CN116997549A

CN116997549A - Pyrrolo [3,2-C ] pyridin-4-one derivatives for the treatment of cancer

Info

Publication number: CN116997549A
Application number: CN202180078489.2A
Authority: CN
Inventors: B·C·米尔格拉姆; R·D·怀特; D·小圣让; A·古兹曼-佩雷斯
Original assignee: Scorpion Therapeutics Inc
Current assignee: Scorpion Therapeutics Inc
Priority date: 2020-09-23
Filing date: 2021-09-22
Publication date: 2023-11-03

Abstract

The present disclosure provides chemical entities (e.g., compounds or pharmaceutically acceptable salts, and/or hydrates, and/or co-crystals, and/or pharmaceutical combinations of the compounds) that inhibit epidermal growth factor receptor (EGFR, ERBB 1) and/or human epidermal growth factor receptor 2 (HER 2, ERBB 2). These chemical entities are e.g. used for the treatment of a condition, disease or disorder in which increased (e.g. excessive) EGFR and/or HER2 activity contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g. cancer) in a subject (e.g. a human). The present disclosure also provides methods comprisingCompositions of physical entities and methods of use and manufacture thereof.

Description

Pyrrolo [3,2-C ] pyridin-4-one derivatives for the treatment of cancer

Cross Reference to Related Applications

The present application claims priority from U.S. provisional application serial No. 63/082,324 filed 9/23 in 2020 and U.S. provisional application serial No. 63/092,970 filed 10/16 in 2020, each of which is incorporated herein by reference in its entirety.

Technical Field

The present disclosure provides chemical entities (e.g., compounds or pharmaceutically acceptable salts, and/or hydrates, and/or co-crystals, and/or pharmaceutical combinations of the compounds) that inhibit epidermal growth factor receptor (EGFR, ERBB 1) and/or human epidermal growth factor receptor 2 (HER 2, ERBB 2). These chemical entities are e.g. used for the treatment of a condition, disease or disorder in which increased (e.g. excessive) EGFR and/or HER2 activity contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g. cancer) in a subject (e.g. a human). The disclosure also provides compositions comprising the chemical entities and methods of use and manufacture thereof.

Background

Epidermal growth factor receptor (EGFR, ERBB 1) and human epidermal growth factor receptor 2 (HER 2, ERBB 2) are members of a family of proteins that regulate cellular processes associated with tumor growth, including proliferation and differentiation. Several researchers have demonstrated the role of EGFR and HER2 in development and cancer (see, e.g., crit. Rev. Oncol. Hematol et al (1995) 19:183-232, klapper et al adv. Cancer Res. (2000) 77,25-79, and Hynes and Stern Biochim. Biophys. Acta (1994) 1198:165-184). EGFR overexpression is present in at least 70% of human cancers, such as non-small cell lung cancer (NSCLC), breast cancer, glioma and prostate cancer. HER2 overexpression occurs in about 30% of all breast cancers. It is also associated with other human cancers, including colon, ovary, bladder, stomach, esophagus, lung, uterus and prostate. HER2 overexpression is also associated with poor prognosis of human cancers, including metastasis and early recurrence.

EGFR and HER2 are therefore widely recognized as targets for the design and development of therapies that can specifically bind and inhibit tyrosine kinase activity and its signaling pathways in cancer cells, and thus can be used as diagnostic or therapeutic agents. For example, EGFR Tyrosine Kinase Inhibitors (TKIs) are an effective clinical therapy for patients with EGFR mutant advanced non-small cell lung cancer (NSCLC). However, the vast majority of patients develop disease progression following successful treatment with EGFR TKI. Common resistance mechanisms include the acquired secondary mutation T790M, C797S and EGFR exon 20 insertion mutation. For example, NSCLC tumors may have EGFR exon 20 insertion mutations that are inherently resistant to current EGFR TKIs.

Overexpression of another protein BUB1 (BUB 1) kinase is often associated with proliferating cells, including cancer cells and tissues (Bolanos-Garcia VM and Bluntell TL, trends biochem. Sci.36,141, 2010). Such proteins are an important component of a complex protein network that forms mitotic checkpoints. The primary function of an unmet mitotic checkpoint is to keep the late-promoting complex/cell cycle body (APC/C) in an inactive state. Once the checkpoint is met, APC/C ubiquitin ligase proteolytically degrades targeting cyclin B and the isolating enzyme inhibitor protein, resulting in the separation of the paired chromosomes and exit from mitosis.

Incomplete mitotic checkpoint function is associated with aneuploidy and tumorigenesis (see Weaver BA and Cleveland DW, cancer res.67,10103,2007; king RW, biochim Biophys Acta 1786,4,2008). In contrast, complete inhibition of mitotic checkpoints has been thought to lead to severe chromosomal false separations and induction of tumor Cell apoptosis (see Kops GJ et al, nature rev. Cancer 5,773,2005;Schmidt M and Medema RH, cell Cycle 5,159,2006;Schmidt M and bastims H, drug res. Updates 10,162,2007). Thus, inhibition of mitotic checkpoints by inhibiting BUB1 kinase represents a method of treating proliferative disorders, including solid tumors associated with uncontrolled cell proliferation, such as carcinomas, sarcomas, leukemias, and lymphoid malignancies or other disorders.

Disclosure of Invention

In one aspect, the present disclosure provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein R ^1c 、R ^2a 、R ^2b 、R ^3a 、R ^3b Ring A, R ⁴ 、X ¹ 、R ⁷ And n may be as defined anywhere herein.

In one aspect, the present disclosure provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ selected from the group consisting of: (a) -O-L ¹ -R ⁵ The method comprises the steps of carrying out a first treatment on the surface of the And (b)

L ¹ And L ² Independently selected from the group consisting of: bond and optionally 1-6R ^a Substituted C _1-10 An alkylene group;

R ⁵ selected from the group consisting of:

heteroaryl comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heteroaryl is optionally substituted with 1-4R ^c Substitution;

optionally by 1-4R ^c Substituted C _6-10 An aryl group;

·C _3-10 cycloalkyl or C _3-10 Cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of: oxo and R ^c ；

Wherein ring D is a heterocyclylene or heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^X 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene or heterocyclylene is optionally substituted with 1-4 substituents, each substituent independently selected from the group consisting of: oxo and-R ^c ；

·-S(O) _0-2 (C _1-6 Alkyl) optionally substituted with 1-6R ^a Substitution;

·-R ^g2 -R ^W or-R ^g2 -R ^Y ；

·-L ⁵ -R ^g The method comprises the steps of carrying out a first treatment on the surface of the And

·-L ⁵ -R ^g2 -R ^W or-L ⁵ -R ^g2 -R ^Y ；

Provided that when L ¹ When it is a bond, R ⁵ Not optionally substituted by 1-6R ^a substituted-S (O) _0-2 (C _1-6 An alkyl group); -L ⁵ -R ^g ；-L ⁵ -R ^g2 -R ^W The method comprises the steps of carrying out a first treatment on the surface of the or-L ⁵ -R ^g2 -R ^Y ；

R ⁶ Selected from the group consisting of:

h is formed; halogen; -OH; -NR ^e R ^f ；-R ^g ；-L ⁶ -R ^g ；-R ^g2 -R ^W or-R ^g2 -R ^Y ；-L ⁶ -R ^g2 -R ^W or-L ⁶ -R ^g2 -R ^Y The method comprises the steps of carrying out a first treatment on the surface of the and-C _1-6 Alkoxy or-S (O) _0-2 (C _1-6 Alkyl), each of which is optionally substituted with 1 to 6R ^a Substitution;

L ⁵ and L ⁶ independently-O-, -S (O) _0-2 -NH or-N (R) ^d )-；

R ^W is-L ^W -W,

Wherein L is ^W Is C (=O), S (O) _1-2 、OC(＝O)*、NHC(＝O)*、NR ^d C(＝O)*、NHS(O) _1-2 * Or NR (NR) ^d S(O) _1-2 * Wherein the asterisks represent the points of attachment to W, an

W is C _2-6 Alkenyl groups; c (C) _2-6 Alkynyl; or C _3-10 Cumulatively dienyl, each of which is optionally substituted with 1-3R ^a Substituted and also optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W Thereby providing an α, β -unsaturated system; and is also provided with

R ^X Is C (=O) (C _1-6 Alkyl) or S (O) ₂ (C _1-6 Alkyl), each of which is optionally substituted with 1 to 6R ^a Substitution;

R ^Y selected from the group consisting of: r is R ^g And- (L) ^g ) _g -R ^g ；

R ^1c 、R ^2a 、R ^2b 、R ^3a And R is ^3b Each independently selected from the group consisting of: h is formed; halogen; -OH; -C (O) OH or-C (O) NH ₂ ；-CN；-R ^b ；-L ^b -R ^b ；-C _1-6 Alkoxy or-C _1-6 Thioalkoxy groups, each of which is optionallyGround cover 1-6R ^a ；NR ^e R ^f ；R ^g And- (L) ^g ) _g -R ^g Substitution; provided that R ^1c Not halogen, -CN or-C (O) OH; or alternatively

Alternatively, the variable R ^1c 、R ^2a 、R ^2b 、R ^3a And R is ^3b Together with the ring atoms of ring B to which they are each attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms;

wherein 0 to 2 ring atoms are each independently selected heteroatoms (in-N (R) ^1c ) -forming part of condensed saturated or unsaturated ring, not-N (R ^1c ) (-), wherein the independently selected heteroatoms are each selected from the group consisting of: n, NH, N (R) ^d ) O and S (O) _0-2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

Wherein the fused saturated or unsaturated ring of 3 to 12 ring atoms is optionally substituted with 1 to 4 substituents independently selected from oxo and R ^c ；

Ring A is R ^g ；

R ⁴ Selected from the group consisting of: h and R ^d ；

Each R ⁷ R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the n is 0,1,2 or 3;

r of each occurrence ^a Independently selected from the group consisting of: -OH; halogen; -NR ^e R ^f ；C _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy groups; -C (=o) O (C _1-4 An alkyl group); -C (=o) (C _1-4 An alkyl group); -C (=o) OH; -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 Alkyl) and cyano;

r of each occurrence ^b Independently C _1-6 Alkyl, C _2-6 Alkenyl or C _2-6 Alkynyl groups, each of which is optionally substituted with 1 to 6R ^a Substitution;

l of each occurrence ^b Independently C (=o); c (=o) O; s (O) _1-2 ；C(＝O)NH*；C(＝O)NR ^d *；S(O) _1- ₂ NH; or S (O) _1-2 N(R ^d ) Wherein asterisks represent the linkage to R ^b Is a point of (2);

r of each occurrence ^c Independently selected from the group consisting of: halogen; cyano group; r is independently selected from 1 to 6 ^a Optionally substituted C _1-10 An alkyl group; c (C) _2-6 Alkenyl groups; c (C) _2-6 Alkynyl; c (C) _1-4 Alkoxy, optionally C _1-4 Alkoxy or C _1-4 Haloalkoxy substitution; c (C) _1-4 Haloalkoxy groups; s (O) _1-2 (C _1-4 An alkyl group); -S (O) (=nh) (C _1-4 An alkyl group); -NR ^e R ^f ；–OH；-S(O) _1-2 NR’R”；-C _1-4 Thioalkoxy; -NO ₂ ；-C(＝O)(C _1-10 An alkyl group); -C (=o) O (C _1-4 An alkyl group); -C (=o) OH; -C (=o) NR' R "; and-SF ₅ ；

R of each occurrence ^d Independently selected from the group consisting of: c (C) _1-6 Alkyl, optionally substituted with 1-3 independently selected R ^a Substitution; -C (O) (C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; and C _1-4 An alkoxy group;

r of each occurrence ^e And R is ^f Independently selected from the group consisting of: h is formed; c (C) _1-6 Alkyl optionally substituted with 1-3 substituents, each substituent independently selected from the group consisting of: NR 'R', -OH, C _1-6 Alkoxy, C _1-6 Haloalkoxy and halogen; -C (O) (C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; and C _1-4 An alkoxy group;

r of each occurrence ^g Independently selected from the group consisting of:

·C _3-10 cycloalkyl or C _3-10 Cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from oxo and R ^c ；

Heterocyclyl or heterocycloalkenyl comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And (2) at the same timeAnd wherein the heterocyclyl or heterocyclenyl is optionally substituted with 1-4 substituents independently selected from oxo and R ^c ；

Heteroaryl comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c Substitution; and

·C _6-10 aryl, optionally substituted with 1-4R ^c Substitution;

l of each occurrence ^g Independently selected from the group consisting of: -O-, -NH-, -NR ^d 、-S(O) _0-2 C (O) and optionally 1-3R ^a Substituted C _1-3 An alkylene group;

each g is independently 1, 2 or 3;

each R ^g2 Is divalent R ^g A group; and is also provided with

Each occurrence of R 'and R' is independently selected from the group consisting of: h is formed; -OH; and C _1-4 An alkyl group.

In some embodiments, when R is defined as ^2a 、R ^2b 、R ^3a And R is ^3b Each is H, R ^1c Is H or methyl; ring a is phenyl optionally substituted with 1-2F; x is X ¹ is-O-L ¹ -R ⁵ The method comprises the steps of carrying out a first treatment on the surface of the and-L ¹ Is CH ₂ And when the method is used, the following steps are carried out:

R ⁵ not unsubstituted phenyl or unsubstituted cyclopropyl; and is also provided with

Further, provision is made for the compound not to be: 3- ((3-fluoro-2-methoxyphenyl) amino) -2- (3- ((1-phenylpropan-2-yl) oxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one.

In one aspect, the disclosure features compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ selected from the group consisting ofThe following groups: (a) -O-L ¹ -R ⁵ The method comprises the steps of carrying out a first treatment on the surface of the And (b)

R ⁵ selected from the group consisting of:

heteroaryl comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c Substitution;

optionally by 1-4R ^c Substituted C _6-10 An aryl group;

·C _3-10 cycloalkyl or C _3-10 Cycloalkenyl, each optionally substituted with 1-4 substituents, each substituent independently selected from oxo and R ^c ；

Wherein ring D is a heterocyclylene or heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^X 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene or heterocyclylene group is optionally substituted with 1-4 substituents, each substituent independently selected from oxo and-R ^c ；

·-S(O) _0-2 (C _1-6 Alkyl) optionally substituted with 1-6R ^a Substitution;

·-R ^W ；

·-R ^g2 -R ^W or-R ^g2 -R ^Y ；

·-L ⁵ -R ^g2 -R ^W or-L ⁵ -R ^g2 -R ^Y ；

R ⁶ Selected from the group consisting of:

·H；

halogen;

·-OH；

·-NR ^e R ^f ；

·-R ^g ；

·-R ^w

·-L ⁶ -R ^g ；

·-R ^g2 -R ^W or-R ^g2 -R ^Y ；

·-L ⁶ -R ^g2 -R ^W or-L ⁶ -R ^g2 -R ^Y The method comprises the steps of carrying out a first treatment on the surface of the And

·-C _1-6 alkoxy or-S (O) _0-2 (C _1-6 Alkyl) each optionally substituted with 1-6R ^a Substitution;

L ⁵ and L ⁶ independently-O-, -S (O) _0-2 -NH or-N (R) ^d )-；

R ^W is-L ^W -W，

R ^X Is C (=O) (C _1-6 Alkyl) or S (O) ₂ (C _1-6 Alkyl groups), each of which is optionally covered by 1-6R ^a Substitution;

R ^Y selected from the group consisting of: -R ^g And- (L) ^g ) _g -R ^g ；

R ^1c 、R ^2a 、R ^2b 、R ^3a And R is ^3b Each independently selected from the group consisting of: h is formed; halogen; -OH; -C (O) OH or-C (O) NH ₂ ；-CN；-R ^b ；-L ^b -R ^b ；-C _1-6 Alkoxy or-C _1-6 Thioalkoxy groups, each of which is optionally substituted with 1-6R ^a Substitution; -NR ^e R ^f ；-R ^g And- (L) ^g ) _g -R ^g The method comprises the steps of carrying out a first treatment on the surface of the Provided that R ^1c Not halogen, -CN or-C (O) OH; or alternatively

Variable R ^1c 、R ^2a 、R ^2b 、R ^3a And R is ^3b Together with the ring atoms of ring B to which they are each attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms;

wherein 0 to 2 ring atoms are each independently selected heteroatoms (in-N (R) ^1c ) -when forming part of a condensed saturated or unsaturated ring, is not-N (R ^1c ) (-), wherein the independently selected heteroatoms are each selected from the group consisting of: n, NH, N (R) ^d ) O and S (O) _0-2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

Wherein the fused saturated or unsaturated ring of 3 to 12 ring atoms is optionally substituted with 1 to 4 substituents independently selected from oxo, R ^c And R is ^W ；

Ring A is R ^g ；

R ⁴ Selected from the group consisting of: h and R ^d ；

r of each occurrence ^a Independently selected from the group consisting of: -OH; halogen; -NR ^e R ^f ；C _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy groups; -C (=o) O (C _1-4 An alkyl group); -C (=o) (C _1-4 An alkyl group); -C (=o) OH; -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 Alkyl) and cyanogenA base;

r of each occurrence ^b Independently C _1-6 Alkyl, C _2-6 Alkenyl or C _2-6 Alkynyl, each of which is optionally substituted with 1-6R ^a Substitution;

r of each occurrence ^c Independently selected from the group consisting of: halogen; cyano group; r is independently selected from 1 to 6 ^a Optionally substituted C _1-10 An alkyl group; c (C) _3-5 Cycloalkyl; c (C) _2-6 Alkenyl groups; c (C) _2-6 Alkynyl; optionally by C _1-4 Alkoxy or C _1-4 Haloalkoxy-substituted C _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy groups; s (O) _1-2 (C _1-4 An alkyl group); -S (O) (=nh) (C _1-4 An alkyl group); -NR ^e R ^f ；–OH；-S(O) _1-2 NR’R”；-C _1-4 Thioalkoxy; -NO ₂ ；-C(＝O)(C _1-10 An alkyl group); -C (=o) O (C _1-4 An alkyl group); -C (=o) OH; -C (=o) NR' R "; and-SF ₅ ；

R of each occurrence ^d Independently selected from the group consisting of: c (C) _1-6 Alkyl, optionally R independently selected by 1-3 ^a Substitution; -C (O) (C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; and C _1-4 An alkoxy group;

r of each occurrence ^e And R is ^f Independently selected from the group consisting of: h is formed; optionally by 1-3C _1-3 Alkyl substituted C _3-5 Cycloalkyl; heterocyclyl comprising 3 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 They are optionally substituted with 1 to 4 substituents, each substituent independently selected from oxo and R ^c The method comprises the steps of carrying out a first treatment on the surface of the And C optionally substituted with 1-3 substituents _1-6 Alkyl, each substituent being independently selected from NR 'R', -OH, C _1-6 Alkoxy, C _1-6 Haloalkoxy and halogen; -C (O) (C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; c (C) _1-4 An alkoxy group;

r of each occurrence ^g Independently selected from the group consisting of:

Heterocyclyl or heterocycloalkenyl comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl or heterocyclenyl is optionally substituted with 1-4 substituents independently selected from oxo and R ^c ；

optionally by 1-4R ^c Substituted C _6-10 An aryl group;

each g is independently 1,2 or 3;

each R ^g2 Is divalent R ^g A group; and is also provided with

Each occurrence of R 'and R' is independently selected from the group consisting of: h is formed; -OH and C _1-4 An alkyl group;

in some embodiments, when R ^2a 、R ^2b 、R ^3a And R is ^3b Each is H; r is R ^1c Is H or methyl; ring a is phenyl optionally substituted with 1-2F; x is X ¹ is-O-L ¹ -R ⁵ The method comprises the steps of carrying out a first treatment on the surface of the and-L ¹ Is CH ₂ And when the method is used, the following steps are carried out:

It is also specified that the compound is not: 3- ((3-fluoro-2-methoxyphenyl) amino) -2- (3- ((1-phenylpropan-2-yl) oxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one.

Also provided herein are pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

Also provided herein is a method of treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

Provided herein is a method of treating an EGFR-related disease or disorder in a subject, the method comprising: administering to a subject identified or diagnosed as having an EGFR-related disease or disorder a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

The present disclosure also provides a method of treating an EGFR-related disease or disorder in a subject, the method comprising: determining that the cancer of the subject is an EGFR-related disease or disorder; and administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein. Also provided herein is a method of treating an EGFR-related cancer in a subject, the method comprising: administering to a subject identified or diagnosed as having EGFR-related cancer a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

The present disclosure also provides a method of treating an EGFR-associated cancer in a subject, the method comprising: determining that the cancer of the subject is an EGFR-associated cancer; and administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

Provided herein is a method of treating a subject, the method comprising: administering to a subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, the clinical record of which is indicative of abnormal expression or activity or level of EGFR gene, EGFR kinase, or any of them, in the subject.

Also provided herein is a method of treating a subject having cancer, wherein the method comprises:

(a) Administering one or more doses of a first EGFR inhibitor to a subject over a period of time;

(b) After (a), determining whether cancer cells in a sample obtained from the subject have at least one EGFR inhibitor resistance mutation that increases the resistance of the cancer cells or tumor to treatment with the first EGFR inhibitor of step (a); and

(c) If the subject is determined to have at least one EGFR inhibitor resistance mutation in the cancer cells and the resistance mutation is such that the cancer cells or tumor have increased resistance to treatment with the first EGFR inhibitor of step (a), administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with another anticancer agent; or alternatively

(d) If the subject is not determined to have at least one EGFR inhibitor resistance mutation in the cancer cell and the resistance mutation is such that the cancer cell or tumor has increased resistance to treatment with the first EGFR inhibitor of step (a), then an additional dose of the first EGFR inhibitor of step (a) is administered to the subject.

(a) Determining whether cancer cells in a sample obtained from a subject having cancer and previously administered one or more doses of a first EGFR inhibitor have one or more EGFR inhibitor resistance mutations that increase the resistance of the cancer cells or tumor to treatment with the first EGFR inhibitor previously administered to the subject; and

(b) If a subject is determined to have at least one EGFR inhibitor resistance mutation in a cancer cell and the resistance mutation is such that the cancer cell or tumor has increased resistance to treatment with a first EGFR inhibitor previously administered to the subject, then administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, administered as monotherapy or in combination with another anticancer agent; or alternatively

(c) If the subject is not determined to have at least one EGFR inhibitor resistance mutation in the cancer cells and the resistance mutation is such that the cancer cells or tumor have increased resistance to treatment with a first EGFR inhibitor previously administered to the subject, then an additional dose of the first EGFR inhibitor is administered to the subject.

(a) Determining that cancer cells in a sample obtained from a subject having cancer and previously administered one or more doses of a first EGFR inhibitor have one or more EGFR inhibitor resistance mutations that increase the resistance of the cancer cells or tumor to treatment with the first EGFR inhibitor previously administered to the subject; and

(b) Administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with another anticancer agent.

(a) Determining that cancer cells in a sample obtained from a subject having cancer and previously administered one or more doses of a first EGFR inhibitor do not have one or more EGFR inhibitor resistance mutations that increase the resistance of the cancer cells or tumor to treatment with the first EGFR inhibitor previously administered to the subject; and

(b) An additional dose of the first EGFR inhibitor is administered to the subject.

The present disclosure also provides a method of inhibiting EGFR in mammalian cells, the method comprising: contacting a mammalian cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with dysregulation of expression or activity or level of HER2 gene, HER2 kinase, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

Also provided herein is a method of treating HER 2-related cancer in a subject, the method comprising: administering to a subject identified or diagnosed as having HER 2-associated cancer a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

The present disclosure also provides a method of treating HER 2-related cancer in a subject, the method comprising: determining that the cancer of the subject is HER 2-related cancer; and administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

Provided herein is a method of treating a subject having cancer, the method comprising: administering to a subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, the clinical record of which is indicative of abnormal expression or activity or level of HER2 gene, HER2 kinase, or any of them in the subject.

(a) Administering one or more doses of a first HER2 inhibitor to the subject over a period of time;

(b) After (a), determining whether cancer cells in a sample obtained from the subject have at least one HER2 inhibitor resistance mutation that increases the resistance of the cancer cells or tumor to treatment with the first HER2 inhibitor of step (a); and

(c) If the subject is determined to have at least one HER2 inhibitor resistance mutation in the cancer cells and the resistance mutation is such that the cancer cells or tumor have increased resistance to treatment with the first HER2 inhibitor of step (a), administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with another anticancer agent; or alternatively

(d) If the subject is not determined to have at least one HER2 inhibitor resistance mutation in the cancer cells and the resistance mutation is such that the cancer cells or tumor have increased resistance to treatment with the first HER2 inhibitor of step (a), then administering an additional dose of the first HER2 inhibitor of step (a) to the subject.

(a) Determining whether cancer cells in a sample obtained from a subject having cancer and previously administered one or more doses of a first HER2 inhibitor have one or more HER2 inhibitor resistance mutations that increase the resistance of the cancer cells or tumor to treatment with the first HER2 inhibitor previously administered to the subject; and

(b) If the subject is determined to have at least one HER2 inhibitor resistance mutation in the cancer cells and the resistance mutation is such that the cancer cells or tumor have increased resistance to treatment with a first HER2 inhibitor previously administered to the subject, then administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, administered as monotherapy or in combination with another anticancer agent; or alternatively

(c) If the subject is not determined to have at least one HER2 inhibitor resistance mutation in the cancer cells and the resistance mutation is such that the cancer cells or tumor have increased resistance to treatment with the first HER2 inhibitor previously administered to the subject, then an additional dose of the first HER2 inhibitor is administered to the subject.

(a) Determining that cancer cells in a sample obtained from a subject having cancer and having previously been administered one or more doses of a first HER2 inhibitor have one or more HER2 inhibitor resistance mutations that increase the resistance of the cancer cells or tumor to treatment with the first HER2 inhibitor previously administered to the subject; and

(a) Determining that cancer cells in a sample obtained from a subject having cancer and having previously been administered one or more doses of a first HER2 inhibitor do not have one or more HER2 inhibitor resistance mutations that increase the resistance of the cancer cells or tumor to treatment with the previously administered first HER2 inhibitor of the subject; and

(b) Administering to the subject an additional dose of a first HER2 inhibitor.

The present disclosure also provides a method of inhibiting HER2 in a mammalian cell, the method comprising: contacting a mammalian cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any of them, and that the cancer is associated with dysregulation of expression or activity or level of a HER2 gene, an HER2 kinase, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

Also provided herein is a method of treating EGFR-related and HER 2-related cancers in a subject, the method comprising: administering to a subject identified or diagnosed as having EGFR-related and HER 2-related cancers a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

The present disclosure also provides a method of treating EGFR-related and HER 2-related cancers in a subject, the method comprising: determining that the cancer of the subject is an EGFR-related and HER 2-related cancer; and administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

Provided herein is a method of treating a subject, the method comprising: administering to a subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, the clinical record of which is indicative of abnormal expression or activity or level regulation of the EGFR gene, EGFR kinase, or any of them, and HER2 gene, HER2 kinase, or any of them, in the subject.

The present disclosure also provides a method of inhibiting EGFR and HER2 in a mammalian cell, the method comprising: contacting a mammalian cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In addition to the above, provided herein is a method of inhibiting BUB (benzimidazole breakdown of budding inhibition, BUB 1-3) kinase. In some embodiments, the methods provided herein include methods for inhibiting BUB 11. For example, a method for inhibiting BUB1 in a mammalian cell, the method comprising: contacting a mammalian cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Other embodiments include those described in the detailed description and/or claims.

Additional definitions

In order to facilitate an understanding of the disclosure set forth herein, a number of additional terms are defined below. In general, the nomenclature used herein and the laboratory procedures in organic chemistry, pharmaceutical chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications cited in this specification and the appendix are incorporated herein by reference in their entirety.

As used herein, the term "acceptable" with respect to a formulation, composition or ingredient refers to having no persistent deleterious effect on the overall health of the subject being treated.

"API" refers to the active pharmaceutical ingredient.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a chemical entity administered sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent. The result includes a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein required to provide clinically significant relief of symptoms of a disease. In any independent case, an appropriate "effective" amount is determined using any suitable technique, such as a dose escalation study.

The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation, and is suitable for contact with tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit/risk ratio. See, e.g., ramington: pharmaceutical science and practice (Remington: the Science and Practice of Pharmacy), 21 st edition, lippincott Williams & Wilkins, philadelphia, pennsylvania, 2005; handbook of pharmaceutical excipients (Handbook of Pharmaceutical Excipients), 6 th edition, rowe et al, editions of pharmaceutical publishers and American pharmaceutical society (The Pharmaceutical Press and the American Pharmaceutical Association): 2009; and handbook of pharmaceutical additives (Handbook of Pharmaceutical Additives), 3 rd edition, ash and Ash writing, gower publishing company 2007; pharmaceutical Pre-formulation and formulation (Pharmaceutical Preformulation and Formulation), 2 nd edition, gibson, CRC Press Co., ltd., bokapton, florida, 2009.

The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some cases, pharmaceutically acceptable salts are obtained by reacting a compound having an acidic group as described herein with a base to form a salt, such as an ammonium salt, an alkali metal salt (e.g., sodium or potassium salt), an alkaline earth metal salt (e.g., calcium or magnesium salt), a salt of an organic base (e.g., dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine), and a salt with an amino acid (e.g., arginine, lysine, etc.), or by other previously determined methods. The pharmacologically acceptable salt is not particularly limited as long as it can be used for a pharmaceutical agent. Examples of salts of the compounds described herein with bases include the following: salts with inorganic bases, for example, sodium, potassium, magnesium, calcium and aluminum salts; salts with organic bases, for example, methylamine, ethylamine and ethanolamine salts; salts with basic amino acids, such as lysine and ornithine; and ammonium salts. The salt may be an acid addition salt, and specifically, an acid addition salt formed with: inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids, for example, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents, and/or thickening agents. The pharmaceutical compositions may facilitate administration of the compounds to an organism. There are a number of techniques in the art for administering compounds including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary and topical administration.

The term "subject" refers to an animal, including but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein when referring to a mammalian subject (e.g., a human), for example.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "oxo" refers to a divalent double bond bonded oxygen atom (i.e., "=o"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl group.

The term "alkyl" refers to a saturated acyclic hydrocarbon group, which may be straight or branched, containing the indicated number of carbon atoms. For example, C _1-10 The indicator group may have 1 to 10 carbon atoms in it. The alkyl group may be unsubstituted or substituted with one or more substituents. Non-limiting examples include: methyl, ethyl, isopropyl, tert-butyl, n-hexyl. The term "saturated" as used in this context means that there is only a single bond between the constituent carbon atoms and other valences occupied by hydrogen and/or other substituents as defined herein.

The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by an independently selected halogen.

The term "alkoxy" refers to-O-alkyl (e.g., -OCH) ₃ )。

The term "alkylene" refers to a divalent alkyl group (e.g., -CH ₂ -). Similarly, the terms "cycloalkylene" and "heterocyclylene" refer to divalent cycloalkyl and heterocyclyl, respectively. For the avoidance of doubt, in "cycloalkylene" and "heterocyclylene" two (root) groups may be on the same ring carbon atom (e.g., geminal, e.g.,) Or on different ring atoms [ e.g., ring carbon and/or nitrogen atoms (e.g., adjacent ring carbon and/or nitrogen atoms)](e.g.)>

The term "alkenyl" refers to an acyclic hydrocarbon chain having one or more carbon-carbon double bonds, which may be straight or branched. The alkenyl moiety comprises the indicated number of carbon atoms. For example, C _2-6 The indicator group may have 2 to 6 (inclusive) carbon atoms therein. Alkenyl groups may be unsubstituted or substituted with one or more substituents. Alkenyl groups may be trans or cis.

The term "alkynyl" refers to an acyclic hydrocarbon chain having one or more carbon-carbon triple bonds, which may be straight or branched. The alkynyl moiety contains the indicated number of carbon atoms. For example, C _2-6 The indicator group may have 2 to 6 (inclusive) carbon atoms therein. Alkynyl groups may be unsubstituted or substituted with one or more substituents.

The term "aryl" refers to a 6-20 carbon monocyclic, bicyclic, tricyclic, or polycyclic group wherein at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted with substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

The term "cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein cycloalkyl may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Cycloalkyl groups may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl groups include: bicyclo [1.1.0] butane, bicyclo [2.1.0] pentane, bicyclo [1.1.1] pentane, bicyclo [3.1.0] hexane, bicyclo [2.1.1] hexane, bicyclo [3.2.0] heptane, bicyclo [4.1.0] heptane, bicyclo [2.2.1] heptane, bicyclo [3.1.1] heptane, bicyclo [4.2.0] octane, bicyclo [3.2.1] octane, bicyclo [2.2.2] octane, and the like. Cycloalkyl also includes spiro rings (e.g., spiro bicyclic rings in which two rings are connected by only one atom). Non-limiting examples of spirocycloalkyl groups include: spiro [2.2] pentane, spiro [2.5] octane, spiro [3.5] nonane, spiro [4.4] nonane, spiro [2.6] nonane, spiro [4.5] decane, spiro [3.6] decane, spiro [5.5] undecane, and the like. The term "saturated" as used in this context means that there is only a single bond between the constituent carbon atoms.

The term "cycloalkenyl" as used herein refers to partially unsaturated cyclic hydrocarbon groups having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl groups may be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As partially unsaturated cyclic hydrocarbon groups, cycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds are present in the ring, none of the rings in the ring system are aromatic, and cycloalkenyl groups are generally not fully saturated. Cycloalkenyl groups may include a plurality of fused and/or bridged and/or spiro rings.

The term "heteroaryl" as used herein means a monocyclic, bicyclic, tricyclic or polycyclic group having 5 to 20 ring atoms, or 5, 6, 9, 10 or 14 ring atoms; wherein at least one ring in the system comprises one or more heteroatoms independently selected from N, O and S, and at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include: thienyl, pyridyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, and the like pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl A group, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazole, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido [2,3-d ]]Pyrimidinyl, pyrrolo [2,3-b]Pyridinyl, quinazolinyl, quinolinyl, thieno [2,3-c]Pyridinyl, pyrazolo [3,4-b]Pyridinyl, pyrazolo [3,4-c]Pyridinyl, pyrazolo [4,3-c]Pyrido, pyrazolo [4,3-b]Pyridyl, tetrazolyl, chromane, 2, 3-dihydrobenzo [ b ]][1,4]Dioxins and benzo [ d ]][1,3]M-dioxole, 2, 3-dihydrobenzofuran, tetrahydroquinoline, 2, 3-dihydrobenzo [ b ]][1,4]Oxathiamine (oxathiamine), isoindoline, and the like. In some embodiments, heteroaryl is selected from thienyl, pyridyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For clarity, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, wherein each ring nitrogen adjacent to the carbonyl group is a tertiary nitrogen (i.e., all trivalent is occupied by a non-hydrogen substituent), such as one or more of the following: pyridone (e.g., ) Pyrimidinone (e.g.)>) Pyridazinone (e.g.)>) Pyrazinones (e.g.)>) And imidazolinones (e.g.)>) Wherein each ring nitrogen adjacent to the carbonyl group (i.e., oxo group (i.e., "=o"), here being part of a heteroaryl ring) is a tertiary nitrogen.

The term "heterocyclyl" refers to a mono-, bi-, tri-or polycyclic saturated ring system having 3 to 16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system), which has 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic, which are selected from O, N or S (e.g., heteroatoms having carbon atoms and 1 to 3 (if monocyclic), 1 to 6 (if bicyclic), or 1 to 9 (if tricyclic) N, O or S), wherein 0, 1, 2, or 3 atoms of each ring may be substituted with substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. The heterocyclyl may include a plurality of fused and bridged rings. Non-limiting examples of fused/bridged heterocyclyl groups include: 2-azabicyclo [1.1.0] butane, 2-azabicyclo [2.1.0] pentane, 2-azabicyclo [1.1.1] pentane, 3-azabicyclo [3.1.0] hexane, 5-azabicyclo [2.1.1] hexane, 3-azabicyclo [3.2.0] heptane, octahydrocyclopentan [ c ] pyrrole, 3-azabicyclo [4.1.0] heptane, 7-azabicyclo [2.2.1] heptane, 6-azabicyclo [3.1.1] heptane, 7-azabicyclo [4.2.0] octane, 2-azabicyclo [2.2.2] octane, 3-azabicyclo [3.2.1] octane, 2-oxabicyclo [1.1.0] butane, 2-oxabicyclo [2.1.0] pentane, 2-oxabicyclo [1.1.1] pentane, 3-oxabicyclo [3.1.0] hexane, 5-oxabicyclo [ 3.1.1.0 ] heptane, 7-oxabicyclo [ 3.1.1.1 ] heptane, 7-oxabicyclo [ 2.1.1.0 ] octane, 2.1-oxabicyclo [ 3.1.1.1 ] heptane, 2.0-oxabicyclo [ 2.1.1.1.0 ] heptane, 2-oxabicyclo [ 3.1.1.0 ] octane, 2.1-oxabicyclo [ 2.1.1.0 ] octane. Heterocyclyl also includes spiro rings (e.g., spiro bicyclic rings in which two rings are connected by only one atom). Non-limiting examples of spiroheterocyclyl groups include 2-azaspiro [2.2] pentane, 4-azaspiro [2.5] octane, 1-azaspiro [3.5] nonane, 2-azaspiro [3.5] nonane, 7-azaspiro [3.5] nonane, 2-azaspiro [4.4] nonane, 6-azaspiro [2.6] nonane, 1, 7-diazaspiro [4.5] decane, 7-azaspiro [4.5] decane 2, 5-diazaspiro [3.6] decane, 3-azaspiro [5.5] undecane 2-oxaspiro [2.2] pentane, 4-oxaspiro [2.5] octane, 1-oxaspiro [3.5] nonane, 2-oxaspiro [3.5] nonane, 7-oxaspiro [3.5] nonane, 2-oxaspiro [4.4] nonane, 6-oxaspiro [2.6] nonane, 1, 7-dioxaspiro [4.5] decane, 2, 5-dioxaspiro [3.6] decane, 1-oxaspiro [5.5] undecane, 3-oxa-9-azaspiro [5.5] undecane and the like. The term "saturated" as used in this context means that there is only a single bond between the constituent ring atoms and other valences occupied by hydrogen and/or other substituents as defined herein.

