluoromethyl) phenyl) -6-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-5-yl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester.

To a stirred solution of 7- (5- (bis (4-methoxybenzyl) amino) -3-methyl-2- (trifluoromethyl) phenyl) -6-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-ol (55 mg,0.072 mmol) in acetonitrile (2 mL) was added BOP (47.4 mg,0.107 mmol) andTEA (0.015 mL,0.107 mmol). After stirring for 5min, (1S, 6R) -3, 9-diazabicyclo [4.2.1 ] is added]Nonane-9-carboxylic acid tert-butyl ester (20.23 mg,0.089 mmol) and the mixture was stirred at 40℃for 16h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residue which was purified by column chromatography (Biotage, neutral alumina) using 30% -40% ethyl acetate in petroleum ether to afford (1 s,6 r) -3- (7- (5- (bis (4-methoxybenzyl) amino) -3-methyl-2- (trifluoromethyl) phenyl) -6-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-5-yl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (55 mg,0.052mmol,73% yield). LCMS (ESI) m/z 979.51[ M+H ] ] ⁺ 。

Example 4-1

To (1 s,6 r) -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, 9-diazabicyclo [4.2.1]To a stirred solution of tert-butyl nonane-9-carboxylate (55 mg,0.056 mmol) in TFA (1 mL) was added water (0.01 mL) and triethylsilane (0.898. Mu.L, 5.62. Mu. Mol). The reaction was allowed to stir at 40 ℃ for 16h. The reaction mixture was then concentrated under reduced pressure to obtain a crude residue which was purified by silica gel column chromatography using 5% -7% methanol in DCM to obtain 6- (4- ((1 s,6 r) -3, 9-diazabicyclo [ 4.2.1)]Non-3-yl) -6-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (16 mg,0.023mmol,41% yield))。LCMS(ESI)m/z:638.3[M+H] ⁺ 。 ¹ H-NMR(400MHz,MeOD):δ7.97(s,1H),6.62(s,1H),5.33(d,J＝54.00Hz,2H),4.50(d,J＝13.20Hz,1H),4.22-4.48(m,2H),4.01-4.03(m,1H),3.72-3.94(m,4H),3.24-3.33(m,2H),3.04-3.06(m,1H),2.47(s,3H),2.14-2.29(m,9H),1.98-2.02(m,1H),1.70-1.72(m,2H)ppm。

The examples in Table 3 were prepared from the appropriate starting materials according to the procedure described in example 4-1.

TABLE 3 Table 3

Example 5

6- (2- { [ (2S, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediates 5A (isomer 1) and 5B (isomer 2): 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

Copper (I) (21 g,24.50 mmol) was added to a stirred solution of 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 (21 g,24.50 mmol) in anhydrous DMA (210 mL) in a sealed tube under nitrogen atmosphere. The reaction mixture was degassed for 10min and then methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (21 g, 24.50)mmol) and the reaction mixture was heated at 90 ℃ for 12h. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (200 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3 x 50 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude residue which was purified by silica gel column chromatography using 30% ethyl acetate in petroleum ether to obtain 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 (15.1 g,16.44mmol,67% yield) as a pale yellow solid. The atropisomers were separated using SFC (column: chiralpak IH (250 mm x 4.6x5μ), mobile phase-25% isopropyl alcohol), with peak 1 (intermediate 5A) eluting at retention time = 6.00 minutes (0.73 g,0.98mmol,37% yield); LCMS (ESI) m/z 825.2[ M+H ] ] ⁺ And peak 2 (intermediate 5B) eluted at retention time = 9.262 min (0.77 g,0.97mmol, 38%); LCMS (ESI) m/z 825.2[ M+H ]] ⁺ 。

Preparation of intermediate 5C: 4- (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) piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of ((2 s,7 as) -2-fluorotetrahydro-1H-pyrrolazin-7 a (5H) -yl) methanol (100 mg,0.626 mmol) in THF (5 mL) at 0 ℃ was added sodium hydride (60% in mineral oil, 25.02mg,0.626 mmol) and the reaction mixture was stirred for 30min. Intermediate 5B (250 mg,0.313 mmol) in THF (5 mL) was added dropwise to the reaction mixture at 0 ℃ followed by stirring at ambient temperature for 2h. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water and brine, then over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. Product 4- (7- (6- (bis (4-methoxy)Benzyl) 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) piperazine-1-carboxylic acid tert-butyl ester (398 mg,0.246mmol,79% yield) was used in the next reaction without any further purification. LCMS (ESI) m/z 938.3[ M+H ] ] ⁺ . Preparation of intermediate 5D: 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-ol

To a stirred solution of tert-butyl 4- (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-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) carboxylate (390 mg,0.424 mmol) in EtOH (5 mL) and THF (1 mL) was added NaOH (1M aqueous solution, 1696mg,4.98 mmol). After stirring at 70 ℃ for 48H, the reaction mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by column chromatography (Biotage, neutral alumina) using 30% -40% ethyl acetate in petroleum ether to obtain 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-ol (150 mg,0.175mmol,41% yield) as a pale yellow oil. LCMS (ESI) m/z 770.2[ M+H ]] ⁺ 。

Preparation of intermediate 5E: (1 s,6 r) -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, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester.

To 7- (6- (bis (4-methoxybenzyl) amino) -4To a stirred solution of 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-ol (30 mg,0.039 mmol) in acetonitrile (1 mL) was added TEA (8.14 μl,0.058 mmol) and BOP (25.8 mg,0.058 mmol). After stirring for 5min, (1S, 6R) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (11.02 mg,0.049 mmol) was added to the reaction mixture and the mixture was heated at 40℃for 24h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound. The crude residue was purified by column chromatography (Biotage, neutral alumina) using 45% ethyl acetate in petroleum ether to give (1 s,6 r) -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, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (28 mg,0.027mmol,69% yield). LCMS (ESI) m/z 979.5[ M+H ] ] ⁺ 。

Example 5

6- (2- { [ (2S, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1]

To (1S, 6R) -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, 9-diazabicyclo [4.2.1]To a stirred solution of t-butyl nonane-9-carboxylate (28 mg,0.029 mmol) in TFA (1 mL) was added triethylsilane (0.457. Mu.L, 2.86. Mu. Mol) and water (0.05 mL,2.78 mmol). The reaction was allowed to stir at 40 ℃ for 16h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Biotage, sfar KP-amino) by 50 in petroleum etherElution with 100% ethyl acetate to obtain 6- (4- ((1S, 6R) -3, 9-diazabicyclo [ 4.2.1)]Non-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 (11.4 mg,0.018mmol,62% yield). LCMS (ESI) m/z 638.08[ M+H ]] ⁺ 。 ¹ H-NMR(400MHz,MeOD)δ7.97(d,J＝1.60Hz,1H),6.63(s,1H),5.37(d,J＝52.80Hz,1H),4.41-4.89(m,3H),4.02-4.13(m,1H),3.88-3.94(m,4H),3.49-3.50(m,2H),2.88-3.28(m,3H),2.50-2.16(m,1H),0.47(s,3H),2.19-2.47(m,1H),2.12-2.18(m,4H),1.91-2.02(m,3H),1.79-1.88(m,2H)ppm。

Example 6

4- { 6-chloro-4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoro-2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } quinazolin-7-yl } naphthalen-2-ol

Preparation of intermediate 6A (isomer 1) and 6B (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

To (1R, 5S) -3- (7-bromo-6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a degassed solution of tert-butyl octane-8-carboxylate (1.0 g,2.042 mmol)) in 1, 4-dioxane (60 mL) was added 2- (3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxapentaborane (1.28 g,4.08 mmol), cs ₂ CO ₃ (1.3g，4.08mmol)、Pd ₂ (dba) ₃ (93 mg,0.102 mmol) and pentacenyl (di-t-butylphosphino) ferrocene (0.073 g,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, which was purified by silica gel column chromatography using 30% acetic acid in petroleum etherPurification of ethyl ester 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]Octane-8-carboxylic acid tert-butyl ester (1.0 g,1.591mmol, 78%). LCMS (ESI) m/z 597.2[ M+H ]] ⁺ . The purified compound was subjected to SFC to separate the atropisomers (column: chiralpak ADH (250 mm x 4.6x5 μ), mobile phase-30% isopropanol)), with peak 1 (intermediate 6A) eluting at retention time = 2.72 minutes (230 mg, 46%); LCMS (ESI) m/z 597.2[ M+H ] ] ⁺ And peak 2 (intermediate 6B) eluted at retention time = 5.47 minutes (205 mg, 41%); LCMS (ESI) m/z 597.2[ M+H ]] ⁺ 。