The term "heterocycloalkenyl" refers to a partially unsaturated cyclic ring system having 3-16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system), which has 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, selected from O, N or S (e.g., heteroatoms having carbon atoms and 1-3 (if monocyclic), 1-6 (if bicyclic), or 1-9 (if tricyclic) N, O or S), wherein 0, 1, 2, or 3 atoms of each ring may be substituted with substituents. Examples of heterocycloalkenyl groups include, but are not limited to, tetrahydropyridinyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl (dihydrothiophenyl). As partially unsaturated cyclic hydrocarbon groups, heterocyclenyl groups may have any degree of unsaturation provided that one or more double bonds are present in the ring, none of the rings in the ring system are aromatic, and heterocyclenyl groups are generally not fully saturated. Heterocycloalkenyl groups can include multiple fused and/or bridged and/or spiro rings.

As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like.

As used herein, when a ring is described as "partially unsaturated," it means that the ring has one or more additional unsaturations (in addition to the unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between the constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

For the avoidance of doubt, unlessIt is further provided that for rings and ring groups (e.g., aryl, heteroaryl, heterocyclyl, heterocyclenyl, cycloalkenyl, cycloalkyl, etc., as described herein) containing a sufficient number of ring atoms to form a bicyclic or higher ring system (e.g., tricyclic, polycyclic system), it is to be understood that such rings and ring groups include those having fused rings, including those in which the fused point is located (i) on an adjacent ring atom (e.g., [ x.x.0)]Ring systems in which 0 represents zero atomic bridges (e.g) A) is provided; (ii) On a single ring atom (spiro-condensed ring system) (e.g) Or (iii) on ring atoms of successive arrays (e.g. all bridge lengths)>0) (e.g. +. >)。

Furthermore, the atoms constituting the compounds of the present embodiment are intended to include all isotopic forms of those atoms. Isotopes as used herein include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, isotopes of carbon include ¹³ C and C ¹⁴ C。

Furthermore, compounds disclosed herein, either generically or specifically, are intended to include all tautomeric forms. Thus, for example, comprisesPartial compounds cover compounds comprising +>Partially tautomeric forms. Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted with hydroxy encompass pyridone or pyrimidinone tautomeric forms.

The compounds provided herein may comprise various stereochemical forms. The compounds also include diastereomers as well as optical isomers, e.g., mixtures of enantiomers, including racemic mixtures, as well as individual enantiomers and diastereomers resulting from structural asymmetry of certain compounds. Unless otherwise indicated, when a disclosed compound is named or described by structure but does not specify stereochemistry and has one or more chiral centers, it is to be understood as meaning all possible stereoisomers of the compound.

The details of one or more aspects of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

Detailed Description

The present disclosure provides chemical entities (e.g., compounds or pharmaceutically acceptable salts, and/or hydrates, and/or co-crystals, and/or pharmaceutical combinations of the compounds) that inhibit epidermal growth factor receptor (EGFR, ERBB 1) and/or human epidermal growth factor receptor 2 (HER 2, ERBB 2). These chemical entities are e.g. used for the treatment of a condition, disease or disorder in which increased (e.g. excessive) EGFR and/or HER2 activity contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g. cancer) in a subject (e.g. a human). In some embodiments, a chemical entity provided herein can inhibit EGFR kinase and/or HER2 having an exon 20 mutation (e.g., any of the exon 20 mutations described herein). Exon 20 mutations can confer intrinsic resistance to EGFR and/or HER2 inhibitors, and only limited targeted therapies are currently approved for subjects with these mutations. The disclosure also provides compositions comprising the chemical entities provided herein, and methods of use and manufacture thereof.

A compound of formula (I)

In one aspect, the disclosure features compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R ⁵ selected from the group consisting of:

optionally by 1-4R ^c Substituted C _6-10 An aryl group;

·-S(O) _0-2 (C _1-6 Alkyl) optionally substituted with 1-6R ^a Substitution;

·-R ^g2 -R ^W or-R ^g2 -R ^Y ；

·-L ⁵ -R ^g2 -R ^W or-L ⁵ -R ^g2 -R ^Y ；

R ⁶ Selected from the group consisting of:

·H；

halogen;

·-OH；

·-NR ^e R ^f ；

·-R ^g ；

·-L ⁶ -R ^g ；

·-R ^g2 -R ^W or-R ^g2 -R ^Y ；

·-L ⁶ -R ^g2 -R ^W Or L ⁶ -R ^g2 -R ^Y The method comprises the steps of carrying out a first treatment on the surface of the And

L ⁵ and L ⁶ independently-O-, -S (O) _0-2 -NH or-N (R) ^d )-；

R ^W is-L ^W -W，

R ^X Is C (=O) (C _1-6 Alkyl) or S (O) ₂ (C _1-6 Alkyl group) Each of which is optionally substituted with 1 to 6R ^a Substitution;

R ^Y selected from the group consisting of: -R ^g And- (L) ^g ) _g -R ^g ；

R ^1c 、R ^2a 、R ^2b 、R ^3a And R is ^3b Each independently selected from the group consisting of: h is formed; halogen; -OH; -C (O) OH or-C (O) NH ₂ ；-CN；-R ^b ；-L ^b -R ^b ；-C _1-6 Alkoxy or-C _1-6 Thioalkoxy groups, each of which is optionally substituted with 1-6R ^a Substitution; -NR ^e R ^f ；-R ^g The method comprises the steps of carrying out a first treatment on the surface of the And- (L) ^g ) _g -R ^g The method comprises the steps of carrying out a first treatment on the surface of the Provided that R ^1c Not halogen, -CN or-C (O) OH; or alternatively

wherein 0 to 2 ring atoms are each independently selected heteroatoms (in-N (R) ^1c ) -when forming part of a condensed saturated or unsaturated ring, is not-N (R ^1c ) -beyond), wherein the independently selected heteroatoms are each selected from the group consisting of: n, NH, N (R) ^d ) O and S (O) _0-2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

Ring A is R ^g ；

R ⁴ Selected from the group consisting of: h and R ^d ；

r of each occurrence ^e And R is ^f Independently selected from the group consisting of: h is formed; c optionally substituted with 1-3 substituents _1-6 Alkyl, each substituent being independently selected from NR 'R', -OH, C _1-6 Alkoxy, C _1-6 Haloalkoxy and halogen; -C (O) (C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; and C _1-4 Alkoxy radicalA base;

r of each occurrence ^g Independently selected from the group consisting of:

optionally by 1-4R ^c Substituted C _6-10 An aryl group;

each g is independently 1,2 or 3;

each R ^g2 Is divalent R ^g A group; and is also provided with

In one aspect, the disclosure features compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R ⁵ selected from the group consisting of:

optionally by 1-4R ^c Substituted C _6-10 An aryl group;

Wherein ring D is a heterocyclylene or heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^X 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene or heterocyclylene is optionally substituted with 1-4 substituents, each substituent independently selected from oxo and-R ^c ；

·-S(O) _0-2 (C _1-6 Alkyl) optionally substituted with 1-6R ^a Substitution;

·-R ^g2 -R ^W or-R ^g2 -R ^Y ；

·-L ⁵ -R ^g2 -R ^W or-L ⁵ -R ^g2 -R ^Y ；

R ⁶ Selected from the group consisting of:

·H；

halogen;

·-OH；

·-NR ^e R ^f ；

·-R ^g ；

·-L ⁶ -R ^g ；

·-R ^g2 -R ^W or-R ^g2 -R ^Y ；

L ⁵ and L ⁶ independently-O-, -S (O) _0-2 -NH or-N (R) ^d )-；

R ^W is-L ^W -W，

W is C _2-6 Alkenyl groups; c (C) _2-6 Alkynyl; or C _3-10 Cumulatively dienyl, each of which is optionally substituted with 1-3R ^a Substituted and also optionally substituted with R ^g Substitution, where W is through sp ² Or sp hybridized carbon atom to L ^W Thereby providing an α, β -unsaturated system; and is also provided with

R ^X Is C (=O) (C _1-6 Alkyl) or S (O) ₂ (C _1-6 Alkyl) each optionally substituted with 1-6R ^a Substitution;

R ^1c 、R ^2a 、R ^2b 、R ^3a And R is ^3b Each independently selected from the group consisting of: h is formed; halogen; -OH; -C (O) OH or-C (O) NH ₂ ；-CN；-R ^b ；-L ^b -R ^b ；-C _1-6 Alkoxy or-C _1-6 Thioalkoxy groups, each of which is optionally substituted with 1-6R ^a Substitution; NR (NR) ^e R ^f ；-R ^g The method comprises the steps of carrying out a first treatment on the surface of the And- (L) ^g ) _g -R ^g The method comprises the steps of carrying out a first treatment on the surface of the Provided that R ^1c Not halogen, -CN or-C (O) OH; or alternatively

Ring A is R ^g ；

R ⁴ Selected from the group consisting of: h and R ^d ；

r of each occurrence ^a Independently selected from the group consisting of: -OH; halogen; -NR ^e R ^f ；C _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy groups; -C (=o) O (C _1-4 An alkyl group); -C (=o) (C _1-4 An alkyl group); -C (=o) OH; -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); and cyano;

each of which isL of occurrence ^b Independently C (=o); c (=o) O; s (O) _1-2 ；C(＝O)NH*；C(＝O)NR ^d *；S(O) _1- ₂ NH; or S (O) _1-2 N(R ^d ) Wherein asterisks represent the linkage to R ^b Is a point of (2);

r of each occurrence ^e And R is ^f Independently selected from the group consisting of: h is formed; c optionally substituted with 1-3 substituents _1-6 Alkyl, each substituent being independently selected from NR 'R', -OH, C _1-6 Alkoxy, C _1-6 Haloalkoxy and halogen; -C (O) (C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; and C _1-4 An alkoxy group;

r of each occurrence ^g Independently selected from the group consisting of:

optionally by 1-4R ^c Substituted C _6-10 An aryl group;

each g is independently 1,2 or 3;

each R ^g2 Is divalent R ^g A group; and is also provided with

Each occurrence of R 'and R' is independently selected from the group consisting of: h is formed; -OH; and C _1-4 An alkyl group;

in some embodiments, when R is defined as ^2a ,R ^2b ,R ^3a And R is ^3b Each is H; r is R ^1c Is H or methyl; ring a is phenyl optionally substituted with 1-2F; x is X ¹ is-O-L ¹ -R ⁵ The method comprises the steps of carrying out a first treatment on the surface of the and-L ¹ is CH ₂ And when the method is used, the following steps are carried out:

In one aspect, the disclosure features compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R ⁵ selected from the group consisting of:

optionally by 1-4R ^c Substituted C _6-10 An aryl group;

·-S(O) _0-2 (C _1-6 Alkyl) optionally substituted with 1-6R ^a Substitution;

·-R ^W

·-R ^g2 -R ^W or-R ^g2 -R ^Y ；

·-L ⁵ -R ^g2 -R ^W or-L ⁵ -R ^g2 -R ^Y ；

R ⁶ Selected from the group consisting of:

·H；

halogen;

·-OH；

·-NR ^e R ^f ；

·-R ^g ；

·-R ^w

·-L ⁶ -R ^g ；

·-R ^g2 -R ^W or-R ^g2 -R ^Y ；

L ⁵ and L ⁶ independently-O-, -S (O) _0-2 -NH or-N (R) ^d )-；

R ^W is-L ^W -W，

R ^X is C(＝O)(C _1-6 Alkyl) or S (O) ₂ (C _1-6 Alkyl) each optionally substituted with 1-6R ^a Substitution;

R ^Y selected from the group consisting of: -R ^g And- (L) ^g ) _g -R ^g ；

Ring A is R ^g ；

R ⁴ Selected from the group consisting of: h and R ^d ；

r of each occurrence ^c Independently selected from the group consisting of: halogen; cyano group; r is independently selected from 1 to 6 ^a Optionally substituted C _1-10 An alkyl group; c (C) _3-5 Cycloalkyl; c (C) _2-6 Alkenyl groups; c (C) _2-6 Alkynyl; c (C) _1-4 Alkoxy, optionally C _1-4 Alkoxy or C _1-4 Haloalkoxy substitution; c (C) _1-4 Haloalkoxy groups; s (O) _1-2 (C _1-4 An alkyl group); -S (O) (=nh) (C _1-4 An alkyl group); -NR ^e R ^f ；–OH；-S(O) _1-2 NR’R”；-C _1-4 Thioalkoxy; -NO ₂ ；-C(＝O)(C _1-10 An alkyl group); -C (=o) O (C _1-4 An alkyl group); -C (=o) OH; -C (=o) NR' R "; and-SF ₅ ；

R of each occurrence ^d Independently selected from the group consisting of: c (C) _1-6 Alkyl, optionally substituted with 1-3 independently selected R ^a Substitution; -C (O) (C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; c (C) _1-4 An alkoxy group;

r of each occurrence ^e And R is ^f Independently selected from the group consisting of: h is formed; optionally by 1-3C _1-3 Alkyl substituted C _3-5 Cycloalkyl; heterocyclyl comprising 3 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatomIndependently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 Which is optionally substituted with 1 to 4 substituents, each substituent being independently selected from oxo and R ^c The method comprises the steps of carrying out a first treatment on the surface of the And C optionally substituted with 1-3 substituents _1-6 Alkyl, each substituent being independently selected from NR 'R', -OH, C _1-6 Alkoxy, C _1-6 Haloalkoxy and halogen; -C (O) (C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; c (C) _1-4 An alkoxy group;

r of each occurrence ^g Independently selected from the group consisting of:

Heterocyclyl or heterocycloalkenyl comprising 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl or heterocyclenyl is optionally substituted with 1-4 substituents independently selected from oxo and R ^c ；

optionally by 1-4R ^c Substituted C _6-10 An aryl group;

l of each occurrence ^g Independently selected from the group consisting of: -O-, -NH-, -NR ^d 、-S(O) _0-2 C (O), and optionally by 1-3R ^a Substituted C _1-3 An alkylene group;

each g is independently 1, 2 or 3;

each R ^g2 Is divalent R ^g A group; and is also provided with

In some embodiments, when R ⁵ Or R is ⁶ When heteroaryl, the heteroaryl is not an aromatic lactam, an aromatic cyclic urea, or an vinylogous analog thereof, wherein each ring nitrogen adjacent to the carbonyl group is a tertiary nitrogen (i.e., all three valences are occupied by a non-hydrogen substituent, e.g., one or more of pyridone (e.g.) Pyrimidinone (e.g.)>) Pyridazinone (e.g.)>) Pyrazinones (e.g.)> ) And imidazolinones (e.g) Wherein each ring nitrogen adjacent to the carbonyl group (i.e., oxo group (i.e., "=o"), here being part of a heteroaryl ring) is a tertiary nitrogen.

In some embodiments, when R ⁵ Or R is ⁶ In the case of heteroaryl, the heteroaryl is not substituted by-OH.

Variable X ¹

When X is ¹ is-O-L ¹ -R ⁵ Embodiment of the invention

In some embodiments, X ¹ is-O-L ¹ -R ⁵ 。

In some of these embodiments, R ⁵ Is a heteroaryl group comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

In certain embodiments, R ⁵ Is a monocyclic heteroaryl group comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroaryl group is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

In some of the foregoing embodiments, R ⁵ Is a monocyclic heteroaryl group comprising 5 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroaryl group is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

In certain embodiments, R ⁵ Selected from the group consisting of: furyl, thienyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, each of which is optionally substituted with 1-2R ^cA Substituted, and the ring nitrogen is optionally substituted by R ^d Substitution, wherein each R ^cA R is independently selected ^c 。

As a non-limiting example of the foregoing embodiment, R ⁵ May be selected from the group consisting of: each of which is optionally substituted with 1-2R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

In certain embodiments, R ⁵ Selected from the group consisting of: furyl, thienyl, oxadiazolyl, thiadiazolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, each of which is optionally substituted with 1-2R ^cA Substituted, and the ring nitrogen is optionally substituted by R ^d Substitution, wherein each R ^cA R is independently selected ^c 。

As a non-limiting example of the foregoing embodiment, R ⁵ May be selected from the group consisting of: each of which is optionally substituted with 1-2R ^cA Substitution, wherein each R ^cA R is independently selected ^c . For example, R ⁵ Can be +.>As a further non-limiting example, R ⁵ Can be +.> And optionally R ^d May be C _1-3 An alkyl group.

In certain embodiments, R ⁵ Is a monocyclic heteroaryl group comprising 6 ring atoms, wherein 1 to 4 ring atoms are ring nitrogen atoms, and wherein the heteroaryl group is optionally substituted with 1 to 4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

In certain embodiments, R ⁵ Selected from the group consisting of: pyridyl, pyridonyl, pyrimidinyl, pyrazinyl and pyridazinylEach of which is optionally substituted with 1 to 3R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

As a non-limiting example of the foregoing embodiment, R ⁵ May be selected from the group consisting of: for example, a->For example, a->Each of which is optionally R ^cA Further substitution, wherein each R ^cA R is independently selected ^c 。

In some of these embodiments, R ⁵ Selected from the group consisting of: pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, each of which is optionally substituted with 1-3R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

As a non-limiting example of the foregoing embodiment, R ⁵ May be selected from the group consisting of: (e.g.)>) The method comprises the steps of carrying out a first treatment on the surface of the And->(e.g.)>) Each of which is optionally R ^cA Further substitution of each ofR is a number of ^cA R is independently selected ^c 。

As a non-limiting example, R ⁵ May be selected from the group consisting of:(e.g.)>) Each of which is optionally R ^cA Further substitution, wherein each R ^cA R is independently selected ^c 。

In certain embodiments, R ⁵ Is a bicyclic heteroaryl group comprising 8 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

In some of these embodiments, R ⁵ Is a bicyclic heteroaryl group comprising 8 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

As a non-limiting example of the foregoing embodiment, R ⁵ May be selected from the group consisting of: each of which is optionally substituted with 1-2R ^cA Further substitution, wherein each R ^cA R is independently selected ^c 。

As a non-limiting example, R ⁵ May be selected from the group consisting of: each of which is optionally substituted with 1-2R ^cA Further substitution, wherein each R ^cA R is independently selected ^c 。

In certain embodiments, R ⁵ Is a bicyclic heteroaryl group comprising 9 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

In some of these embodiments, R ⁵ Is imidazopyridinyl, pyrazolopyridinyl or benzotriazole, each of which is optionally substituted with 1-2R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

As a non-limiting example of the foregoing embodiment, R ⁵ May be Each of which is optionally substituted with 1-2R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

In certain embodiments, R ⁵ Is a bicyclic 10 membered heteroaryl wherein 1-4 ring atoms are heteroatoms, each heteroatom independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

In certain embodiments, each R ^cA Independently selected from the group consisting of: halogen; cyano group; -OH; optionally R is selected from 1 to 6 independently ^a Substituted C _1-6 An alkyl group; c (C) _1-4 Alkoxy, optionally C _1-4 Alkoxy or C _1-4 Haloalkoxy substitution; c (C) _1-4 Haloalkoxy groups; and-C (=o) NR' R ".

In certain embodiments, R is present at one time ^cA Is an independently selected halogen, for example, -F or-Cl.

In certain embodiments, R is present at one time ^cA Is cyano.

In certain embodiments, R is present at one time ^cA Is optionally selected from 1 to 6R ^a Substituted C _1-6 An alkyl group.

In certain embodiments, R is present at one time ^cA Is C _1-6 Alkyl radicals, e.g. C _1-3 An alkyl group.

In certain embodiments, R is present at one time ^cA is-OH or-NR ^e R ^f Substituted C _1-6 An alkyl group. For example, R occurs once ^cA Can be-OH or NH ₂ Substituted C _1-3 An alkyl group.

In certain embodiments, R is present at one time ^cA Is C _1-4 Alkoxy, optionally C _1-4 Alkoxy or C _1-4 Haloalkoxy substitution. For example, R occurs once ^cA May be C _1-4 Alkoxy (e.g., methoxy or ethoxy).

In certain embodiments, R is present at one time ^cA is-C (=O) NR' R "(e.g., C (=O) NH) ₂ )。

In certain embodiments, R ⁵ Is thatWherein ring D is a heterocyclylene or heterocyclylene (e.g., heterocyclylene) comprising 3-10 ring atoms, wherein 0-2 ring atoms (other than bonded to R ^X 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene or heterocyclylene (e.g., heterocyclylene) is optionally substituted with 1-4 substituents, each substituent independently selected from oxo and-R ^c 。

In some of these embodiments, R ⁵ Is thatWhich is optionally substituted with 1-2R ^c Substitution, wherein x1 and x2 are each independently 0, 1 or 2.

In some of the foregoing embodiments, x1=0 and x2=0.

In certain embodiments, x1=0 and x2=1.

In certain embodiments, x1=0 and x2=2.

As a non-limiting example, when R ⁵ Is that(e.g.)>) When R is ⁵ May be selected from the group consisting of:(e.g.)>)；/>(e.g.)>) The method comprises the steps of carrying out a first treatment on the surface of the And(e.g.)>)。

In certain embodiments, R ^X Is C (=O) (C _1-4 Alkyl) or S (O) ₂ (C _1-4 Alkyl).

In some of these embodiments, R ^X Is C (=O) (C _1-4 Alkyl) (e.g., C (=o) Me or C (=o) Et).

In some casesIn embodiments, R ^X Is S (O) ₂ (C _1-4 Alkyl) (e.g., S (O) ₂ Me)。

In certain embodiments, R ⁵ is-R ^g2 -R ^W 。

In some of these embodiments, R ⁵ is-R ^g2 -R ^W The method comprises the steps of carrying out a first treatment on the surface of the and-R ^g2 -R ^W In the presence of-R ^g2 Is a heterocyclylene or heterocyclylene group comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene or heterocyclylene is optionally substituted with 1-4 substituents independently selected from oxo and R ^c 。

In some of the foregoing embodiments, -R ⁵ Is thatWherein ring D is a heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^W 0-2 ring atoms other than the ring nitrogen atom of (2) are each independently selected from N, N (H), N (R) ^d ) O and S (O) _-0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from oxo and-R ^c 。

In some of these embodiments, -R ⁵ Is thatWhich is optionally substituted with 1-2R ^c Substitution, wherein x1 and x2 are each independently 0, 1 or 2./>

In some of the foregoing embodiments, x1=0 and x2=0.

In certain embodiments, x1=0 and x2=1.

In certain embodiments, x1=0 and x2=2.

In certain embodiments, x1=0 and x2=1; or x1=0 and x2=2.

As a non-limiting example, when R ⁵ Is that(e.g.)>) When R is ⁵ May be selected from the group consisting of:for example->For example-> For example- >For example->For example

In some embodiments, R ⁵ Is R ^W 。

In certain embodiments, R ^W is-L ^W -W; and L is ^W Is C (=o).

In certain embodiments, R ^W is-L ^W -W; and L is ^W Is C (=O) NHC (=O) or NHS (O) _1-2 * Wherein the asterisks represent the points of attachment to W.

In some of these embodiments, W is C _2-6 Alkenyl, which is optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Having hybridised carbon atoms to L ^W 。

In some of these embodiments, W is C _2-6 Alkenyl or C _2-6 Alkynyl, optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W 。

In some of the foregoing embodiments, W is C _2-4 Alkenyl, which is optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Having hybridised carbon atoms to L ^W . As a non-limiting example of the foregoing embodiment, W may be ch=ch ₂ 。

In some of these preceding embodiments, W is C _2-4 Alkenyl or C _2-4 Alkynyl, optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W . As a non-limiting example of the foregoing embodiment, W may be ch=ch ₂ 、CH＝CHCH ₂ NMe ₂ Or (b)

In certain embodiments, -L ^W -W is-C (=o) ch=ch ₂ 。

As a non-limiting example, -L ^W -W may be-C (=o) ch=ch ₂ 、–C(＝O)CH＝CHCH ₂ NMe ₂ Or (b)

In certain embodiments, R ⁵ is-R ^g2 -R ^Y 。

In some of these embodiments, R ⁵ is-R ^g2 -R ^Y Wherein, -R ^g2 -R ^Y In the presence of-R ^g2 Is a heterocyclylene or heterocyclylene group comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene or heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from oxo and R ^c 。

In certain embodiments (when R ⁵ is-R ^g2 -R ^Y When, -R ⁵ Is thatWherein ring D is a heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^Y 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from oxo and-R ^c 。

In some of the foregoing embodiments, -R ⁵ Is thatWhich is optionally substituted with 1-2R ^c Substitution, wherein x1 and x2 are each independently 0, 1 or 2.

In some of these embodiments, x1=0, and x2=0.

In certain embodiments, x1=0, and x2=1.

In certain embodiments, x1=0, and x2=2.

As a non-limiting example, when R ⁵ Is that(e.g.)>) When R is ⁵ May be selected from the group consisting of:(e.g.)>)；/>(e.g.)>For example->

In certain embodiments, R ⁵ is-R ^g2 -R ^Y The method comprises the steps of carrying out a first treatment on the surface of the and-R ^g2 -R ^Y In the presence of-R ^g2 Is a monocyclic heteroarylene group comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroarylene group is optionally substituted with 1-3R ^c And (3) substitution.

In these embodimentsIn some of the modes, R ⁵ is-R ^g2 -R ^Y The method comprises the steps of carrying out a first treatment on the surface of the and-R ^g2 -R ^Y In the presence of-R ^g2 Is a monocyclic heteroarylene group comprising 5 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroarylene group is optionally substituted with 1-2R ^c And (3) substitution.

As a non-limiting example of the foregoing embodiment, R ⁵ May be selected from the group consisting of:

in certain embodiments (when R ⁵ is-R ^g2 -R ^Y When) in-R ^Y is-R ^g 。

In some of these embodiments, -R ^Y Selected from the group consisting of:

optionally by 1-4R ^c Substituted C _6-10 Aryl groups.

In some of the foregoing embodiments, -R ^Y Is optionally substituted with 1 to 4R ^c Substituted C _6-10 Aryl groups.

As a non-limiting example of the foregoing embodiment, -R ^Y May be phenyl, which is optionally substituted with 1-3R ^c And (3) substitution.

In certain embodiments, -R ^Y Is a heteroaryl group comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

In some of these embodiments, -R ^Y Is composed of 5-6 ringsMonocyclic heteroaryl of atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

As a non-limiting example of the foregoing embodiment, -R ^Y May be selected from the group consisting of: pyridinyl and pyrazolyl, each of which is optionally substituted with 1-2R ^c And (3) substitution.

In certain embodiments, R ⁵ Is C _3-10 Cycloalkyl or C _3-10 Cycloalkenyl groups, each optionally substituted with 1-4 substituents, each independently selected from: oxo and R ^c 。

In some of these embodiments, R ⁵ Is C substituted by 1-4 substituents _3-10 Cycloalkyl, each substituent is independently selected from: oxo and R ^c 。

In certain embodiments, R ⁵ Is quilt C _1-4 Alkoxy or C _1-4 Haloalkoxy-substituted C _3-6 Cycloalkyl; and R is ⁵ Further optionally substituted with 1-2 substituents, each substituent independently selected from: oxo and R ^c 。

In certain embodiments, R ⁵ Is quilt C _1-4 Alkoxy or C _1-4 Haloalkoxy-substituted cyclopropyl. For example, R ⁵ May be(e.g.)>)。

In certain embodiments, R ⁵ is-S (O) _0-2 (C _1-6 Alkyl) optionally substituted with 1-6R ^a And (3) substitution.

In some of these embodiments, R ⁵ is-S (O) ₂ (C _1-6 Alkyl) optionally substituted with 1-6R ^a And (3) substitution.

As a non-limiting example of the foregoing embodiment, R ⁵ Can be-S (O) ₂ (C _1-6 Alkyl) (e.g., -S (O) ₂ (C _1-3 Alkyl)).

In certain embodiments, R ⁵ Selected from the group consisting of: -L ⁵ -R ^g 、-L ⁵ -R ^g2 -R ^Y and-L ⁵ -R ^g2 -R ^W 。

In some of these embodiments, R ⁵ is-L ⁵ -R ^g . In some of the foregoing embodiments, R ⁵ is-O-R ^g .

In certain embodiments, R ⁵ is-O-R ^g The method comprises the steps of carrying out a first treatment on the surface of the and-O-R ^g R present in (a) ^g Is C _3-10 Cycloalkyl or C _3-10 Cycloalkenyl groups, each optionally substituted with 1-4 substituents, each independently selected from: oxo and R ^c 。

In certain embodiments, R ⁵ is-O- (C) _3-6 Cycloalkyl), wherein C _3-6 Cycloalkyl is optionally substituted with 1-3R ^c And (3) substitution. For example, R ⁵ May be

In some embodiments, L ¹ Is optionally substituted with 1 to 6R ^a Substituted C _1-10 An alkylene group.

In some of these embodiments, L ¹ Is optionally substituted with 1 to 6R ^a Substituted C _1-6 An alkylene group. In some of the foregoing embodiments, L ¹ Is optionally substituted with 1 to 6R ^a Substituted C _1-3 An alkylene group. In certain embodiments, L ¹ Is C _1-3 An alkylene group. For example, L ¹ Can be-CH ₂ . As another non-limiting example, L ¹ Can be-CH ₂ CH ₂ -。

In some of these embodiments, L ¹ Is optionally substituted with 1 to 6R ^a Substituted C _1-4 An alkylene group. In some of these foregoing embodiments, L ¹ Is C _1-4 An alkylene group. As a means ofNon-limiting examples of the foregoing embodiments, L ¹ Can be-CH ₂ -or-CH ₂ CH ₂ -. As another non-limiting example of the foregoing embodiment, L ¹ May beWherein asterisks represent the linkage to R ^W Is a point of (2).

In some embodiments, L ¹ Is a key.

When X is ¹ Is thatEmbodiment of the invention

In some embodiments, X ¹ Is that

In some of these embodiments, R ⁶ Is R ^g 。

In certain embodiments, R ⁶ Is a heterocyclic or heterocycloalkenyl group comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl or heterocyclenyl is optionally substituted with 1-4 substituents independently selected from oxo and R ^c 。

In certain embodiments, R ⁶ Is a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from oxo and R ^c 。

In some of these embodiments, R ⁶ Is a heterocyclic group containing 4 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-2 substituents independently selected from oxoAnd R is ^c 。

In certain embodiments, R ⁶ Selected from the group consisting of: pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, each of which is optionally substituted with 1-2 substituents independently selected from oxo and R ^c Wherein the ring nitrogen of pyrrolidinyl or piperidinyl is optionally substituted with R ^d Substitution, e.g. where R ⁶ Is that(e.g.)>

In some of the foregoing embodiments, R ⁶ Selected from the group consisting of: pyrrolidinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, each of which is optionally substituted with 1-2 substituents independently selected from oxo and R ^c Wherein the ring nitrogen of pyrrolidinyl or piperidinyl is optionally substituted with R ^d And (3) substitution. As a non-limiting example of the foregoing embodiment, R ⁶ May be As another non-limiting example, R ⁶ Can be +.>(e.g.)>)。

In certain embodiments (when R ⁶ Is R ^g When), R is ⁶ Is C _3-8 Cycloalkyl or C _3-8 Cycloalkenyl groups each optionally substituted with 1-4 substituents, which substituentsThe radicals being independently selected from oxo and R ^c . In some of these embodiments, R ⁶ Is C _3-8 Cycloalkyl optionally substituted with 1-2R ^c The substitution (e.g.,for example->)。

In certain embodiments (when R ⁶ Is R ^g When), R is ⁶ Is a heteroaryl group comprising 5 to 10 (e.g., 5 to 6) ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c And (3) substitution. In some of these embodiments, R ⁶ Is a heteroaryl group comprising 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heteroaryl is optionally substituted with 1-2R ^c And (3) substitution. For example, R ⁶ May beFor example->As another non-limiting example, R ⁶ May be

In certain embodiments, R ⁶ Is a heteroaryl group comprising 6 ring atoms, wherein 1 to 4 ring atoms are ring nitrogen atoms, and wherein the heteroaryl group is optionally substituted with 1 to 4R ^c And (3) substitution. For example, R ⁶ May be

In certain embodiments, R ⁶ Is that ^– R ^g2 -R ^W or-R ^g2 -R ^Y 。

In some of these embodiments, R ⁶ Is that ^– R ^g2 -R ^W 。

In some of the foregoing embodiments, -R ⁶ Is thatWherein ring D is a heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^W 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from oxo and-R ^c 。

In some of the foregoing embodiments, -R ⁶ Is thatWherein ring D is a heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^W 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from oxo and-R ^c The method comprises the steps of carrying out a first treatment on the surface of the Optionally, wherein-R ⁶ Is a monocyclic heterocyclylene ring comprising 3 to 10 ring atoms as defined herein, and the nitrogen atom is bonded to R ^W (e.g.)>For example-> For example->) The method comprises the steps of carrying out a first treatment on the surface of the Optionally, wherein, -R ⁶ Is a bicyclic heterocyclylene ring comprising 3-10 ring atoms as defined above, and the nitrogen atom is bonded to R ^W (e.g.)>For exampleFor exampleFor example->)。

In some of these embodiments, -R ⁶ Is thatWhich is optionally substituted with 1-2R ^c Substitution, wherein x1 and x2 are each independently 0, 1 or 2.

In certain embodiments, x1=0 and x2=0. In certain embodiments, x1=0 and x2=1. In certain embodiments, x1=0 and x2=2.

In certain embodiments, x1=0 and x2=0; or x1=0 and x2=1; or x1=0 and x2=2.

As a non-limiting example, when R ⁶ Is that(e.g.)>) When R is ⁶ May be selected from the group consisting of:(e.g.)>(e.g.(e.g.)>)。

As a non-limiting example, when R ⁶ Is that(e.g.)>) When R is ⁶ May be selected from the group consisting of:for example->For example->For example->For example->For example->Or (b)

In certain embodiments, R ⁶ Is covered by R ^W Substituted C ₃ -C ₆ Cycloalkyl (e.g., cyclobutyl); or by R ^W Substituted oxetanyl; or by R ^W Substituted tetrahydrofuranyl.

In certain embodiments, R ⁶ is-R ^W 。

In certain embodiments (when R ⁶ Is that ^– R ^g2 -R ^W When) in-R ^W is-L ^W -W; and L is ^W Is C (=o).

In certain embodiments (when R ⁶ Is that ^– R ^g2 -R ^W Or when R is ⁶ Is R ^W When) in-R ^W is-L ^W -W; and L is ^W Is C (=O) NHC (=O), NR ^d C (=o) (e.g. NMeC (=o)) or NHS (O) _1-2 * Wherein the asterisks represent the points of attachment to W.

In some of these embodiments, W is C _2-6 Alkenyl or C _2-6 Optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W 。

In some of the foregoing embodiments, W is C _2-4 Alkenyl, which is optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Having hybridised carbon atoms to L ^W . For example, W may be ch=ch ₂ 。

In some of the foregoing embodiments, W is C _2-4 Alkenyl (e.g., ch=ch ₂ ) Or C _2-4 Alkynyl groups (e.g.,) Optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W 。/>

In certain embodiments, -L ^W -W is-C (=o) ch=ch ₂ 。

In certain embodiments, -L ^W -W is-C (=o) ch=ch ₂ ；–C(＝O)NHCH＝CH ₂ ；C(＝O)CH＝CHCH ₂ NR ^e R ^f (e.g., C (=o) ch=chch ₂ N(HMe)、C(＝O)CH＝CHCH ₂ NMe ₂ 、

In certain embodiments, R ⁶ is-C _1-6 Alkoxy or-S (O) _0-2 (C _1-6 Alkyl) each optionally substituted with 1-6R ^a And (3) substitution.

In some of these embodiments, R ⁶ is-C _1-6 An alkoxy group. For example, R ⁶ Can be-C _1-3 Alkoxy (e.g., methoxy).

In certain embodiments, L ² Is a key.

In certain embodiments, L ² Is optionally substituted with 1 to 6R ^a Substituted C _1-10 An alkylene group.

In certain embodiments, L ² Is optionally substituted with 1 to 6R ^a Substituted C _1-10 Alkylene group, wherein R is ^a is-NR ^e R ^f (e.g., NMe) ₂ ) Halogen (e.g., fluorine), alkoxy (e.g., methoxy).

In some of these embodiments, L ² Is optionally substituted with 1 to 6R ^a Substituted C _1-6 An alkylene group. In some of the foregoing embodiments, L ² Is branched C _3-6 An alkylene group. As a non-limiting example of the foregoing embodiment, L ² May be

In certain embodiments, L ² Is optionally substituted with 1 to 6R ^a Substituted C _1-6 Alkylene group, wherein R is ^a is-NR ^e R ^f (e.g., NMe) ₂ ) Halogen (e.g., fluorine), alkoxy (e.g., methoxy)). In some of these foregoing embodiments, L ² Is optionally substituted with 1 to 6R ^a Substituted branching C _3-6 Alkylene group, wherein R is ^a is-NR ^e R ^f (e.g., NMe) ₂ ) Halogen (e.g., fluorine), alkoxy (e.g., methoxy).

As a non-limiting example of the foregoing embodiment, L ² May be(e.g., (e.g.)>(e.g.,(e.g.)> (e.g.,(e.g.)>

Variable R ^1c 、R ^2a 、R ^2b 、R ^3a And R is ^3b

In some embodiments, R ^1c Is H.

In some embodiments，R ^2a And R is ^2b Is H.

In some embodiments, R ^2a And R is ^2b One of 1-2 (e.g., one) is a substituent other than H.

In some of these embodiments, R ^2a And R is ^2b One of which is optionally substituted with 1-3R ^a Substituted C _1-3 Alkyl (e.g., C _1-3 An alkyl group); and R is ^2a And R is ^2b The other of (2) is H.

In some embodiments, R ^3a And R is ^3b Is H.

In some embodiments, R ^3a And R is ^3b One of 1-2 (e.g., one) is a substituent other than H.

In some of these embodiments, R ^3a And R is ^3b One of which is optionally substituted with 1-3R ^a Substituted C _1-3 Alkyl (e.g., C optionally substituted with 1-3-F) _1-3 An alkyl group); and R is ^2a And R is ^2b The other of (2) is H.

In some embodiments, R ^3a And ^3b together with the ring atoms of the ring B to which they are each attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms;

wherein 0-2 ring atoms are each independently selected heteroatoms, wherein the independently selected heteroatoms are each selected from the group consisting of: n, NH, N (R) ^d ) O and S (O) _0-2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

Wherein the fused saturated or unsaturated ring of 3 to 12 ring atoms is optionally substituted with 1 to 4 substituents independently selected from oxo, R ^c And R is ^W 。

In certain embodiments, R ^3a And R is ^3b Together with the ring atoms of ring B to which they are each attached, form a fused saturated ring of 4 to 8 ring atoms;

Wherein 4-8The condensed saturated ring of ring atoms being optionally substituted with 1-4 substituents independently selected from oxo, R ^c And R is ^W 。

In some of these embodiments, R ^3a And R is ^3b Together with the ring atoms of the ring B to which they are each attached form:which is optionally substituted with 1-2 substituents independently selected from oxo and R ^c Wherein:

p1 and p2 are independently 0, 1 or 2;

R ^Q is H, R ^d C (=O) -W or S (O) ₂ W is a metal; and is also provided with

cc represents a bond to C (R ^2a R ^2b ) Is a point of (2).

In some of these embodiments, R ^Q Is H. In certain embodiments, R ^Q Is R ^d . In certain embodiments, R ^Q Is C _1-6 Alkyl, optionally substituted with 1-3 independently selected R ^a And (3) substitution. In certain embodiments, R ^Q Is C (=O) -W or S (O) ₂ W. In some of these embodiments, W is C _2-4 Alkenyl groups. For example, R ^Q Can be C (=O) -CH ₂ ＝CH ₂ 。

In some of these embodiments, R ^3a And R is ^3b Together with the ring atoms of the ring B to which they are each attached form Wherein R is ^Q Is H, R ^d C (=O) -W or S (O) ₂ W is a metal; and cc represents a bond to C (R ^2a R ^2b ) Is a point of (2). In some of these embodiments, R ^Q Is H. In certain embodiments, R ^Q Is R ^d . In certain embodiments, R ^Q Is C _1-6 Alkyl groups, optionally substituted with 1-3 unitsR of vertical selection ^a And (3) substitution. In certain embodiments, R ^Q Is C (=O) -W or S (O) ₂ W. In some of these embodiments, W is C _2-4 Alkenyl groups. For example, R ^Q Can be C (=O) -CH ₂ ＝CH ₂ 。

In certain embodiments, R ^3a And R is ^3b Together with the ring atoms of the ring B to which they are each attached form a fused ring selected from the group consisting of:for example->For example->For example(e.g.)>For example->For example-> For example->For example->(e.g.)>) Wherein R is ^Q Is H, R ^d C (=O) -W or S (O) ₂ W is a metal; and cc represents a bond to C (R ^2a R ^2b ) Is a point of (2). In some of these embodiments, R ^Q Is H. In certain embodiments, R ^Q Is R ^d . In certain embodiments, R ^Q Is C _1-6 Alkyl, optionally substituted with 1-3 independently selected R ^a And (3) substitution. In certain embodiments, R ^Q Is C (=O) -W or S (O) ₂ W. In some of these embodiments, W is C _2-4 Alkenyl groups. For example, R ^Q Can be C (=O) -CH ₂ ＝CH ₂ 。

Variable ring A

In some embodiments, ring a isWherein each R is ^cB R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And m is 0, 1,2, 3 or 4.

In some of these embodiments, m is 1,2, or 3. For example, m may be 1 or 2 (e.g., 2).

In certain embodiments, ring a is(e.g.)>) Wherein each R ^cB R is independently selected ^c 。

In certain embodiments, each R ^cB Independently selected from the group consisting of: halogen, such as-Cl and-F; -CN; c (C) _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy groups; c (C) _1-3 An alkyl group; and C substituted with 1-6 independently selected halogens _1-3 An alkyl group.

In certain embodiments, ring a isWherein R is ^cB1 Is R ^c The method comprises the steps of carrying out a first treatment on the surface of the And R is ^cB2 Is H or R ^c 。

In these embodimentsIn some of (2), R ^cB1 Is halogen (e.g., -F or-Cl (e.g., -F)).

In certain embodiments, R ^cB2 Is C _1-4 Alkoxy or C _1-4 Haloalkoxy groups; (e.g., C _1-4 Alkoxy (e.g., methoxy)).

As a non-limiting example of the foregoing embodiment, ring A may be/>

In certain embodiments, ring A is a heteroaryl group comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

In some of these embodiments, ring A is a bicyclic heteroaryl group comprising 9-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

As non-limiting examples of the foregoing embodiments, ring a may be quinolinyl, indazolyl, pyrazolopyridinyl or isothiazolopyridinyl, each of which is optionally substituted with 1-2R ^c Substituted, wherein the ring nitrogen is optionally substituted with R ^d And (3) substitution. For example, ring a may be: (e.g., (e.g.,(e.g.)>) Each of which is further optionally R ^c And (3) substitution. As another non-limiting example, ring A may be +.>Which is further optionally R ^c And (3) substitution.

Variable n, R ⁷ And R is ⁴

In some embodiments, n is 0. In some embodiments, n is 1 or 2. In some of these embodiments, n is 1. In certain embodiments, R is present at one time ⁷ Is NR ^e R ^f (e.g., NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ ). In some of these embodiments, R is present at one time ⁷ Is NH ₂ Or NH (C) _1-3 Alkyl). For example, R occurs once ⁷ Can be NH ₂ 。

In some embodiments of the present invention, in some embodiments,part is->In some of these embodiments, R is present at one time ⁷ Is NR ^e R ^f (e.g., NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ ). In some of the foregoing embodiments, R is present at one time ⁷ Is NH ₂ Or NH (C) _1-3 Alkyl). For example, R occurs once ⁷ Can be NH ₂ 。

In some embodiments, R ⁴ Is H.

Non-limiting combinations

In certain embodiments, the compound of formula (I) is a compound of formula (I-a)

Or a pharmaceutically acceptable salt thereof,

wherein ring D1 is selected from the group consisting of:

monocyclic heteroaryl comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroaryl group is optionally substituted with 1-4R ^cA Substitution; and

·-R ^g2 -R ^Y wherein-R is ^g2 -R ^Y In the presence of-R ^g2 Is a monocyclic heteroarylene group comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroarylene group is optionally substituted with 1-3R ^cA Instead of the above-mentioned,

wherein each R ^cA R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

L ¹ Is a bond or is optionally substituted with 1 to 6R ^a Substituted C _1-3 An alkylene group.

In certain embodiments of formula (I-a), ring D1 is a monocyclic heteroaryl group comprising 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroaryl group is optionally substituted with 1-4R ^cA And (3) substitution.

As non-limiting examples of the foregoing embodiments, ring D1 may be selected from the group consisting of: each of which is optionally substituted with 1-2R ^cA And (3) substitution. As non-limiting examples of the foregoing embodiments, ring D1 may be selected from the group consisting of: each of which is optionally substituted with 1-2R ^cA And (3) substitution.

In certain embodiments of formula (I-a), ring D1 is a monocyclic heteroaryl group comprising 6 ring atoms, wherein 1-4 ring atoms are ring nitrogen atoms, and wherein the heteroaryl group is optionally substituted with 1-4R ^cA And (3) substitution.

As non-limiting examples of the foregoing embodiments, ring D1 may be selected from the group consisting of: for example->For example-> For exampleEach of which is optionally R ^cA Further substitution.

As non-limiting examples of the foregoing embodiments, ring D1 may be selected from the group consisting of: (e.g.)>(e.g., (e.g.)>) Each of which is optionally R ^cA Further substitution.

In certain embodiments of formula (I-a), ring D1 is-R ^g2 -R ^Y The method comprises the steps of carrying out a first treatment on the surface of the and-R ^g2 -R ^Y In the presence of-R ^g2 Is a monocyclic heteroarylene group comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroarylene group is optionally substituted with 1-3R ^cA And (3) substitution.

In some of these embodiments, ring D1 is-R ^g2 -R ^Y The method comprises the steps of carrying out a first treatment on the surface of the and-R ^g2 -R ^Y In the presence of-R ^g2 Is a monocyclic heteroarylene group containing 5 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroarylene group is optionally substituted with 1-2R ^cA And (3) substitution. For example, ring D1 may be

In certain embodiments of formula (I-a) (when ring D1 is-R) ^g2 -R ^Y When), R ^Y Selected from the group consisting of:

optionally by 1-3R ^c A substituted phenyl group; and

monocyclic heteroaryl comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

In certain embodiments of formula (I-a), n is 0.

In certain embodiments of formula (I-a), n is 1 or 2. For example, n may be 1.

In certain embodiments of formula (I-a),

in certain embodiments of formula (I-a), R ⁷ Is NR ^e R ^f For example, NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

In certain embodiments, the compound of formula (I) is a compound of formula (I-b)

Or a pharmaceutically acceptable salt thereof,

wherein ring D2 is a bicyclic heteroaryl group comprising 8-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

In certain embodiments of formula (I-b), ring D2 is a heteroaryl group comprising 8 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

As non-limiting examples of the foregoing embodiments, ring D2 may be selected from the group consisting of: each of which is provided withOptionally by 1-2R ^cA Further substitution, wherein each R ^cA R is independently selected ^c 。

As non-limiting examples, ring D2 may be selected from the group consisting of: each of which is optionally substituted with 1-2R ^cA Further substitution, wherein each R ^cA R is independently selected ^c 。/>

In certain embodiments of formula (I-b), ring D2 is a bicyclic heteroaryl group containing 9 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

In some of these embodiments, ring D2 is imidazopyridinyl, pyrazolopyridinyl, or benzotriazolyl, each of which is optionally substituted with 1-2R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

As a non-limiting example of the foregoing embodiment, ring D2 may be Each of which is optionally substituted with 1-2R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

In certain embodiments of formula (I-b), n is 0.

In certain embodiments of formula (I-b), n is 1 or 2. For example, n may be 1.

In certain embodiments of formula (I-b),

in certain embodiments of formula (I-b), R ⁷ Is NR ^e R ^f For example NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

In certain embodiments of formula (I-a) or (I-b), each R ^cA Independently selected from the group consisting of: halogen; cyano group; -OH; optionally R is selected from 1 to 6 independently ^a Substituted C _1-6 An alkyl group; c (C) _1-4 Alkoxy, optionally C _1-4 Alkoxy or C _1-4 Haloalkoxy substitution; c (C) _1-4 Haloalkoxy groups; and-C (=o) NR' R ".

In certain embodiments, R is present at one time ^cA Is an independently selected halogen, such as-F or-Cl. In certain embodiments, R is present at one time ^cA Is cyano. In certain embodiments, R is present at one time ^cA Is optionally selected from 1 to 6R ^a Substituted C _1-6 An alkyl group. In certain embodiments, R is present at one time ^cA Is C _1-6 Alkyl radicals, e.g. C _1-3 An alkyl group. In certain embodiments, R is present at one time ^cA is-OH or-NR ^e R ^f Substituted C _1-6 An alkyl group. For example, R occurs once ^cA Can be-OH or NH ₂ Substituted C _1-3 An alkyl group. In certain embodiments, R is present at one time ^cA Is C _1-4 Alkoxy, optionally C _1-4 Alkoxy or C _1-4 Haloalkoxy substitution; for example, R occurs once ^cA May be C _1-4 Alkoxy (e.g., methoxy or ethoxy).

In certain embodiments, the compound of formula (I) is a compound of formula (I-c)

Or a pharmaceutically acceptable salt thereof,

wherein the ringD is a heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^Z 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from oxo and-R ^c ；

R ^Z Is R ^X Or R is ^Y The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

In certain embodiments of formula (I-c), R ^Z Is R ^X 。

In some of these embodiments, R ^Z Is C (=O) (C _1-4 Alkyl).

In certain embodiments, R ^Z Is S (O) ₂ (C _1-4 Alkyl).

In certain embodiments of formula (I-b), R ^Z Is R ^Y 。

In some of these embodiments, R ^Z Is R ^g 。

In some of the foregoing embodiments, R ^Z Selected from the group consisting of:

optionally by 1-3R ^c A substituted phenyl group; and

In certain embodiments of formula (I-c), n is 0.

In certain embodiments of formula (I-c), n is 1 or 2, e.g., wherein n is 1.

In certain embodiments of formula (I-c),

in certain embodiments of formula (I-c), R ⁷ Is NR ^e R ^f For example, NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

In certain embodiments, the compound of formula (I) is a compound of formula (I-d):

or a pharmaceutically acceptable salt thereof,

wherein ring D is a heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^W 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from oxo and-R ^c The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

In certain embodiments of formula (I-d), R ^W is-L ^W -W; and L is ^W is C(＝O).

In some of these embodiments, W is C _2-6 Alkenyl, which is optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Having hybridised carbon atoms to L ^W . For example, W may be ch=ch ₂ 。

In some of these embodiments, W is C _2-6 Alkenyl or C _2-6 Alkynyl, optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W . As a non-limiting example, W may be ch=ch _2、 CH＝CHCH ₂ NMe ₂ Or (b)

In certain embodiments of formula (I-c) or (I-D), ring D isWhich is optionally substituted with 1-2R ^c Substitution, wherein x1 and x2 are each independently 0, 1 or 2. In some of these embodiments, x1 is 0.

As non-limiting examples of the foregoing embodiments, ring D may be selected from the group consisting of:(e.g.)>Or (b)(e.g.)>(e.g.)>

As non-limiting examples of the foregoing embodiments, ring D may be selected from the group consisting of:for example For example->For example->For example-> For example->

In certain embodiments of formulas (I-d), n is 0.

In certain embodiments of formula (I-d), n is 1 or 2. For example, n may be 1.

In certain embodiments of formula (I-d),

in certain embodiments of formula (I-d),

in certain embodiments of formula (I-d), R ⁷ Is NR ^e R ^f For example, NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

In certain embodiments, the compound of formula (I) is a compound of formula (I-e):

or a pharmaceutically acceptable salt thereof,

wherein R is ^5A is-L ⁵ -R ^g or-S (O) _0-2 (C _1-6 Alkyl) optionally substituted with 1-6R ^a Substitution; and is also provided with

L ¹ Is optionally substituted with 1 to 6R ^a Substituted C _1-10 An alkylene group.

In certain embodiments of formula (I-e), R ^5A is-L ⁵ -R ^g . In some of these embodiments, R ^5A is-O-R ^g 。

In some of the foregoing embodiments, R ^5A is-O-R ^g The method comprises the steps of carrying out a first treatment on the surface of the and-O-R ^g R present in (a) ^g Is C _3-10 Cycloalkyl or C _3-10 Cycloalkenyl groups, each optionally substituted with 1-4 substituents, each independently selected from: oxo and R ^c 。

In certain embodiments, R ^5A is-O- (C) _3-6 Cycloalkyl), wherein C _3-6 Cycloalkyl is optionally substituted with 1-3R ^c And (3) substitution. For example, R ⁵ May be

In certain embodiments of formula (I-e), R ^5A is-S (O) _0-2 (C _1-6 Alkyl) optionally substituted with 1-6R ^a And (3) substitution. In some of these embodiments, R ^5A is-S (O) ₂ (C _1-6 Alkyl) optionally substituted with 1-6R ^a And (3) substitution. As a non-limiting example of the foregoing embodiment, R ^5A Can be-S (O) ₂ (C _1-3 Alkyl) (e.g., -S (O) ₂ Me)。

In certain embodiments of formula (I-e), n is 0.

In certain embodiments of formula (I-e), n is 1 or 2, e.g., wherein n is 1.

In certain embodiments of formula (I-e),

in certain embodiments of formula (I-e), R ⁷ Is NR ^e R ^f For example, NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), or (I-e), L ¹ Is optionally substituted with 1 to 6R ^a Substituted C _1-3 An alkylene group.

In one of these embodimentsIn some cases, L ¹ Is C _1-3 An alkylene group. For example, L ¹ Can be-CH ₂ -. As another non-limiting example, L ¹ Can be-CH ₂ CH ₂ -。

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), or (I-e), L ¹ Is a key.

In certain embodiments, the compound of formula (I) is a compound of formula (I-f):

or a pharmaceutically acceptable salt thereof,

wherein ring D3 is C substituted with 1-4 substituents _3-10 Cycloalkyl groups, the substituents each being independently selected from oxo and R ^c 。

In certain embodiments of formula (I-f), ring D3 is C _1-4 Alkoxy or C _1-4 Haloalkoxy-substituted C _3-6 Cycloalkyl; and R is ⁵ Further optionally substituted with 1-2 substituents, each substituent independently selected from: oxo and R ^c 。

In some of these embodiments, R ⁵ Is quilt C _1-4 Alkoxy or C _1-4 Haloalkoxy-substituted cyclopropyl. For example, R ⁵ The method can be as follows:(e.g.) >)。

In certain embodiments of formula (I-f), n is 0.

In certain embodiments of formula (I-f), n is 1 or 2, e.g., wherein n is 1.

In certain embodiments of formula (I-f),/>

in certain embodiments of formula (I-f), R ⁷ Is NR ^e R ^f For example, NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

In some of these embodiments, the compound of formula (I) is a compound of formula (I-g):

or a pharmaceutically acceptable salt thereof,

wherein L is ² Is optionally substituted with 1 to 6R ^a Substituted C _1-6 An alkylene group; and is also provided with

R ^6A Selected from the group consisting of: optionally by 1-6R ^a substituted-C _1-6 An alkoxy group; NR (NR) ^e R ^f The method comprises the steps of carrying out a first treatment on the surface of the H is formed; halogen; and-OH.

In certain embodiments of formula (I-g), R ^6A Is optionally substituted with 1 to 6R ^a substituted-C _1-6 An alkoxy group.

In some of these embodiments, R ^6A is-C _1-3 Alkoxy (e.g., methoxy).

In certain embodiments, R ^6A Is NR ^e R ^f 。

In certain embodiments, R ^6A Is H, halogen or-OH.

In certain embodiments of formula (I-g), L ² Is branched C _3-6 An alkylene group. As a non-limiting example of the foregoing embodiment, L ² May be

In certain embodiments of formula (I-g), L ² Is C _1-3 Alkylene radicals, e.g. -CH ₂ -。

In certain embodiments of formula (I-g), n is 0.

In certain embodiments of formula (I-g), n is 1 or 2, e.g., wherein n is 1.

In certain embodiments of formula (I-g),

in certain embodiments of formula (I-g), R ⁷ Is NR ^e R ^f For example, NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

In certain embodiments, the compound of formula (I) is a compound of formula (I-h):

or a pharmaceutically acceptable salt thereof,

wherein ring D4 is R ^g 。

In certain embodiments of formula (I-h), ring D4 is selected from the group consisting of:

·C _3-10 cycloalkyl or C _3-10 Cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from oxo and R ^c The method comprises the steps of carrying out a first treatment on the surface of the And

heterocyclyl or heterocycloalkenyl containing 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl or heterocyclenyl is optionally substituted with 1-4 substituents independently selected from oxo and R ^c 。

In some of these embodiments, ring D4 is a heterocyclic group comprising 4-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from oxo and R ^c 。

In some of the foregoing embodiments, ring D4 is selected from pyrrolidinyl, piperdine A pyridinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl group, each optionally substituted with 1-2 substituents independently selected from oxo and R ^c Wherein the ring nitrogen of pyrrolidinyl or piperidinyl is optionally substituted with R ^d And (3) substitution. As a non-limiting example of the foregoing embodiment, ring D4 may be: (e.g.

In certain of the foregoing embodiments, ring D4 is selected from: pyrrolidinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, each of which is optionally substituted with 1-2 substituents independently selected from oxo and R ^c Wherein the ring nitrogen of pyrrolidinyl or piperidinyl is optionally substituted with R ^d And (3) substitution. As a non-limiting example of the foregoing embodiment, ring D4 may be

In certain embodiments of formula (I-H), ring D4 is a heteroaryl group comprising 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c And (3) substitution. For example, R ⁶ May be

In certain embodiments of formula (I-h), n is 0.

In certain embodiments of formula (I-h), n is 1 or 2, e.g., wherein n is 1.

In certain embodiments of formula (I-h), />

In certain embodiments of formula (I-h), R ⁷ Is NR ^e R ^f For example NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

In certain embodiments, the compound of formula (I) is a compound of formula (I-I):

or a pharmaceutically acceptable salt thereof,

wherein ring D is a heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^W 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from oxo and-R ^c 。

In certain embodiments of formula (I-I), R ^W is-L ^W -W; and L is ^W Is C (=o).

In certain embodiments of formula (I-I), W is C _2-6 Alkenyl, which is optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Having hybridised carbon atoms to L ^W . As a non-limiting example of the foregoing embodiment, W may be ch=ch ₂ 。

In certain embodiments of formula (I-I), W is C _2-6 Alkenyl or C _2-6 Alkynyl, optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W . As a non-limiting example of the foregoing embodiment, W may be ch=ch ₂ 、CH＝CHCH ₂ NMe ₂ Or (b)

In certain embodiments of formula (I-I), -L ^W -W is-C (=o) ch=ch ₂ ；–C(＝O)NHCH＝CH ₂ ；C(＝O)CH＝CHCH ₂ NR ^e R ^f (e.g., C (=o) ch=chch ₂ N(HMe)、C(＝O)CH＝CHCH ₂ NMe ₂ 、

In certain embodiments of formula (I-I), ring D isWhich is optionally substituted with 1-2R ^c Substitution, wherein x1 and x2 are each independently 0, 1 or 2.

In some of these embodiments, x1 is 0.

As non-limiting examples of the foregoing embodiments, ring D may be selected from the group consisting of:(e.g.)> (e.g.)>(e.g.,)。

as further non-limiting examples of the foregoing embodiments, ring D may be selected from the group consisting of:for example->Or (b)For example->For example->For example->For example->

In certain embodiments of formula (I-I),is bonded to R ^W And heterocyclic groups containing 3 to 10 ring atoms, 0 to 2 of which are (except bonded to R ^W 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from the group consisting of: oxo and-R ^c The method comprises the steps of carrying out a first treatment on the surface of the Optionally, wherein->Is a monocyclic heterocyclylene ring comprising 3 to 10 ring atoms as defined above, wherein the nitrogen atom is bonded to R ^W (e.g.)>For example For example->) The method comprises the steps of carrying out a first treatment on the surface of the Optionally, wherein the first and second heat exchangers, respectively,is a bicyclic heterocyclylene ring comprising 3 to 10 ring atoms as defined above, wherein the nitrogen atom is bonded to R ^W (e.g.)>Or->For example-> For exampleFor example->)。

In certain embodiments of formula (I-I), n is 0.

In certain embodiments of formula (I-I), n is 1 or 2, e.g., wherein n is 1.

In certain embodiments of formula (I-I),

in certain embodiments of formula (I-I),

in certain embodiments of formula (I-I), R ⁷ Is NR ^e R ^f For example, NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

In certain embodiments, the compound of formula (I) is a compound of formula (I-j):

or a pharmaceutically acceptable salt thereof,

wherein L is ² Is optionally substituted with 1 to 6R ^a Substituted C _1-6 An alkylene group; and R is ^6B is-R ^W 。

In certain embodiments of the compounds of formula (I-j), R ^W is-L ^W -W; and L is ^W Is C (=O), NHC (=O) or NHS (O) _1-2 * Wherein the asterisks represent the points of attachment to W.

In certain embodiments of the compounds of formula (I-j), W is C _2-6 Alkenyl or C _2-6 Alkynyl, optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W is through sp ² Or sp hybridized carbon atom to L ^W . As a non-limiting example of the foregoing embodiment, W may be ch=ch ₂ 、CH＝CHCH ₂ NMe ₂ Or (b)/>

In certain embodiments of the compounds of formula (I-j), -L ^W -W is-C (=o) ch=ch ₂ 、–C(＝O)CH＝CHCH ₂ NMe ₂ Or (b)

In certain embodiments of the compounds of formula (I-j), L ² Is optionally substituted with 1 to 6R ^a Substituted C _1-3 Alkylene group, wherein R ^a Can be-NR ^e R ^f (e.g., nme ₂ ) Halogen [ ]For example, fluorine) or alkoxy (e.g., methoxy).

As a non-limiting example of the foregoing embodiment of formula (I-j), L ² May be(e.g.)>(e.g.)>(e.g.)> (e.g.)>(e.g.)> (e.g.)>)。

In certain embodiments of the compounds of formula (I-j), n is 0.

In certain embodiments of the compounds of formula (I-j), n is 1 or 2, e.g., wherein n is 1.

In certain embodiments of the compounds of formula (I-j),

in certain embodiments of the compounds of formula (I-j),

in certain embodiments of the compounds of formula (I-j), R ⁷ Is NR ^e R ^f For example NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

In certain embodiments, the compound of formula (I) is a compound of formula (I-k):

or a pharmaceutically acceptable salt thereof,

wherein ring D5 is R ^g2 。

In certain embodiments of the compounds of formula (I-k), ring D5 is selected from the group consisting of:

·C _3-10 cycloalkylene or C _3-10 A cycloalkenylene group, each of which is optionally substituted with 1-4 substituents independently selected from oxo and R ^c The method comprises the steps of carrying out a first treatment on the surface of the And

heterocyclylene or heterocyclylene groups comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene or heterocyclylene is optionally substituted with 1-4 substituents independently selected from oxo and R ^c 。

In certain embodiments of the compounds of formula (I-k), ring D5 is a heterocyclylene comprising 4-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from oxo and R ^c 。

In certain embodiments of the compounds of formula (I-k), ring D5 is C ₃ -C ₆ Cycloalkylene (e.g., cyclobutylene), oxetylene, or tetrahydrofuranylene.

In the formulaIn certain embodiments of the compounds of (I-k), R ^W is-L ^W -W; and L is ^W Is C (=O) or NHC (=O), NR ^d C(＝O)*、NHS(O) _1-2 * Wherein the asterisks represent the points of attachment to W.

In certain embodiments of the compounds of formula (I-k), W is C _2-6 Alkenyl or C _2-6 Alkynyl, optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W . As a non-limiting example, W may be ch=ch ₂ 、CH＝CHCH ₂ NMe ₂ Or (b)

In certain embodiments of the compounds of formula (I-k), -L ^W -W is-C (=o) ch=ch ₂ 、–C(＝O)CH＝CHCH ₂ NMe ₂ Or (b)

In certain embodiments of the compounds of formula (I-k), n is 0.

In certain embodiments of the compounds of formula (I-k),

in certain embodiments of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k), R ^3a And R is ^3b Together with the ring atoms of ring B to which they are each attached, form a fused saturated ring of 4 to 8 ring atoms;

wherein 0 to 2 ring atoms are each independently selected heteroatoms, wherein the independently selected heteroatoms are each selected from N, NH, N (R ^d ) O and S (O) _0-2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

The condensed saturated ring of 4-8 ring atoms is optionally substituted with 1-4 substituents independently selected from oxo, R ^c And R is ^W 。

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k), R ^3a And R is ^3b Together with the ring atoms of the ring B to which they are each attached form:which is optionally substituted with 1-2 substituents independently selected from oxo and R ^c Wherein:

p1 and p2 are independently 0, 1 or 2;

R ^Q is H, R ^d C (=O) -W or S (O) ₂ W is a metal; and is also provided with

cc represents a bond to C (R ^2a R ^2b ) Is a point of (2).

In some of these embodiments, R ^Q Is H. In certain embodiments, R ^Q Is R ^d . In certain embodiments, R ^Q Is optionally selected from 1 to 3R ^a Substituted C _1-6 An alkyl group. In certain embodiments, R ^Q Is C (=O) -W or S (O) ₂ -W. In some of these embodiments, W is C _2-4 Alkenyl groups. For example, R ^Q Can be C (=O) -CH ₂ ＝CH ₂ 。

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k), R ^3a And R is ^3b Together with the ring atoms of the ring B to which they are each attached formWherein R is ^Q Is H, R ^d C (=O) -W or S (O) ₂ W is a metal; and cc represents a bond to C (R ^2a R ^2b ) Is a point of (2). In some of these embodiments, R ^Q Is H. In certain embodiments, R ^Q Is R ^d . In certain embodiments, R ^Q Is optionally selected from 1 to 3R ^a Substituted C _1-6 An alkyl group. In certain embodiments, R ^Q Is C (=O) -W or S (O) ₂ W. In these embodimentsIn some of the formulae, W is C _2-4 Alkenyl groups. For example, R ^Q Can be C (=O) -CH ₂ ＝CH ₂ 。

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k), R ^3a And R is ^3b Together with the ring atoms of the ring B to which they are each attached form a fused ring selected from the group consisting of:for example->For example->For example->(e.g.) > For example->For example->Example->For example->(e.g.)>) Wherein R is ^Q Is H, R ^d C (=O) -W or S (O) ₂ W is a metal; and cc represents a connectionTo C (R) ^2a R ^2b ) Is a point of (2). In some of these embodiments, R ^Q Is H. In certain embodiments, R ^Q Is R ^d . In certain embodiments, R ^Q Is C _1-6 Alkyl, optionally substituted with 1-3 independently selected R ^a And (3) substitution. In certain embodiments, R ^Q Is C (=O) -W or S (O) ₂ W. In some of these embodiments, W is C _2-4 Alkenyl groups. For example, R ^Q Can be C (=O) -CH ₂ ＝CH ₂ 。

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k), R ^1c Is H.

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k), R ^2a And R is ^2b Is H.

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k), R ^3a And R is ^3b Is H.

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k), ring A isWherein each R is ^cB R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And m is 1, 2 or 3. In some of these embodiments, m is 1 or 2, e.g., 2.

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k), ring A isWherein each R is ^cB Independently selected from the group consisting of: halogen, such as-Cl and-F; -CN; c (C) _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy groups; c (C) _1-3 An alkyl group; and C substituted with 1-6 independently selected halogens _1-3 An alkyl group.

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k), ring A isWherein R is ^cB1 Is R ^c The method comprises the steps of carrying out a first treatment on the surface of the And R is ^cB2 Is H or R ^c 。

In certain embodiments, R ^cB1 Halogen, for example-F or-Cl, for example-F.

In certain embodiments, R ^cB2 Is C _1-4 Alkoxy or C _1-4 Haloalkoxy radicals, e.g. C _1-4 Alkoxy groups such as methoxy.

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k), ring A is

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-H), (I-I), (I-j) or (I-k), ring A is a bicyclic heteroaryl group comprising 9-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

As non-limiting examples of the foregoing embodiments, ring a may be quinolinyl, indazolyl, pyrazolopyridinyl or isothiazolopyridinyl, each of which is optionally substituted with 1-2R ^c Substituted, wherein the ring nitrogen is optionally substituted with R ^d And (3) substitution. For example, ring a may be: (e.g., (e.g.,(e.g.)>) Each of which is further optionally R ^c And (3) substitution.

In certain embodiments of formulas (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k), n is 0.

In certain embodiments of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k), R ⁴ Is H.

Compound provision

In some embodiments, the compound is not a compound selected from the group consisting of the structures represented below:

in some embodiments, the compound is not one or more compounds disclosed in WO 2019/081486, WO 2016/120196, or U.S. patent 10,428,063, each of which is incorporated herein by reference in its entirety.

In some embodiments, when R is defined as ^2a 、R ^2b 、R ^3a And R is ^3b Each is H; r is R ^1c Is H or methyl; ring a is phenyl optionally substituted with 1-2F; x is X ¹ is-O-L ¹ -R ⁵ The method comprises the steps of carrying out a first treatment on the surface of the and-L ¹ Is CH ₂ And when the method is used, the following steps are carried out:

R ⁵ not unsubstituted phenyl or unsubstituted cyclopropyl; and

In some embodiments, R ⁵ Not unsubstituted phenyl. In some embodiments, R ⁵ Not unsubstituted cyclopropyl.

In some embodiments, ring a is not phenyl optionally substituted with 1-2F.

Non-limiting exemplary Compounds

In certain embodiments, the compound is selected from the group consisting of the compounds of table C1 or a pharmaceutically acceptable salt thereof.

Table C1

For some compounds, the symbol at the chiral center indicates that the chiral center has been resolved (i.e., is a single epimer), whereas the absolute stereochemistry of the center is not determined.

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Pharmaceutical composition and administration

SUMMARY

In some embodiments, the chemical entity (e.g., an EGFR and/or HER2 inhibiting compound or a pharmaceutically acceptable salt thereof, and/or a hydrate, and/or co-crystal, and/or a pharmaceutical combination thereof) is administered as a pharmaceutical composition comprising the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

In some embodiments, the chemical entity may be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopheryl polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms such as tween, poloxamer or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers and lanolin. Cyclodextrins such as alpha-, beta-and gamma-cyclodextrins or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2-and 3-hydroxypropyl-beta-cyclodextrins or other solubilized derivatives may also be used to enhance delivery of the compounds described herein. Dosage forms or compositions may be prepared comprising in the range of 0.005% -100% of the chemical entities described herein, with the balance being complemented by non-toxic excipients. Contemplated compositions may comprise from 0.001% to 100% of the chemical entities provided herein, in one embodiment from 0.1% to 95%, in another embodiment from 75% to 85%, and in yet another embodiment from 20% to 80%. The actual methods of preparing such dosage forms are known or will be readily understood by those skilled in the art; see, for example, ramington: pharmaceutical science and practice (Remington: the Science and Practice of Pharmacy), 22 nd edition (pharmaceutical press in london, uk (Pharmaceutical Press), 2012).

Routes of administration and composition Components

In some embodiments, the chemical entities described herein or pharmaceutical compositions thereof may be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, oral, dermal, cervical, dou Daona, intratracheal, enteral, epidural (epidural), interstitial, intraperitoneal, intraarterial, intrabronchial, intracapsular, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intrathecal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, meningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intracavitary, intraspinal, intrasynovial, testicular, intrathecal, intravascular, intravenous, nasal, nasogastric, oral, parenteral, transdermal, epidural (peridial), rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal administration. In certain embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

The compositions may be formulated for parenteral administration, e.g., formulated for injection by intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such compositions may be prepared as injectables, which may be liquid solutions or suspensions; can also be prepared in solid form suitable for use in preparing solutions or suspensions by adding liquids prior to injection; and the formulation may also be emulsified. The preparation of such formulations will be known to those skilled in the art in light of the present disclosure.

Pharmaceutical forms suitable for injectable use may include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form needs to be sterile and have a degree of fluidity such that it is easy to inject. It must also be stable under the conditions of manufacture and storage and be resistant to the contaminating action of microorganisms such as bacteria and fungi during storage.

The carrier may also be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycols, and the like), and suitable mixtures thereof, as well as vegetable oils. 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. The prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars or sodium chloride. The absorption of the injectable composition may be prolonged by the use in the composition of agents delaying absorption, such as aluminum monostearate and gelatin.

Sterile injectable solutions may be prepared by incorporating the active compound in the required amount in the appropriate solvent with various other components enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by adding the different sterile active ingredients to a sterile vehicle which contains an alkaline dispersion medium and the other required ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder with the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Discussion of intratumoral injection is found, for example, in Lammers et al, "Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems" (influence of intratumoral injection on biodistribution and therapeutic potential of HPMA copolymer-based drug delivery systems), neoplasia 2006,10,788-795.