Preparation of intermediate 6C: 3- (6-chloro-8-fluoro-7- (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 a stirred solution of (S) - (1-methylpyrrolidin-2-yl) methanol (38.6 mg,0.335 mmol) in THF (5 mL) at 0 ℃ was added NaH (60% dispersion in mineral oil, 12.06mg,0.301 mmol) and the reaction mixture was stirred for 30min, then intermediate 6A (100 mg, 0.67 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 2h, then quenched with saturated aqueous ammonium chloride (10 mL) followed by extraction with ethyl acetate (2×20 mL). The combined organic layers were washed with water and brine solution, then over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (Grace50g snap, dry fill) was purified on neutral alumina using 50-100% ethyl acetate in petroleum ether. The desired fractions were pooled and concentrated under reduced pressure to give 3- (6-chloro-8-fluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3,8 as a pale yellow oil Diazabicyclo [3.2.1 ]]Tert-butyl octane-8-carboxylate (90 mg,0.118mmol,71% yield). LCMS (ESI) m/z 691.8[ M+H ]] ⁺ . Preparation of intermediate 6D: 6-chloro-8-fluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-ol

To 3- (6-chloro-8-fluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) 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 ethanol (5 mL) was added NaOH (1M aqueous solution, 199mg,0.498 mmol). The reaction was allowed to stir at 70 ℃ for 48h. The reaction mixture was then concentrated under reduced pressure to give a crude residue which was purified by column chromatography (Biotage, neutral alumina) using 30% -40% ethyl acetate in petroleum ether to give 6-chloro-8-fluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-ol (35 mg,0.069mmol,40% yield) as an off-white solid. LCMS (ESI) m/z 500.1[ M+H ]] ⁺ 。

Preparation of intermediate 6E: (1S, 6R) -3- (6-chloro-8-fluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidine)

-2-yl) methoxy) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester.

To a stirred solution of 6-chloro-8-fluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-ol (35 mg,0.070 mmol) in acetonitrile (1 mL) was added TEA (0.015 mL,0.105 mmol) and BOP (46.6 mg,0.105 mmol). After stirring for 5min, (1S, 6R) -3, 9-diazabicyclo [4.2.1] is added]Nonane-9-carboxylic acid tert-butyl ester (19.88 mg,0.088 mmol) the reaction mixture was then heated at 40℃for 24h. The reaction mixture was quenched with water (10mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound. The residue was purified by column chromatography (Biotage, neutral alumina) using 40% ethyl acetate in petroleum ether to provide (1S, 6 r) -3- (6-chloro-8-fluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (30 mg,0.039mmol,56% yield). LCMS (ESI) m/z 707.2[ M+H] ⁺ 。

Example 6

To (1S, 6R) -3- (6-chloro-8-fluoro-7- (3- (methoxymethoxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] at ice-cold temperature]To a stirred solution of tert-butyl nonane-9-carboxylate (30 mg,0.042 mmol) in methanol (1 mL) was added HCl solution (4.0M in dioxane, 0.1598 mL,0.637 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, which was passed through a preparative HPLC [ column: xselect C18 (150 x 19) mm,5 microns, mobile phase A: 10mM ammonium acetate in water, phase B: acetonitrile]Purification to give 4- (4- ((1S, 6R) -3, 9-diazabicyclo [ 4.2.1)]Non-3-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) naphthalen-2-ol (4 mg,6.67 μmol,16% yield). LCMS (ESI) m/z 707.2[ M+H] ⁺ 。 ¹ H-NMR(400MHz,MeOD):δ8.11(d,J＝1.60Hz,1H),7.78(d,J＝8.40Hz,1H),7.42-7.46(m,1H),7.21-7.29(m,4H),7.05(s,1H),4.52-4.67(m,3H),3.93-4.00(m,5H),3.33-3.34(m,1H),2.83(s,4H),2.18-2.28(m,4H),2.00-2.04(m,3H),1.85-1.96(m,2H)ppm。

Example 7

4- (2- { [ (2R, 7 aR) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- [ (1S, 6R) -3, 9-diazabicyclo

[4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) naphthalen-2-ol

Preparation of intermediate 7A: 3- (6-chloro-8-fluoro-2- (((2R, 7 aR) -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 r,7 ar) -2-fluorotetrahydro-1H-pyrrolazin-7 a (5H) -yl) methanol (53.3 mg,0.335 mmol) in THF (5 mL) at 0 ℃ was added NaH (60% dispersion in mineral oil, 12.06mg,0.301 mmol) and the reaction mixture was stirred for 30min. Intermediate 6A (100 mg,0.167 mmol) in THF (1 mL) was then added dropwise. The reaction mixture was stirred at ambient temperature for 2h, then quenched with saturated aqueous ammonium chloride (10 mL) followed by extraction with ethyl acetate (2×20 mL). The combined organic layers were washed with water and brine solution, then over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (Grace50g snap, dry fill) was purified on neutral alumina using 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 r,7 ar) -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 yellow oil]Tert-butyl octane-8-carboxylate (120 mg,0.150mmol,90% yield). LCMS (ESI) m/z 735.8[ M+H ]] ⁺ 。

Preparation of intermediate 7B: 6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-ol

To 3- (6-chloro-8-fluoro-2- (((2 r,7 ar) -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 (230 mg,0.312 mmol) i in ethanol (5 mL) was added NaOH (1M aqueous solution, 1249mg,3.12 mmol). The reaction was allowed to stir at 70 ℃ for 48h. The reaction mixture was then concentrated under reduced pressure to obtain a crude residue, which was purified by column chromatography (Biotage, neutral alumina) using 30% -40% ethyl acetate in petroleum ether to obtain 6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-ol (35 mg,0.061mmol,19% yield) as an off-white solid. LCMS (ESI) m/z 542.2[ m+h] ⁺ 。

Preparation of intermediate 7C: synthesis of tert-butyl (1S, 6R) -3- (6-chloro-8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylate

To a stirred solution of 6-chloro-8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-ol (35 mg,0.065 mmol) in acetonitrile (1 mL) was added TEA (0.014 mL,0.097 mmol) and BOP (42.8 mg,0.097 mmol). After stirring for 5min, (1S, 6R) -3, 9-diazabicyclo [4.2.1] is added ]Nonane-9-carboxylic acid tert-butyl ester (18.27 mg,0.081 mmol) and the reaction mixture was heated at 40℃for 24h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sulfurThe sodium acid was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound. The residue was purified by column chromatography (Biotage, neutral alumina) using 30% -40% ethyl acetate in petroleum ether to provide (1 s,6 r) -3- (6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 9-diazabicyclo [ 4.2.1)]Nonane-9-carboxylic acid tert-butyl ester (38 mg,0.048mmol,75% yield). LCMS (ESI) m/z 751.2[ M+H ]] ⁺ 。

Example 7

4- (2- { [ (2 r,7 ar) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) naphthalen-2-ol

To (1S, 6R) -3- (6-chloro-8-fluoro-2- (((2R, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -7- (3- (methoxymethoxy) naphthalen-1-yl) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] at ice-cold temperature]To a stirred solution of tert-butyl nonane-9-carboxylate (30 mg,0.042 mmol) in methanol (1 mL) was added HCl (4.0M in dioxane, 0.1598 mL,0.637 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, which was passed through a preparative HPLC [ column: xselect C18 (150 x 19) mm,5 microns, mobile phase A: 10mM ammonium acetate in water, phase B: acetonitrile ]Purification to give 4- (4- ((1 s,6 r) -3, 9-diazabicyclo [ 4.2.1) as an off-white solid]Non-3-yl) -6-chloro-8-fluoro-2- (((2 r,7 ar) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-7-yl) naphthalen-2-ol (7 mg,0.01 μmol,35% yield). LCMS (ESI) m/z 562.3[ M+H ]] ⁺ 。 ¹ H-NMR(400MHz,MeOD):δ8.11(d,J＝1.60Hz,1H),7.78(d,J＝8.40Hz,1H),7.42-7.46(m,1H),7.21-7.29(m,4H),7.05(s,1H),4.52-4.67(m,3H),3.93-4.00(m,5H),3.33-3.34(m,1H),2.83(s,4H),2.18-2.28(m,4H),2.00-2.04(m,3H),1.85-1.96(m,2H)ppm。

Examples 8-1 and 8-2

4- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol

Preparation of intermediate 8A: 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 30min. Then, 3- (7-bromo-6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] is added]A solution of tert-butyl octane-8-carboxylate (500 mg,1.021 mmol) in THF (2 mL) and the mixture was 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 and brine, then 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 8B: 3- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-7- [ 8-ethyl-3- (methoxymethoxy) naphthalen-1-yl ] -8-fluoroquinazolin-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 (700 mg,1.113 mmol) in 1, 4-dioxane (5 mL) was added 2- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (457 mg,1.336 mmol) and tripotassium phosphate (1.5M in water) (1.284 mL,2.226 mmol). The reaction mixture was purged with nitrogen for 5 minutes, then charged with Pd (Ph ₃ P) ₄ (129 mg,0.111 mmol). The reaction mixture was again purged with nitrogen for 3 minutes and heated at 85 ℃ for 16h. The reaction mixture was cooled, filtered through a celite pad and the filtrate concentrated under reduced pressure to give the crude compound which was purified by silica gel chromatography using CombiFlash instrument (24 gA column; petroleum ether-ethyl acetate as eluent). The desired product was eluted with 60% -70% ethyl acetate in petroleum ether. The pure fractions were combined and evaporated to dryness under reduced pressure to give 3- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl as a brown solid]Methoxy } -6-chloro-7- [ 8-ethyl-3- (methoxymethoxy) naphthalen-1-yl]-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (350 mg,0.458mmol,41.1% yield). MS (ESI) m/z 764.3[ M+H ]] ⁺ 。

Preparation of intermediate 8C: 2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-7- [ 8-ethyl-3- (methoxymethoxy) naphthalen-1-yl ] -8-fluoro-3, 4-dihydroquinazolin-4-one

3- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl]Methoxy } -6-chloro-7- [ 8-ethyl-3- (methoxymethoxy) naphthalen-1-yl]-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 ]A suspension of tert-butyl octane-8-carboxylate (200 mg,0.262 mmol) in EtOH (2 mL) was treated with NaOH (1M aqueous solution) (2.62 mL,2.62 mmol). The reaction mixture was stirred at 70℃for 16h. The reaction mixture was then concentrated under reduced pressure and the residue was diluted with ethyl acetate and washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated to give the compound 2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl as a white solid]Methoxy } -6-chloro-7- [ 8-ethyl-3-methoxymethoxy) naphthalen-1-yl]-8-fluoro-3, 4-dihydroquinazolin-4-one (160 mg, crude). MS (ESI) m/z 570.2[ M+H ]] ⁺ 。

Preparation of intermediate 8D: (1S, 6R) -3- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-7- [ 8-ethyl-3- (methoxymethoxy) naphthalen-1-yl ] -8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl]Methoxy } -6-chloro-7- [ 8-ethyl-3- (methoxymethoxy) naphthalen-1-yl]8-fluoro-3, 4-dihydroquinazolin-4-one (160 mg, 0.281mmol), (1S, 6R) -3, 9-diazabicyclo [ 4.2.1)]A solution of nonane-9-carboxylic acid tert-butyl ester (76 mg,0.337 mmol) and BOP (186 mg, 0.426 mmol) in acetonitrile (2 mL) was treated with TEA (0.078 mL, 0.560 mmol) and the reaction mixture was stirred at 80℃for 8h. The reaction mixture was then concentrated under reduced pressure to give a crude residue. The crude compound was purified by silica gel column chromatography using a CombiFlash instrument with 0-10% meoh/DCM (containing 0.5% tea) to give the desired compound (1 s,6 r) -3- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl) ]Methoxy } -6-chloro-7- [ 8-ethyl-3- (methoxymethoxy) naphthalen-1-yl]-8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (80 mg,0.103mmol,36.6% yield). MS (ESI) m/z 778.3[ M+H ]] ⁺ 。

Examples 8-1 and 8-2

4- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1]

Non-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol

To a solution of tert-butyl (1 s,6 r) -3- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -6-chloro-7- [ 8-ethyl-3- (methoxymethoxy) naphthalen-1-yl ] -8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylate (80 mg,0.103 mmol) in MeOH (2 mL) was added HCl (4M in 1, 4-dioxane) (2 mL,65.8 mmol) dropwise at 0 ℃ and the reaction mixture was stirred at room temperature for 1H. The reaction mixture was then concentrated under reduced pressure, co-distilled with toluene (twice), neutralized with DIPEA and concentrated again under reduced pressure to provide a crude residue. The crude compound was purified by preparative HPLC, then chiral separation using chiral HPLC to give atropisomers 1 and 2:4- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolazin-7 a-yl ] methoxy } -6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-ethylnaphthalen-2-ol.

Preparative HPLC conditions: column name: YMC-EXRS (250 x 21.2 mm), 5 μ; mobile phase a = 10mM ammonium bicarbonate in water (pH 9.5), mobile phase B = acetonitrile: meOH (1:1), flow rate: 20mL/min; retention time = 12.6min.

Preparation chiral conditions: column name: CELLULOSE-C5 (250 x 21), 5 μ; mobile phase: 0.1% dea in MeOH; flow rate: 20mL/min; retention time of peak 1 = 5.3 minutes and retention time of peak 2 = 6.3 minutes.

Example 8-1: MS (ESI) M/z 634.3, [ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δ＝11.0(bs,1H),7.97(s,1H),7.68-7.66(m,1H),7.40-7.33(m,1H),7.28(d,J＝2.6Hz,1H),7.13-7.11(m,1H),6.86(d,J＝2.6Hz,1H),5.39-5.17(m,1H),4.38-4.34(m,1H),4.13-4.09(m,1H),4.00(d,J＝10.4Hz,1H),3.95-3.79(m,3H),3.72-3.64(m,3H),3.12-3.06(m,4H),3.04-2.98(m,2H),2.88-2.78(m,2H),2.36-2.26(m,2H),2.16-2.10(m,1H),2.01-1.95(m,1H),1.90-1.84(m,3H),1.56-1.30(m,3H),0.87(t,J＝7.4Hz,3H)。

Example 8-2: MS (ESI) M/z 634.3, [ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δ＝7.97(s,1H),7.68-7.66(m,1H),7.38-7.34(m,1H),7.28(d,J＝2.6Hz,1H),7.12-7.11(m,1H),6.87(d,J＝2.6Hz,1H),5.38-5.18(m,1H),4.47-4.43(m,1H),4.11(d,J＝10.4Hz,1H),3.99(d,J＝10.4Hz,1H),3.93-3.82(m,3H),3.70-3.64(m,3H),3.11-3.05(m,4H),3.09-2.99(m,2H),2.88-2.77(m,2H),2.36 -2.30(m,2H),2.15-2.07(m,1H),2.08-2.00(m,1H),1.91-1.81(m,3H),1.47-1.26(m,3H),0.86(t,J＝7.4Hz,3H)。

The examples in table 4 were prepared from the appropriate starting materials according to the procedure described in example 8.