Pharmacologically acceptable excipients that may be used in the rectal administration of the composition as a gel, cream, enema or rectal suppository include, but are not limited to, any one or more of the following: cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerol, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols and polyethylene glycol fatty acid esters of various molecular weights such as petrolatum, anhydrous lanolin, shark liver oil, saccharin sodium, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, methyl parahydroxybenzoate sodium, sodium propyl parahydroxybenzoate, diethylamine, carbomers, carbopol, methoxybenzoate, polyethylene glycol cetostearyl ether, cocoyl octyl decanoate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapeseed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins (e.g., vitamins A and E) and potassium acetate.

In certain embodiments, suppositories may be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers (e.g. cocoa butter, polyethylene glycol or a suppository wax) which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

In other embodiments, the compounds described herein or pharmaceutical compositions thereof are suitable for topical delivery to the digestive tract or Gastrointestinal (GI) tract (e.g., solid or liquid dosage forms) by oral administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the chemical entity is admixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dibasic calcium phosphate and/or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants, such as, for example, glycerol, d) disintegrants, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarders, such as, for example, paraffin wax, f) absorption accelerators, such as, for example, quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as, for example, kaolin and bentonite clay, and i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols and the like.

In one embodiment, the composition will take the form of a single dosage form, such as a pill or tablet, and thus, the composition may comprise, in addition to the chemical entities provided herein: diluents such as lactose, sucrose, dibasic calcium phosphate, etc.; lubricants, such as magnesium stearate, etc.; and binders such as starch, acacia, polyvinylpyrrolidone, gelatin, cellulose derivatives, and the like. In another solid dosage form, a powder, pellet, solution or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based). Also contemplated are unit dosage forms that physically separate one or more chemical entities or additional active agents provided herein, e.g., capsules (or tablets in capsules) having various drug particles; bilayer tablets; double-chamber gel capsules, and the like. Enteric coated or sustained release oral dosage forms are also contemplated.

Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives which are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

In certain embodiments, the excipient is sterile, generally free of undesirable substances. These compositions may be sterilized by conventional well-known sterilization techniques. For various oral dosage forms, excipients (e.g., tablets and capsules) need not be sterile. USP/NF standards are generally sufficient.

In certain embodiments, the solid oral dosage form may further comprise one or more components that chemically and/or structurally facilitate the delivery of the composition to the stomach or lower digestive tract of a chemical entity; for example, the ascending and/or transverse and/or distal colon and/or small intestine. Exemplary formulation techniques are described, for example, in Filipski, K.J., et al, current Topics in Medicinal Chemistry (current subject matter of pharmaceutical chemistry), 2013,13,776-802, which is incorporated herein by reference in its entirety.

Examples include upper gut targeting techniques such as Accordion hill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

Other examples include lower gut targeting techniques. To target different regions of the intestinal tract, several enteric/pH-responsive coatings and excipients may be used. These materials are typically polymers designed to dissolve or erode over a specific pH range, which is selected based on the region of the gastrointestinal tract where drug release is desired. These materials are also used to protect acid-labile drugs from gastric juice, or to limit exposure (e.g., hydroxypropyl methylcellulose phthalate series, coaterics (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, eudragit (Eudragit) series (methacrylic acid-methyl methacrylate copolymer) and MARCOAT. Other techniques include dosage forms that are responsive to the local flora of the gastrointestinal tract, pressure-controlled colon delivery capsules and Pulsincap (pulse tamponade), in the event that the active ingredient may stimulate the upper GI.

The ophthalmic composition may include, but is not limited to, any one or more of the following: viscous materials (e.g., carboxymethyl cellulose, glycerol, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., pluronic (triblock copolymers), cyclodextrins); preservatives (e.g., benzalkonium chloride, ETDA, softzia (boric acid, propylene glycol, sorbitol, and zinc chloride; ai Kang Gongsi (Alcon Laboratories, inc.)), purite (stable oxy-chloro complex; ai lrgan, inc.).

Topical compositions may include ointments and creams. Ointments are semisolid preparations, usually based on petrolatum or other petroleum derivatives. The cream containing the selected active agent is typically a viscous liquid or semi-solid emulsion, typically oil-in-water or water-in-oil. The cream base is typically water washable and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes also referred to as the "internal" phase, generally comprises petrolatum and fatty alcohols (such as cetyl or stearyl alcohol); the volume of the aqueous phase is typically (but not necessarily) greater than the oil phase and generally contains a wetting agent. The emulsifier in a cream formulation is typically a nonionic, anionic, cationic or amphoteric surfactant. Like other carriers or excipients, the ointment base should be inert, stable, non-irritating and non-sensitizing.

In any of the foregoing embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipid, multilamellar vesicles crosslinked between bilayers, biodegradable poly (D, L-lactic-co-glycolic acid) [ PLGA ] based or polyanhydride based nanoparticles or microparticles, and nanoporous particle supported lipid bilayers.

Dosage of

The dosage may vary depending on the needs of the patient, the severity of the condition being treated, and the particular compound being used. The person skilled in the art can determine the appropriate dosage according to the particular circumstances. The total daily dose may be administered in several portions of the day or by means of providing continuous delivery.

In some embodiments, the compounds described herein are administered at the following doses: about 0.001mg/Kg to about 500mg/Kg (e.g., about 0.001mg/Kg to about 200mg/Kg; about 0.01mg/Kg to about 150mg/Kg; about 0.01mg/Kg to about 100mg/Kg; about 0.01mg/Kg to about 50mg/Kg; about 0.01mg/Kg to about 10mg/Kg; about 0.01mg/Kg to about 5mg/Kg; about 0.01mg/Kg to about 1mg/Kg; about 0.01mg/Kg to about 0.5mg/Kg; about 0.01mg/Kg to about 0.1mg/Kg; about 0.1mg/Kg to about 200mg/Kg; about 0.1mg/Kg to about 150mg/Kg; about 0.1mg/Kg to about 100mg/Kg; about 50mg/Kg; about 0.1mg/Kg to about 10mg/Kg; about 1mg/Kg; about 0.1mg/Kg to about 1mg/Kg; about 0.1mg/Kg to about 0.5 mg/Kg).

Scheme for the production of a semiconductor device

The aforementioned dosages may be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or on a non-daily basis (e.g., every other day, every other two days, every third day, once a week, twice a week, once a month).

In some embodiments, the compounds described herein are administered for a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In another embodiment, the time to discontinue administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In one embodiment, the therapeutic compound is administered to the individual for a period of time followed by a separate period of time. In another embodiment, the therapeutic compound is administered at a first period of time and a second period of time after the first period of time, and the administration is stopped during the second period of time, followed by a third period of time in which the administration of the therapeutic compound is started, followed by a fourth period of time after the administration in the third period of time is stopped. In one aspect of this embodiment, the time of administration of the therapeutic compound and the time of subsequent cessation of administration are repeated for a defined or indeterminate period of time. In another embodiment, the time of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In another embodiment, the time to discontinue administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more.

Therapeutic method

Indication of disease

Provided herein are methods for inhibiting epidermal growth factor receptor tyrosine kinase (EGFR) and/or human epidermal growth factor receptor 2 (HER 2). For example, provided herein are EGFR inhibitors that can be used to treat or prevent diseases or disorders associated with abnormal expression or activity or level of the EGFR gene, EGFR kinase, or any of them (i.e., EGFR-related diseases or disorders), such as central nervous system diseases, pulmonary diseases, cardiovascular diseases, ischemia, liver diseases, gastrointestinal diseases, viral or bacterial infections, inflammatory and/or autoimmune diseases or cancers (e.g., EGFR-related cancers). In some embodiments, provided herein are HER2 inhibitors useful for treating or preventing diseases or disorders associated with aberrant expression or activity or level of the HER2 gene, HER2 kinase, or any of them, such as cancer (e.g., HER 2-related cancer). In some embodiments, provided herein are inhibitors of EGFR and HER 2.

As used herein, "EGFR inhibitor" includes any compound that exhibits EGFR inactivating activity (e.g., inhibiting or reducing). In some embodiments, the EGFR inhibitor may be selective for EGFR kinase having one or more mutations. For example, EGFR inhibitors can bind to Adenosine Triphosphate (ATP) binding sites in the tyrosine kinase domain. In some embodiments, the EGFR inhibitor is an allosteric inhibitor.

The compounds provided herein can inhibit EGFR. In some embodiments, the compound can bind to an EGFR Adenosine Triphosphate (ATP) binding site in a tyrosine kinase domain.

The ability of the test compounds to act as EGFR inhibitors can be demonstrated by assays known in the art. The activity of a compound or composition provided herein as an EGFR inhibitor can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of kinase and/or atpase activity. Alternative in vitro assays quantify the ability of the inhibitor to bind protein kinase, which may be measured by radiolabeling the compound prior to binding, isolating the compound/kinase complex and determining the amount of radiolabel bound, or by conducting competition experiments in which novel compounds are incubated with kinase bound to known radioligands. In some cases, EGFR inhibitors can be evaluated by their effect on the initial rate of EGFR tyrosine kinase catalyzed peptide phosphorylation (e.g., cancer cell by Yun et al 2007;11 (3): 217-227). In some embodiments, fluorescence kinetics can be used to determine the binding constant of EGFR inhibitors (e.g., cancer cell by Yun et al 2007;11 (3): 217-227). Examples of Surface Plasmon Resonance (SPR) binding assays include those disclosed in Li, shiqing et al Cancer cell 7.4 (2005): 301-311. Additional EGFR inhibitor assays can be found, for example, in WO 2019/246541 and WO 2019/165358, both of which are incorporated herein by reference in their entirety.

Assays may include, for example, proliferation inhibition assays, such as those measuring Cell growth inhibition, such as the MTS assay, or Cell viability assays by Cell Titer GloTo perform such assays, cells are seeded onto cell culture plates and allowed to grow, and then exposed to test compounds for various durations. The viability of the cells after exposure was then assessed. Normalizing the data relative to untreated cells and graphically displayingAnd (3) displaying the formula. A nonlinear regression model with a sigmoidal dose response can be used to fit the growth curve. For another example, western blot analysis may be used. In such assays, cells are seeded onto and grown on culture plates and then treated with test compounds for a different duration the next day. Cells were washed with PBS and lysed. Lysates were separated using SDS-PAGE gels, which were transferred onto nitrocellulose membranes, probed with appropriate antibodies (e.g., phosphorylated-EGFR (Tyrl 068) (3777), total EGFR (2232), p-Akt (Ser 473) (4060), total Akt (9272), p-ERK (Thr 202/Tyr 204) (4370), total ERK (9102), and HSP90 (SC-7947)).

Additional assays may include, for example, ALPHALISA based (see, e.g., promega, inc.)>EGF/EGFR binding kit). Such assays use luminescent oxygen channel chemistry to detect molecules of interest, such as buffers, cell culture media, serum, and plasma. For example, biotinylated EGF was bound to streptavidin-coated Alpha donor beads and EGFR-Fc was captured by anti-human IgG Fc-specific Alpha LISA acceptor beads. When EGF binds EGFR, the donor and acceptor beads are in close proximity, and excitation of the donor bead causes release of singlet oxygen molecules, triggering a cascade of energy transfer in the acceptor bead. This results in a sharp light emission peak at 615 nm. Such assays may be used, for example, in competitive binding assays.

Other examples of assays may include Sox-based assays (see, e.g., fromBased on->Homogenizing, kinetics or endpoint/red fluorescence assay of Sox). Such assays utilize chelate enhanced fluorescence (CHEF), use peptides orThe sulphinylamino-oxine (Sox) chromophore in the protein substrate was used to create a phosphorylated real-time sensor. See, for example, U.S. patent nos. 8,586,570 and 6,906,194.

Efficacy of EGFR inhibitors as provided herein may be achieved by EC ₅₀ The value is determined. Relative to EC ₅₀ Higher value compounds, EC determined under substantially similar conditions ₅₀ Compounds with lower values are more potent inhibitors. In some embodiments, substantially similar conditions include determining the level of EGFR-dependent phosphorylation in vitro or in vivo (e.g., in tumor cells, a431 cells, ba/F3 cells, or 3T3 cells that express wild-type EGFR, mutant EGFR, or any fragment thereof).

Efficacy of EGFR inhibitors as provided herein may also be achieved by IC ₅₀ The value is determined. Relative to IC ₅₀ Higher value compounds, IC's determined under substantially similar conditions ₅₀ Compounds with lower values are more potent inhibitors. In some embodiments, substantially similar conditions include determining the level of EGFR-dependent phosphorylation in vitro or in vivo (e.g., in tumor cells, a431 cells, ba/F3 cells, or 3T3 cells that express wild-type EGFR, mutant EGFR, or any fragment thereof).

Selectivity between wild-type EGFR and EGFR comprising one or more mutations described herein can also be measured using a cell proliferation assay, wherein cell proliferation is dependent on kinase activity. For example, a suitable version of wild-type EGFR (e.g., VIII; containing wild type EGFR kinase domain) or by L858R/T790M, del/T790M/L718Q, L858R/T790M/L718Q, L858R/T790M/C797S, del/T790M/C797S, L858R/T790M/I941R, exon 19 deletion/T790M or exon 20 insertion (e.g., V769-D770 insX, D770-N771 insX, N771-P772 insX, P772-H773 insX or H773-V774 insX (e.g., A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H2773 dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H2773 insDNP, P772_H2773 insPNP, H2773_V 774insNPH, H2773_V 774insPH, H2773_V 774insAH or P772_773 inspH) transfected with a dye And (5) cells. Proliferation assays were performed at a range of inhibitor concentrations (e.g., 10. Mu.M, 3. Mu.M, 1.1. Mu.M, 330nM, 110nM, 33nM, 11nM, 3nM, 1 nM), and EC was calculated ₅₀ 。

An alternative method of measuring the effect on EGFR activity is to determine EGFR phosphorylation. Wild-type or mutant L858R/T790M, del/T790M, del/T790M/L718Q, L858R/T790M/C797S, del/T790M/C797S, L858R/T790M/I941R or L858R/T790M/L718Q) EGFR may be transfected into cells that do not normally express endogenous EGFR and the ability of the inhibitors (e.g., using the concentrations described above) to inhibit EGFR phosphorylation may be assayed. Cells were exposed to increased inhibitor concentration and stimulated with EGF. The effect on EGFR phosphorylation was determined by Western blotting using a phospho-specific EGFR antibody.

In some embodiments, the compounds provided herein may exhibit potent and selective inhibition of EGFR. For example, the compounds provided herein can bind to an EGFR Adenosine Triphosphate (ATP) binding site in a tyrosine kinase domain. In some embodiments, the compounds provided herein may exhibit nanomolar potency against EGFR kinases including activating mutations or EGFR inhibitor resistance mutations, including, for example, resistance mutations in table 2a and table 2b (e.g., L747S, D761Y, T790M and T854A), and minimal activity against related kinases (e.g., wild-type EGFR). Inhibition of wild-type EGFR can cause undesirable side effects (e.g., diarrhea and rash), which can affect quality of life and compliance. In some cases, inhibiting wild-type EGFR can result in dose-limiting toxicity. See, e.g., morphy.j.med.chem.2010,53,4,1413-1437 and peters.j.med.chem.2013,56,22,8955-8971.

In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, can selectively target EGFR kinase. For example, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may selectively target EGFR kinase but not another kinase or a non-kinase.

In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is greater inhibition of EGFR comprising one or more mutations described herein (e.g., one or more mutations as described in tables 1a and 1 b) relative to inhibiting wild-type EGFR. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of EGFR comprising one or more mutations described herein relative to inhibiting wild-type EGFR. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: up to 1000-fold greater inhibition of EGFR comprising one or more mutations described herein relative to inhibition of wild-type EGFR. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is up to 10000-fold greater inhibition of EGFR with the combination of mutations described herein relative to inhibition of wild-type EGFR.

In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is about 2-fold to about 10-fold greater inhibition of EGFR comprising one or more mutations described herein relative to inhibiting wild-type EGFR. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: about 10-fold to about 100-fold greater inhibition of EGFR comprising one or more mutations described herein relative to inhibiting wild-type EGFR. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: about 100-fold to about 1000-fold greater inhibition of EGFR comprising one or more mutations described herein relative to inhibiting wild-type EGFR. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is about 1000-fold to about 10000-fold greater inhibition of EGFR comprising one or more mutations described herein relative to inhibiting wild-type EGFR.

In other embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second EGFR inhibitor may exhibit: there is greater inhibition of EGFR comprising one or more mutations described herein (e.g., one or more mutations as described in tables 1a and 1 b) relative to inhibiting wild-type EGFR. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second EGFR inhibitor may exhibit: there is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of EGFR comprising one or more mutations described herein relative to inhibiting wild-type EGFR. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second EGFR inhibitor may exhibit: up to 1000-fold greater inhibition of EGFR comprising one or more mutations described herein relative to inhibition of wild-type EGFR. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second EGFR inhibitor may exhibit: there is up to 10000-fold greater inhibition of EGFR comprising one or more mutations described herein relative to inhibition of wild-type EGFR.

In other embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second EGFR inhibitor may exhibit: there is about 2-fold to about 10-fold greater inhibition of EGFR comprising one or more mutations described herein relative to inhibiting wild-type EGFR. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second EGFR inhibitor may exhibit: about 10-fold to about 100-fold greater inhibition of EGFR comprising one or more mutations described herein relative to inhibiting wild-type EGFR. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second EGFR inhibitor may exhibit: about 100-fold to about 1000-fold greater inhibition of EGFR comprising one or more mutations described herein relative to inhibiting wild-type EGFR. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second EGFR inhibitor may exhibit: there is about 1000-fold to about 10000-fold greater inhibition of EGFR comprising one or more mutations described herein relative to inhibiting wild-type EGFR.

The compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or pharmaceutically acceptable salts or solvates thereof are useful in treating diseases and disorders that can be treated by EGFR inhibitors, e.g., EGFR-related diseases and disorders, e.g., central nervous system diseases (e.g., neurodegenerative diseases), pulmonary diseases, cardiovascular diseases, ischemia, liver diseases, gastrointestinal diseases, viral or bacterial infections, inflammatory and/or autoimmune diseases (e.g., psoriasis and atopic dermatitis), as well as proliferative disorders, e.g., cancers, including hematological cancers and solid tumors (e.g., advanced solid tumors).

As used herein, "HER2 inhibitor" includes any compound that exhibits HER2 inactivating activity (e.g., inhibiting or reducing). In some embodiments, the HER2 inhibitor may be selective for HER2 kinase having one or more mutations. In some embodiments, the HER2 inhibitor may bind to a HER2 Adenosine Triphosphate (ATP) binding site in the tyrosine kinase domain.

The compounds provided herein can inhibit HER2. For example, the compound may bind to a HER2 Adenosine Triphosphate (ATP) binding site in the tyrosine kinase domain. In some embodiments, a compound provided herein can inhibit wild-type HER2. In some embodiments, a compound provided herein can inhibit HER2 having one or more mutations described herein.

The ability of the test compound to act as a HER2 inhibitor can be demonstrated by assays known in the art. The activity of a compound or composition provided herein as a HER2 inhibitor may be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of kinase and/or atpase activity. Alternative in vitro assays quantify the ability of the inhibitor to bind protein kinase, which may be measured by radiolabeling the compound prior to binding, isolating the compound/kinase complex and determining the amount of radiolabel bound, or by conducting competition experiments in which novel compounds are incubated with kinase bound to known radioligands. In some cases, HER2 inhibitors can be evaluated by their effect on the initial rate of HER2 tyrosine kinase-catalyzed peptide phosphorylation (e.g., cancer cell by Yun et al, 2007;11 (3): 217-227). For example, assays that indirectly measure ADP formed by the HER2 kinase reaction can be used (see, e.g., ATP/NADH coupled assay systems and luminescent kinase assays, e.g., ADP-GLO from Promega corporation ^TM Kinase assay). See, e.g., hanker et al Cancer discover.2017, month 6; 7 (6) 575-585; nat Med.2018, month 5 of Robichaux et al; 24 (5):638-64 6, preparing a base material; yun et al Proc Natl Acad Sci U S a.2008, 2 months, 12 days; 105 (6):2070-5. In some embodiments, assays that utilize labeled anti-phosphotyrosine antibodies to detect substrate phosphorylation may be used (see, e.g., rabindoran et al Cancer Res.2004Jun 1;64 (11): 3958-65). In some embodiments, fluorescence kinetics can be used to determine the binding constant of HER2 inhibitors (e.g., cancer cell by Yun et al 2007;11 (3): 217-227). Examples of SPR binding assays include those disclosed in Li, shiqing et al Cancer cell 7.4 (2005): 301-311. In some embodiments, mass spectrometry can be used to detect covalent binding of HER2 inhibitors to HER2, e.g., mol Cancer ther.2019, month 4 of Irie et al; 18 (4):733-742. Additional HER2 inhibitor assays can be found, for example, in U.S. patent No. 9,920,060, WO 2019/241715, and U.S. publication No. 2017/0166598, each of which is incorporated herein by reference in its entirety.

Efficacy of HER2 inhibitors as provided herein may be achieved by EC ₅₀ The value is determined. Relative to EC ₅₀ Higher value compounds, EC determined under substantially similar conditions ₅₀ Compounds with lower values are more potent inhibitors. In some embodiments, substantially similar conditions include determining HER 2-dependent phosphorylation levels in vitro or in vivo (e.g., in tumor cells or Ba/F3 cells expressing wild-type HER2, mutated HER2, or any fragment thereof).

Efficacy of HER2 inhibitors as provided herein may also be achieved by IC ₅₀ The value is determined. Relative to IC ₅₀ Higher value compounds, IC's determined under substantially similar conditions ₅₀ Compounds with lower values are more potent inhibitors. In some embodiments, substantially similar conditions include determining HER 2-dependent phosphorylation levels in vitro or in vivo (e.g., in tumor cells or Ba/F3 cells expressing wild-type HER2, mutated HER2, or any fragment thereof).

Assays may include, for example, proliferation inhibition assays, such as those measuring Cell growth inhibition, such as the MTS assay, or Cell viability assays by Cell Titer GloTo perform such assays, cells are seeded onto cell culture plates and allowed to grow, and then exposed to test compounds for various durations. The viability of the cells after exposure was then assessed. The data were normalized to untreated cells and can be displayed graphically. A nonlinear regression model with a sigmoidal dose response can be used to fit the growth curve. For another example, western blot analysis may be used. In such assays, cells are seeded onto and grown on culture plates and then treated with test compounds for a different duration the next day. Cells were washed with PBS and lysed. Lysates were separated using SDS-PAGE gels, transferred onto nitrocellulose membranes, and probed with appropriate antibodies (e.g., phospho-HER 2 (Tyr 1248) (2247), phospho-EGFR-Tyr 1173 phospho-HER 2-Tyr877, phospho-HER 2-Tyr1221, total HER2, phospho-AKT-Thr 308, phospho-AKT-Ser 374, total AKT, phospho-p 44/42MAPK-Thr202/Tyr204 and p44/42 MAPK).

The selectivity between wild-type HER2 and HER2 comprising one or more mutations described herein can also be measured using a cell proliferation assay, wherein cell proliferation is dependent on kinase activity. For example, it is possible to use: murine Ba/F3 cells transfected with a suitable version of wild-type HER2, or Ba/F3 cells transfected with HER2 having one or more mutations such as: S310F, S310Y, R678Q, R678W, R678P, I767M, V M, V777L, V842I, M774AYVM, M774del insWLV, A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G776C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V insV, V777_G778insCG, G778_S779insCPG, or P780_Y781insGSP. Proliferation assays were performed at a range of inhibitor concentrations (e.g., 10. Mu.M, 3. Mu.M, 1.1. Mu.M, 330nM, 110nM, 33nM, 11nM, 3nM, 1 nM), and EC was calculated ₅₀ 。

An alternative method of measuring the effect on HER2 activity is to determine HER2 phosphorylation. Wild-type or mutant (S310F, S310Y, R678Q, R678W, R678P, I M, V773M, V777L, V842I, M AYVM, M774del insWLV, a775_g776 insvma, a775_g776insAVMA, a775_g776insSVMA, a775_g776insVAG, a775insV G776C, A775_g776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V777insV, V777_g778insCG, G778_s779insCPG or P780_y781 insGSP) HER2 may be transfected into cells that do not normally express endogenous HER2 and the ability of the inhibitor (e.g., using the above concentrations) to inhibit HER2 acidification may be determined. Cells were exposed to increased inhibitor concentration and stimulated with EGF. The effect on HER2 phosphorylation was determined by Western blotting using a phosphate-specific HER2 antibody.

In some embodiments, the compounds provided herein may exhibit potent and selective inhibition of HER 2. For example, a compound provided herein can bind to a HER2 Adenosine Triphosphate (ATP) binding site in a tyrosine kinase domain. In some embodiments, compounds provided herein may exhibit nanomolar potency against HER2 kinase including activating mutations or EGFR inhibitor resistance mutations, including, for example, exon 20 insertion and/or resistance mutations in table 5 (e.g., L755S, L755P, T798I and T798M), with minimal activity against related kinases (e.g., wild-type EGFR).

In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, can selectively target HER2 kinase. For example, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may selectively target HER2 kinase but not another kinase (e.g., wild-type EGFR) or a non-kinase. Because undesired side effects (e.g., diarrhea and rash) may affect quality of life and compliance, it is desirable to selectively target HER2 kinase rather than wild-type EGFR kinase. See, e.g., morphy.j.med.chem.2010,53,4,1413-1437 and peters.j.med.chem.2013,56,22,8955-8971.

In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein (e.g., one or more mutations as described in table 3) relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: up to 1000-fold greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein relative to inhibition of another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: up to 10000-fold greater inhibition of wild-type HER2 or a combination having mutations described herein relative to inhibition of another kinase (e.g., wild-type EGFR) or a non-kinase target.

In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is about 2-fold to about 10-fold greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is about 10-fold to about 100-fold greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is about 100-fold to about 1000-fold greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is about 1000-fold to about 10000-fold greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target.

In other embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second EGFR inhibitor may exhibit: there is greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein (e.g., one or more mutations as described in table 3) relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second HER2 inhibitor may exhibit: there is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second HER2 inhibitor may exhibit: up to 1000-fold greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein relative to inhibition of another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second HER2 inhibitor may exhibit: up to 10000-fold greater inhibition of wild-type HER2 or HER2 with a combination of mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target.

In other embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second HER2 inhibitor may exhibit: there is about 2-fold to about 10-fold greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second HER2 inhibitor may exhibit: there is about 10-fold to about 100-fold greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second HER2 inhibitor may exhibit: there is about 100-fold to about 1000-fold greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, and a second HER2 inhibitor may exhibit: there is about 1000-fold to about 10000-fold greater inhibition of wild-type HER2 or HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target.

The compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or pharmaceutically acceptable salts or solvates thereof, are useful in treating diseases and disorders that can be treated by HER2 inhibitors, e.g., HER 2-related diseases and disorders, e.g., proliferative disorders, such as cancers (e.g., HER 2-related cancers), including hematological cancers and solid tumors (e.g., advanced solid tumors).

In some embodiments, the compounds provided herein may also inhibit EGFR and HER2, as described herein.

In some embodiments, the compounds provided herein may exhibit potent and selective inhibition of EGFR and HER 2. In some embodiments, the compounds provided herein may exhibit nanomolar potency against EGFR kinase having one or more mutations (including, for example, one or more of table 1a, 1b, 2a, and 2 b) and HER2 kinase having one or more mutations (including, for example, the mutations in table 3), and minimal activity against related kinases (e.g., wild-type EGFR).

In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, can selectively target EGFR and HER2 kinase. For example, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may selectively target EGFR and HER2 kinase but not another kinase or a non-kinase.

In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is greater inhibition of EGFR comprising one or more mutations as described herein, as well as wild-type HER2 or HER2 comprising one or more mutations as described herein (e.g., one or more mutations as described in tables 3-5), relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of EGFR comprising one or more mutations as described herein, as well as wild-type HER2, or HER2 comprising one or more mutations as described herein, relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: up to 1000-fold greater inhibition of EGFR comprising one or more mutations as described herein, as well as wild-type HER2 or HER2 comprising one or more mutations as described herein, relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: up to 10000-fold greater inhibition of EGFR comprising one or more mutations as described herein, as well as wild-type HER2 or HER2 having one or more mutations as described herein, relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target.

In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is about 2-fold to about 10-fold greater inhibition of EGFR comprising one or more mutations as described herein, as well as wild-type HER2 or HER2 comprising one or more mutations as described herein, relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is about 10-fold to about 100-fold greater inhibition of EGFR comprising one or more mutations as described herein, as well as wild-type HER2 or HER2 comprising one or more mutations as described herein, relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is about 100-fold to about 1000-fold greater inhibition of EGFR comprising one or more mutations as described herein, as well as wild-type HER2 or HER2 comprising one or more mutations as described herein, relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof may exhibit: there is about 1000-fold to about 10000-fold greater inhibition of EGFR comprising one or more mutations as described herein, as well as wild-type HER2 or HER2 comprising one or more mutations as described herein, relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target.

In other embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof with a second EGFR and/or second HER2 inhibitor may exhibit: there is greater inhibition of EGFR comprising one or more mutations as described herein as well as wild-type HER2 or HER2 comprising one or more mutations as described herein (e.g., one or more mutations as described in table 3) relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, with a second EGFR and/or second HER2 inhibitor may exhibit: there is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of EGFR comprising one or more mutations as described herein, as well as wild-type HER2, or HER2 comprising one or more mutations as described herein, relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, with a second EGFR and/or second HER2 inhibitor may exhibit: up to 1000-fold greater inhibition of EGFR comprising one or more mutations as described herein, as well as wild-type HER2 or HER2 comprising one or more mutations as described herein, relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, with a second EGFR and/or second HER2 inhibitor may exhibit: up to 10000-fold greater inhibition of EGFR comprising one or more mutations as described herein, as well as wild-type HER2 or HER2 comprising one or more mutations as described herein, relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target.

In other embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof with a second EGFR and/or second HER2 inhibitor may exhibit: there is about 2-fold to about 10-fold greater inhibition of EGFR comprising one or more mutations as described herein and HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, with a second EGFR and/or second HER2 inhibitor may exhibit: there is about 10-fold to about 100-fold greater inhibition of EGFR comprising one or more mutations as described herein and HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, with a second EGFR and/or second HER2 inhibitor may exhibit: there is about 100-fold to about 1000-fold greater inhibition of EGFR comprising one or more mutations as described herein and HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target. In some embodiments, a combination of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, with a second EGFR and/or second HER2 inhibitor may exhibit: there is about 1000-fold to about 10000-fold greater inhibition of EGFR comprising one or more mutations as described herein and HER2 comprising one or more mutations as described herein relative to inhibiting another kinase (e.g., wild-type EGFR) or a non-kinase target.

Also provided herein are methods of inhibiting BUB (benzimidazole budding inhibition release, BUB 1-3) kinase. For example, provided herein are inhibitors of BUB1, which are useful for treating or preventing diseases or disorders associated with enhanced uncontrolled proliferative cellular processes, such as cancer, inflammation, arthritis, viral diseases, cardiovascular diseases, or fungal diseases. See, e.g., WO 2013/050438, WO 2013/092512, WO 2013/167698, WO 2014/147203, WO 2014/147204, WO 2014/202590, WO 2014/202588, WO 2014/202584, WO 2014/202583, WO 2015/063503, WO2015/193339, WO 2016/202755, and WO 2017/021348. In some embodiments, the disease or disorder is cancer.

As used herein, "BUB1 inhibitor" includes any compound that exhibits BUB1 inactivating activity (e.g., inhibiting or reducing). In some embodiments, the BUB1 inhibitor is selective for BUB1 over others (e.g., wild-type EGFR).

The compounds provided herein inhibit Bub kinase. In some embodiments, the compounds provided herein can inhibit BUB1 kinase.

The ability of the test compounds to act as BUB1 inhibitors can be demonstrated by assays known in the art. The activity of a compound or composition provided herein as a BUB1 inhibitor can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine kinase inhibition. For example, the BUB1 inhibition of the compounds provided herein can be determined using a time-resolved fluorescence energy transfer (TR-FRET) assay that measures the phosphorylation of synthetic peptides (e.g., biotin-AHX-VLLPKKSFAEPG (C-terminal in amide form) by the (recombinant) catalytic domain of human BUB1 (amino acids 704-1085), expressed in Hi5 insect cells with an N-terminal His6 tag and purified by affinity chromatography (Ni-NTA) and size exclusion chromatography. See, for example, WO 2017/021348. Furthermore, BUB1 activity can be determined at high ATP concentrations using BUB1 TR-FRET high ATP kinase assays using similar methods as described above. See, for example, WO 2019/081486.

In some embodiments, a compound provided herein inhibits Central Nervous System (CNS) exogenesis. For example, such compounds are capable of crossing the Blood Brain Barrier (BBB) and inhibiting EGFR and/or HER2 kinase in the brain and/or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood brain barrier in a therapeutically effective amount. For example, treating a cancer patient (e.g., having an EGFR-related cancer or a HER 2-related cancer, such as an EGFR or HER 2-related brain cancer or CNS cancer, or an EGFR-related or HER 2-related cancer that metastasizes to the brain or CNS) can include administering (e.g., orally administering) the compound to the patient.

The ability of the compounds described herein to cross the BBB can be demonstrated by assays known in the art. Such assays include BBB models, such as transwell systems, hollow fiber (dynamic in vitro BBB) models, other microfluidic BBB systems, BBB sphere platforms, and othersBBB model based on cell aggregates. See, e.g., cho et al, nat commun.2017;8:15623; drug Des development ter.2019 by Bagchi et al; 13:3591-3605; curr Opin Biomed Eng.2018, gastfriend et al, 3 months; 5:6-12 and Wang et al Biotechnol bioeng.2017, month 1; 114 184-194. In some embodiments, the compounds described herein are fluorescently labeled, and the fluorescent label can be detected using a microscope (e.g., confocal microscope). In some such embodiments, the ability of a compound to penetrate the surface barrier of a model may be represented by fluorescence intensity at a given depth below the surface. In some assays, such as calcein-AM based assays, the fluorescent label is non-fluorescent prior to penetration into living cells and hydrolysis by a cytolactonase to produce a fluorescent compound that is retained in the cells and can be quantified using a spectrophotometer. Non-limiting examples of fluorescent labels that can be used in the assays described herein include Cy5, rhodamine, infrared CW-800 (LICOR#929-71012), far infrared650 (LICOR#929-70020), sodium fluorescein (Na-F), fluorescein (LY), 5' carboxyfluorescein and calcein-acetoxymethyl ester (calcein-AM). In some embodiments, the BBB model (e.g., tissue or cell aggregates) can be sectioned, and the compounds described herein can be detected in one or more sections using mass spectrometry (e.g., MALDI-MSI analysis). In some embodiments, the ability of a compound described herein to cross the blood brain barrier by transcellular transport systems, such as Receptor Mediated Transport (RMT), carrier Mediated Transport (CMT), or Active Efflux Transport (AET), can be demonstrated by assays known in the art. See, e.g., wang et al Drug deliv.2019;26 (1):551-565. In some embodiments, the assay to determine whether a compound can be exported by a P-glycoprotein (Pgp) comprises a single layer efflux assay in which the passage of a compound through Pgp is quantified by measuring the movement of digoxin, a model Pgp substrate(see, e.g., doan et al 2002.J Pharmacol Exp Ther.303 (3): 1029-1037). Alternative in vivo assays for identifying compounds that pass the blood brain barrier include phage-based systems (see, e.g., peng et al, 2019.ChemRxiv.Preprint doi.org/10.26434/chemrxiv.8242871. V1). In some embodiments, the binding of a compound described herein to brain tissue is quantified. For example, brain binding assays can be performed using equilibrium dialysis, and LC-MS/MS can be used to detect the fraction of compounds described herein that do not bind to brain tissue (cytox: brain Tissue Binding Assay (brain tissue binding assay), www.cyprotex.com/admepk/protein_binding/brain-tissue-binding /).

The compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt or solvate thereof, are useful in treating diseases or disorders treatable with EGFR inhibitors, HER2 inhibitors, dual EGFR and HER2 inhibitors, and/or BUB1 inhibitors, such as those described herein, e.g., cancers. Accordingly, provided herein is a method of treating a disease or disorder as provided herein in a subject in need thereof, the method comprising: providing a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt or solvate thereof to a subject. In some embodiments, the disease or disorder is cancer.

The terms "treatment" or "therapeutic" as used herein refer to a therapeutic or palliative measure. Beneficial or desired clinical results include, but are not limited to, detectable or undetectable complete or partial alleviation of symptoms associated with a disease or disorder or condition, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (partial or complete). "treatment" may also mean an increase in survival relative to the expected survival without treatment.

As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.

In some embodiments, the subject has been identified or diagnosed as having a cancer (e.g., EGFR-associated cancer) with dysregulated expression or activity or level of the EGFR gene, EGFR protein, or any of them (e.g., as determined using regulatory agency-approved (e.g., FDA-approved) assays or kits). In some embodiments, the subject has a tumor positive for expression or activity or dysregulation of the EGFR gene, EGFR protein, or one of them (as determined using regulatory agency-approved assays or kits). For example, the subject suffers from a tumor positive for the mutations described in table 1a and table 1 b. The subject may be a subject with a tumor that is positive for an abnormal expression or activity or level of EGFR gene, EGFR protein, or any of them (e.g., positive using regulatory agency-approved (e.g., FDA-approved) assays or kits). The subject may be a subject whose tumor has an EGFR gene, EGFR protein, or whose expression or activity or level is dysregulated (e.g., wherein the tumor is identified as such using regulatory agency-approved (e.g., FDA-approved) assays or kits). In some embodiments, the subject is suspected of having EGFR-associated cancer. In some embodiments, the clinical record of the subject indicates that the subject has a tumor, and the tumor has abnormal expression or activity or level of EGFR gene, EGFR protein, or any of them (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein).

In some embodiments, the subject has been identified or diagnosed as having a cancer (e.g., HER 2-related cancer) with aberrant expression or activity or level of the HER2 gene, HER2 protein, or any of them (e.g., as determined using regulatory agency-approved (e.g., FDA-approved) assays or kits). In some embodiments, the subject has a tumor positive for aberrant expression or activity or level of HER2 gene, HER2 protein, or any thereof (as determined using regulatory agency-approved assays or kits). For example, the subject has a tumor positive for the mutations described in table 3. The subject may be a subject with a tumor that is positive for aberrant expression or activity or level regulation of the HER2 gene, HER2 protein, or any of them (e.g., positive using a regulatory agency-approved (e.g., FDA-approved) assay or kit). The subject may be a subject whose tumor has an aberrant expression or activity or level of HER2 gene, HER2 protein, or a HER2 protein (e.g., wherein the tumor is identified as such using regulatory agency-approved (e.g., FDA-approved) assays or kits). In some embodiments, the subject is suspected of having HER 2-related cancer. In some embodiments, the clinical record of the subject indicates that the subject has a tumor, and the tumor has abnormal expression or activity or level of HER2 gene, HER2 protein, or any of them (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein).

In some embodiments, the subject is a pediatric subject.

The term "pediatric subject" as used herein refers to a subject that is less than 21 years of age at the time of diagnosis or treatment. The term "pediatric" may be further divided into various subgroups, including: neonates (first month from birth to birth); infants (1 month to two years); children (two to 12 years) and adolescents (12 to 21 years (but not including 22 years of birth)). Berhman RE, kliegman R, arvin AM, nelson we. Nelson Textbook of Pediatrics (nielsen science), 15 th edition, philadelphia: w.b. samanders, 1996; rudolph AM et al, rudolph's Pediatrics (Ludoff science), 21 st edition, N.Y.: mcGraw-Hill, 2002; and Avery MD, first LR (First LR). Pediatric Medicine (pediatric medical), 2 nd edition, barlmo: williams & Wilkins company; 1994. in some embodiments, the pediatric subject is from birth to the first 28 days of birth; from day 29 to less than 2 years old, from two to less than 12 years old, or from 12 to 21 years old (up to but excluding 22 years of birthday). In some embodiments, the pediatric subject is from 29 days to less than 1 year old, from one month to less than four months of age, from three months to less than seven months of age, from six months to less than 1 year old, from 1 year to less than 2 years old, from 2 years to less than 3 years old, from 2 years to less than 7 years old, from 3 years old to less than 5 years old, from 5 years old to less than 10 years old, from 6 years old to less than 13 years old, from 10 years old to less than 15 years old, or from 15 years old to less than 22 years old from the first 28 days after birth.

In certain embodiments, compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt or solvate thereof, are useful for preventing a disease or disorder as defined herein (e.g., autoimmune disease, inflammatory disease, pulmonary disease, cardiovascular disease, ischemia, liver disease, gastrointestinal disease, viral or bacterial infection, central nervous system disease (e.g., neurodegenerative disease), and cancer). The term "preventing" as used herein means delaying the onset, recurrence or transmission of a disease or disorder or symptoms thereof, as described herein, either entirely or partially.

The term "EGFR-related disease or disorder" as used herein refers to a disease or disorder associated with dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase (also referred to herein as an EGFR kinase protein), or any (e.g., one or more) thereof (e.g., any type of dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase domain, or any of them described herein). Non-limiting examples of EGFR-related diseases or conditions include, for example, cancer, central nervous system diseases, pulmonary diseases, cardiovascular diseases, ischemia, liver diseases, gastrointestinal disorders, viral or bacterial infections, and inflammatory and/or autoimmune diseases (e.g., psoriasis, eczema, atopic dermatitis, and atherosclerosis).

In some embodiments of any of the methods or uses described herein, the inflammatory and/or autoimmune disease is selected from arthritis, systemic lupus erythematosus, atherosclerosis, and skin related disorders, such as psoriasis, eczema, and atopic dermatitis. See, e.g., wang et al, am J trans res.2019;11 (2) 520-528; starosyla et al, world J Pharmacol.2014, 12, 9; 162-173; choi et al, biomed Res int.2018, 5 months 15 days; 2018:9439182; and Wang et al, sci Rep.2017;7:45917.

In some embodiments of any of the methods or uses described herein, the central nervous system disease is a neurodegenerative disease. In some embodiments, the central nervous system disorder is selected from the group consisting of alzheimer's disease, parkinson's disease, huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, peripheral neuropathy, cerebral ischemia, and psychotic disorders such as schizophrenia. See, for example, iwakura and nawa.front Cell neurosci.2013, month 2, 13; 7:4; and Chen et al Sci rep.2019, month 2, 21; 9 (1):2516.

The term "EGFR-related cancer" as used herein refers to a cancer associated with or having dysregulation of expression or activity or levels of the EGFR gene, EGFR kinase (also referred to herein as EGFR kinase protein), or any of them. Non-limiting examples of EGFR-related cancers are described herein.

The phrase "abnormal expression or activity or level of EGFR gene, EGFR kinase, or any of them" refers to a genetic mutation (e.g., an EGFR gene mutation that results in expression of an EGFR protein comprising at least one amino acid deletion compared to a wild-type EGFR protein, an EGFR gene mutation that results in expression of an EGFR protein comprising one or more point mutations compared to a wild-type EGFR protein, an EGFR gene mutation that results in expression of an EGFR protein comprising at least one insertion amino acid compared to a wild-type EGFR protein, a genetic replication that results in increased levels of EGFR protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in increased levels of EGFR protein in a cell, an alternatively spliced form of EGFR mRNA that results in EGFR protein comprising at least one amino acid deletion compared to a wild-type EGFR protein, or increased expression (e.g., increased levels) of wild-type EGFR kinase in a mammalian cell due to abnormal cell signaling and/or deregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, the expression or activity or dysregulation of the EGFR gene, EGFR protein, or any of them, may be a mutation in the EGFR gene encoding the EGFR protein that has constitutive activity or has increased activity compared to the protein encoded by the EGFR gene that does not comprise the mutation. Non-limiting examples of EGFR kinase protein point mutations/insertions/deletions are described in tables 1a and 1 b. Other examples of EGFR kinase protein mutations (e.g., point mutations) are EGFR inhibitor resistance mutations (e.g., EGFR inhibitor mutations). Non-limiting examples of EGFR inhibitor resistance mutations are described in tables 2a and 2 b. For example, the one or more EGFR inhibitor resistance mutations can include a substitution at amino acid positions 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S or T854A). Such mutations and overexpression have been associated with the occurrence of a variety of cancers (Shan et al, cell2012,149 (4) 860-870).

In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any of them, may be caused by activating mutations in the EGFR gene. In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any of them, may be caused by a genetic mutation that results in EGFR kinase expression, which has increased resistance to EGFR inhibitors, tyrosine Kinase Inhibitors (TKIs), and/or Multiple Kinase Inhibitors (MKIs), e.g., as compared to wild-type EGFR kinase (see, e.g., amino acid substitutions in tables 2a and 2 b). In some embodiments, dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any of them, may be caused by a nucleic acid mutation encoding an altered EGFR protein (e.g., an EGFR protein with a mutation (e.g., a primary mutation)) that results in increased resistance of the altered expression of the EGFR protein to inhibition by an EGFR inhibitor, a Tyrosine Kinase Inhibitor (TKI), and/or a Multiple Kinase Inhibitor (MKI), e.g., as compared to a wild-type EGFR kinase (see, e.g., amino acid substitutions in tables 2a and 2 b). The exemplary EGFR kinase point mutations, insertions, and deletions shown in tables 1a, 1b, 2a, and 2b may be caused by activating mutations and/or may result in EGFR kinase expression with increased resistance to EGFR inhibitors, tyrosine Kinase Inhibitors (TKIs), and/or Multiple Kinase Inhibitors (MKIs).

In some embodiments, the individual has two or more EGFR inhibitor resistance mutations that increase the resistance of the cancer to the first EGFR inhibitor. For example, an individual may have two EGFR inhibitor resistance mutations. In some embodiments, the two mutations occur in the same EGFR protein. In some embodiments, the two mutations occur in different EGFR proteins. In some embodiments, the individual may have three EGFR inhibitor resistance mutations. In some embodiments, the three mutations occur in the same EGFR protein. In some embodiments, the three mutations occur in different EGFR proteins. For example, an individual has two or more EGFR inhibitor resistance mutations selected from the group consisting of: del 19/L718Q, del/T790M, del/L844V, del/T790M/L718Q, del/T790M/C797S, del/T790M/L844V, L858R/L718Q, L858R/L844V, L858R/T790M, L858R/T790M/L718Q, L858R/T790M/C797S and L858R/T790M/I941R, or any combination thereof; for example, any two of the aforementioned EGFR inhibitor resistance mutations.

The term "activating mutation" in relation to EGFR describes a mutation in the EGFR gene that results in the expression of EGFR kinase having increased kinase activity, e.g. when measured under the same conditions, as compared to wild type EGFR kinase. For example, an activating mutation can be a mutation in the EGFR gene that results in expression of an EGFR kinase having one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein), resulting in increased kinase activity, e.g., when measured under the same conditions, as compared to a wild-type EGFR kinase. In another example, the activating mutation may be a mutation in the EGFR gene that results in expression of the EGFR kinase, e.g., having one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid deletions compared to the wild-type EGFR kinase, e.g., when measured under the same conditions. In another example, the activating mutation can be a mutation in the EGFR gene that results in expression of an EGFR kinase having at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20) amino acid insertion compared to a wild-type EGFR kinase (e.g., an exemplary wild-type EGFR kinase described herein), e.g., when measured under the same conditions. Additional examples of activating mutations are known in the art.

The term "wild-type" or "wild-type" describes a nucleic acid (e.g., EGFR gene or EGFR mRNA) or protein (e.g., EGFR protein) sequence that is typically found in a subject that is free of a disease or disorder associated with a reference nucleic acid or protein.

The term "wild-type EGFR" or "wild-type EGFR" describes EGFR nucleic acids (e.g., EGFR genes or EGFR mRNA) or proteins (e.g., EGFR proteins) found in subjects without EGFR-related disease (e.g., EGFR-related cancer) (and optionally without increasing the risk of having EGFR-related disease and/or without being suspected of having EGFR-related disease) or in cells or tissues of subjects without EGFR-related disease (e.g., EGFR-related cancer) (and optionally without increasing the risk of having EGFR-related disease and/or without being suspected of having EGFR-related disease).

Provided herein is a method of treating cancer (e.g., EGFR-associated cancer) 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) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein is a method of treating EGFR-related cancer in a subject in need of such treatment, the method comprising: a) Detecting dysregulation of expression or activity or level of an EGFR gene, EGFR kinase, or any thereof in a sample from a subject; and b) administering a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof. In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any thereof, comprises one or more EGFR kinase protein point mutations/insertions. Non-limiting examples of EGFR kinase protein point mutations/insertions/deletions are described in tables 1a and 1 b. In some embodiments, the EGFR kinase protein point mutation/insertion/deletion is selected from the group consisting of: g719S, G719C, G719A, L S, D761Y, T790M, T854A, L858R, L861Q, exon 19 deletion (e.g., L747_a750 del), and exon 20 insertion (e.g., V769_d770insX, D770_n771insX, n771_p772insx, p772_h773insX, or h773_v774 insX). In some embodiments, the EGFR kinase protein point mutation/insertion/deletion is selected from the group consisting of: L858R, exon 19 deletion (e.g., L747 a750 del), L747S, D761Y, T790M, and T854A. In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion. In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: v769_d770insX, d770_n771insX, n771_p772insx, p772_h773insX and h773_v774insX. For example, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H2773 dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H2773 insDNP, P772_H2773 insPNP, H2773_V774 insNPH, H2773_V774 insPH, H2773_V774 insAH, and P772_H2773 insIndH. Or any combination thereof; for example, any two or more independently selected exons 20 are inserted; for example, any two independently selected exons 20 are inserted (e.g., V769D 770insASV and D770N 771 insSVD).

In some embodiments of any of the methods or uses described herein, the cancer (e.g., EGFR-related cancer) is selected from: hematological cancers (e.g., acute lymphocytic carcinoma, hodgkin lymphoma, non-hodgkin lymphoma, and leukemia, such as acute-myelogenous leukemia (AML), chronic Myelogenous Leukemia (CML), acute promyelocytic leukemia, and Acute Lymphoblastic Leukemia (ALL)), central or peripheral nervous system tissue cancers, endocrine or neuroendocrine cancers, including various neuroendocrine type I and type II tumors, li Famei ni (Li-Fraumeni) tumors, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, anal canal cancer or colorectal cancer, eye cancer, hepatobiliary tract cancer, joint cancer, neck cancer, gall bladder or pleura, nose, nasal or middle ear, mouth, oropharynx, nasopharynx (nasopharyngeal cancer), respiratory tract, genitourinary system, vulva, colon, esophagus, trachea, cervical, gastrointestinal carcinoid, hypopharynx, kidney, larynx, liver, lung, malignant mesothelioma, melanoma, multiple myeloma, nasopharynx (nasopharynx cancer), ovary, pancreas including islet cell, peritoneum, large omentum and mesenteric, pharynx, prostate, rectum, kidney (e.g., renal Cell Carcinoma (RCC)), small intestine, soft tissue, stomach, testes, thyroid, parathyroid, pituitary, adrenal gland, ureter, biliary tract and bladder. In some embodiments, the cancer is selected from the group consisting of: head and neck, ovary, cervix, bladder and esophagus, pancreas, gastrointestinal tract, stomach, breast, endometrium and colorectal cancers, hepatocellular, glioblastoma, bladder, lung cancer, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar cancer. In some embodiments, the cancer is pancreatic cancer, head and neck cancer, melanoma, colon cancer, renal cancer, leukemia, lung cancer, or breast cancer. In some cases, the cancer is melanoma, colon cancer, renal cancer, leukemia, or breast cancer.

In some such embodiments, the compounds provided herein are useful for treating primary brain tumors or metastatic brain tumors. For example, the compounds may be used to treat one or more gliomas, such as glioblastomas (also known as glioblastomas multiforme), astrocytomas, oligodendrogliomas, ependymomas and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (schwannomas) and craniopharyngeal tube tumors (see, e.g., liu et al J Exp Clin Cancer res.2019, 5 months 23; 38 (1): 219); and Ding et al Cancer Res.2003, 3 months 1 day; 63 (5):1106-13). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the brain tumor is a metastatic brain tumor, e.g., a metastatic brain tumor that metastasizes from lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, renal cancer, bladder cancer, or undifferentiated cancer. In some embodiments, the brain tumor is a metastatic brain tumor from lung cancer (e.g., non-small cell lung cancer). In some embodiments, the compounds provided herein exhibit brain and/or Central Nervous System (CNS) outstretches. In some embodiments, the patient has previously been treated with another anti-cancer agent, e.g., another EGFR and/or HER2 inhibitor (e.g., a compound other than a compound of formula I) or a multi-kinase inhibitor.

In some embodiments, the cancer is a B cell derived cancer. In some embodiments, the cancer is a lineage dependent cancer. In some embodiments, the cancer is a lineage dependent cancer, wherein abnormal expression or activity or level of EGFR or an EGFR gene, EGFR kinase, or any thereof, contributes to the occurrence and/or progression of the cancer.

In some embodiments, the cancer is an EGFR-related cancer. Accordingly, also provided herein is a method of treating a subject diagnosed with or identified as having an EGFR-related cancer, such as any of the exemplary EGFR-related cancers disclosed herein, comprising: administering to the subject a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein.

In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any thereof, comprises one or more deletions (e.g., amino acid deletions at position 4), insertions, or point mutations in the EGFR kinase. In some embodiments, dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any thereof, comprises at least one deletion, insertion, or point mutation in the EGFR gene that results in the production of an EGFR kinase having one or more of the amino acid substitutions, insertions, or deletions in table 1a and table 1 b. In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any thereof, comprises a deletion of one or more residues of the EGFR kinase, resulting in constitutive activity of the EGFR kinase domain.

In some embodiments, dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any of them, comprises at least one point mutation in the EGFR gene, resulting in the production of an EGFR kinase having one or more amino acid substitutions, insertions, or deletions compared to the wild-type EGFR kinase (see, e.g., point mutations listed in table 1a and table 1 b). In some embodiments, the dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any thereof, comprises at least one point mutation in the EGFR gene that results in the production of an EGFR kinase having one or more of the amino acid substitutions, insertions, or deletions in table 1a and table 1 b.

In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any of them, comprises insertion of one or more residues in exon 20 of the EGFR gene (e.g., any exon 20 insertion described in tables 1a and 1 b). Exon 20 of EGFR has two main regions, c-helix (residues 762-766) and c-helix post-loop (residues 767-774). Studies have shown that for some exon 20 insertions (e.g., insertions after residue 764), a stable ridge active conformation induces resistance to first generation EGFR inhibitors. In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any thereof, comprises insertion of one or more residues in exon 20 selected from the group consisting of: v769_d770insX, d770_n771insX, n771_p772insx, p772_h773insX and h773_v774insX. For example, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H2773 dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H2773 insDNP, P772_H2773 insPNP, H2773_V774 insNPH, H2773_V774 insPH, H2773_V774 insAH, and P772_H2773 insIndH. Or any combination thereof; for example, any two or more independently selected exons 20 are inserted; for example, any two independently selected exons 20 are inserted (e.g., V769D 770insASV and D770N 771 insSVD).

Table 1a: EGFR protein amino acidsSubstitution/insertion/deletion ^A

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^A The EGFR mutations shown can be activating mutations and/or increasing EGFR resistance to EGFR inhibitors and/or multi-kinase inhibitors (MKI), e.g., as compared to wild type EGFR

^B Potentially oncogenic variations. See, e.g., kohsaka, shinji, et al, science translational medicine (science conversion medicine) 9.416 (2017): ean 6566.

¹ PCT patent application publication No. WO2019/246541.

² Grosse A, grosse C, rechsteiner M, soltermann A.Diagn Pathol.2019;14 (1) 18.2019, 2 and 11 days. doi 10.1186/s13000-019-0789-1.

³ Stewart EL,Tan SZ,Liu G,Tsao MS.Transl Lung Cancer Res.2015；4(1):67–81.doi:10.3978/j.issn.2218-6751.2014.11.06。

⁴ Pines,Gur,Wolfgang J.And yoref yarden. FEBS letters (FEBS express) 584.12 (2010): 2699-2706.

⁵ Yasuda, hiroyuki, susumu Kobayashi and Daniel B.costa.the Lancet Oncology (Lancet Oncology) 13.1 (2012): e23-e31.

⁶ Kimey, cho EN, park HS, et al, cancer Biol ther.2016;17 (3) 237-245.Doi:10.1080/15384047.2016.1139235.

⁷ Shah, riyaz and Jason f.lester.clinical Lung Cancer (clinical Lung Cancer) (2019).

⁸ Aran, veronica and Jasminka Omeriovic.International journal of molecular sciences (journal of molecular sciences) 20.22 (2019): 5701.Doi:10.3390/ijms20225701.

⁹ Beau-Faller, michele, et al, (2012): 10507-10507.Doi:10.1016/j. Semcaner.2019.09.015.

¹⁰ Masood, ashiq, rama Krishna Kancha and Janakiraman Subramannian.Semingars in oncology (Innova oncology) WB Saunders, 2019.doi:10.1053/j.Semingcol.2019.08.004.

¹¹ Kohsaka, shinji, et al Science translational medicine 9.416 (2017): ean 6566.

¹² Vyse and Huang et al Signal Transduct Target ther.2019, 3 months 8; 4:5.doi:10.1038/s41392-019-0038-9.

¹³ PCT patent application publication No. WO2019/046775.

¹⁴ PCT patent application publication No. WO 2018/094225.

Table 1b: EGFR protein amino acid substitutions/insertions/deletions ^A

/>

^A The EGFR mutations shown may be activating mutations and/or increasing EGFR resistance to EGFR inhibitors and/or multi-kinase inhibitors (MKI), e.g., compared to wild-type EGFR.

^B Potentially oncogenic variations. See, e.g., kohsaka, shinji, et al, science translational medicine 9.416 (2017): ean 6566.

¹ PCT patent application publication No. WO2019/246541.

² Grosse A, grosse C, rechsteiner M, soltermann A.Diagn Pathol.2019;14 (1) publication No. doi:10.1186/s13000-019-0789-1, month 2 of 18.2019.

⁴ Pines,Gur,Wolfgang J.and Yosef Yarden.FEBS letters 584.12(2010):2699-2706。

⁵ Yasuda, hiroyuki, susumu Kobayashi, and Daniel B.Costa. The Lancet Oncology 13.1 (2012): e23-e31.

⁷ Shah, riyaz and Jason f.lester.clinical Lung Cancer (2019).

⁸ Aran, veronica and Jasminka Omerivic. International journal of molecular sciences 20.22.20.22 (2019): 5701.Doi:10.3390/ijms20225701.

¹⁰ Masood, ashiq, rama Krishna Kancha, and Janakiraman Subramannian.Semingars in onmorphology.WB Saunders, 2019.doi:10.1053/j.Semingcol.2019.08.004.

¹² Vyse and Huang et al, signal Transduct Target th.2019, day 3 month 8; 4:5.doi:10.1038/s41392-019-0038-9.

¹³ PCT patent application publication No. WO2019/046775.

¹⁴ PCT patent application publication No. WO 2018/094225.

¹⁵ Mondeal, gourish, et al, acta Neuropatch.2020; 139 (6):1071-1088

¹⁶ Udager, aaron M., et al, cancer Res,2015;75 (13):2600-2606

In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any of them, comprises a splice change in EGFR mRNA that results in the expressed protein being an alternative splice isomer of EGFR, the deletion of at least one residue (as compared to wild-type EGFR kinase), resulting in constitutive activity of the EGFR kinase domain.

In some embodiments, dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any of them, comprises at least one point mutation in the EGFR gene that results in the produced EGFR kinase having one or more amino acid substitutions or insertions or deletions in the EGFR gene, resulting in the produced EGFR kinase having one or more amino acids inserted or removed as compared to the wild-type EGFR kinase. In some cases, the resulting EGFR kinase is more resistant to inhibition (e.g., inhibits signaling activity) of one or more first EGFR inhibitors than a wild-type EGFR kinase or an EGFR kinase that does not comprise the same mutation. Optionally, the mutation does not decrease the sensitivity of a cancer cell or tumor having an EGFR kinase to treatment with a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof (e.g., as compared to a cancer cell or tumor that does not include a particular EGFR inhibitor resistance mutation).

In other embodiments, dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any of them, comprises at least one point mutation in the EGFR gene that results in the production of an EGFR kinase having one or more amino acid substitutions compared to a wild-type EGFR kinase, and which has increased resistance to a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, compared to a wild-type EGFR kinase or an EGFR kinase that does not comprise the same mutation. In such embodiments, the EGFR inhibitor resistance mutation may be such that the resulting EGFR kinase has an increased V in the presence of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, compared to a wild-type EGFR kinase or an EGFR kinase that does not comprise the same mutation in the presence of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof) _{Maximum value} Reduced K _m And reduced K _D One or more of the following.

Exemplary adult EGFR protein sequence (UniProtKB entry P00533) (SEQ ID NO: 1)

In some embodiments, the dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any of them, comprises at least one EGFR inhibitor resistance mutation in the EGFR gene that results in the production of an EGFR kinase having one or more of the amino acid substitutions, insertions, or deletions in tables 2a and 2 b. In some embodiments, compounds of formula (I) (e.g., formula (I-a), (I-b), (I-C), (I-D), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or pharmaceutically acceptable salts and solvates thereof) may be used to treat a subject having cancer and having an EGFR inhibitor resistance mutation (e.g., the EGFR inhibitor resistance mutation results in increased resistance to a first EGFR inhibitor, e.g., substitution at amino acid position 718,747,761,790,797 or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A) and/or one or more EGFR inhibitor resistance mutations listed in tables 2a and 2 b) by co-administration or as a subsequent or additional (e.g., subsequent) therapy to an existing drug therapy (e.g., other EGFR inhibitors; e.g., first and/or second EGFR inhibitors).

Table 2a: EGFR protein amino acid resistance mutations

¹ PCT patent application publication No. WO2019/246541

² Stewart EL,Tan SZ,Liu G,Tsao MS.Transl Lung Cancer Res.2015；4(1):67–81.doi:10.3978/j.issn.2218-6751.2014.11.06

³ Yasuda, hiroyuki, susumu Kobayashi, and Daniel B.Costa. The Lancet Oncology 13.1 (2012): e23-e31.

⁴ Kimey, cho EN, park HS, et al, cancer Biol ther.2016;17 (3) 237-245.Doi:10.1080/15384047.2016.1139235

⁵ Shah, rimaz, and Jason f.lester.clinical Lung Cancer (2019).

⁶ Aran, veronica, and Jasminka Omerivic International journal of molecular sciences 20.22(2019):5701.doi:10.3390/ijms20225701。

⁷ Beau-Faller, michele et al, (2012): 10507-10507. Doi:10.1016/j.semcaner.2019.09.015

⁸ Masood, ashiq, rama Krishna Kancha, and Janakiraman Subramannian.Semingars in onmorphology.WB Saunders, 2019.doi:10.1053/j.Semingcol.2019.08.004.

Table 2b: EGFR protein amino acid resistance mutations

/>

¹ PCT patent application publication No. WO2019/246541

⁵ Shah, rimaz, and Jason f.lester.clinical Lung Cancer (2019).

⁶ Aran, veronica, and Jasminka Omerivic. International journal of molecular sciences 20.22.22 (2019): 5701.Doi:10.3390/ijms20225701.

⁸ Masood, ashiq, rama Krishna Kancha, and Janakiraman Subramannian.Semingars in onmorphology.WB Saunders, 2019.doi:10.1053/j.Semingcol.2019.08.004

⁹ Papanadimittrakopoulou, V.A., et al, annals of Oncology (annual oncology) 2018;29 supplement 8VIII741.

In some embodiments, the amino acid substitutions/insertions/deletions of the EGFR protein include any one or more of, or any two or more of (e.g., any two of) the amino acid substitutions/insertions/deletions of the EGFR proteins described in tables 1a, 1b and/or tables 2a, 2 b; for example, any one or more or any two or more (e.g., any two) of the following independently selected amino acid substitutions/insertions/deletions of the EGFR protein: V769L; V769M; m766delinsMASVx2; A767_V769dupASV; a767 dellinsa svdx3; a767 dellinsa svg; s768_v769insX; v769_d770insX; v769_d770insASV; d770delinsDN; d770delinsDNPH; d770_n771inssv; n771delinsNPH; N771_H2773 dup; L858R/C797S (or C797G); or Del_19 and C797S (or C797G); or any combination thereof.

As used herein, a "first inhibitor of EGFR" or "first EGFR inhibitor" is an EGFR inhibitor as defined herein, but it does not include a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) as defined herein, or a pharmaceutically acceptable salt thereof. As used herein, a "second inhibitor of EGFR" or "second EGFR inhibitor" is an EGFR inhibitor as defined herein, but it does not include a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) as defined herein, or a pharmaceutically acceptable salt thereof. When the first and second inhibitors of EGFR are present together in the methods provided herein, the first and second inhibitors of EGFR are different. In some embodiments, the first and/or second inhibitor of EGFR is bound in a different location than the compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)). For example, in some embodiments, the first and/or second inhibitor of EGFR can inhibit dimerization of EGFR, while the compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) can inhibit the active site. In some embodiments, the first and/or second EGFR inhibitor can be an allosteric inhibitor of EGFR, and the compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) can inhibit an EGFR active site.

Exemplary first and second inhibitors of EGFR are described herein. In some embodiments, the first or second inhibitor of EGFR may be selected from the group consisting of: oritinib, gefitinib, erlotinib, afatinib, lapatinib, lenatinib, AZD-9291, CL-387785, CO-1686 or WZ4002.

In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt or solvate thereof is used to treat a cancer identified as having one or more EGFR inhibitor resistance mutations (which result in increased resistance to a first or second inhibitor of EGFR, e.g., the substitutions described in tables 2a and 2b, including the substitutions at amino acid positions 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T M, C797S, T854A)). In some embodiments, the one or more EGFR inhibitor resistance mutations occur in a nucleic acid sequence encoding a mutant EGFR protein (e.g., a mutant EGFR protein having any of the mutations described in table 2a and table 2 b), which results in a mutant EGFR protein that exhibits EGFR inhibitor resistance.

The Epidermal Growth Factor Receptor (EGFR) belongs to the ErbB family of Receptor Tyrosine Kinases (RTKs) that provide a vital function in epithelial cell physiology (schlesinger J (2014) Cold Spring Harb Perspect Biol 6 (cold spring harbor biology expectation), a 008912). It is frequently mutated and/or overexpressed in different types of human cancers and is the target of multiple Cancer therapies employed in current clinical practice (Yarden Y and Pines G (2012) Nat Rev Cancer 12, 553-563).

Accordingly, provided herein are methods of treating a subject diagnosed with (or identified as) having cancer, the method comprising: providing a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof to a subject.

Also provided herein are methods of treating a subject identified or diagnosed as having an EGFR-associated cancer, the method comprising: providing a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject. In some embodiments, the subject is identified or diagnosed as having EGFR-associated cancer by using, for example, an FDA-approved test or assay approved by a regulatory agency to identify dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any of them in the subject or in a biopsy sample from the subject, or by performing any non-limiting example of an assay described herein. In some embodiments, the test or assay is provided in a kit. In some embodiments, the cancer is an EGFR-related cancer. For example, the EGFR-related cancer may be a cancer comprising one or more EGFR inhibitor resistance mutations.

The term "regulatory agency" refers to the national agency approving the pharmaceutical agent for medical use in that country. For example, one non-limiting example of a regulatory agency is the United states Food and Drug Administration (FDA).

Also provided are methods of treating cancer in a subject in need thereof, the methods comprising: (a) detecting EGFR-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods include: administering to the subject another anticancer agent (e.g., a second EGFR inhibitor, a second compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, or immunotherapy). In some embodiments, the subject has been previously treated with the first EGFR inhibitor, or has been previously treated with another anticancer agent, e.g., at least partially resecting the tumor or radiation therapy. In some embodiments, the subject is determined to have EGFR-associated cancer by using, for example, an FDA-approved test or assay approved by a regulatory agency to identify dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any of them in the subject or in a biopsy sample from the subject, or by performing any non-limiting example of an assay described herein. In some embodiments, the test or assay is provided in a kit. In some embodiments, the cancer is an EGFR-related cancer. For example, the EGFR-related cancer may be a cancer comprising one or more EGFR inhibitor resistance mutations.

Also provided is a method of treating a subject, the method comprising: assaying a sample obtained from a subject to determine whether the subject has dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any thereof; and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have dysregulation of expression or activity or level of EGFR gene, EGFR kinase, or any of them. Some embodiments of these methods further comprise: administering to the subject another anticancer agent (e.g., a second EGFR inhibitor, a second compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, or immunotherapy). In some embodiments of these methods, the subject has been previously treated with the first EGFR inhibitor, or has been previously treated with another anticancer agent, e.g., at least partially resected tumor or radiation therapy. In some embodiments, the subject is a patient suspected of having EGFR-related cancer, a patient having one or more symptoms of EGFR-related cancer, or a patient at high risk of having EGFR-related cancer. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or isolation FISH (Break Apart FISH) analysis. In some embodiments, the assay is a regulatory agency approved assay, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy. In addition, non-limiting assays that can be used in these methods are described herein. Additional assays are known in the art. In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any thereof, comprises one or more EGFR inhibitor resistance mutations.

Also provided are compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating an EGFR-related cancer in a subject identified or diagnosed as having an EGFR-related cancer, by the steps of: an assay (e.g., an in vitro assay) is performed on a sample obtained from a subject to determine whether the subject has dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any thereof, wherein the presence of dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any thereof is indicative of the subject having an EGFR-associated cancer. Also provided is the use of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating an EGFR-related cancer in a subject identified or diagnosed as having an EGFR-related cancer by: a sample obtained from a subject is assayed to determine whether the subject has dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any thereof, wherein the presence of dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any thereof is indicative of the subject having an EGFR-associated cancer. Some embodiments of any of the methods or uses described herein further comprise: in a clinical record (e.g., computer readable medium) of a subject: by performing the assay, the subject is determined to have dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any of them, and the compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, should be administered. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or Break ApartFISH analysis. In some embodiments, the assay is a regulatory agency approved assay, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy. In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any thereof, comprises one or more EGFR inhibitor resistance mutations.

Also provided herein are compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof) for use in treating cancer in a subject in need thereof or in treating a subject identified or diagnosed as having EGFR-related cancer. Also provided herein is the use of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject identified or diagnosed as having EGFR-associated cancer. In some embodiments, the cancer is an EGFR-related cancer, e.g., an EGFR-related cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, the subject is identified or diagnosed as having EGFR-associated cancer by using a regulatory agency approved, e.g., FDA approved, kit for identifying abnormal expression or activity or level regulation of the EGFR gene, EGFR kinase, or any of them in the subject or a biopsy sample from the subject. As provided herein, EGFR-related cancers include those described herein and known in the art.

In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having cancer with abnormal expression or activity or level of the EGFR gene, EGFR kinase, or any thereof. In some embodiments of any of the methods or uses described herein, the subject has a tumor positive for abnormal expression or activity or level of the EGFR gene, EGFR kinase, or any thereof. In some embodiments of any of the methods or uses described herein, the subject may be a subject with a tumor that is positive for abnormal expression or activity or level of the EGFR gene, EGFR kinase, or any thereof. In some embodiments of any of the methods or uses described herein, the subject may be a subject whose tumor has dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any thereof. In some embodiments of any of the methods or uses described herein, the subject is suspected of having an EGFR-associated cancer (e.g., a cancer having one or more EGFR inhibitor resistance mutations). In some embodiments, provided herein is a method of treating an EGFR-related cancer in a subject in need of treatment for the EGFR-related cancer, the method comprising: a) Detecting dysregulation of expression or activity or level of an EGFR gene, EGFR kinase, or any thereof in a sample from a subject; and b) administering a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof. In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any thereof, comprises one or more EGFR kinase protein point mutations/insertions/deletions. Non-limiting examples of EGFR kinase protein point mutations/insertions/deletions are described in tables 1a and 1 b. In some embodiments, the EGFR kinase protein point mutation/insertion/deletion is selected from the group consisting of: g719S, G719C, G719A, L747S, D761Y, T790M, T854A, L858R, L861Q, exon 19 deletion (e.g., l747_a750 del) and exon 20 insertion. In some embodiments, the EGFR kinase protein point mutation/insertion/deletion is selected from the group consisting of: L858R, exon 19 deletion (e.g., L747 a750 del), L747S, D761Y, T790M, and T854A. In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any thereof, comprises one or more EGFR inhibitor resistance mutations. Non-limiting examples of EGFR inhibitor resistance mutations are described in tables 2a and 2 b. In some embodiments, the EGFR inhibitor resistance mutation is a substitution at amino acid positions 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S and T854A). In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any thereof, comprises one or more point mutations/insertions/deletions in exon 20. Non-limiting examples of EGFR exon 20 mutations are described in tables 1a, 1b, 2a and 2 b. In some embodiments, the EGFR exon 20 mutation is an exon 20 insertion, e.g., V769_d770insX, D770_n771insX, n771_p772insX, P772_h773insX, and h773_v774insX. For example, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H2773 dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H2773 insDNP, P772_H2773 insPNP, H2773_V 774insNPH, H2773_V 774insPH, H2773_V 774insAH, and P772_H2773 insIndH. In some embodiments, the cancer having dysregulation of EGFR gene, EGFR kinase, or expression or activity or level thereof is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, the tumor positive for dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any thereof is a tumor positive for one or more EGFR inhibitor resistance mutations. In some embodiments, tumors with aberrant expression or activity or level of the EGFR gene, EGFR kinase, or any thereof are determined using regulatory agency approval, such as FDA approved assays or kits.

In some embodiments of any of the methods or uses described herein, a clinical record of a subject indicates that the subject has a tumor (e.g., a tumor with one or more EGFR inhibitor resistance mutations) with aberrant expression or activity or level of the EGFR gene, EGFR kinase, or any thereof. Also provided herein are methods of treating a subject, the method comprising: a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof) is administered to a subject having dysregulated expression or activity or levels of the EGFR gene, EGFR kinase, or any of them.