TABLE 4 Table 4

Example 9-1

4- (2- { [ (4 aS,7 aR) -1-methyl-octahydro-1H-cyclopenta [ b ] pyridin-4 a-yl ] methoxy } -4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) naphthalen-2-ol

Preparation of intermediate 9A: (1S, 6R) -3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

To a solution of 7-bromo-2, 4-dichloro-8-fluoroquinazoline (250 mg,0.845 mmol) and DIEA (148 μl,0.845 mmol) in THF (30 mL) at 0 ℃ under nitrogen was added (1 s,6 r) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (191 mg,0.845 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 then diluted with EtOAc (35 mL) and washed with saturated aqueous sodium bicarbonate (2×35 mL). The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel/hexanes-EtOAc 100:0 to 60:40 gradient) to give (1 s,6 r) -3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] as a white foam ]Nonane-9-carboxylic acid tert-butyl ester (362 mg, 0.706 mmol,84% yield). LCMS (ESI) m/z 486[ M+H ]] ⁺ LC retention time: 1.14min (Waters Acquity UPLC BEH C, 2.1X50 mm,1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 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)).

Preparation of intermediate 9B: (1S, 6R) -3- (7-bromo-2, 8-difluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

(1S, 6R) -3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]A mixture of tert-butyl nonane-9-carboxylate (362 mg,0.745 mmol) and potassium fluoride (87 mg,1.490 mmol) in DMSO (5.0 mL) was stirred at 100deg.C for 2 days. The mixture was then diluted with EtOAc (25 mL) and washed with saturated aqueous sodium bicarbonate (2×25 mL). The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel/hexanes-EtOAc 100:0 to 40:60 gradient) to yield a white foam(1S, 6R) -3- (7-bromo-2, 8-difluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (270 mg,0.547mmol,73.3% yield). LCMS (ESI) m/z 470[ M+H ] ] ⁺ LC retention time: 1.09min (Waters Acquity UPLC BEH C, 2.1X50 mm,1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 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)).

Preparation of intermediate 9C: (1S, 6R) -3- (7-bromo-8-fluoro-2- (((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenta [ b ] pyridin-4 a-yl) methoxy) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

To ((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenta [ b ] under nitrogen at 0deg.C]Pyridin-4 a-yl) methanol (72.9 mg,0.430 mmol) and (1S, 6R) -3- (7-bromo-2, 8-difluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]To a solution of tert-butyl nonane-9-carboxylate (202 mg,0.430 mmol) in THF (30 mL) was added a lithium bis (trimethylsilyl) amide solution in THF (646. Mu.l, 0.646 mmol), and the mixture was stirred at 0deg.C for 1 hr and at room temperature for 18 hr. The mixture was then concentrated. The crude product was purified by chromatography (ISCO C18 100g column, flow rate=60 mL/min, gradient=20% a to 100% b over 20min ₂ O/ACN/TFA(90:10:0.1)，B＝H ₂ O/ACN/TFA (10:90:0.1)). The pure fractions were combined and concentrated to give (1 s,6 r) -3- (7-bromo-8-fluoro-2- (((4 as,7 ar) -1-methyl octahydro-4 aH-cyclopenta [ b) as a white solid ]Pyridin-4 a-yl) methoxy) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester. LCMS (ESI) m/z 619[ M+H ]] ⁺ . Retention time: 0.88min (Waters Acquity UPLC BEH C, 2.1X50 mm,1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 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)).

Example 9-1

(1S, 6R) -3- (7-bromo-8-fluoro-2- (((4 aS,7 aR) -1-methyl octahydro-4 aH-cyclopenta [ b) under nitrogen]Pyridin-4 a-yl) methoxy) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (20 mg,0.032 mmol), 2- (3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (10.67 mg,0.034 mmol), [1,1' -bis (di-tert-butylphosphino) ferrocene]A mixture of palladium (II) dichloride (1.054 mg, 1.617. Mu. Mol) and 2.0M tripotassium phosphate (48.5. Mu.l, 0.097 mmol) in 1, 4-dioxane (1 mL) was stirred at 50℃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 the crude product. A solution of the above crude material 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 30x 250mm, flow = 30mL/min, gradient = 20% a to 100% b over 12min ₂ O/ACN/TFA(90:10:0.1)，B＝H ₂ O/ACN/TFA (10:90:0.1)). The combined pure fractions were loaded onto an Oasis MCX cation mix mode polymer cartridge (150 mg), the cartridge was washed with methanol (30 mL) and the product eluted with 0.1N ammonia in methanol (5.0 mL). The ammonia eluent was concentrated. The pure product is then taken from ACN/H ₂ Lyophilization in O (1:1, 5 mL) yielded the desired product as a white powder (9.15 mg,0.015mmol,47.2% yield). LCMS (ESI) m/z 582[ M+H ]] ⁺ LC retention time: 0.69min (Waters Acquity UPLC BEH C, 2.1X50 mm,1.7 μm particles; mobile phase A: water with 0.05% TFA; mobile phase B: ACN with 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, methanol-d) ₄ )δ7.99(d,J＝8.7Hz,1H),7.75(d,J＝8.3Hz,1H),7.51-7.40(m,2H),7.30-7.21(m,3H),7.12(d,J＝2.3Hz,1H),4.77-4.61(m,1H),4.50(br d,J＝11.2Hz,1H),4.30(d,J＝10.7Hz,1H),4.13-3.94(m,2H),3.86-3.78(m,2H),3.72-3.58(m,1H),2.90(br t,J＝5.7Hz,1H),2.69(ddd,J＝11.6,7.4,4.2Hz,1H),2.41-2.32(m,4H),2.26-2.08(m,3H),2.07-1.93(m,2H),1.90-1.69(m,10H),1.67(br s,1H),1.64-1.55(m,1H)。

The examples in Table 5 were prepared from the appropriate starting materials according to the procedure described in example 9-1.

TABLE 5

Example 10-1

6- { 6-chloro-4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -2- ({ 1- [ (dimethylamino) methyl ] cyclopropyl } methoxy) -8-fluoroquinazolin-7-yl } -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 10A: {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 combined organic layers were washed with water, brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to provide {1- [ (dimethylamino) methyl ] as a yellow liquid]Cyclopropyl } methanol (3.7 g,28.6mmol,61.3% yield). ¹ H NMR(300MHz,CDCl ₃ )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 10B: 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 the mixture was stirred at the same temperature for 30 min. Then, intermediate 3K was added and the mixture was gradually warmed to room temperature over a period of 2 h. The reaction mixture was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were 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 (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) ⁺ 。/>

Preparation of intermediate 10C: 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-ol

To 3- [7- (6- { bis [ (4-methoxyphenyl) -methyl)]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]To a solution of tert-butyl octane-8-carboxylate (150 mg,0.161 mmol) in ethanol (2 mL) and THF (2 mL) was added NaOH (1M aqueous solution) (1.605 mL,1.605 mmol) and the reaction mixture was stirred at 70℃for 16h. The reaction mixture was then concentrated and the crude residue was dissolved in ethyl acetate, washed with brine and concentrated under reduced pressure to afford 7- (6- { bis [ (4-methoxyphenyl) methyl) ]Amino } -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2- ({ 1- [ (dimethylamino) methyl group]Cyclopropyl } methoxy) -8-fluoroquinazolin-4-ol (70 mg,0.095mmol,58.9% yield). MS (ESI) M/z 740.2 (M+H) ⁺ 。

Preparation of intermediate 10D: (1S, 6R) -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, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

To 7- (6- { bis [ (4-methoxyphenyl) methyl)]Amino } -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2- ({ 1- [ (dimethylamino) methyl group]Cyclopropyl } methoxy) -8-fluoroquinazolin-4-ol (70 mg,0.095 mmol), (1S, 6R) -3, 9-diazabicyclo [4.2.1]To a solution of tert-butyl nonane-9-carboxylate (25.7 mg,0.113 mmol) and BOP (62.7 mg,0.142 mmol) in ACN (3 mL) was added TEA (0.026 mL,0.189 mmol) and the reaction mixture was stirred at 80℃for 8h. The reaction mixture was then concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give (1 s,6 r) -3- [7- (6- { bis [ (4-methoxyphenyl) methyl ]]Amino } -4-methyl-3- (trifluoromethyl) pyridine2-yl) -6-chloro-2- ({ 1- [ (dimethylamino) methyl group ]Cyclopropyl } methoxy) -8-fluoroquinazolin-4-yl]-3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (70 mg,0.074mmol,78% yield). MS (ESI) M/z 948.2 (M+H) ⁺ 。