In some embodiments, the methods provided herein comprise: samples obtained from a subject are assayed to determine whether the subject has dysregulation of expression or levels of the EGFR gene, EGFR protein, or any of them. In some such embodiments, the method further comprises: providing a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof) to a subject identified as having dysregulation of expression or activity or level of the EGFR gene, EGFR protein, or any of them. In some embodiments, the method comprises: determining that the subject has abnormal expression or level regulation of the EGFR gene, EGFR protein, or any thereof by assaying a sample obtained from the subject. In such embodiments, the method further comprises: administering to the subject a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of expression or activity or level of the EGFR gene, EGFR kinase protein, or any of them is one or more point mutations in the EGFR gene (e.g., any of the one or more EGFR point mutations described herein). The one or more point mutations in the EGFR gene may, for example, result in translation of the EGFR protein with one or more of the following amino acid substitutions, deletions and insertions: g719S, G719C, G719A, L S, D761Y, T790M, T854A, L858R, L861Q, exon 19 deletion (e.g., L747_a75del) and exon 20 insertion (e.g., V769_d770insX, D770_n771insX, n771_p772insx, P772_h773insX and h773_v774 insX). The one or more point mutations in the EGFR gene may, for example, result in translation of the EGFR protein with the following amino acid substitutions or deletions: L858R, exon 19 deletion (e.g., L747_A750del), L747S, D761Y, T790M, and T854A. In some embodiments, the dysregulation of expression or activity or level of the EGFR gene, EGFR kinase protein, or any of them is one or more EGFR inhibitor resistance mutations (e.g., any combination of one or more EGFR inhibitor resistance mutations described herein). In some embodiments, the dysregulation of expression or activity or level of the EGFR gene, EGFR kinase protein, or any of them is one or more EGFR exon 20 insertions (e.g., any of the exon 20 insertions described herein). In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: v769_d770insX, d770_n771insX, n771_p772insx, p772_h773insX and h773_v774insX. In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: v769_d770insX, d770_n771insX, n771_p772insx, p772_h773insX and h773_v774insX. In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H2773 dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H2773 insDNP, P772_H2773 insPNP, H2773_V 774insNPH, H2773_V 774insPH, H2773_V 774insAH, and P772_H2773 insIndH. Some embodiments of these methods further comprise: administering to the subject another anticancer agent (e.g., a second EGFR inhibitor, a second compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, or immunotherapy).

In some embodiments of any of the methods or uses described herein, an assay for determining whether a subject has dysregulation of expression or activity or level of an EGFR gene or EGFR kinase or any thereof using a sample from the subject may include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break Apart FISH analysis, southern blotting, western blotting, FACS analysis, northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, the assay is typically performed, for example, with at least one labeled nucleic acid probe or at least one labeled antibody or antigen binding fragment thereof. Assays may utilize other detection methods known in the art to detect dysregulation of expression or activity or levels of the EGFR gene, EGFR kinase, or any of them (see, e.g., references cited herein). In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any thereof, comprises one or more EGFR inhibitor resistance mutations. In some embodiments, the sample is a biological sample or a biopsy sample from a subject (e.g., a paraffin embedded biopsy sample). In some embodiments, the subject is a subject suspected of having EGFR-related cancer, a subject having one or more symptoms of EGFR-related cancer, and/or a subject at high risk of having EGFR-related cancer.

In some embodiments, dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any of them, can be identified using liquid biopsy (alternatively termed fluid biopsy or fluid phase biopsy). See, e.g., karachialiou et al, "Real-time liquid biopsies become a reality in cancer treatment", ann. Transl. Med.,3 (3): 36,2016. The liquid biopsy method may be used to detect dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any of these and/or total tumor burden. Liquid biopsies can be obtained in biological samples that are relatively easy to obtain from a subject (e.g., by simple blood drawing) and are generally less invasive than traditional methods for detecting dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any of them, and/or total tumor burden. In some embodiments, the liquid biopsy method may be used to detect the presence of dysregulation of expression or activity or level of the EGFR gene, EGFR kinase, or any of them at an earlier stage than traditional methods. In some embodiments, biological samples for liquid biopsies may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage, bile, lymph, cyst fluid, stool, ascites fluid, and combinations thereof. In some embodiments, liquid biopsies can be used to detect Circulating Tumor Cells (CTCs). In some embodiments, liquid biopsies can be used to detect cell free DNA. In some embodiments, the cell free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) from tumor cells. ctDNA analysis (e.g., using sensitive detection techniques such as, but not limited to, next Generation Sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of expression or activity or levels of the EGFR gene, EGFR kinase, or any of these.

The term "HER 2-related disease or disorder" as used herein refers to a disease or disorder associated with dysregulation of expression or activity or level of a HER2 gene, HER2 kinase, or any of them (e.g., one or more), such as any type of dysregulation of expression or activity or level of a HER2 gene, HER2 kinase domain, or any of them described herein. Non-limiting examples of HER2 related diseases or disorders include, for example, cancer.

The term "HER 2-related cancer" as used herein refers to a cancer associated with or having dysregulation of expression or activity or level of the HER2 gene, HER2 kinase (also referred to herein as HER2 kinase protein), or any of them. Non-limiting examples of HER 2-related cancers are described herein.

In some embodiments, the EGFR-related cancer is also HER 2-related cancer. For example, EGFR-related cancers may have dysregulation of expression or activity or levels of the HER2 gene, HER2 kinase, or any of them.

The phrase "abnormal expression or activity or level regulation of a HER2 gene, a HER2 kinase, or any of them" refers to a genetic mutation (e.g., a mutation in the HER2 gene that results in the expression of a HER2 protein comprising at least one amino acid deletion as compared to a wild-type HER2 protein, a mutation in the HER2 gene that results in the expression of a HER2 protein having one or more point mutations as compared to a wild-type HER2 protein, a mutation in the HER2 gene that results in the expression of a HER2 protein having at least one intervening amino acid as compared to a wild-type HER2 protein, a gene replication that results in an increased level of a HER2 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of a HER2 protein in a cell, an alternative spliced form of HER2mRNA that results in the HER2 protein having at least one amino acid deletion as compared to a wild-type HER2 protein, or an increased expression (e.g., increased level) of a wild-type HER2 kinase in a mammalian cell as compared to a control non-cancerous cell. As another example, an expression or activity or level regulation abnormality of the HER2 gene, HER2 kinase, or any of these may be a mutation in the HER2 gene encoding a HER2 protein, which HER2 protein has constitutive activity or has increased activity compared to the protein encoded by the HER2 gene not comprising the mutation. Non-limiting examples of HER2 kinase protein fusions and point mutations/insertions/deletions are described in tables 3-5. Such mutations and overexpression have been associated with the development of a variety of cancers (Moasser. Oncogene.2007, 10 month 4 days; 26 (45): 6469-6487).

The compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or pharmaceutically acceptable salts or solvates thereof are useful in treating diseases and disorders such as HER 2-associated diseases and disorders, for example, proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced solid tumors).

In some embodiments, dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them may be caused by activating mutations in the HER2 gene. Exemplary HER2 kinase fusions or point mutations, insertions and deletions shown in tables 3-5 may be caused by activating mutations.

The term "activating mutation" in relation to HER2 describes a mutation in the HER2 gene that results in the expression of HER2 kinase having increased kinase activity, e.g. when assayed under the same conditions, as the wild-type HER2 kinase. For example, an activating mutation can be a mutation in the HER2 gene that results in the expression of a HER2 kinase having one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) resulting in increased kinase activity, e.g., when measured under the same conditions, as compared to a wild-type HER2 kinase.

The term "wild-type HER2" or "wild-type HER2 kinase" describes a HER2 nucleic acid (e.g., a HER2 gene or a HER2 mRNA) or protein (e.g., a HER2 protein) found in a subject that does not have a HER 2-related disease, e.g., a HER 2-related cancer (and optionally does not increase the risk of having a HER 2-related disease and/or is not suspected of having a HER 2-related disease), or found in cells or tissues of a subject that does not have a HER 2-related disease, e.g., a HER2 gene or a HER2 mRNA.

Provided herein is a method of treating HER 2-related cancer 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) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof. For example, provided herein is a method of treating HER 2-related cancer in a subject in need of treatment for HER 2-related cancer, the method comprising: a) Detecting dysregulation of expression or activity or level of HER2 gene, HER2 kinase, or any thereof in a sample from the subject; and b) administering a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof. In some embodiments, dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of these comprises one or more HER2 kinase protein point mutations/insertions. Non-limiting examples of HER2 kinase protein fusions and point mutations/insertions/deletions are described in tables 3-5. In some embodiments, the HER2 kinase protein point mutation/insertion/deletion is selected from the group consisting of: S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, V842I, Y772_a775dup, a775_g776insYVMA, G776delinsVC, G776delinsVV, v777_g778insGSP, and P780_y781insGSP. In some embodiments, the HER2 kinase protein point mutation/insertion/deletion is an exon 20 point mutation/insertion/deletion selected from the group consisting of: V773M, G776C, G776V, G776S, V777L, V M, S779T, P780L, S783P, M774AYVM, M774del insWLV, A775_G776 insVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G776C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V insV, V777_G778insCG, G778_S779insCPG and P780_Y781insGSP. In some embodiments, the HER2 kinase protein point mutation/insertion/deletion is an exon 20 point mutation/insertion/deletion selected from the group consisting of: y772_a775dup, a775_g776insvma, G776delinsVC, G776delinsVV, v777_g778insGSP, and p780_y781insGSP.

In some embodiments of any of the methods or uses described herein, the cancer (e.g., HER 2-related cancer) is selected from: hematological cancers (e.g., hodgkin's lymphoma, non-hodgkin's lymphoma, and leukemia, such as Acute Myelogenous Leukemia (AML)), chronic Myelogenous Leukemia (CML), acute promyelocytic leukemia, and Acute Lymphoblastic Leukemia (ALL)), alveolar rhabdomyosarcoma, central or peripheral nervous system tissue cancers, endocrine or neuroendocrine cancers, including various neuroendocrine type I and type II tumors, li Famei A tumor, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, anal canal cancer or anal rectal cancer, eye cancer, intrahepatic bile duct cancer, joint cancer, neck cancer, gall bladder cancer or pleural cancer, nasal cancer or middle ear cancer, tracheal cancer, oral cancer, oropharyngeal cancer, nasopharyngeal cancer, respiratory tract cancer, genitourinary system cancer, vulval cancer, colon cancer, esophageal cancer, cervical cancer, gastrointestinal carcinoid, hypopharyngeal cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, malignant mesothelioma, melanoma, multiple myeloma, nasopharyngeal cancer, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer including islet cell cancer, peritoneal cancer, large-mesh membrane cancer and mesenteric cancer, pharyngeal cancer, prostate cancer, rectal cancer, renal cancer (e.g., renal Cell Carcinoma (RCC)), small intestine cancer, soft tissue cancer, stomach cancer, testicular cancer, thyroid cancer, parathyroid cancer, pituitary tumor, adrenal gland cancer, biliary tract cancer and bladder cancer. In some embodiments, the cancer is selected from the group consisting of: head and neck, ovary, cervix, bladder and esophagus, pancreas, gastrointestinal tract, stomach, breast, endometrium and colorectal cancers, hepatocellular, glioblastoma, bladder, lung cancer, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar cancer. In some embodiments, the cancer is pancreatic cancer, head and neck cancer, melanoma, colon cancer, renal cancer, leukemia, lung cancer, or breast cancer. In some cases, the cancer is melanoma, colon cancer, renal cancer, leukemia, or breast cancer.

In some embodiments, the cancer is a B cell derived cancer. In some embodiments, the cancer is a lineage dependent cancer. In some embodiments, the cancer is a lineage dependent cancer, wherein abnormal expression or activity or level of HER2 or HER2 gene, HER2 kinase, or any thereof, plays a role in the occurrence and/or progression of the cancer.

Also provided herein is a method of treating a subject diagnosed with or identified as having a HER 2-related cancer, such as any of the exemplary HER 2-related cancers disclosed herein, comprising: administering to the subject a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein.

In some embodiments, dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them comprises one or more deletions (e.g., amino acid deletions at position 12), insertions, or point mutations in the HER2 kinase. In some embodiments, the dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them comprises a deletion of one or more residues of the HER2 kinase, which results in an increase in signaling activity of the HER2 kinase.

In some embodiments, the dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them comprises at least one point mutation in the HER2 gene resulting in the production of a HER2 kinase having one or more amino acid substitutions, insertions, or deletions compared to the wild-type HER2 kinase (see, e.g., point mutations listed in table 3). In some embodiments, the dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them comprises at least one point mutation in the HER2 gene that results in the production of a HER2 kinase having one or more of the amino acid substitutions, insertions, or deletions in table 3.

In some embodiments, dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them comprises insertion of one or more residues in exon 20 of the HER2 gene (e.g., any exon 20 insertion described in tables 1a and 1 b). Exon 20 of HER2 has two main regions, c-helix (residues 770-774) and c-helix post-loop (residues 775-783). In some embodiments, dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them comprises insertion of one or more residues in exon 20 selected from the group consisting of: y772_a775dup, a775_g776insvma, G776delinsVC, G776delinsVV, v777_g778insGSP, and p780_y781insGSP.

Table 3: amino acid substitutions/insertions/deletions of HER2 proteins ^A

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^A The HER2 mutation shown may be an activating mutation and/or an increased resistance of HER2 to a HER2 inhibitor and/or a multi-kinase inhibitor (MKI), e.g. as compared to wild-type HER 2.

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⁷ Kavuri et al, cancer discover.2015, 8; 5 (8):832-841.

⁸ Robichaux et al, nat Med.2018, month 5; 24 (5):638-646.

⁹ Kosaka et al Cancer res.2017, 5, 15; 77 (10):2712-2721.

¹⁰ Pahuja et al, cancer cell.2018, 11 months 12 days; 34 (5) 792-806.e5.

¹¹ Ross et al, cancer.2018, month 4, day 1; 124 (7):1358-1373.

¹² Gharib et al, J Cell physiol.2019, month 8; 234 (8):13137-13144.

¹³ Krawczyk et al, oncol Lett.2013, month 10; 6 (4):1063-1067.

¹⁴ Lai et al, eur J cancer.2019, month 3; 109:28-35.

¹⁵ Sun et al, J Cell Mol Med.2015, 12 months; 19 (12):2691-2701.

¹⁶ Xu et al, thorac cancer 2020, month 3; 11 (3):679-685.

In some embodiments, dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them, comprises a splice change of HER2 mRNA that results in the expressed protein being an alternative splice isomer of HER2, deletion of at least one residue (as compared to wild-type HER2 kinase), resulting in constitutive activity of the HER2 kinase domain. In some embodiments, the splice isomer of HER2 is Δ16HER-3 or p95HER-2. See, e.g., sun et al, J Cell Mol med.2015, month 12; 19 (12):2691-2701.

In some embodiments, dysregulation of HER2 gene, HER2 kinase, or any of its expression or activity or levels may result from a splice change in HER2 mRNA, which results in altered HER2 protein expression that has increased resistance to inhibition by HER2 inhibitors, tyrosine Kinase Inhibitors (TKIs), and/or Multiple Kinase Inhibitors (MKIs), e.g., as compared to wild-type HER2 kinase (e.g., HER2 isoforms described herein). See, e.g., rexer and Arteaga. Crit Rev Oncog.2012;17 (1):1-16.

In some embodiments, dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them, comprises one or more chromosomal translocations or inversions, which result in HER2 gene fusion, respectively. In some embodiments, dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them is a result of a gene translocation, wherein the expressed protein is a fusion protein containing residues from a non-HER 2 chaperone protein and HER2, and each comprises a minimal functional HER2 kinase domain.

Table 4: exemplary HER2 fusion proteins and cancers

Non-limiting exemplary HER2 fusion	Non-limiting exemplary HER 2-associated cancers
		ZNF207_ex2/HER2_ex18 ¹	Stomach cancer
MDK_ex4/HER2_ex11 ¹	Stomach cancer
		NOS2_ex2/HER2_ex2 ¹	Stomach cancer

¹ Yu et al, J Transl Med.2015;13:116.

In some embodiments, the dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them comprises at least one point mutation in the HER2 gene that results in the produced HER2 kinase having one or more amino acid substitutions or insertions or deletions in the HER2 gene, resulting in the produced HER2 kinase having one or more amino acids inserted or removed as compared to the wild-type HER2 kinase.

In other embodiments, dysregulation of expression or activity or level of a HER2 gene, HER2 kinase, or any of them, comprises at least one point mutation in the HER2 gene that results in the production of a HER2 kinase having one or more amino acid substitutions compared to a wild-type HER2 kinase, and that has increased resistance to a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, compared to a wild-type HER2 kinase or a HER2 kinase that does not comprise the same mutation.

Exemplary adult HER2 protein sequence (UniProtKB entry P04626) (SEQ ID NO: 2)

In some embodiments, the dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them comprises at least one HER2 inhibitor resistance mutation in the HER2 gene that results in the production of a HER2 kinase having one or more of the amino acid substitutions, insertions, or deletions described in table 5. In some embodiments, compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or pharmaceutically acceptable salts and solvates thereof, are useful for treating a subject having cancer and having a HER2 inhibitor resistance mutation (e.g., the HER2 inhibitor resistance mutation results in increased resistance to a first HER2 inhibitor, e.g., substitution at amino acid position 755 or 798 (e.g., L755S, L P, T798I and T798M) and/or one or more of the HER2 inhibitor resistance mutations listed in table 5) by co-administration or as a subsequent or additional (e.g., subsequent) therapy to an existing drug therapy (e.g., other HER2 inhibitor; e.g., first and/or second HER2 inhibitor).

Table 5: amino acid resistance mutation of HER2 protein

¹ Hanker et al, cancer discover.2017, month 6; 7 (6):575-585.

² Sun et al, J Cell Mol Med.2015, 12 months; 19 (12):2691-2701.

As used herein, a "first inhibitor of HER 2" or "first HER2 inhibitor" is a HER2 inhibitor as defined herein, but it does not include a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) as defined herein, or a pharmaceutically acceptable salt thereof. As used herein, a "second inhibitor of HER 2" or "second HER2 inhibitor" is a HER2 inhibitor as defined herein, but it does not include a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) as defined herein, or a pharmaceutically acceptable salt thereof. When the first and second inhibitors of HER2 are present simultaneously in the methods provided herein, the first and second inhibitors of HER2 are different. In some embodiments, the first and/or second inhibitor of HER2 is bound in a different location than the compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)). For example, in some embodiments, the first and/or second inhibitor of HER2 may inhibit dimerization of HER2, while the compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) may inhibit the active site. In some embodiments, the first and/or second HER2 inhibitor may be an allosteric inhibitor of HER2, while the compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) may inhibit the HER2 active site.

Exemplary first and second inhibitors of HER2 are described herein. In some embodiments, the first or second inhibitor of HER2 may be selected from the group consisting of: trazimera (e.g., trazimera,) Pertuzumab (e.g., j>) Enmetrastuzumab (T-DM 1 or ado-Enmetrastuzumab, e.g., in->) Lapatinib, KU004, lenatinib (e.g., +.>) Dacatinib (e.g.)>) AfatinibFig. calitinib (e.g. tukyatm), erlotinib (e.g. +.>) Pyrroltinib, wave Ji Tini, CP-724714, CUDC-101, saprotinib (AZD 8931), tamspiramycin (17-AAG), IPI-504, PF299, perlitinib, S-22261 1 and AEE-788.

In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt or solvate thereof is used to treat a cancer identified as having one or more HER2 inhibitor resistance mutations (which HER2 inhibitor resistance mutations result in increased resistance to a first or second inhibitor of HER2, e.g., substitutions described in table 5, including substitutions at amino acid positions 755 or 798 (e.g., L755S, L P, T798I and T798M)). In some embodiments, the one or more HER2 inhibitor resistance mutations occur in a nucleic acid sequence encoding a mutant HER2 protein (e.g., a mutant HER2 protein having any of the mutations described in table 3), which results in a mutant HER2 protein that exhibits HER2 inhibitor resistance.

Like EGFR, epidermal growth factor receptor 2 (HER 2) belongs to the ErbB family of Receptor Tyrosine Kinases (RTKs) that provide vital functions in epithelial cell physiology (Schlesinger J (2014) Cold Spring Harb Perspect Biol, a008912; and Moassser. Oncogene.2007, 10, 4; 26 (45): 6469-6487). It is frequently mutated and/or overexpressed in different types of human cancers and is the target of multiple cancer therapies employed in current clinical practice (Moasser. Oncogene.2007, 10, 4; 26 (45): 6469-6487).

Accordingly, provided herein are methods of treating a subject identified or diagnosed as having HER 2-related cancer, the method comprising: providing a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject. In some embodiments, the subject is identified or diagnosed as having HER 2-related cancer by using, for example, an FDA-approved test or assay approved by a regulatory agency to identify dysregulation of HER2 gene, HER2 kinase, or expression or activity or level of any of them in the subject or in a biopsy sample from the subject, or by performing any non-limiting example of an assay described herein. In some embodiments, the test or assay is provided in a kit. In some embodiments, the cancer is HER 2-related cancer. Also provided are methods of treating cancer in a subject in need thereof, the methods comprising: (a) detecting HER 2-related cancer in a subject; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise: administering to the subject another anticancer agent (e.g., a second HER2 inhibitor, a second compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, or immunotherapy). In some embodiments, the subject has been previously treated with the first HER2 inhibitor, or has been previously treated with another anti-cancer agent, e.g., at least partially resecting the tumor or radiation therapy. In some embodiments, the subject is determined to have HER 2-related cancer by using, for example, an FDA-approved test or assay approved by a regulatory agency to identify dysregulation of HER2 gene, HER2 kinase, or expression or activity or level of any of them in the subject or in a biopsy sample from the subject, or by performing any non-limiting example of an assay described herein. In some embodiments, the test or assay is provided in a kit. In some embodiments, the cancer is HER 2-related cancer.

Also provided is a method of treating a subject, the method comprising: assaying a sample obtained from a subject to determine whether the subject has dysregulation of expression or activity or level of HER2 gene, HER2 kinase, or any of them; and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have dysregulation of expression or activity or level of HER2 gene, HER2 kinase, or any of them. Some embodiments of these methods further comprise: administering to the subject another anticancer agent (e.g., a second HER2 inhibitor, a second compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, or immunotherapy). In some embodiments of these methods, the subject has been previously treated with the first HER2 inhibitor, or has been previously treated with another anti-cancer agent, e.g., at least partially resected tumor or radiation therapy. In some embodiments, the subject is a patient suspected of having HER 2-related cancer, a patient having one or more symptoms of HER 2-related cancer, or a patient at high risk of having HER 2-related cancer. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or Break Apart FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy. In addition, non-limiting assays that can be used in these methods are described herein. Additional assays are known in the art.

As used herein, a "first inhibitor of HER 2" or "first HER2 inhibitor" is a HER2 inhibitor as defined herein, which does not include a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) as defined herein, or a pharmaceutically acceptable salt thereof. As used herein, a "second inhibitor of HER 2" or "second HER2 inhibitor" is a HER2 inhibitor as defined herein, which does not include a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) as defined herein, or a pharmaceutically acceptable salt thereof. When first and second HER2 inhibitors are present simultaneously in the methods provided herein, the first and second HER2 inhibitors are different.

Also provided are compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a HER 2-related cancer in a subject identified or diagnosed as having a HER 2-related cancer, as identified or diagnosed by the steps of: an assay (e.g., an in vitro assay) is performed on a sample obtained from a subject to determine whether the subject has dysregulation of expression or activity or level of a HER2 gene, a HER2 kinase, or any of them, wherein the presence of dysregulation of expression or activity or level of a HER2 gene, a HER2 kinase, or any of them is indicative of the subject having HER 2-related cancer. Also provided is the use of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating HER 2-related cancer in a subject identified or diagnosed as having HER 2-related cancer by: a sample obtained from a subject is assayed to determine whether the subject has dysregulation of expression or activity or level of a HER2 gene, a HER2 kinase, or any of them, wherein the presence of dysregulation of expression or activity or level of a HER2 gene, a HER2 kinase, or any of them is indicative of the subject having a HER 2-related cancer. Some embodiments of any of the methods or uses described herein further comprise: in a clinical record (e.g., computer readable medium) of a subject: by performing the assay, the subject is determined to have dysregulation of expression or activity or level of HER2 gene, HER2 kinase, or any of them, and the compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, should be administered. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or Break Apart FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy.

Also provided herein are compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof) for use in treating cancer in a subject in need thereof or in treating a subject identified or diagnosed as having HER 2-related cancer. Also provided herein is the use of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject identified or diagnosed as having HER 2-related cancer. In some embodiments, the subject is identified or diagnosed as having HER 2-related cancer by using a regulatory agency approved, e.g., FDA approved, kit for identifying abnormal expression or activity or level regulation of the HER2 gene, HER2 kinase, or any of them in the subject or a biopsy sample from the subject. As provided herein, HER 2-related cancers include those described herein and known in the art.

In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with aberrant expression or activity or level regulation of the HER2 gene, HER2 kinase, or any thereof. In some embodiments of any of the methods or uses described herein, the subject has a tumor positive for aberrant expression or activity or level of HER2 gene, HER2 kinase, or any thereof. In some embodiments of any of the methods or uses described herein, the subject may be a subject with a tumor that is positive for aberrant expression or activity or level regulation of HER2 gene, HER2 kinase, or any thereof. In some embodiments of any of the methods or uses described herein, the subject may be a subject whose tumor has dysregulation of expression or activity or level of HER2 gene, HER2 kinase, or any of them. In some embodiments, the subject is suspected of having HER 2-related cancer. In some embodiments, provided herein is a method of treating a HER 2-related cancer in a subject in need of treatment for a HER 2-related cancer, the method comprising: a) Detecting dysregulation of expression or activity or level of HER2 gene, HER2 kinase, or any thereof in a sample from the subject; and b) administering a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof. In some embodiments, dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of these comprises one or more HER2 kinase protein point mutations/insertions/deletions. Non-limiting examples of HER2 kinase protein fusions and point mutations/insertions/deletions are described in tables 3-5. In some embodiments, the HER2 kinase protein point mutation/insertion/deletion is selected from the group consisting of: a point mutation at amino acid positions 310, 678, 755, 767, 773, 777, or 842 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L and V842I), and/or an insertion or deletion at amino acid positions 772, 775, 776, 777, and 780 (e.g., Y772_a775dup, a775_g776insYVMA, G776delinsVC, G776delinsVV, V777_g778insGSP, and P780_y781 insGSP). In some embodiments, the HER2 kinase protein point mutation/insertion/deletion is an exon 20 point mutation/insertion/deletion. In some embodiments, HER2 exon point mutations/insertions/deletions are point mutations at amino acid positions 773, 776, 777, 779, 780, and 783 (e.g., V773M, G776C, G776V, G776S, V777L, V777M, S779T, P780L and S783P), and/or exon 20 insertions/deletions, e.g., insertions/deletions at amino acid positions 774, 775, 776, 777, 778, and 780. In some embodiments, the HER2 kinase protein insertion is an exon 20 insertion selected from the group consisting of: a775_g776insyvma, a775_g776insavma, a775_g776inssvma, a775_g776insvag, a775 insvg C, A775_g776insi, g776del insVC2, g776del insVV, g776del insLC, g776cv777insC, g776C V777insV, v777_g778inscg, g778_s779insCPG, and p780_y781insGSP. In some embodiments, the HER2 kinase protein mutation/insertion/deletion is an exon 20 insertion/deletion selected from the group consisting of: y772_a775dup, a775_g776insvma, G776delinsVC, G776delinsVV, v777_g778insGSP, or p780_y781insGSP. In some embodiments, the cancer having abnormal expression or activity or level of HER2 gene, HER2 kinase, or a combination thereof is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, the tumor positive for dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them is a tumor positive for one or more HER2 inhibitor resistance mutations. In some embodiments, tumors with aberrant expression or activity or levels of HER2 gene, HER2 kinase, or a combination thereof are determined using regulatory agency approval, such as FDA approved assays or kits.

In some embodiments of any of the methods or uses described herein, the clinical record of the subject indicates that the subject has a tumor with aberrant expression or activity or level of HER2 gene, HER2 kinase, or any thereof. Also provided herein are methods of treating a subject, the method comprising: a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof) is administered to a subject having aberrant expression or activity or level regulation of the HER2 gene, HER2 kinase, or any of them.

In some embodiments, the methods provided herein comprise: samples obtained from a subject are assayed to determine whether the subject has dysregulation of expression or levels of HER2 gene, HER2 protein, or any of these. In some such embodiments, the method further comprises: providing a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof) to a subject identified as having aberrant expression or activity or level of HER2 gene, HER2 protein, or any of them. In some embodiments, the method comprises: determining that a subject has abnormal expression or level regulation of HER2 gene, HER2 kinase, or any of these by assaying a sample obtained from the subject. In such embodiments, the method further comprises: administering to the subject a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of expression or activity or level of the HER2 gene, HER2 kinase protein, or any of them is one or more point mutations in the HER2 gene (e.g., any of the one or more HER2 point mutations described herein). The one or more point mutations in the HER2 gene may, for example, result in translation of the HER2 protein with one or more of the following amino acid substitutions: S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L and V842I. The one or more point mutations in the HER2 gene may, for example, result in translation of the HER2 protein with one or more of the following exon 20 amino acid substitutions: V773M, G776C, G776V, G776S, V777L, V777M, S779T, P780L and S783P. In some embodiments, the dysregulation of expression or activity or level of the HER2 gene, HER2 kinase protein, or any of them is one or more insertions in the HER2 gene (e.g., any HER2 insertion of the one or more HER2 insertions described herein). The one or more insertions in the HER2 gene may, for example, result in translation of the HER2 protein with one or more of the following exon 20 insertions: m774AYVM, M774del insWLV, A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776CV777insV, V777_G778insCG, G778_S779insCPG and P780_Y781insGSP. In some embodiments, the one or more insertions in the HER2 gene may, for example, result in translation of the HER2 protein with one or more of the following exon 20 insertions: y772_a775dup, a775_g776insvma, G776delinsVC, G776delinsVV, v777_g778insGSP, and p780_y781insGSP. Some embodiments of these methods further comprise: administering to the subject another anticancer agent (e.g., a second HER2 inhibitor, a second compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, or immunotherapy).

In some embodiments of any of the methods or uses described herein, an assay for determining whether a subject has dysregulation of HER2 gene or HER2 kinase or expression or activity or level of any of them using a sample from the subject may include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break Apart FISH analysis, southern blotting, western blotting, FACS analysis, northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, the assay is typically performed, for example, with at least one labeled nucleic acid probe or at least one labeled antibody or antigen binding fragment thereof. Assays may utilize other detection methods known in the art to detect dysregulation of expression or activity or levels of the HER2 gene, HER2 kinase, or any of these (see, e.g., references cited herein). In some embodiments, the sample is a biological sample or a biopsy sample from a subject (e.g., a paraffin embedded biopsy sample). In some embodiments, the subject is a subject suspected of having HER 2-related cancer, a subject having one or more symptoms of HER 2-related cancer, and/or a subject at high risk of having HER 2-related cancer.

In some embodiments, dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of these can be identified using liquid biopsy (alternatively collectively referred to as fluid biopsy or fluid phase biopsy). See, e.g., karachialiou et al, "Real-time liquid biopsies become a reality in cancer treatment", ann. Transl. Med.,3 (3): 36,2016. Liquid biopsy methods may be used to detect dysregulation of expression or activity or levels of the HER2 gene, HER2 kinase, or any of these and/or total tumor burden. Liquid biopsies can be obtained from a subject in a biological sample that is relatively easy to obtain (e.g., by simple blood drawing) and generally less invasive than traditional methods for detecting dysregulation of expression or activity or levels of the HER2 gene, HER2 kinase, or any of them, and/or total tumor burden. In some embodiments, the liquid biopsy method may be used to detect the presence of dysregulation of expression or activity or level of HER2 gene, HER2 kinase, or any of them at an earlier stage than conventional methods. In some embodiments, biological samples for liquid biopsies may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage, bile, lymph, cyst fluid, stool, ascites fluid, and combinations thereof. In some embodiments, liquid biopsies can be used to detect Circulating Tumor Cells (CTCs). In some embodiments, liquid biopsies can be used to detect cell free DNA. In some embodiments, the cell free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) from tumor cells. ctDNA analysis (e.g., using sensitive detection techniques such as, but not limited to, next Generation Sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of expression or activity or levels of the HER2 gene, HER2 kinase, or any of these.

Also provided are methods for inhibiting EGFR activity in a cell, the methods comprising: contacting the cell with a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof. Also provided are methods for inhibiting HER2 activity in a cell, the methods comprising: contacting the cell with a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof. Also provided are methods for inhibiting EGFR and HER2 activity in a cell, the methods comprising: contacting the cell with a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises: administering to a subject an effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, cells of the subject having aberrant EGFR activity and/or HER2 activity. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is a cell of any of the cancers described herein. In some embodiments, the cancer cell is a cell of an EGFR-associated cancer. In some embodiments, the cancer cell is a cell of a HER 2-related cancer. The term "contacting" as used herein refers to bringing together the indicated parts in an in vitro system or in vivo system. For example, "contacting" an EGFR kinase with a compound provided herein includes administering the compound provided herein to an individual or subject (e.g., human) having an EGFR kinase, and for example, introducing the compound provided herein into a sample containing a cell or purified preparation containing an EGFR kinase.

Also provided are methods of inhibiting cell proliferation in vitro or in vivo, the methods comprising: contacting the cell with an effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

Also provided herein are methods of increasing cell death in vitro or in vivo, the methods comprising: contacting the cell with an effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. Also provided herein are methods of increasing tumor cell death in a subject. The method comprises the following steps: an effective compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof) is administered to a subject in an amount effective to increase tumor cell death.

The phrase "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject in need of treatment, is sufficient to (i) treat an EGFR kinase related disease or disorder or a HER2 kinase related disease or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k)) or a pharmaceutically acceptable salt thereof) that corresponds to such amount will vary depending on factors such as the particular compound, the disease condition and severity thereof, the identity (e.g., weight) of the subject in need of treatment, but can generally be determined by one of skill in the art.

When used as a medicament, compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), including pharmaceutically acceptable salts or solvates thereof, may be administered in the form of a pharmaceutical composition as described herein.

(a) Determining whether cancer cells in a sample obtained from a subject having cancer or having previously been administered one or more doses of a first EGFR inhibitor have one or more EGFR inhibitor resistance mutations that increase the resistance of the cancer cells or tumor to treatment with the previously administered first EGFR inhibitor of the subject; and

(b) Administering to the subject a therapeutically effective amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, as a monotherapy or in combination with another anticancer agent.

(a) Determining that cancer cells in a sample obtained from a subject having cancer or having previously been administered one or more doses of a first EGFR inhibitor do not have one or more EGFR inhibitor resistance mutations that increase the resistance of the cancer cells or tumor to treatment with the previously administered first EGFR inhibitor of the subject; and

Combined use

In the field of medical oncology, it is common practice to treat each subject with cancer using a combination of different forms of treatment. In medical oncology, other components of such combination therapies or therapies may be, for example, surgery, radiation therapy, and chemotherapeutic agents, such as other kinase inhibitors, signal transduction inhibitors, and/or monoclonal antibodies, in addition to the compositions provided herein. For example, the surgery may be open surgery or minimally invasive surgery. The compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k)) or pharmaceutically acceptable salts or solvates thereof are thus also useful as adjuvants for the treatment of cancer, i.e., they may be used in combination with one or more additional therapies or therapeutic agents, e.g., chemotherapeutic agents that act by the same or different mechanisms of action. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, may be used prior to administration of the additional therapeutic agent or additional therapy. For example, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof) may be administered to a subject in need thereof over a period of time and then subjected to at least partial tumor resection. In some embodiments, treatment with a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof reduces tumor size (e.g., tumor burden) prior to at least partially resecting the tumor. In some embodiments, one or more doses of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof) may be administered to a subject in need thereof over a period of time and subjected to one or more rounds of radiation therapy. In some embodiments, treatment with a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof reduces tumor size (e.g., tumor burden) prior to the one or more rounds of radiation therapy.

In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumor) refractory to or intolerant of standard therapy (e.g., administration of a chemotherapeutic agent, e.g., a first EGFR inhibitor, a first HER2 inhibitor, or a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioiodine)). In some embodiments, the subject has a cancer (e.g., locally advanced or metastatic tumor) refractory or intolerant to prior therapies (e.g., administration of a chemotherapeutic agent, e.g., a first EGFR inhibitor, a first HER2 inhibitor, or a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioiodine)). In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumor) that does not have standard therapy. In some embodiments, the subject has not used an EGFR inhibitor. For example, the subject has not received treatment with a selective EGFR inhibitor. In some embodiments, the subject is not unused with an EGFR inhibitor. In some embodiments, the subject has not used a HER2 inhibitor. For example, the subject has not received treatment with a selective HER2 inhibitor. In some embodiments, the subject is not unused with a HER2 inhibitor. In some embodiments, the subject has undergone prior therapy. For example, treatment with a multi-kinase inhibitor (MKI), an EGFR Tyrosine Kinase Inhibitor (TKI), octreotide, gefitinib, erlotinib, afatinib, lapatinib, lenatinib, AZD-9291, CL-387785, CO-1686 or WZ 4002.

In some embodiments of any of the methods described herein, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents.

Non-limiting examples of additional therapeutic agents include: other EGFR targeted therapeutics (i.e., first or second EGFR inhibitors), other HER2 targeted therapeutics (i.e., first or second HER2 inhibitors), RAS pathway targeted therapeutics, PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase targeted therapeutics (e.g., trk inhibitors or multi-kinase inhibitors)), farnesyl transferase inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators (e.g., obacarat (obaataclax)), cytotoxic chemotherapeutics, angiogenesis targeted therapies, immune targeted agents, including immunotherapy and radiotherapy.

In some embodiments, the other EGFR-targeted therapeutic is a multi-kinase inhibitor that exhibits EGFR inhibitory activity. In some embodiments, the other EGFR targeted therapeutic inhibitor is selective for EGFR kinase.

Non-limiting examples of EGFR targeted therapeutics (e.g., first EGFR inhibitor or second EGFR inhibitor) include EGFR selective inhibitors, panHER inhibitors, and anti-EGFR antibodies. In some embodiments, the EGFR inhibitor is a covalent inhibitor. At the position ofIn some embodiments, the EGFR targeted therapeutic is octreotide (AZD 9291, melitenib, tagrisstrotm), erlotinibGefitinib>Cetuximab->Xituzumab (PORTRAZZATM, IMC-11F 8), lenatinib (HKI-272, -/->) Lapatinib->Panitumumab (ABX-EGF,>) Vandetanib->Luo Xiti Ni (CO-1686), O Mu Tini (OLITATM, HM61713, BI-1482694), nakutinib (naquotinib) (ASP 8273), nazatinib (EGF 816, NVS-816), PF-06747775, ecotinib (BPI-2009H), afatinib (BIBW 2992 )>) Dacotinib (PF-00299804, PF-804, PF-299, PF-299804), eveltinib (AC 0010), AC0010MA EAI045, matuzumab (EMD-7200), nituzumab (h-R3, BIOMAb->) Binding Lu Tushan, MDX447, ditoxizumab (humanized mAb 806, ABT-806), martin-Ditoxizumab (ABT-414), ABT-806, mAb 806, canertinib (canertinib) (CI-1033), shikonin derivatives Substances (e.g., deoxyshikonin, isobutyryl shikonin, acetylshikonin, β -dimethylacryl shikonin, and acetylshikonin), boscalid (NOV 120101, HM 781-36B), AV-412, ibrutinib, WZ4002, bujitinib (AP 26113, belgium)>) Peltitinib (EKB-569), tarloxotinib (TH-4000, PR 610), BPI-15086, hemay022 (Syame 022), ZN-e4, titania (tesevatinib) (KD 019, XL 647), YH25448, ibrutinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988, tile Lin Tini (varlin) ASLAN001, ARRY-334543, AP32788, HLX07, D-0316, AEE788, HS-10296, evitamin tinib, GW572016, pyrroltinib (SHR 1258), SCT200, CPGJ602, m004, MAb-425, zaxib (TAB-H49), futuximab (992 DS), ZMAb, KL-140, 50, 50GN, 62, JNXINYIN-289), disvalnemib (JR-387, and EGFR-387. In some embodiments, the EGFR-targeting therapeutic agent is selected from the group consisting of: oritinib, gefitinib, erlotinib, afatinib, lapatinib, lenatinib, AZD-9291, CL-387785, CO-1686 or WZ4002.

Additional EGFR-targeted therapeutics (e.g., first EGFR inhibitor or second EGFR inhibitor) are included in WO 2019/246541; WO 2019/165385; WO 2014/1761475; and those disclosed in US 9,029,502, each of which is incorporated by reference in its entirety.

In some embodiments, the other HER2 targeted therapeutic is a multi-kinase inhibitor that exhibits HER2 inhibitory activity. In some embodiments, the other HER2 targeted therapeutic inhibitor is selective for HER2 kinase.

Non-limiting examples of HER2 targeted therapeutic agents (e.g., first HER2 inhibitor or second HER2 inhibitor) include HER2 selective inhibitors, panHER inhibitors, and anti-HER 2 antibodies. Exemplary HER 2-targeted therapeutic agents include trazimera (e.g., trazimera,) Pertuzumab (e.g., j>) Enmetrastuzumab (T-DM 1 or ado-Enmetrastuzumab, e.g., in->) Lapatinib, KU004, lenatinib (e.g.,) Dacatinib (e.g.)>) Afatinib->Fig. calitinib (e.g. tukyatm), erlotinib (e.g. +.>) Pyrroltinib, wave Ji Tini, CP-724714, CUDC-101, saprotinib (AZD 8931), tamspiramycin (17-AAG), IPI-504, PF299, perlitinib, S-22261 1 and AEE-788.

Additional HER 2-targeted therapeutic agents (e.g., a first HER2 inhibitor or a second HER2 inhibitor) are included in WO 2019/246541; WO 2019/165385; WO 2014/1761475; and those disclosed in US 9,029,502, each of which is incorporated by reference in its entirety.

As used herein, "RAS pathway targeted therapeutic" includes any compound that exhibits inactivating activity (e.g., kinase inhibition, allosteric inhibition, dimerization inhibition, and degradation induction) of any protein in the RAS pathway. Non-limiting examples of proteins in the RAS pathway include any of the RAS-RAF-MAPK pathway or PI3K/AKT pathway, such as RAS (e.g., KRAS, HRAS, and NRAS), RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, the RAS pathway modulator may be selective for proteins in the RAS pathway, e.g., the RAS pathway modulator may be selective for RAS (also referred to as RAS modulator). In some embodiments, the RAS modulator is a covalent inhibitor. In some embodiments, the RAS pathway targeting therapeutic agent is a "KRAS pathway modulator". KRAS pathway modulators include any compound that exhibits inactivating activity (e.g., kinase inhibition, allosteric inhibition, dimerization inhibition, and degradation induction) of any protein in the KRAS pathway. Non-limiting examples of proteins in the KRAS pathway include any of the proteins in the KRAS-RAF-MAPK pathway or PI3K/AKT pathway, such as KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT and mTOR. In some embodiments, the KRAS pathway modulator may be selective for proteins in the RAS pathway, e.g., the KRAS pathway modulator may be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, the KRAS modulator is a covalent inhibitor. Non-limiting examples of KRAS targeted therapeutic agents (e.g., KRAS inhibitors) include BI 1701963, AMG 510, ARS-3248, ARS1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849.

Additional non-limiting examples of RAS targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vitamin Mo FeiniDarafenib->And Kang Naifei Ni (BRAFTOVITM), BMS-908662 (XL 281), sorafenib, LGX818, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or combinations thereof.

In some embodiments, the MEK inhibitor is trimetinib @GSK 1120212), cobicitinibBimetinib (>MEK 162), semantenib (AZD 6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD 184352), distamycin, or combinations thereof.

In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3-BE (B3 CD, bromoacetoxycalcitol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, MK-8353 (SCH 900353), SCH772984, yolitinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5-7-Oxozenenol (5, 7-octoxazol) 5-iodoybacidin (5-iodotubercidin), GDC0994, ONC201, or a combination thereof.

In some embodiments, the PI3K inhibitor is selected from: bupanib (BKM 120), april (BYL 719), WX-037, copanib (ALIQOPATM, BAY-6946), dacronisib (NVP-BEZ 235, BEZ-235), tasselisiib (Taserist) (GDC-0032, RG 7604), sonolisis (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, piciliib (Pi Keli s) (GDC-0941), picalalisib (Pi Lali s) (XL 147, SAR 245408), ji Dali plug (Gedatolisib) (PF-05212384, PKI-587), serabelisib (Sera Bei Lisi) (TAK-117, MLN 1117) INK 1117), BGT-226 (NVP-BGT 226), PF-04691502, apitolisib (apitretin) (GDC-0980), opaglissib (omiplaisib) (GSK 2126458, GSK 458), wo Dali s (voxtaisib) (XL 756, SAR 245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG 7666), VS-5584 (SB 2343), PKI-402, wortmannin (Wortmannin), LY294002, PI-103, ragaserib (rigosetib), XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, GSK2636771, or combinations thereof.

In some embodiments, the AKT inhibitor is selected from: miltefosineWortmannin NL-71-101, H-89, GSK690693, CCT128930, AZD5363, patadine (GDC-0068, RG 7440), a-675563, a-443654, AT7867, AT13148, niprotil, aforotidine, DC120, 2- [4- (2-aminoprop-2-yl) phenyl ]-3-phenylquinoxaline, MK-2206, edestin, miltefosine, pirifaction, erucyl phosphorylcholine, ai Lufu novel (erufosine), SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, troxirebabine (troxirebabine phosphate monohydrate), API-1, N- (4- (5- (3-acetamidophenyl) -2- (2-aminopyridin-3-yl) -3H-imidazo [4,5-b]Pyridin-3-yl) benzyl) -3-fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-kansuic acid, lactoquinone mycin, boc-Phe-vinyl ketone, pirifunew (D-21266), TCN-P, GSK2141795, ONC201, or combinations thereof.

In some embodiments, the mTOR inhibitor is selected from: MLN0128, AZD-2014, CC-223, AZD2014, CC-115, everolimus (RAD 001), temsirolimus (CCI-779), geothermal limus (ridaforolimus) (AP-23573), sirolimus (rapamycin), or a combination thereof.

Non-limiting examples of farnesyl transferase inhibitors include lonafarnib, tipifarnib, BMS-214662, L778123, L744832 and FTI-277.

In some embodiments, the chemotherapeutic agent comprises an anthracycline, cyclophosphamide, taxane, platinum-based formulation, mitomycin, gemcitabine, eribulin (HALAVENTM), or a combination thereof.

Non-limiting examples of taxanes include paclitaxel, docetaxel, abies (abaxane), and paclitaxel.

In some embodiments, the anthracycline is selected from the group consisting of daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.

In some embodiments, the platinum-based formulation is selected from carboplatin, cisplatin, oxaliplatin, nedaplatin, triplatinum tetranitrate, phenanthriplatin, picoplatin, satraplatin, and combinations thereof.

Non-limiting examples of PARP inhibitors include OlaparibTaraxazopanib, lu Kapa, nilaparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, eniparib (iniparib), IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD 2281), BSI-201, PF-01367338, INO-1001 and JPI-289.

Non-limiting examples of immunotherapy include immune checkpoint therapy, atilizumabAlbumin binds paclitaxel. Non-limiting examples of immune checkpoint therapies include targeted CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodiments, the CTLA-4 inhibitor is ipilimumab (ipilimumab)>. In some embodiments, the PD-1 inhibitor is selected from the group consisting of pamphlebitis (pembrolizumab)/(pembrolizumab) >Nivolumab (nivolumab)/(nivolumab)>Cimipro Li Shan anti (cemiplimab)/(cemiplimab)>Or a combination thereof. In some embodiments, the PD-L1 inhibitor is selected from the group consisting of atilizumabAvermectin->Duvali You Shan anti->Or a combination thereof. In some implementationsIn an embodiment, the LAG-3 inhibitor is IMP701 (LAG 525). In some embodiments, the A2AR inhibitor is CPI-444. For some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enotuzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indomod. See, for example, marin-Acevedo et al, J Hematol Oncol.11:39 (2018).

In some embodiments, the additional therapy or therapeutic agent is a combination of an acter Li Zhushan antibody and albumin-bound paclitaxel (nab-paclitaxel).

Accordingly, also provided herein is a method of treating a subject, the method comprising: administering to a subject in need thereof a pharmaceutical combination for treating cancer comprising (a) an amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use in treating cancer, wherein the amounts of the compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), or (I-k)) or the pharmaceutically acceptable salt thereof, together with the amount of the additional therapeutic agent are effective to treat cancer.

In some embodiments, the additional therapeutic agent comprises any of the therapies or therapeutic agents listed above as a standard of care for cancer, wherein the cancer has dysregulation of expression or level of the EGFR gene, EGFR protein, or any thereof.

In some embodiments, the additional therapeutic agent comprises any of the therapies or therapeutic agents listed above as a standard of care for cancer, wherein the cancer has dysregulation of expression or levels of HER2 gene, HER2 protein, or any of them.

These additional therapeutic agents may be administered with one or more doses of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, as part of the same dosage form or as separate dosage forms, by the same or different routes of administration, and/or according to the same or different administration schedules according to standard pharmaceutical practice known to those skilled in the art.

Also provided herein are (I) pharmaceutical combinations for treating cancer in a subject in need thereof, comprising (a) an amount of a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents known in the art or described herein), and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use in treating cancer, wherein the amounts of the compounds of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or the pharmaceutically acceptable salts thereof, and the amounts of the additional therapeutic agents together are effective for treating cancer; (ii) a pharmaceutical composition comprising said combination; (iii) Use of the combination for the preparation of a medicament for the treatment of cancer; and (iv) commercial packages or products comprising the combination as a combined preparation for simultaneous, separate or sequential use; and methods of treating cancer in a subject in need thereof. In some embodiments, the cancer is an EGFR-related cancer, e.g., an EGFR-related cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, the cancer is a HER 2-related cancer, e.g., a HER 2-related cancer having one or more HER2 inhibitor resistance mutations.

As used herein, the term "pharmaceutical combination" refers to a pharmacotherapy resulting from the mixing or combining of more than one active ingredient, which includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the compounds of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k)), or pharmaceutically acceptable salts thereof, and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) are administered simultaneously to a subject in the form of a single composition or dose. The term "non-fixed combination" means a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k)), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) are formulated as separate compositions or doses such that they can be administered to a subject simultaneously, simultaneously or sequentially, and with variable intervention times, wherein such administration provides effective levels of two or more compounds in the subject. These also apply to cocktail therapies, for example, the administration of two or more active ingredients.

Accordingly, also provided herein is a method of treating cancer, the method comprising: administering to a subject in need thereof a pharmaceutical combination comprising (a) a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k)) or a pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, wherein the compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j) or (I-k)) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously, separately or sequentially, wherein the compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I), the amount of the compound of (I-j) or (I-k)) or a pharmaceutically acceptable salt thereof, together with the amount of the additional therapeutic agent, is effective for treating cancer. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously as separate doses. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered sequentially in any order as separate doses in combination with a therapeutically effective amount, e.g., in daily or intermittent doses. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof and an additional therapeutic agent are administered simultaneously as a combined dose as separate dosage forms. In some embodiments, the cancer is an EGFR-related cancer, e.g., an EGFR-related cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, the cancer is a HER 2-related cancer, e.g., a HER 2-related cancer having one or more HER2 inhibitor resistance mutations.

In some embodiments, the presence of one or more EGFR inhibitor resistance mutations in the tumor results in the tumor being more resistant to treatment with the first EGFR inhibitor. When an EGFR inhibitor resistance mutation results in a tumor that is more resistant to treatment with the first EGFR inhibitor, the methods that can be used are described below. For example, provided herein is a method of treating a subject having cancer, the method comprising: identifying that cancer cells of the subject have one or more EGFR inhibitor mutations; and administering to the identified subject a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof is administered in combination with a first EGFR inhibitor. Also provided are methods of treating a subject identified as having cancer cells and the cancer cells having one or more EGFR inhibitor mutations, the method comprising: a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof) is administered to a subject. In some embodiments, a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof is administered in combination with a first EGFR inhibitor. In some embodiments, the one or more EGFR inhibitor resistance mutations confer increased resistance to treatment with the first EGFR inhibitor on the cancer cell or tumor. In some embodiments, the one or more EGFR inhibitor resistance mutations comprise one or more EGFR inhibitor resistance mutations listed in table 2a and table 2 b. For example, the one or more EGFR inhibitor resistance mutations can include substitutions at amino acid positions 718, 747, 761, 790, 797, and 854 (e.g., L718Q, L747S, D761Y, T790M, C797S and T854A).

For example, provided herein is a method of treating EGFR-related cancer in a subject in need of treatment, the method comprising: a) Detecting dysregulation of expression or activity or level of an EGFR gene, EGFR kinase, or any thereof in a sample from a subject; and b) administering to the subject a therapeutically effective amount of a first EGFR inhibitor, wherein the first EGFR inhibitor is selected from the group consisting of: oritinib, gefitinib, erlotinib, afatinib, lapatinib, lenatinib, AZD-9291, CL-387785, CO-1686 or WZ4002. In some embodiments, the method further comprises: (after (b), (c) determining whether cancer cells of a sample obtained from the subject have at least one EGFR inhibitor resistance mutation; and (d) if the subject is determined to have at least one EGFR inhibitor resistance mutation in the cancer cells, administering to the subject a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with another anticancer agent; or (e) administering an additional dose of the first EGFR inhibitor of step (b) to the subject if the subject is not determined to have at least one EGFR inhibitor resistance mutation in the cancer cells.

Described herein are methods that can be used when HER2 activating mutations are present in tumors. For example, provided herein is a method of treating a subject having cancer, the method comprising: identifying cancer cells of the subject as having one or more HER2 activating mutations; and administering to the identified subject a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof. Also provided are methods of treating a subject identified as having a cancer and having one or more HER2 activating mutations, comprising: a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)) or a pharmaceutically acceptable salt thereof) is administered to a subject. In some embodiments, the one or more HER2 activating mutations comprise one or more HER2 activating mutations listed in tables 3-5.

Described herein are methods that can be used when activating mutations (e.g., HER2 activating mutations) are present in a tumor of a subject. For example, provided herein is a method of treating a subject having cancer, the method comprising: identifying cancer cells of the subject as having one or more HER2 activating mutations; and administering to the identified subject a compound of formula (I) (e.g., formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-I), (I-j), or (I-k)), or a pharmaceutically acceptable salt thereof.

Preparation of Compounds

The compounds disclosed herein can be prepared in various ways using commercially available starting materials, compounds known in the literature or compounds derived from readily prepared intermediates, by using standard synthetic methods known to those skilled in the art or in accordance with the teachings herein. The synthesis of the compounds disclosed herein can generally be accomplished by scheme 1 below, with modifications to the specifically desired substituents.

Standard synthetic methods and procedures for organic molecule preparation and functional group transformation and manipulation may be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or more sources, useful and well-recognized organic synthetic reference textbooks known to those skilled in the art may be as follows: larock, comprehensive Organic Transformations, VCH Press (1989); fieser and M.Fieser, fieser and Fieser's Reagents for Organic Synthesis, john Willi parent-child publishing company (1994); smith, M.B., march, J., march's Advanced Organic Chemistry: reactions, mechanics, and Structure, 5 th edition, john's Willi parent-child publishing company, new York, 2001; and Greene, t.w., wuts, p.g.m., protective Groups in Organic Synthesis, 3 rd edition, john wili parent-child publishing company: new York, 1999. The following synthetic method descriptions are intended to illustrate, but not limit, the general procedure used to prepare the compounds of the present disclosure.

The synthetic processes disclosed herein can tolerate a wide variety of functional groups; thus, various substituted starting materials may be used. The process generally provides the final compound at or near the end of the overall process, but in some cases it may be desirable to further convert the compound into a pharmaceutically acceptable salt thereof.

Preparation of Compounds

Example 1 (S) -2- (3- ((6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazol-5-yl) methoxy) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 133 a)

Part 1: synthesis of Int1B

3-fluoro-2-methoxyaniline and CSCl ₂ Reacted to provide Int1A. Coupling of Int1A with tert-butyl 4-hydroxy-6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylate provides Int1B.

Part 2: synthesis of Compound 133a

Coupling of 3-chloroisonicotinic nitrile with benzyl alcohol (BnOH) under basic conditions (e.g., naH) in a polar aprotic solvent (e.g., dimethylformamide (DMF)) to provide 3- (benzyloxy) isonicotinic nitrile in the presence of nickel and hydrogen (H) ₂ ) Nitrile reduction of 3- (benzyloxy) isonicotinic acid nitrile in the presence of (3- (benzyloxy) pyridin-4-yl) methylamine is provided. The coupling of Int1B and (3- (benzyloxy) pyridin-4-yl) methylamine provides Int1C. Next, int1C is oxidized (e.g., under H ₂ O ₂ In the presence of (D) cyclisation provides Int1D-Bn. Under hydrogenation conditions (e.g., pd/C and H ₂ ) Lower benzyl deprotection provides Int1D. Int1D and (S) - (6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Mitsunobu (Wangyang) coupling of triazol-5-yl) methanol provided compound 133a.

EXAMPLE 2- (3- ((6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-3-yl) methoxy) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 150)

Int1D was prepared using the method described in example 1. Mitsunobu coupling of (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-3-yl) methanol with Int1D provides compound 150.

EXAMPLE 3 2- (3- ((6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-5-yl) methoxy) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 128)

Int1D was prepared using the method described in example 1. Mitsunobu coupling of Int1D with (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-5-yl) methanol provides compound 128.

EXAMPLE 4 3- ((3-fluoro-2-methoxyphenyl) amino) -2- (3- ((1, 4,5, 6-tetrahydrocyclopenta [ c ] pyrazol-3-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 151)

Int1D was prepared using the method described in example 1. Mitsunobu coupling of Int1D with (1, 4,5, 6-tetrahydrocyclopenta [ c ] pyrazol-3-yl) methanol afforded compound 151.

EXAMPLE 5 Synthesis of (S) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 142 a)

Under basic conditions (e.g., in the presence of NaH), in a polar aprotic solvent such as Dimethylformamide (DMF), (S)) -tert-butyl 2- (hydroxymethyl) pyrrolidine-1-carboxylate was coupled with 3-chloroisonicotinic nitrile to provide (S) -tert-butyl 2- (((4-cyanopyridin-3-yl) oxy) methyl) pyrrolidine-1-carboxylate. Nitrile reduction of (S) -2- (((4-cyanopyridin-3-yl) oxy) methyl) pyrrolidine-1-carboxylic acid ester (e.g., in the presence of Raney nickel and hydrogen) then provides (S) -2- (((4- (aminomethyl) pyridin-3-yl) oxy) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester. The coupling of Int2B and (S) -2- (((4- (aminomethyl) pyridin-3-yl) oxy) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester then provides (S) -Int2C. (S) -Int2C under oxidizing conditions (e.g., at H ₂ O ₂ In the presence of (c) cyclisation then affords (S) -Int2D. BOC deprotection of (S) -Int2D in the presence of an acid (e.g., TFA, e.g., in Dichloromethane (DCM)) provides (S) -Int1E. Finally, sulfonamide formation of (S) -Int1E in the presence of methanesulfonyl chloride provides compound 142a.

Example 6 (S) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((1-propionylpyrrolidin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 139)

Int1E was prepared using the method described in example 5. Amidation of Int1E in the presence of propionyl chloride provides compound 139.

Example 7 (S) -2- (3- ((1-Acropopyrrolidin-2-yl) methoxy) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 138 b)

Int1E was prepared using the method described in example 5. Amidation of Int1E in the presence of acryloyl chloride provides compound 138b.

EXAMPLE 8 Synthesis of (S) -2- (3- ((1-acetylpyrrolidin-2-yl) methoxy) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 141 a)

Int1E was prepared using the method described in example 5. Amidation of Int1E in the presence of acetyl chloride provides compound 141a.

Example 9 (R) -2- (3- ((1-Acropopyrrolidin-2-yl) methoxy) pyridin-4-yl) -3- ((3-fluoro-2-methylphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 140)

Under basic conditions (e.g., in the presence of NaH), in a polar aprotic solvent such as Dimethylformamide (DMF), tert-butyl (R) -2- (hydroxymethyl) pyrrolidine-1-carboxylate is coupled with 3-chloroisonicotinic acid to provide tert-butyl (R) -2- (((4-cyanopyridin-3-yl) oxy) methyl) pyrrolidine-1-carboxylate. The nitrile reduction of (R) -2- (((4-cyanopyridin-3-yl) oxy) methyl) pyrrolidine-1-carboxylic acid ester, then (e.g., in the presence of Raney nickel and hydrogen) provides tert-butyl (R) -2- (((4- (aminomethyl) pyridin-3-yl) oxy) methyl) pyrrolidine-1-carboxylic acid. The coupling of Int1' B-H (see preparation methods below) and (R) -2- (((4- (aminomethyl) pyridin-3-yl) oxy) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester then provided (R) -Int2C. Next (R) -Int2C is oxidized (e.g., under H ₂ O ₂ In the presence of (2) to provide (R) -Int2D. BOC deprotection of (R) -Int2D in the presence of an acid (e.g., TFA, etc., in, e.g., dichloromethane (DCM)) provides (R) -Int1E. Amidation of (R) -Int1E in the presence of methanesulfonyl chloride provides compound 140.

Preparation of Int1' B-H:

coupling of tert-butyl 2, 4-dioxopiperidine-1-carboxylate with 1-fluoro-3-isothiocyanato-2-methylbenzene (e.g., in the presence of a base, such as DBU, which is in acetonitrile, for example) provides Int1' B-Boc. Then, removal of the Boc protecting group on Int1'B-Boc provides Int1' B-H.

Example 10 (R) -2- (3- ((1-propenoylazetidin-2-yl) methoxy) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 145 a)

(R) -tert-butyl 2- (hydroxymethyl) azetidine-1-carboxylate and 3-chloroisonicotinic acid are coupled under basic conditions (e.g., in the presence of NaH) in a polar aprotic solvent such as Dimethylformamide (DMF) to provide tert-butyl (R) -2- (((4-cyanopyridin-3-yl) oxy) methyl) azetidine-1-carboxylate. Nitrile reduction of (R) -2- (((4-cyanopyridin-3-yl) oxy) methyl) azetidine-1-carboxylic acid tert-butyl ester (e.g., in the presence of raney nickel and hydrogen) then provides (R) -2- (((4- (aminomethyl) pyridin-3-yl) oxy) methyl) azetidine-1-carboxylic acid tert-butyl ester. Next, the coupling of Int2B-H and (R) -2- (((4- (aminomethyl) pyridin-3-yl) oxy) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester provides (R) -Int3C. Then, (R) -Int3C is oxidized (e.g., under H ₂ O ₂ In the presence of (c) cyclisation provides (R) -Int3D. BOC deprotection of (R) -Int3D in Dichloromethane (DCM) in the presence of an acid (e.g., TFA, etc.) provides (R) -Int2E. Finally, (R) -Int2E amidation in the presence of acryloyl chloride provides compound 145a.

EXAMPLE 11 Synthesis of 2- (3- (2-Cyclopropyloxyethoxy) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 135)

Part 1: synthesis of 4- (aminomethyl) pyridin-3-ol

By reacting 3-hydroxyisonicotinal with hydroxylamine hydrochloride (NH) ₂ OH HCl) to provide 3-hydroxyisonicotinaldehyde oxime. Hydrogenation of imines of 3-hydroxyisonicotinal oximes in methanol (e.g., in palladium and H ₂ In the presence of (2) provides 4- (aminomethyl) pyridin-3-ol.

Part 2:

3-fluoro-2-methoxyaniline and CSCl ₂ To provide 1-fluoro-3-isothiocyanato-2-methoxybenzene. Coupling of 1-fluoro-3-isothiocyanato-2-methoxybenzene and piperidine-2, 4-dione in acetonitrile (e.g., in the presence of DBU) provides Int2B-H. Coupling of Int2B-H with 4- (aminomethyl) pyridin-3-ol provides Int2C-H. Next, int2C-H is oxidized (e.g., under H ₂ O ₂ In the presence of (2) cyclisation provides Int2D-H. Mitsunobu coupling of Int2D-H and 2-cyclopropoxyethyl-1-ol provides compound 135.

EXAMPLE 12 Synthesis of 3- ((3-fluoro-2-methoxyphenyl) amino) -2- (3- ((1R, 2S) -2-methoxycyclopropyloxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 136 b)

(vinyloxy) methyl) benzene and bromoform (CHBr) ₃ ) Under alkaline conditions (e.g., at KOH and n-Bu ₄ In DCM in the presence of NHSO 4) to provide ((2, 2-dibromocyclopropyloxy) methyl) benzene. ((2, 2-dibromocyclopropyloxy) methyl) benzene is subsequently debrominated continuously under reducing conditions (e.g., with zinc) by basic hydrolysis (e.g., in the presence of NaOH) to provide (1 r,2 r) -2- (benzyloxy) cyclopropan-1-ol. Methylation of (1 r,2 r) -2- (benzyloxy) cyclopropyl-1-ol (e.g., in the presence of NaH and MeI) provides (((1 r,2 r) -2-methoxycyclopropyloxy) methyl) benzene. Hydrogenolysis of ((1R, 2R) -2-methoxycyclopropyloxy) methyl) benzene followed by Mitsunobu coupling with Int2D-H provides compound 136b.

EXAMPLE 13 Synthesis of (R) -2- (3- ((1-propenylpyrrolidin-2-yl) ethynyl) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 147 b)

Part 1: synthesis of (3-bromopyridin-4-yl) methylamine

3-Bromoisonicotinic nitrile in acetic acid under hydrogenation conditions (e.g., raney Nickel and H ₂ ) The lower reduction provides (3-bromopyridin-4-yl) methylamine.

Synthesis of part 2 (R) -2-ethynyl pyrrolidine-1-carboxylic acid tert-butyl ester

(R) -2-formylpyrrolidine-1-carboxylic acid tert-butyl ester reaction (for example, in Bestmann-Ohira reagent and K ₂ CO ₃ In the presence of (R) -2-ethynyl pyrrolidine-1-carboxylic acid tert-butyl ester.

Part 3:

3-fluoro-2-methoxyaniline and CSCl ₂ Under alkaline conditions (e.g., naHCO ₃ In DCM) to provide 1-fluoro-3-isothiocyanato-2-methoxybenzene. The coupling of 1-fluoro-3-isothiocyanato-2-methoxybenzene and piperidine-2, 4-dione provides N- (3-fluoro-2-methoxyphenyl) -4-hydroxy-2-oxo-1, 2,5, 6-tetrahydropyridine-3-thiocarboxamide. The reaction of N- (3-fluoro-2-methoxyphenyl) -4-hydroxy-2-oxo-1, 2,5, 6-tetrahydropyridin-3-carbothioic acid amide with (3-bromopyridin-4-yl) methylamine in a polar aprotic solvent (e.g., DMA) provides Int5C. Int5C under oxidizing conditions (e.g., at H ₂ O ₂ In the presence of (c) cyclisation then affords Int4D. Coupling of (R) -tert-butyl 2-ethynyl-pyrrolidine-1-carboxylate with Int4D provides (R) -Int3E-BOC. BOC deprotection of (R) -Int3E-BOC provides (R) -Int3E, which is further reacted with acryloyl chloride to provide compound 147b.

EXAMPLE 14 Synthesis of (S) -2- (3- ((1-propenylpyrrolidin-2-yl) ethynyl) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 147 a)

(S) -2-formylpyrrolidine-1-carboxylic acid tert-butyl ester reaction (for example, in Bestmann-Ohira reagent and K ₂ CO ₃ In the presence of (S) -2-ethynyl pyrrolidine-1-carboxylic acid tert-butyl ester. Int4D and (S) -2-ethynyl-pyrrolidine-1-carboxylic acid tert-butyl ester (e.g., in Pd (PPh) ₃ ) ₄ In the presence of CuI and TEA) to provide (S) -Int3E-BOC. BOC deprotection of (R) -Int3E-BOC provides (R) -Int3E, which is further reacted with acryloyl chloride to provide compound 147a.

EXAMPLE 15 Synthesis of (S) -3- ((3-fluoro-2-methoxyphenyl) amino) -2- (3- ((tetrahydrofuran-2-yl) ethynyl) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 148 a) and (R) -3- ((3-fluoro-2-methoxyphenyl) amino) -2- (3- ((tetrahydrofuran-2-yl) ethynyl) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 148 b)

tetrahydrofuran-2-Formaldehyde reaction (for example, in Bestmann-Ohira reagent and K ₂ CO ₃ In the presence of (2) ethynyl tetrahydrofuran) to provide 2-ethynyl tetrahydrofuran. Sonogashira coupling of Int4D and 2-ethynyl tetrahydrofuran (e.g., in Pd (PPh ₃ ) ₄ In the presence of CuI and TEA) provides an enantiomeric mixture comprising 148a and 148b, which is then separated by chiral supercritical chromatography to provide compound 148a and compound 148b.

EXAMPLE 16- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (3-methoxy-3-methylbut-1-yn-1-yl) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (compound 188)

Cyanopyridine Int1A in the presence of hydrogen and a catalyst (e.g., raney Nickel) in polarityHydrogenation in protic solvents such as MeOH and weak acids such as HOAc gives Int1B. Int1C with thiophosgene under modified Schotten-Baumann conditions (e.g., naHCO) ₃ In water/DCM) to give the corresponding thioisocyanate Int1D. Treating Int1D with Int1E in the presence of a strong base such as DBU in a polar aprotic solvent such as ACN gives Int1F. In polar aprotic solvents such as DMA, in dehydrating agents such asIn the presence of molecular sieves, heating (e.g., 120 ℃) to condense Int1F with Int1B provides Int1G. In a polar protic solvent such as MeOH, in a weak oxidant such as H ₂ O ₂ In the presence of Int1G to give Int1H. Int1H and Int1I are coupled under Sonogashira coupling conditions (e.g., cuI, pd (PPh) ₃ ) ₄ And TEA) to give the title compound.

EXAMPLE 17 Synthesis of (R) -217- (3- ((1-propenoylpyrrolidin-2-yl) methoxy) pyridin-4-yl) -3- (benzo [ d ] thiazol-4-ylamino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 171)

Aminobenzothiazole Int2A with thiophosgene under modified Schotten-Baumann conditions (e.g., naHCO ₃ In water/DCM) to give the corresponding thioisocyanate, which is then reacted with Int2B under strong base conditions such as DBU in a polar aprotic solvent such as ACN to give Int2C. Deprotection of Int2C is accomplished with a strong acid (e.g., TFA in DCM), followed by NaHCO ₃ (aqueous) neutralization to give Int2D. At room temperature, chloropyridine Int2E is reacted with Int2F in a polar aprotic solvent such as DMF in the presence of a strong base such as NaH to yield Int2G. The hydrogenation of Int2G is accomplished with hydrogen and a catalyst such as ranini in a polar protic solvent such as MeOH to provide Int2H. In polar aprotic solvents such as DMA, in dehydrating agents such asIn the presence of molecular sieves, int2H is condensed with Int2D by heating (e.g., 120 ℃) to provide Int2I. In a polar protic solvent such as MeOH, in a weak oxidant such as H ₂ O ₂ In the presence of Int2I, to give Int2J. Deprotection of Int2J with a strong acid such as TFA followed by treatment with acryloyl chloride under weakly basic conditions gives the title compound.

Example 18:2- (3- [ [ (2R) -1-acetylpyrrolidin-2-yl ] methoxy ] pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 141 b)

18.1: synthesis of chloro-3-isothiocyanato-2-methoxybenzene

3-chloro-2-methoxyaniline (4.00 g,25.3mmol,1.00 eq.) and thiophosgene (3.21 g,27.9mmol,1.10 eq.) are stirred in DCM (10.00 mL) and NaHCO at 0deg.C under nitrogen ₃ Sat (saturated NaHCO) ₃ ) (10.00 mL) for 1h (hour). The resulting mixture was treated with CH ₂ Cl ₂ (2X 100 mL) extraction. The combined organic layers were washed with brine (1×50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gave 1-chloro-3-isothiocyanato-2-methoxybenzene (3.5 g, 69.07%) as a pale yellow oil.

LC-MS (M+H) + actual: 200.0.

18.2: synthesis of tert-butyl 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -4-hydroxy-2-oxo-5, 6-dihydropyridine

A solution of 1-chloro-3-isothiocyanato-2-methoxybenzene (3.50 g,17.5mmol,1.00 eq.) and tert-butyl 2, 4-dioxopiperidine-1-carboxylate (3.74 g,17.531mmol,1.00 eq.) and DBU (4.00 g, 26.298 mmol,1.50 eq.) in MeCN (50.00 mL) was stirred for 2h at room temperature under nitrogen. The reaction was quenched by the addition of water (100 mL) at room temperature. The mixture was acidified to pH 7 with concentrated HCl. The precipitated solid was collected by filtration and washed with water (1×10 mL). This gave 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (6.9 g, 95.33%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 413.3.

18.3: synthesis of tert-butyl (2R) -2- [ [ (4-cyanopyridin-3-yl) oxy ] methyl ] pyrrolidine-1-carboxylate

To a solution of tert-butyl (2R) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (5.00 g,24.8mmol,1.00 eq.) in DMF (50.00 mL) was added NaH (596 mg,24.8mmol,1.00 eq.) and stirred at 0deg.C for 0.5h, and 3-chloropyridine-4-carbonitrile (3.79 g,27.3mmol,1.10 eq.) was added and stirred at 0deg.C under nitrogen for 2h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (1×50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (5:1) to provide (2R) -2- [ [ (4-cyanopyridin-3-yl) oxy]Methyl group]Pyrrolidine-1-carboxylic acid tert-butyl ester (3.2 g, 42.46%) was a pale yellow oil.

LC-MS:(M-56) ⁺ Actual: 248.2.