Example 10-1

A stirred solution of TFA (1.5 mL,19.47 mmol) and triethylsilane (0.5 mL,3.13 mmol) was added to (1S, 6R) -3- [7- (6- { bis [ (4-methoxyphenyl) methyl)]Amino } -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-2- ({ 1- [ (dimethylamino) methyl group]Cyclopropyl } methoxy) -8-fluoroquinazolin-4-yl]-3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (70 mg,0.074 mmol) and the resulting reaction mixture was heated at 40℃for 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 which was purified by preparative HPLC (column/size: column name: waters XBridge C18 (150mm x 19mm ID,5 μ); mobile phase a=10 mM ammonium acetate, mobile phase b=acetonitrile; flow rate: 20mL/min; retention time=1.748 min) to give 6- { 6-chloro-4- [ (1 s,6 r) -3, 9-diazabicyclo [ 4.2.1) ]Non-3-yl]-2- ({ 1- [ (dimethylamino) methyl)]Cyclopropyl } methoxy) -8-fluoroquinazolin-7-yl } -4-methyl-5- (trifluoromethyl) pyridin-2-amine (2.4 mg,3.68 μmol,4.98% yield). LCMS (ESI) m/z 608.2[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δppm 7.87(s,1H),6.85(s,2H),6.50(s,1H),5.36-5.01(m,1H),4.40-4.32(m,1H),4.28-4.17(m,2H),4.13-4.06(m,1H),4.03-3.84(m,2H),3.79-3.62(m,2H),2.38(m,4H),2.32-2.27(m,2H),2.21(m,7H),1.91(m,3H),1.72-1.60(m,1H),0.64(m,2H),0.46-0.38(m,2H)。

The examples in Table 6 were prepared from the appropriate starting materials according to the procedure described in example 10-1.

TABLE 6

Example 11-1

4- {4- [ (1 s,6 r) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -2- ({ 1- [ (dimethylamino) methyl ] cyclopropyl } methoxy) -8-fluoroquinazolin-7-yl } -5-ethynyl-6-fluoronaphthalen-2-ol

Preparation of intermediate 11A: (1S, 6R) -3- [ 7-bromo-2- ({ 1- [ (dimethylamino) methyl ] cyclopropyl } methoxy) -8-fluoroquinazolin-4-yl ] -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

To a solution of (1- ((dimethylamino) methyl) cyclopropyl) methanol (186 mg,1.441 mmol) in THF (2 mL) at 0 ℃ was slowly added NaH (57.6 mg,1.441 mmol) and the reaction mixture was stirred at the same temperature for 30 min. Then, (1S, 6R) -3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1 is added]Nonane-9-carboxylic acid tert-butyl ester (350 mg,0.720 mmol) and the mixture was slowly warmed to room temperature and stirred for 2h. However, the method is thatThe reaction mixture was then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried, filtered and concentrated to provide the crude product (1 s,6 r) -3- (7-bromo-2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (350 mg,0.605mmol,84% yield). MS (ESI) M/z 580.1 (M+H+2).

Preparation of intermediate 11B: (1 s,6 r) -3- [2- ({ 1- [ (dimethylamino) methyl ] cyclopropyl } methoxy) -8-fluoro-7- [ 7-fluoro-3- (methoxymethoxy) -8- {2- [ tris (prop-2-yl) silyl ] ethynyl } naphthalen-1-yl ] quinazolin-4-yl ] -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester.

To (1S, 6R) -3- (7-bromo-2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (300 mg, 0.719 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (319 mg,0.622 mmol) and Na ₂ CO ₃ (0.778 mL, 1.552 mmol) to a degassed solution in 1, 4-dioxane (5 mL) was added bis (triphenylphosphine) palladium (II) dichloride (36.4 mg,0.052 mmol) and the reaction mixture was heated at 100deg.C for 2h. The reaction was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried, filtered and concentrated to provide a crude residue that is purified by silica gel column chromatography to give (1 s,6 r) -3- (2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (130 mg,0.147mmol,28.4% yield). MS (ESI) M/z 884.5 (M+1).

Example 11-1

To 4- (4- ((1S, 6R) -3, 9-diazabicyclo [ 4.2.1) at room temperature]To a solution of non-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -8-fluoroquinazolin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol (120 mg,0.162 mmol) in DMF (3 mL) was added CsF (123 mg,0.811 mmol) and the reaction mixture was stirred at 55 ℃ for 24h. The reaction mixture was then concentrated to provide a crude residue. The crude material was purified by preparative HPLC (conditions: column-Waters XBiridge C18 (19X 150mM,5 μm particles), mobile phase A:10mM ammonium acetate, mobile phase B: acetonitrile, gradient: 10-35% B over 20 minutes then 5 minutes at 100% B; flow rate: 20 mL/min), followed by SFC purification to give 4- (4- ((1S, 6R) -3, 9-diazabicyclo [ 4.2.1) ]Non-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) methoxy) -8-fluoroquinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (0.9 mg,1.388 μmol,0.856% yield). MS (ESI) m/z 584.3[ M+H ]] ⁺ 。

The examples in Table 7 were prepared in accordance with the procedure described in example 11-1 from intermediate 9A and the appropriate starting materials.

TABLE 7

Example 12-1

4- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-fluoronaphthalen-2-ol

Preparation of intermediate 12A-1: (1S, 6R) -3- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -7-bromo-8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

To a stirred solution of ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (246 mg,1.544 mmol) in THF (20 mL) was added sodium hydride (49.4 mg,2.059 mmol) and the mixture was stirred at 0deg.C for one hour. To this reaction mixture was added (1S, 6R) -3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (500 mg,1.029 mmol) and the reaction mixture was slowly warmed to room temperature and allowed to stir for 2h. The reaction mixture was quenched with water, extracted with ethyl acetate (50 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1 s,6 r) -3- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl as a yellow solid ]Methoxy } -7-bromo-8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester. MS (ESI) m/z 608.2[ M+H ]] ⁺ 。

Preparation of intermediate 12A: (1S, 6R) -3- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -8-fluoro-7- (4, 5-tetramethyl-1, 3, 2-dioxapentaborolan-2-yl) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

To (1S, 6R) -3- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl]Methoxy } -7-bromo-8-fluoroquinazolin-4-yl) -3, 9-diazaBicyclo [4.2.1]To a degassed solution of nonane-9-carboxylic acid tert-butyl ester (120 mg, 0.197mmol), bis (pinacolato) diboron (75 mg, 0.298 mmol), potassium acetate (38.7 mg, 0.390 mmol) in 1, 4-dioxane (3 mL) was added PdCl ₂ (dppf) (14.43 mg, 0.020mmol) and heating the reaction mixture at 120℃for 1.5h. The reaction mixture was then filtered through a celite pad and the filtrate was continued for the next step without further work-up or purification.

Preparation of intermediate 12B: (1S, 6R) -3- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -7- (6- { bis [ (4-methoxyphenyl) methyl ] amino } -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

To (1S, 6R) -3- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl]Methoxy } -8-fluoro-7- (4, 5-tetramethyl-1, 3, 2-dioxapentalan-2-yl) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]To a 1.5M aqueous solution (0.305 mL,0.458 mmol) of t-butyl nonane-9-carboxylate (100 mg,0.153 mmol) in 1, 4-dioxane (2 mL) was added PdCl, 6-chloro-N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (CAS: 2411793-22-9) (83 mg, 0.183mmol) and tripotassium phosphate ₂ (dppf) (11.16 mg,0.015 mmol) and the reaction mixture was stirred at 100deg.C for 6h. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried, filtered and concentrated to provide a crude residue. The crude residue was purified by column chromatography on silica gel (24 g)Column, gradient elution with 60% -100% EtOAc in petroleum ether). Fractions containing the desired product were evaporated to give (1 s,6 r) -3- (2- { [ (2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl]Methoxy } -7- (6- { bis [ (4-methoxyphenyl) methyl)]Amino } -4-methyl-3- (trifluoromethyl) pyridine-2-yl) -8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1 ]Tert-butyl nonane-9-carboxylate (70 mg,0.074mmol,48.6% yield) LCMS (ESI) m/z 944.3[ M+H ]] ⁺ 。

Example 12-1

4- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ] methoxy } -4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -5-fluoronaphthalene-2 ]

A stirred solution of TFA (1.5 mL,19.47 mmol) and triethylsilane (0.5 mL,3.13 mmol) was added to (1S, 6R) -3- (2- { [ (2R, 7 aS) -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) -8-fluoroquinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (70 mg,0.074 mmol) and the resulting reaction mixture was heated at 40℃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 which was purified by preparative HPLC [ HPLC conditions: column/size: column name: kineex EVO (250mm x 21mm 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 = 11.72min.]Purification to give 6- (2- { [ (2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl ]Methoxy } -4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1]Non-3-yl]-8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (18 mg,0.030mmol,40.2% yield). LCMS (ESI) m/z 604.5[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δppm 7.86-7.79(m,1H),7.18-7.07(m,1H),6.82-6.71(m,2H),6.47-6.44(m,1H),5.39-5.15(m,1H),4.53-4.40(m,1H),4.13-4.05(m,1H),4.02-3.92(m,1H),3.88-3.77(m,2H),3.70-3.60(m,2H),3.46-3.38(m,2H),3.12-3.05(m,2H),3.04-2.98(m,1H),2.86-2.77(m,1H),2.37-2.35(m,3H),2.16-2.09(m,1H),2.01-1.92(m,3H),1.84-1.80(s,3H),1.79-1.68(m,3H),1.50-1.36(m,2H)。

The examples in Table 8 were prepared from the appropriate starting materials according to the procedure described in example 12-1.

TABLE 8

Example 13-1

6- (2- { [ (6 ' R,7' aR) -6' -fluoro-hexahydrospiro [ cyclopropan-1, 2' -pyrrolizine ] -7' a-yl ] methoxy } -6-chloro-4- [ (1S, 6R) -3, 9-diazabicyclo [4.2.1] non-3-yl ] -8-fluoroquinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Preparation of intermediate 13A: 1- (tert-butyl) 2-methyl (2R, 4R) -2- (2- (chloromethyl) allyl) -4-fluoropyridine-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-fluoropyridine-1, 2-dicarboxylic acid ester (50 g,202 mmol) at-45℃while maintaining the temperature at-45℃under nitrogen atmosphere. After stirring at this temperature for 1h, a solution of 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 x 200 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 packing) over silica gel (230-400 mesh) by eluting with 10% -30% ethyl acetate in petroleum ether. The desired fractions were pooled and concentrated under reduced pressure to obtain 1- (tert-butyl) 2-methyl (2R, 4R) -2- (2- (chloromethyl) as a colorless liquid) Allyl) -4-fluoropyridine-1, 2-dicarboxylic acid ester (64 g,91mmol,45% yield). LCMS (ESI) m/z 336.1[ M+H ]] ⁺ 。

Preparation of intermediate 13B: (2R, 4R) -2- (2- (chloromethyl) allyl) -4-fluoropyridine-2-carboxylic acid methyl ester

To a stirred solution of 1- (tert-butyl) 2-methyl (2 r,4 r) -2- (2- (chloromethyl) allyl) -4-fluoropyridine-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, followed by concentration under reduced pressure to give methyl (2 r,4 r) -2- (2- (chloromethyl) allyl) -4-fluoropyridine-2-carboxylate, HCl (50 g,180mmol,94% yield) as a pale brown solid. LCMS (ESI) m/z 236.2[ M+H ]] ⁺ 。

Preparation of intermediate 13C: (2R, 7 aR) -2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester

To a stirred solution of (2R, 4R) -2- (2- (chloromethyl) allyl) -4-fluoropyridine-2-carboxylic acid methyl ester (50 g,212 mmol) in anhydrous acetonitrile (500 mL) was added TEA (44.4 mL,318 mmol). The reaction mixture was stirred at ambient temperature for 16h. The reaction mixture was then diluted with water (50 mL) and then treated with aqueous bicarbonate solution (70 mL). The resulting solution was extracted with DCM (2X 300 mL) and 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 methyl (2 r,7 ar) -2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7 a (5H) -carboxylate (35 g,176mmol,83% yield) as a brown liquid. LCMS (ESI) m/z 200.1[ M+H ]] ⁺ 。

Preparation of intermediate 13D: (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) (1M solution in hexanes) was added dropwise. 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 Drying, filtration and concentration under reduced pressure to obtain a crude residue, which is purified by silica gel column chromatography (neutral alumina) using 40% -50% ethyl acetate in petroleum ether to obtain (6 'r,7a' r) -6 '-fluorodihydro-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 13E: ((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 and then quenched with saturated aqueous ammonium chloride at 0 ℃. Once bubbling stopped, anhydrous sodium sulfate was added to the reaction mixture followed by DCM (20 mL). The reaction mixture was stirred for 20 minutes, after which it was filtered. The filtrate was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain ((6 ' r,7a ' r) -6' -fluorodihydro-1 ' as a colorless liquid ' H,3 'H-spiro [ cyclopropane-1, 2' -pyrrolizine]7a '(5' H) -yl) methanol (110 mg,0.592mmol,6% yield). LCMS-ELSD (ESI) m/z 186.2[ M+H ]] ⁺ 。

Preparation of intermediate 13F: 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((6 'r,7a' r) -6 '-fluorodihydro' H,3 'H-spiro [ cyclopropane-1, 2' -pyrrolizine ] -7a '(5' H) -yl) methoxy) quinazolin-4 ]

Phenyl) -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 (0.090 g, 0.480 mmol) in anhydrous THF (5.0 mL) was added sodium hydride (60% dispersion in mineral oil, 0.019g, 0.480 mmol) and the reaction mixture was stirred at the same temperature for 30min. A solution of intermediate 3K (0.2 g,0.242 mmol) in THF (2 mL) was added dropwise while maintaining the temperature at 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 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (Grace, 50g snap, dry packing) on neutral alumina using 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) -6 '-fluoro 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]Tert-butyl octane-8-carboxylate (0.21 g,0.199mmol,82% yield). LCMS (ESI) m/z 990.4[ M+H ]] ⁺ 。

Preparation of intermediate 13G: 7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((6 'r,7a' r) -6 '-fluoro dihydro-1' h,3'h spiro [ cyclopropan-1, 2' -pyrrolizine ] -7a '(5' h) -yl) methoxy) quinazolin-4-ol

To 3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((6 'r,7a' r) -6 '-fluorodihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine)]-7a '(5' H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1]To a stirred solution of tert-butyl octane-8-carboxylate (240 mg,0.242 mmol) in ethanol (5 mL) was added 10% NaOH solution (2.42 mL,2.423 mmol). The reaction was heated at 70℃for 48h. The reaction mixture was then concentrated under reduced pressure to obtain a crude residue, which was purified by column chromatography (Biotage, al ₂ O ₃ -neutral) purification using 30% -40% ethyl acetate in petroleum ether to obtain 7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((6 'r,7a' r) -6 '-fluoro dihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine) as a gummy liquid ]-7a '(5' H) -yl) methoxy) quinazolin-4-ol (172 mg,0.110mmol,46% yield). LCMS (ESI) m/z 796.2[ M+H ]] ⁺ 。

Preparation of intermediate 13H: (1S, 6R) -3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((6 'R,7a' R) -6 '-fluorodihydro-1' H,3 'H-spiro [ cyclopropane-1, 2' -pyrrolizine ] -7a '(5' H) -yl) methoxy) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1] nonane-9-carboxylic acid tert-butyl ester

To 7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((6 'r,7a' r) -6 '-fluorodihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine)]To a stirred solution of 7a '(5' H) -methoxy) quinazolin-4-ol (0.17 g,0.214 mmol) in acetonitrile (2 mL) were added BOP (0.142 g,0.320 mmol) and TEA (0.045 mL,0.320 mmol). After stirring for 5min, (1S, 6R) -3, 9-diazabicyclo [4.2.1] is added]Nonane-9-carboxylic acid tert-butyl ester (0.097 g,0.427 mmol) andthe mixture was stirred at 40℃for 16h. The reaction mixture was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 70mg of crude product. The residue was purified by column chromatography (Biotage, neutral alumina) using 30% -40% ethyl acetate in petroleum ether to afford (1 s,6 r) -3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-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-4-yl) -3, 9-diazabicyclo [4.2.1]Nonane-9-carboxylic acid tert-butyl ester (150 mg,0.103mmol,48% yield). LCMS (ESI) m/z 1004.4[ M+H ]] ⁺ 。

Example 13-1

To (1 s,6 r) -3- (7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((6 'r,7a' r) -6 '-fluorodihydro-1' h,3 'h-spiro [ cyclopropane-1, 2' -pyrrolizine)]-7a '(5' H) -yl) methoxy) quinazolin-4-yl) -3, 9-diazabicyclo [4.2.1]To a stirred solution of t-butyl nonane-9-carboxylate (0.15 g,0.149 mmol) in TFA (1 mL) was added water (0.01 mL) and triethylsilane (0.024 mL,0.149 mmol). The reaction was allowed to stir at 40 ℃ for 16h. The reaction mixture was then concentrated under reduced pressure to obtain a crude residue which was passed through a preparative HPLC [ column: xbridge C18 (250 x 19) mm,5 microns, mobile phase A: 0.1% ammonium formate in water, mobile phase B: acetonitrile, flow rate: 15mL/min, gradient: 30-70% of mobile phase B in mobile phase A within 15min ]Purification was performed to obtain the desired compound as an off-white solid (10 mg,0.012mmol,8% yield). LCMS (ESI) m/z 664.4[ M+H ]] ⁺ 。 ¹ H-NMR(400MHz,DMSO-d6)δ: ¹ H NMR(400MHz,CD ₃ SOCD ₃ ,298K)δ:8.27-8.16(m,1H),7.96-7.78(m,1H),6.92-6.76(m,1H),6.50(s,1H),5.54-5.24(m,1H),4.43-4.24(m,1H),4.19-4.03(m,1H),3.95-3.83(m,1H),3.82-3.75(m,2H),3.74-3.62(m,2H),3.34-3.23(m,3H),3.08-2.88(m,1H),2.86-2.77(m,5H),2.68(td,J＝1.8,3.5Hz,2H),2.63(d,J＝10.0Hz,1H),2.41-2.29(m,3H),2.13-1.71(m,5H),1.46(br s,1H),0.63-0.36(m,2H)ppm。

Preparation of intermediate 14-1: n- (5-bromonaphthalen-1-yl) -1, 1-trimethyl-N- (trimethylsilyl) silaneamine

At 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 at-78deg.C. The reaction mixture was slowly warmed to 20 ℃ over 30min and then cooled back to-78 ℃ again. A solution of TMSCl (48.3 mL,378 mmol) in anhydrous THF was added dropwise to the reaction mixture at-78deg.C and warmed slowly over 1h to 20deg.C. 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 concentrated under reduced pressure to give the crude product as a red oil, which was purified by flash column chromatography (silica gel 100-200) 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 14-2: 5-fluoronaphthalen-1-amine

At N ₂ To N- (5-bromonaphthalen-1-yl) -1, 1-trimethyl-N- (trimethylsilyl) silane amine (100 g,273 mmol) in anhydrous THF (1400 mL) at-78deg.C under an atmosphereN-butyllithium (164 mL,409 mmol) was added dropwise over 30 min. After complete addition, the reaction mixture was stirred for 10min, then a solution of N-fluorobenzenesulfonamide (138 g,437 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 x 800 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 chromatography (silica gel 100-200) 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% aqueous ammonium formate solution. 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 14-3: 2, 4-dibromo-5-fluoronaphthalen-1-amine

To a stirred solution of 5-fluoronaphthalen-1-amine (40 g,228 mmol) in acetic acid (800 mL) at 0 ℃ was carefully added bromine (25.9 mL,502 mmol) 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 x 200 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 14-4: 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 ice-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), which was used in the next step without any purification. LCMS (ESI) m/z 265.9[ M+H ]] ⁺ 。

Preparation of intermediate 14-5: 4-bromo-5-fluoronaphthalen-2-ol

To 5-bromo-6-fluoronaphtho [1,2-d ] under nitrogen at 0deg.C][1,2,3]Oxadiazole (40 g,118 mmol)) in ethanol (500 mL) and tetrahydrofuran (250 mL) over 30min 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 over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give 4-bromo-5-fluoronaphthalen-2-ol (30 g,86mmol,73% yield), which is used in the next step without further purification. LCMS (ESI) m/z 241.08[ M+H ]] ⁺ 。

Preparation of intermediate 14-6: 1-bromo-8-fluoro-3- (methoxymethoxy) naphthalene

MOM-Cl (7.83 mL,103 mmol) was added dropwise over 10min to a stirred solution of 4-bromo-5-fluoronaphthalen-2-ol (30 g,86 mmol) and DIPEA (22.50 mL,129 mmol) in anhydrous dichloromethane (300 mL) 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 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 chromatography (silica gel 100-200) 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 14-7: 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 x 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 chromatography (silica 100-200 mesh) 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% aqueous ammonium formate as eluent. The pure fractions were concentrated under reduced pressure to give 2- (8-fluoro-3- (methoxy) as an off-white solid Methoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (9 g,26.6mmol,53.2% yield). 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 15-1: 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 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 x 100 ml), the filtrates were combined and concentrated in vacuo to give a crude residue. The crude product was purified by flash column chromatography (silica 100-200 mesh) using 12% -15% ethyl acetate in petroleum ether as eluent. The pure fraction was concentrated under reduced pressure to give 8- ((triisopropylsilyl) ethynyl) naphthalene-1, 3-diol (30 g,85mmol,67.7% yield). LCMS (ESI) m/z 341.55[ M+H ]] ⁺ 。

Preparation of intermediate 15-2: 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-ol

DIPEA (38.5 mL,220 mmol) was added 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. 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 purified 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 chromatography (silica 100-200 mesh) 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 pale yellow oil. LCMS (ESI) m/z 385.60[ M+H ]] ⁺ 。

Preparation of intermediate 15-3: tetanoic acid 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl ester

To a stirred solution of 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-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℃was added dropwise pivaloyl chloride (12.80 mL,104 mmol) for 10min under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 2h. The reaction mixture was then diluted with 200mL of DCM 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 chromatography (silica 100-200 mesh) using 10% -15% ethyl acetate in petroleum ether as eluent. The pure fraction was concentrated under reduced pressure to give 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate as a pale yellow oil (23 g,49.1mmol,94% yield). LCMS (ESI) m/z 469.2[ M+H ]] ⁺ 。

Preparation of intermediate 15-4: pivalic acid 8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl ester

To a stirred solution of 3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate (12 g,25.6 mmol) in anhydrous DMF (130 mL) under nitrogen at room temperature 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 chromatography (silica 100-200 mesh) 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 15-5: teentanoic acid 8-ethyl-3-methoxymethoxy) naphthalen-1-yl ester

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 H ₂ Purging several times. At H ₂ The mixture was stirred for 5 hours at 25℃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 chromatography (silica 100-200 mesh) 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 as a pale yellow oil (6.56 g,17.83mmol,80% yield). LCMS (ESI) m/z 316.1[ M+H ]] ⁺ 。

Preparation of intermediate 15-6: 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 chromatography (silica 100-200 mesh) 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 15-7: trifluoromethanesulfonic acid 8-ethyl-3- (methoxymethoxy) naphthalen-1-yl ester

To a stirred solution of 8-ethyl-3- (methoxymethoxy) naphthalen-1-ol (3 g,12.92 mmol) and DIPEA (22.50 mL,129 mmol) in anhydrous dichloromethane (50 mL) under nitrogen at-40 ℃ 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, and concentrated under reduced pressure to obtain a crude residue. The crude compound was purified by flash column chromatography (silica gel 100-200) 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 pale yellow oil. LCMS (ESI) m/z 365.3[ M+H ] ] ⁺ 。

Preparation of intermediate 15-8: 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 at 100 ℃ for 3h under nitrogen. 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 chromatography (silica 100-200 mesh) using 2% -4% ethyl acetate in petroleum ether as eluent. The pure fraction was concentrated under reduced pressure to give a brown gum, which was purified again by reverse phase column chromatography using 80% acetonitrile in 0.01% aqueous ammonium formate 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 16-1: 7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalene-1, 3-diol

Stirring 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) at room temperature under nitrogenTo the stirred solution was added dichloro (p-cymene) ruthenium (II) dimer (6.87 g,11.23 mmol). The resulting mixture was stirred at 110 ℃ under nitrogen 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 chromatography (silica 100-200 mesh) 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 pale yellow oil. LCMS (ESI) m/z 359.1[ M+H ]] ⁺ 。

Preparation of intermediate 16-2: 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-ol.

DIEA (14.61 mL,84 mmol) was added to a stirred solution of 7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalene-1, 3-diol (10 g,27.9 mmol) in anhydrous DCM (100 mL) under nitrogen at 0deg.C. 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 (2×100 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 chromatography (silica 100-200 mesh) 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 16-3: 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate

To a stirred solution of 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-ol (17 g,42.2 mmol) in anhydrous DCM (170 mL) under nitrogen at 0deg.C 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 ice-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 chromatography (silica 100-200 mesh) using 20% -25% ethyl acetate in petroleum ether as eluent. The pure fraction was 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 16-4: 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate

To a stirred solution of 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate (20 g,41.1 mmol) in anhydrous DMF (150 mL) under nitrogen at room temperature 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 chromatography (silica 100-200 mesh) using 5% -8% ethyl acetate in petroleum ether as eluent. Concentrating the pure fraction under reduced pressure to obtain8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl pivalate (12 g,32.7mmol,80% yield) was obtained as a pale yellow oil. LCMS (ESI) m/z 331.2[ M+H ]] ⁺ 。

Preparation of intermediate 16-5: pivalic acid 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl ester.

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 treated with H ₂ Purging several times. At H ₂ The mixture was stirred at 25℃for 5 hours under (1 atm). The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude residue. The crude product was purified by flash column chromatography (silica 100-200 mesh) 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 pale yellow oil. LCMS (ESI) m/z 335.1[ M+H ]] ⁺ 。

Preparation of intermediate 16-6: 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) under nitrogen at room temperature 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 chromatography (silica 100-200 mesh) As eluent 25% -30% ethyl acetate in petroleum ether was used. 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 16-7: trifluoromethanesulfonic acid 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl ester

To a stirred solution of 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-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 ice-cold water (500 mL) and then extracted with DCM (2×500 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 chromatography (silica gel 100-200) 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 pale yellow oil. LCMS (ESI) m/z 383.0[ M+H ] ] ⁺ 。

Preparation of intermediate 16-8: 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 borane (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, willPdCl 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 chromatography (silica 100-200 mesh) using 2% -4% ethyl acetate in petroleum ether as eluent. The pure fraction was concentrated under reduced pressure to give a brown gum, which was purified again by reverse phase column chromatography using 80% acetonitrile in 0.01% aqueous ammonium formate 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 17-1: 1- (tert-butyl) 2-methyl- (S) -4, 4-difluoropyrrolidine-1, 2-dicarboxylic acid ester

DAST (81 mL, 611 mmol) was added dropwise 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 packing) over silica (230-400 mesh), eluting with 20% -50% ethyl acetate in petroleum ether. The desired fractions were pooled and concentrated under reduced pressure to give 1- # as a pale brown liquidTert-butyl) 2-methyl (S) -4, 4-difluoropyrrolidine-1, 2-dicarboxylic acid ester (28 g,90mmol,73.4% yield). LCMS-ELSD (ESI) m/z 166.2[ M+H-Boc ]] ⁺ 。

Preparation of intermediate 17-2: 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, and then 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 x 100 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under vacuum. 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,80mmol,76% yield) as a pale brown liquid. LCMS-ELSD (ESI) m/z 388.2[ M+H-Boc ]] ⁺ 。

Preparation of intermediate 17-3: 1- (tert-butyl) 2-methyl-4, 4-difluoro-2- (3-hydroxypropyl) pyrrolidine-1, 2-dicarboxylic acid ester

TBAF (1M in THF, 80mL,80 mmol) was added dropwise 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℃and stirred at the same temperature4h. 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 x 150 ml). The combined organic layers were dried over anhydrous sodium sulfate 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 17-4: 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), imidazole (8.42 g,124 mmol) and the reaction mixture stirred for 10min at 0deg.C, followed by iodine (62.8 g,247 mmol). The reaction mixture was stirred at room temperature for 12h, then quenched with saturated aqueous sodium thiosulfate (30 mL). The suspension was extracted with dichloromethane (2 x 200 ml). The combined organic layers were dried over anhydrous sodium sulfate 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-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 17-5: 4, 4-difluoro-2- (3-iodopropyl) pyrrolidine-2-carboxylic acid methyl ester

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

Preparation of intermediate 17-6: 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 (11.5 g,51.5 mmol) in THF (120.0 mL) was added TEA (35.9 mL,258 mmol) at 0 ℃ followed by heating at 45 ℃ for 16h. The reaction mixture was concentrated under reduced pressure to obtain a crude residue, 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) as a brown liquid.

Preparation of intermediate 17-7: (2, 2-Difluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol

LiAlH was added dropwise over 10min 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) under nitrogen at 0deg.C 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 bubbling 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 and under reduced pressure Concentrated under reduced pressure to give a crude residue of (2, 2-difluorotetrahydro-1H-pyrrolizine-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 18-1: 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 } naphthalen-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 stirred at the same temperature for 30min. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, brine, and dried over anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure to provide a crude residue that 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 18-2: {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. The reaction mixture was cooled, filtered through a 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 gColumn, 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 ] ] ⁺ 。

Biological activity

KRAS ^G12D RAF failure assay

KRAS G12D (5 nM) loaded with recombinant GMPPNP was treated with compound in assay buffer (50mM Tris pH 7.5, 10 0mM NaCl,1mM MgCl2,1mM DTT,100ug/mL BSA) for 20 min at room temperature. 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 And IC is calculated from the dose-response curve ₅₀ Values.

KRAS ^G12D Nucleotide exchange assay

KRAS G12D (20 nM) loaded with recombinant GDP was incubated in assay buffer (10mM Hepes pH 7.4, 150mM NaCl,5mM MgCl) ₂ 0.0025% Igepal-CA630,0.05%BSA,1mM DTT,0.5nM SA-Tb) for 20 minutes with the compound. BIODIPY-labeled GDP (400 nM) and recombinant SOS (10 nM) were added and the reaction incubated for 30 min. Measuring HTRF signals(PerkinElmer Envision) calculating the signal ratio (lambda _em 520/λ _em 495 And IC is calculated from the dose-response curve ₅₀ Values.

Table 9 shows the IC50 values for the compounds described herein.

TABLE 9

It is to be understood 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 or 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;

n is 0, 1, 2, 3 or 4;

Representing an attachment point to the parent molecular moiety;

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

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof; wherein R is ⁴ Selected from:

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

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is- (C) ₁ -C ₃ Alkyl) -R ⁶ 。

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Selected from:

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

7. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereofR in (B) 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. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is that

Wherein q is 0 or1, a step of; and wherein R is ^x Selected from C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halo C ₁ -C ₃ Alkyl and hydroxy.

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

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is naphthyl, wherein said naphthyl is substituted with hydroxy and optionally with a member selected from C ₁ -C ₃ Alkyl, C ₂ -C ₄ One or two additional groups of alkynyl and halo are further substituted.

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

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

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

19. A compound according to any one of claims 1 to 14 or a salt thereofPharmaceutically acceptable salts, wherein R ¹ Is that

20. 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.

21. 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.

22. 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

Representation and parentAttachment points for the molecular moiety; and is also provided with

R ⁵ Selected from:

wherein the method comprises the steps of

Indicating the point of attachment to the parent molecular moiety.

23. A compound selected from the group consisting of:

Or a pharmaceutically acceptable salt thereof.

24. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

26. A method for treating cancer sensitive 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 24, or a pharmaceutically acceptable salt thereof.

27. 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 1-24, or a pharmaceutically acceptable salt thereof.

28. 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 24, or a pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer, colorectal cancer, lung cancer, and/or gastric cancer.