18.4: synthesis of (2R) -2- ([ [4- (aminomethyl) pyridin-3-yl ] oxy ] methyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Stirring (2R) -2- [ [ (4-cyanopyridin-3-yl) oxy group at room temperature under hydrogen atmosphere]Methyl group]Pyrrolidine-1-carboxylic acid tert-butyl ester (6.00 g,19.7mmol,1.00 eq.) and Raney Ni (2.54 g,29.6mmol,1.50 eq.) and NH ₃ (30 mL,7M in MeOH) in MeOH (60.00 mL) overnight. The resulting mixture was filtered and the filter cake was washed with MeOH (2X 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography and the following conditions were used: (MeCN/H) ₂ O=10%) to give (2R) -2- ([ [4- (aminomethyl) pyridin-3-yl)]Oxy group]Tert-butyl methyl-pyrrolidine-1-carboxylate (5.0 g, 82.24%) was a pale yellow oil.

LC-MS:(M+H) ⁺ Actual: 308.2.

18.5: synthesis of tert-butyl 4- [ [ (3- [ [ (2R) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl ] methoxy ] pyridin-4-yl) methyl ] amino ] -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydropyridine-1-carboxylate

A solution of 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (1.50 g,3.6mmol,1.00 eq.) and (2R) -2- ([ [4- (aminomethyl) pyridin-3-yl ] oxy ] methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.11 g,3.6mmol,1.00 eq.) and HOAc (218 mg,3.6mmol,1.00 eq.) in toluene (20.00 mL) was stirred at 110deg.C under nitrogen for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 2:1) to give tert-butyl 4- [ [ (3- [ [ (2R) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl ] methoxy ] pyridin-4-yl) methyl ] amino ] -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydropyridine-1-carboxylate (1.4 g, 54.87%) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 702.2.

18.6: synthesis of tert-butyl (2R) -2- [ ([ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl ] oxy) methyl ] pyrrolidine-1-carboxylate

Stirring 4- [ [ (3- [ [ (2R) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl ] at 60℃under nitrogen atmosphere]Methoxy group]Pyridin-4-yl) methyl]Amino group]-3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl]-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (1.40 g,1.9mmol,1.00 eq.), TFA (454 mg,3.987mmol,2.00 eq.) and H ₂ O ₂ (30%) (271mg, 7.9mmol,4.00 eq.) in MeOH (20.00 mL) for 1h. The resulting mixture was concentrated under reduced pressure. This gives (2R) -2- [ ([ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl]Oxy) methyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (660 mg, 66.06%) was a pale yellow solid.

LC-MS:(M-100) ⁺ Actual: 568.2.

18.7: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

(2R) -2- [ ([ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino ] was stirred at room temperature under a nitrogen atmosphere]-4-oxo-1H, 6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl]Oxy) methyl]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (750 mg,1.1mmol,1.00 eq.) and TMSCL (4817 mg,4.490mmol,4.00 eq.) KI (745 mg,4.4mmol,4.00 eq.) in MeCN (10.00 mL) for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ MeOH 5:1) purification to afford 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- [3- [ (2R) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (230 mg, 43.79%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 468.1.

18.8: synthesis of 2- (3- [ [ (2R) -1-acetylpyrrolidin-2-yl ] methoxy ] pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a solution of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (60 mg,0.1mmol,1.00 eq.) and TEA (25 mg,0.2mmol,2.00 eq.) in DCM (1.00 mL) were added acetyl chloride (10 mg,0.1mmol,1.00 eq.) under nitrogen at room temperature and stirred for 1h. The resulting mixture was concentrated under reduced pressure. The crude product (mg) was purified by preparative HPLC and using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase A: water (10 MMOL/L NH4HCO 3), mobile phase B: ACN; flow rate: 60mL/min; gradient: 25% B to 45% B,8 min; wavelength: 254nm; RT1 (min): 7.5;) to afford 2- (3- [ [ (2R) -1-acetylpyrrolidin-2-yl ] methoxy ] pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (7.0 mg, 10.70%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 510.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.47(s,1H),8.39(s,1H),7.97(d,J＝5.1Hz,1H),7.42(s,1H),7.33(d,J＝5.2Hz,1H),7.11(s,1H),6.66(d,J＝5.2Hz,2H),6.10(q,J＝4.3,3.7Hz,1H),4.52(s,1H),4.28(dd,J＝9.8,7.0Hz,1H),4.12(dd,J＝9.8,4.3Hz,1H),3.86(s,3H),3.81(s,3H),3.48(d,J＝7.9Hz,2H),3.39(d,J＝2.6Hz,4H),2.93(s,2H),2.02(s,2H),1.96(d,J＝38.6Hz,4H)。

example 19:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [ [ (2R) -1-methylsulfonylpyrrolidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 142 b)

To a solution of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (60 mg,0.1mmol,1.00 eq.) and TEA (25 mg,0.2mmol,2.00 eq.) in DCM (1.00 mL) was added methanesulfonyl chloride (14 mg,0.1mmol,1.00 eq.) at 0 room temperature and stirred under nitrogen for 1h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC and using the following conditions (column: XBridge Prep OBD C18, 30 x 150mm,5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 15% B to 30% B,8 min; wavelength: 254nm; RT1 (min): 6;) to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [ [ (2R) -1-methylsulfonylpyrrolidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (9.5 mg, 13.57%) as a yellow solid.

LC-MS (M+H) + actual: 546.1.

¹ H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.40(s,1H),8.02(d,J＝5.1Hz,1H),7.42(s,1H),7.30(d,J＝4.8Hz,1H),7.11(s,1H),6.70–6.60(m,2H),6.13(dd,J＝7.0,2.8Hz,1H),4.24-4.09(m,3H),3.60-3.35(m,4H),2.97(s,3H),2.84(t,J＝6.7Hz,2H),2.01-1.87(m,4H)。

example 20:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [ [ (2R) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 138 a)

20.1: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [ [ (2R) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a solution of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (50 mg,0.1mmol,1.00 eq.) and TEA (21 mg,0.2mmol,2.00 eq.) in DCM (1.00 mL) was added acryloyl chloride (9 mg,0.1mmol,1.00 eq.) at 0 ℃ and stirred at room temperature under nitrogen for 1h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC and using the following conditions (column: XBridge Prep OBD C18 column, 30 x 150mm,5 μm; mobile phase A: water (10 MMOL/L NH4HCO 3), mobile phase B: ACN; flow rate: 60mL/min; gradient: 25% B to 45% B,8 min; wavelength: 254nm; RT1 (min): 7.5; injection volume: 1mL; running number: 2) to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [ [ (2R) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (4.3 mg, 7.71%) as a yellow solid.

LC-MS (M+H) + actual: 522.1.

¹ H NMR(400MHz,DMSO-d6)δ11.52(s,1H),8.40(s,1H),7.97(d,J＝5.0Hz,1H),7.42-7.33(m,2H),7.13–7.04(m,1H),6.69–6.53(m,3H),6.21(dd,J＝16.7,2.3Hz,1H),6.15–5.98(m,1H),5.73(dd,J＝10.3,2.3Hz,1H),4.64(s,1H),4.34(dd,J＝9.8,7.1Hz,1H),4.11(ddd,J＝30.2,9.8,5.1Hz,1H),3.84(d,J＝17.9Hz,3H),3.62(dd,J＝7.5,4.5Hz,2H),2.96(t,J＝6.8Hz,2H),1.99(dq,J＝13.7,7.3Hz,2H),1.95–1.83(m,4H)。

example 21:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- [5H,6H, 7H-pyrrolo [1,2-a ] imidazol-7-ylmethoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 124)

21.1: synthesis of 3- [5H,6H, 7H-pyrrolo [1,2-a ] imidazol-7-ylmethoxy ] pyridine-4-carbonitrile

At 0℃to 5H,6H, 7H-pyrrolo [1,2-a ]]A mixture of imidazol-7-yl-methanol (138 mg,1.0mmol,1.00 eq.) in DMF (2 mL) was added NaH (48 mg,2.0mmol,2.00 eq.). The mixture was stirred at room temperature for 0.5h and 3-chloropyridine-4-carbonitrile (139 mg,1.0mmol,1.00 eq.) was added. The resulting mixture was stirred at room temperature for 2h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (1×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 15:1) to provide 3- [5H,6H, 7H-pyrrolo [1,2-a ]]Imidazol-7-ylmethoxy]Pyridine-4-carbonitrile (144 mg, 59.74%) was an off-white solid.

LC-MS (M+H) + actual: 181.6.

21.2: synthesis of- [5H,6H, 7H-pyrrolo [1,2-a ] imidazol-7-ylmethoxy ] pyridin-4-yl) methylamine

Stirring 3- [5H,6H, 7H-pyrrolo [1,2-a ] under hydrogen atmosphere at room temperature]Imidazol-7-ylmethoxy]Pyridine-4-carbonitrile (140 mg,0.58mmol,1.00 eq.) and Raney Ni (199mg, 2.33mmol,4.00 eq.) in NH3 (5 mL,7M in MeOH) and MeOH (5 mL) for 2h. The resulting mixture was filtered and the filter cake was washed with MeOH (1X 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ MeOH 1:1) to afford 1- (3- [5h,6h,7 h-pyrrolo [1, 2-a)]Imidazol-7-ylmethoxy]Pyridin-4-yl) methylamine (80 mg, 56.20%) as a yellow oil.

LC-MS (M+H) + actual: 245.1,

21.3: synthesis of tert-butyl 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-4- [ [ (3- [5H,6H, 7H-pyrrolo [1,2-a ] imidazol-7-ylmethoxy ] pyridin-4-yl) methyl ] amino ] -5, 6-dihydropyridine-1-carboxylate

Stirring 1- (3- [5H,6H, 7H-pyrrolo [1, 2-a) under nitrogen at room temperature]Imidazol-7-ylmethoxy]Pyridin-4-yl) methylamine (80 mg,0.32mmol,1.00 eq.) and 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl]A solution of tert-butyl 4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylate (129 mg,0.32mmol,1.00 eq.) PyBOP (221 mg,0.42mmol,1.30 eq.) and DIEA (126 mg,0.98mmol,3.00 eq.) in DMF (2 mL) for 2h. The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (1×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl]-2-oxo-4- [ [ (3- [5H,6H, 7H-pyrrolo [1, 2-a)]Imidazole-7-ylmethoxy ]Pyridin-4-yl) methyl]Amino group]-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (65 mg, 31.88%) as a yellow oil.

LC-MS (M-56) +actual: 623.2.

21.4: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- [5H,6H, 7H-pyrrolo [1,2-a ] imidazol-7-ylmethoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Stirring 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl at 60℃under nitrogen atmosphere]-2-oxo-4- [ [ (3- [5H,6H, 7H-pyrrolo [1, 2-a)]Imidazol-7-ylmethoxy]Pyridin-4-yl) methyl]Amino group]-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (65 mg,0.10mmol,1.00 eq.), TFA (0.03 mL,0.41mmol,4.00 eq.) and H ₂ O ₂ (30%) (7 mg,0.20mmol,2.00 eq.) in MeOH (1 mL) for 1h. The reaction was carried out by adding saturated Na at room temperature ₂ SO ₃ (aqueous) (1 mL) quench. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography and the following conditions were used: (MeCN/H) ₂ O-40%) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- [5H,6H, 7H-pyrrolo [1, 2-a)]Imidazol-7-ylmethoxy]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (2.5 mg, 4.90%) was an off-white solid.

LC-MS (M+H) + actual: 489.1

¹ H NMR(300MHz,DMSO-d6)δ13.49(s,1H),8.37(m,2H),7.96(d,J＝5.0Hz,1H),7.61(s,1H),7.34(d,J＝5.1Hz,1H),7.23(d,J＝1.2Hz,1H),7.17–7.07(m,2H),6.66(td,J＝8.2,6.0Hz,1H),6.51(ddd,J＝10.0,8.4,1.4Hz,1H),6.05(d,J＝8.2Hz,1H),4.68(dd,J＝8.9,5.1Hz,1H),4.13(dt,J＝9.1,5.3Hz,2H),4.05(dd,J＝12.0,8.4Hz,3H),3.94(s,2H),3.75(s,2H),3.12–3.00(m,3H)。

EXAMPLE 22 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- [ imidazo [2,1-b ] [1,3] thiazol-3-ylmethoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 130)

Synthesis of 22.1.3- [ imidazo [2,1-b ] [1,3] thiazol-3-ylmethoxy ] pyridine-4-carbonitrile

Imidazo [2,1-b ] at 0deg.C][1,3]A mixture of thiazol-3-ylmethanol (155.80 mg,1.010mmol,1.00 eq.) in DMF (2.00 mL) was added NaH (80.83 mg,2.020mmol,2.00 eq., 60%) and stirred for 0.5h. 3-chloropyridine-4-carbonitrile (140.00 mg,1.010mmol,1.00 eq.) was added to the mixture at room temperature under nitrogen and stirred for 2h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3X 25 mL). The combined organic layers were washed with brine (1×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ MeOH 12:1) purification to afford 3- [ imidazo [2,1-b ]][1,3]Thiazol-3-ylmethoxy]Pyridine-4-carbonitrile (215 mg, 83.02%) was a pale yellow solid.

LC-MS (M+H) + actual: 257.15.

22.2: synthesis of 1- (3- [4H,5H, 6H-pyrrolo [1,2-b ] pyrazol-3-ylmethoxy ] pyridin-4-yl) methylamine

Under nitrogen atmosphere, 3- [ imidazo [2,1-b ]][1,3]Thiazol-3-ylmethoxy]A solution of pyridine-4-carbonitrile (184.00 mg, 0.428 mmol,1.00 eq.) in MeOH solution of ammonia (7.0M) (5.00 mL) was added Raney Ni (123.02 mg,1.436mmol,2.00 eq.). The mixture was hydrogenated under a hydrogen atmosphere using a hydrogen balloon for 4h, filtered through a Celite (Celite) pad and concentrated under reduced pressure. The resulting mixture was treated with CH ₂ Cl ₂ (2 mL) dilution. The residue was purified by preparative TLC (CH ₂ Cl ₂ MeOH 10:1) to afford 1- (3- [4h,5h,6 h-pyrrolo [1, 2-b)]Pyrazol-3-ylmethoxy]Pyridin-4-yl) methylamine (134 mg, 48.25%) as a pale yellow oil.

LC-MS (M+H) + actual: 261.

22.3: synthesis of tert-butyl 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-4- [ [ (3- [4H,5H, 6H-pyrrolo [1,2-b ] pyrazol-3-ylmethoxy ] pyridin-4-yl) methyl ] amino ] -5, 6-dihydropyridine-1-carboxylate

To 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl at room temperature under nitrogen atmosphere]-4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (180.00 mg,0.454mmol,1.00 eq.) 1- (3- [4H,5H, 6H-pyrrolo [1, 2-b)]Pyrazol-3-ylmethoxy]A mixture of pyridin-4-yl) methylamine (122.02 mg,0.499mmol,1.10 eq.) and PyBOP (354.43 mg,0.681mmol,1.50 eq.) in DMF (5.00 mL) was added dropwise DIEA (117.37 mg, 0.328 mmol,2.00 eq.). The mixture was stirred at 60℃for 2h. The resulting mixture was treated with CH ₂ Cl ₂ (3X 30 mL) extraction. The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ MeOH 10:1) purification to afford 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl ]-2-oxo-4- [ [ (3- [4H,5H, 6H-pyrrolo [1, 2-b)]Pyrazol-3-ylmethoxy]Pyridin-4-yl) methyl]Amino group]-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (300 mg, 96.76%) as a yellow solid.

LC-MS (M+1) + actual: 639.1.

22.4: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- [ imidazo [2,1-b ] [1,3] thiazol-3-ylmethoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At room temperature under nitrogen atmosphere with H ₂ O ₂ (30%) (13.85 mg,0.408mmol,2.00 eq.) of the 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl group]-4- [ [ (3- [ imidazo [2, 1-b)][1,3]Thiazol-3-ylmethoxy]Pyridin-4-yl) methyl]Amino group]-2-A solution of tert-butyl oxo-5, 6-dihydropyridine-1-carboxylate (130.00 mg,0.204mmol,1.00 eq.) in MeOH (5.00 mL) for 2min (min), followed by dropwise addition of TFA (92.83 mg, 0.812 mmol,4.00 eq.) at room temperature. The resulting mixture was stirred at 60℃under nitrogen for 3h. The resulting mixture was treated with CH ₂ Cl ₂ (3X 30 mL) extraction. The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC using the following conditions (column: XSelect CSH fluorophenyl, 30 x 150mm,5 μm; mobile phase A: water (10 MMOL/LNH4HCO 3), mobile phase B: meOH; flow rate: 60mL/min; gradient: 42% B to 55% B over 10 min; wavelength: 254nm; RT1 (min): 9.08;) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group ]-2- (3- [ imidazo [2, 1-b)][1,3]Thiazol-3-ylmethoxy]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (3.5 mg, 3.41%) was a yellow solid.

LC-MS (M+H) + actual: 505.05.

¹ H NMR(400MHz,DMSO-d6)δ11.18(s,1H),8.63(s,1H),8.03(d,J＝5.1Hz,1H),7.73(d,J＝1.5Hz,1H),7.45–7.35(m,2H),7.28(d,J＝5.0Hz,1H),7.22(t,J＝1.3Hz,1H),7.16–7.06(m,1H),6.54–6.39(m,2H),5.71(m,J＝7.9,1.5Hz,1H),5.56(s,2H),3.85(d,J＝0.6Hz,3H),3.41(dd,J＝6.9,2.5Hz,2H),2.83(t,J＝6.8Hz,2H)。

example 23:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- [5H,6H, 7H-pyrrolo [2,1-c ] [1,2,4] triazol-3-ylmethoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 131)

To a stirred mixture of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3-hydroxypyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (200.00 mg,0.5mmol,1.00 eq.) and 5h,6h,7 h-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl methanol (113.33 mg,0.8mmol,1.50 eq.) in toluene (2.00 mL) was added CMBP (392.54 mg,1.6mmol,3.00 eq.) under argon at room temperature. The resulting mixture was stirred at 90℃under argon for 2h. The resulting mixture was concentrated in vacuo. The resulting mixture was concentrated under reduced pressure and the crude product (200 mg) was purified by preparative HPLC and using the following conditions (column: XBridge Shield RP OBD column, 30 x 150mm,5 μm; mobile phase A: water (10 MMOL/L NH4HCO 3), mobile phase B: ACN; flow rate: 60mL/min; gradient: 18% B to 30%, within 8 min; wavelength: 220nm; RT1 (min): 7.5%) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- [5H,6H, 7H-pyrrolo [2,1-c ] [1,2,4] triazol-3-ylmethoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (5.8 mg, 2.18%) as a white solid.

LC-MS (M+H) + actual: 490.35.

¹ H NMR(300MHz,DMSO-d6)δ11.71(s,1H),8.55(s,1H),8.07(d,J＝5.0Hz,1H),7.44(s,1H),7.32(d,J＝5.0Hz,1H),7.13(s,1H),6.61(m,1H),6.47(m,1H),5.96(m,1H),5.50(s,2H),3.92–3.82(m,5H),3.42(m,2H),2.84(m,4H),2.61(q,J＝7.3Hz,2H).

example 24:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [ [ (2R) -1-propionylpyrrolidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 470)

Propionyl chloride (9 mg,0.1mmol,1.00 eq.) was added to a solution of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (50 mg,0.1mmol,1.00 eq.) and TEA (21 mg,0.2mmol,2.00 eq.) in DCM (1.00 mL) at C and stirred at room temperature under nitrogen for 1h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC and using the following conditions (column: XBridge Prep C18 OBD column, 19X 150mm,5 μm; mobile phase A: water (10 MMOL/L NH4HCO 3), mobile phase B: ACN; flow rate: 60mL/min; gradient: 41% B to 45% B,8 min; wavelength: 254nm; RT1 (min): 6;) to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [ [ (2R) -1-propionylpyrrolidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-C ] pyridin-4-one (12.9 mg, 23.04%) as a yellow solid.

LC-MS (M+H) + actual: 524.1.

¹ H NMR(400MHz,DMSO-d6)δ11.53(s,1H),8.39(s,1H),7.97(d,J＝5.0Hz,1H),7.45(s,1H),7.33(d,J＝5.0Hz,1H),7.12(d,J＝2.6Hz,1H),6.71–6.61(m,2H),6.16–6.07(m,1H),4.58–4.52(m,1H),4.29(dd,J＝9.8,7.2Hz,1H),4.11(dd,J＝9.8,4.1Hz,1H),3.87(s,3H),3.57–3.44(m,4H),2.96(td,J＝6.6,2.1Hz,2H),2.38–2.22(m,2H),1.92(ddd,J＝29.2,14.0,8.4Hz,4H),0.98(t,J＝7.3Hz,3H)。

example 25:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- (pyridin-2-ylmethoxy) pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 472)

25.1: synthesis of 1-fluoro-3-isothiocyanato-2-methoxybenzene

At 0 ℃, N ₂ To a stirred mixture of 3-fluoro-2-methoxyaniline (5.00 g,35.425mmol,1.00 eq.) and saturated NaHCO3 (50 mL) in DCM (50.00 mL) under an atmosphere was added thiophosgene (8.15 g,70.849mmol,1.00 eq.) dropwise. The resulting mixture was stirred at 0℃for 2h. TLC (Et 0Ac: hexane) showed complete conversion. The DCM layer was separated and washed with saturated NaHCO3, brine, filtered through a hydrophobic filter and concentrated to give 1-fluoro-3-isothiocyanato-2-methoxybenzene (12 g, 92.45%) as a yellow oil.

25.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl ] -4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester

DBU (14.96 g, 98.803 mmol,1.50 eq.) was added dropwise to a stirred mixture of 1-fluoro-3-isothiocyanato-2-methoxybenzene (12.00 g,65.502mmol,1.00 eq.) and 4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (13.97 g,65.502mmol,1.00 eq.) in MeCN (100.00 mL) at 0deg.C. The resulting mixture was stirred at 0℃for 2h. The reaction was quenched with water at 0 ℃. The mixture was acidified to pH 7 with concentrated HCl. The precipitated solid was collected by filtration, washed with water and concentrated under reduced pressure. This gave 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl ] -4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (19.5 g, 75.10%) as a pale yellow solid.

25.3: synthesis of 3- (benzyloxy) pyridine-4-carbonitrile

A solution of benzyl alcohol (9.37 g,86.611mmol,1.20 eq.) in DMF (70.00 mL) was treated with NaH (3.75 g,93.829mmol,1.30 eq., 60%) at 0deg.C under nitrogen at room temperature for 5min. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 30min. 3-chloropyridine-4-carbonitrile (10.00 g,72.176mmol,1.00 eq.) was added in portions to the above mixture over 5min at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was carried out by adding saturated NH at room temperature ₄ Aqueous Cl (10 mL) was quenched. The resulting mixture was extracted with EtOAc (3X 200 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gave 3- (benzyloxy) pyridine-4-carbonitrile (15 g, 84.03%) as a yellow solid.

LC-MS: M+Hactual: 211.1.

25.4: synthesis of 1- [3- (benzyloxy) pyridin-4-yl ] methylamine

Raney nickel (9.17 g,107.033mmol,1.5,0 eq.) was added to a solution of 3- (benzyloxy) pyridine-4-carbonitrile (15.00 g,71.348mmol,1.00 eq.) in ammonia (7.0M in ethanol, 150.00 mL) in a 250mL round bottom flask under nitrogen atmosphere. The mixture was hydrogenated at room temperature using a hydrogen balloon under a hydrogen atmosphere for 2h, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography and the following conditions were used: column, C18 silica gel; a mobile phase, ACN in water, gradient from 10% to 30% within 30 min; a detector: UV 254nm. This gave 1- [3- (benzyloxy) pyridin-4-yl ] methylamine (7 g, 44.64%) as a colorless oil.

LC-MS: M+Hactual: 215.20.

25.5: synthesis of tert-butyl 4- ([ [3- (benzyloxy) pyridin-4-yl ] methyl ] amino) -3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydropyridine-1-carboxylate

To 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl at room temperature under nitrogen atmosphere]A stirred mixture of tert-butyl-4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylate (8.20 g,20.685mmol,1.00 eq.) and PyBOP (11.84 g,22.754mmol,1.10 eq.) in DMF (80.00 mL) was added DIEA (5.35 g,41.370mmol,2.00 eq.) and 1- [3- (benzyloxy) pyridin-4-yl]Methylamine (4.88 g,22.753mmol,1.10 eq.). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was extracted with EtOAc (3X 200 mL). The combined organic layers were washed with xylene (3×500 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (10:1) to provide 4- ([ [3- (benzyloxy) pyridin-4-yl)]Methyl group]Amino) -3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl]-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (4.0 g, 28.39%) as an orange solid.

LC-MS: M+Hactual: 593.15

25.6: synthesis of 2- [3- (benzyloxy) pyridin-4-yl ] -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At room temperature under nitrogen atmosphere, 4- ([ [3- (benzyloxy) pyridin-4-yl)]Methyl group]Amino) -3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl]-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (3.80 g,6.411mmol,1.00 eq.) and H ₂ O ₂ A stirred mixture of (2.18 g,19.227mmol,3.00 eq., 30%) in MeOH (40.00 mL) was added TFA (1.10 g, 9.611 mmol,1.50 eq.). The resulting mixture was stirred at 80℃for 1h. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The reaction was quenched with saturated aqueous NaHSO3 at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography and the following conditions were used: column, C18 silica gel; a mobile phase, ACN in water, gradient from 10% to 50% over 10 min; a detector: UV 254nm. This gives 2- [3- (benzyloxy) pyridin-4-yl]-3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (1.3 g, 32.73%) was an orange oil.

LC-MS: M+Hactual: 459.00.

25.7: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- [3- (benzyloxy) pyridin-4-yl ] at room temperature under nitrogen atmosphere]-3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (600.00 mg,1.309mmol,1.00 eq.) in MeOH/AcOH (6.00 mL/6.00 mL) was added Pd/C (278.53 mg, 2.611 mmol,2.00 eq.). The resulting mixture was stirred at 50℃under a hydrogen atmosphere overnight. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ MeOH 10:1) purification to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (200 mg, 36.80%) was a yellow solid.

LC-MS: M+Hactual: 368.95.

25.8: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- (pyridin-2-ylmethoxy) pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

A solution of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (100.00 mg,0.271mmol,1.00 eq.) and 2-pyridinemethanol (59.25 mg,0.543mmol,2.00 eq.) in toluene (1.00 mL) was treated with 2- (tributyl-. Lamda.5-phosphoranylidene) acetonitrile (131.04 mg,0.543mmol,2.00 eq.) and stirred overnight at 90℃under nitrogen. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with 2ml of DMF. The crude product (100 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH F-phenyl OBD column, 19X 250mm,5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25mL/min; gradient: 19% B to 22% B over 10 min; wavelength: 254nm; RT1 (min): 7.27;) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- (pyridin-2-ylmethoxy) pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (14.7 mg, 11.79%) as a light brown solid.

LC-MS: M+Hactual: 460.05.

¹ H NMR(400MHz,DMSO-d6)δ12.30(s,1H),8.72(dt,J＝4.7,1.4Hz,1H),8.45(s,1H),8.03(d,J＝5.1Hz,1H),7.91(td,J＝7.7,1.8Hz,1H),7.59–7.49(m,2H),7.44(m,1H),7.37(d,J＝5.1Hz,1H),7.19(t,J＝2.6Hz,1H),6.65(td,J＝8.3,6.0Hz,1H),6.52(m,1H),6.05(dt,J＝8.2,1.3Hz,1H),5.55(s,2H),3.91(s,3H),3.47(td,J＝6.8,2.5Hz,2H),2.98(t,J＝6.8Hz,2H)。

example 26:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- (1, 3-oxazol-2-ylmethoxy) pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 474)

Stirring 3- [ at 90deg.C under argon atmosphere(3-fluoro-2-methoxyphenyl) amino group]-2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A mixture of pyridin-4-one (300.00 mg,0.814mmol,1.00 eq), 2- (tributyl-. Lamda.5-phosphoranylidene) acetonitrile (786.25 mg,3.256mmol,4.00 eq.) and 1, 3-oxazol-2-ylmethanol (161.40 mg, 1.6278 mmol,2.00 eq.) in toluene (5.00 mL) for 4h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH C18 OBD column 30.150 mm 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 15% B to 26% B,8 min; wavelength: 254/220nm; RT1 (min): 7.65;) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- [3- (1, 3-oxazol-2-ylmethoxy) pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-one (4.1 mg, 1.09%) was a white solid.

LC-MS (M+H) + actual: 450.05.

¹ H NMR(400MHz,DMSO-d6)δ11.52(s,1H),8.50(s,1H),8.21(s,1H),8.05(d,J＝5.1Hz,1H),7.48(s,1H),7.37–7.29(m,2H),7.15(d,J＝2.7Hz,1H),6.62(td,J＝8.3,6.0Hz,1H),6.48(m,1H),5.99(d,J＝8.2Hz,1H),5.53(s,2H),3.90(s,3H),3.44(s,2H),2.89(t,J＝6.8Hz,2H)。

example 27:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- [ imidazo [1,2-a ] pyridin-8-ylmethoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 475)

27.1: synthesis of 3- [ imidazo [1,2-a ] pyridin-8-ylmethoxy ] pyridine-4-carbonitrile

At 0 ℃, imidazo [1,2-a ]]A mixture of pyridin-8-yl-methanol (149 mg,1.01mmol,1.00 eq.) in DMF (2 mL) was added NaH (48 mg,2.0mmol,2.00 eq.) and stirred at room temperature for 0.5h. 3-chloropyridine-4-carbonitrile (140 mg,1.01mmol,1.00 eq.) was added to the mixture and nitrogen at room temperatureStirring for 1h under an atmosphere. The resulting mixture was extracted with EtOAc (3X 15 mL). The combined organic layers were washed with brine (1×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ MeOH 15:1) purification to afford 3- [ imidazo [1,2-a ]]Pyridin-8-ylmethoxy]Pyridine-4-carbonitrile (210 mg, 83.04%) was a pale yellow solid.

LC-MS (M+H) + actual: 251.2.

27.2: synthesis of 1- (3- [ imidazo [1,2-a ] pyridin-8-ylmethoxy ] pyridin-4-yl) methylamine

Stirring 3- [ imidazo [1,2-a ] under hydrogen atmosphere at room temperature ]Pyridin-8-ylmethoxy]Pyridine-4-carbonitrile (210 mg,0.83mmol,1.00 eq.) and Raney Ni (143 mg,1.67mmol,2.00 eq.) in NH3 (5 mL,7M in MeOH) and MeOH (5 mL) for 2h. The resulting mixture was filtered and the filter cake was washed with MeOH (1X 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ MeOH 1:1) purification to afford 1- (3- [ imidazo [1, 2-a)]Pyridin-8-ylmethoxy]Pyridin-4-yl) methylamine (90 mg, 42.18%) as a pale yellow solid.

LC-MS (M+H) + actual: 255.2.

27.3: synthesis of tert-butyl 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl ] -4- [ [ (3- [ imidazo [1,2-a ] pyridin-8-ylmethoxy ] pyridin-4-yl) methyl ] amino ] -2-oxo-5, 6-dihydropyridine-1-carboxylate

Stirring 1- (3- [ imidazo [1,2-a ] under nitrogen at room temperature]Pyridin-8-ylmethoxy]Pyridin-4-yl) methylamine (46 mg,0.18mmol,1.00 eq.) and 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl]Tert-butyl 4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylate (71 mg,0.18mmol,1.00 eq.), pyBOP (113 mg,0.21mmol,1.20 eq.), DIEA (47 mg,0.36mmol,2.00 eq.) in DMF (1 mL) was stirred overnight. The resulting mixture was extracted with EtOAc (2X 10 mL). The combined organic layers were washed with brine (1×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl]-4- [ [ (3- [ imidazo [1, 2-a)]Pyridin-8-ylmethoxy]Pyridin-4-yl) methyl]Amino group]-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (25 mg, 21.84%) as a pale yellow oil.

LC-MS (M+H) + actual: 633.2.

27.4: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- [ imidazo [1,2-a ] pyridin-8-ylmethoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Stirring 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl at 60℃under nitrogen atmosphere]-4- [ [ (3- [ imidazo [1, 2-a)]Pyridin-8-ylmethoxy]Pyridin-4-yl) methyl]Amino group]-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (80 mg,0.12mmol,1.00 eq.), TFA (57 mg,0.50mmol,4.00 eq.) and H ₂ O ₂ (30%) (8 mg,0.25mmol,2.00 eq.) in MeOH (1 mL). The reaction was quenched by addition of saturated aqueous NaHSO3 (1 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography and the following conditions were used: (MeCN/H) ₂ O=40%) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group ]-2- (3- [ imidazo [1, 2-a)]Pyridin-8-ylmethoxy]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (5.5 mg, 8.73%) was an off-white solid.

LC-MS (M+H) + actual: 499.0

¹ H NMR(300MHz,DMSO-d6)δ12.41(s,1H),8.69–8.56(m,2H),8.11(d,J＝1.3Hz,1H),7.96(d,J＝5.0Hz,1H),7.80(d,J＝1.3Hz,1H),7.58(d,J＝7.3Hz,2H),7.26(d,J＝5.0Hz,1H),7.15(d,J＝2.6Hz,1H),7.02(t,J＝6.8Hz,1H),6.63(td,J＝8.3,6.0Hz,1H),6.49(ddd,J＝10.0,8.4,1.5Hz,1H),6.01(dt,J＝8.2,1.3Hz,1H),5.70(s,2H),3.91(s,3H),3.41(td,J＝6.8,2.5Hz,2H),2.89(t,J＝6.8Hz,2H)。

Example 28:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- [ (3-methoxypyridin-2-yl) methoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 476)

A solution of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (100.00 mg,0.271mmol,1.00 eq.) and (3-methoxypyridin-2-yl) methanol (75.55 mg, 0.552 mmol,2.00 eq.) in toluene (1.00 mL) was treated with 2- (tributyl-. Lamda.5-phosphoranylidene) acetonitrile (131.04 mg, 0.540 mmol,2.00 eq.). The mixture was stirred overnight at 90℃under nitrogen. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with 2ml of DMF. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase A: water (10 MMOL/L NH4HCO 3), mobile phase B: ACN; flow rate: 50mL/min; gradient: 35% B to 50% B,8 min; wavelength: 254nm; RT1 (min): 7.6;) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- [ (3-methoxypyridin-2-yl) methoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (6.6 mg, 4.90%) as a white solid.

LC-MS (M+H) + actual: 489.95

¹ H NMR(400MHz,DMSO-d6)δ12.80(s,1H),8.52(s,1H),8.34(dd,J＝4.8,1.2Hz,1H),8.01(d,J＝5.1Hz,1H),7.62(dd,J＝8.5,1.2Hz,1H),7.58(s,1H),7.50(dd,J＝8.3,4.8Hz,1H),7.39(d,J＝5.1Hz,1H),7.20(t,J＝2.5Hz,1H),6.69(td,J＝8.3,6.0Hz,1H),6.55m,1H),6.05(dt,J＝8.1,1.2Hz,1H),5.60(s,2H),3.98–3.92(m,6H),3.48(td,J＝6.8,2.5Hz,2H),3.03(t,J＝6.8Hz,2H)。

Example 29:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- [ (5-methylpyrimidin-2-yl) methoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 477)

Stirring 3- [ (3-fluoro-2-methoxyphenyl) amino group at 90℃under argon atmosphere]-2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A mixture of pyridin-4-one (150.00 mg,0.407mmol,1.00 eq), 2- (tributyl-. Lamda.5-phosphoranylidene) acetonitrile (786.25 mg,3.256mmol,8.00 eq) and (5-methylpyrimidin-2-yl) methanol (202.20 mg, 1.6278 mmol,4.00 eq) in toluene (5.00 mL) for 4h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was diluted with DMF (2 mL). The crude product (30 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase A: water (10 MMOL/L NH4HCO 3), mobile phase B: ACN; flow rate: 60mL/min; gradient: 32% B to 42% B,8 min; wavelength: 254nm; RT1 (min): 6;) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- [3- [ (5-methylpyrimidin-2-yl) methoxy group ]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (12.2 mg, 6.26%) was a light brown solid.

LC-MS (M+H) + actual: 475.35.

¹ H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.85(s,2H),8.51(s,1H),8.02(d,J＝5.2Hz,1H),7.58(s,1H),7.39(d,J＝5.2Hz,1H),7.21(t,J＝2.6Hz,1H),6.69(td,J＝8.3,5.9Hz,1H),6.60–6.51(m,1H),6.05(d,J＝8.2Hz,1H),5.64(s,2H),3.95(s,3H),3.48(m,2H),3.03(t,J＝6.8Hz,2H),2.36(s,3H)。

example 30:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- (pyrimidin-4-ylmethoxy) pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 478)

Stirring 3- [ (3-fluoro-2-methoxyphenyl) ammonia at 90 ℃ under argon atmosphereBase group]-2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A mixture of pyridin-4-one (290.00 mg,0.787mmol,1.00 eq), 2- (tributyl-. Lamda.5-phosphoranylidene) acetonitrile (380.02 mg,1.575mmol,2 eq.) and pyrimidin-4-ylmethanol (173.38 mg,1.575mmol,2.00 eq.) in toluene (2.00 mL) was stirred overnight. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC and using the following conditions (column: XBridge Shield RP OBD column, 30.150 mm,5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 15% B to 30% B,8 min; wavelength: 254nm; RT1 (min): 6.2;) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group ]-2- [3- (pyrimidin-4-ylmethoxy) pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (2.7 mg, 0.74%) was a pale yellow solid.

LC-MS (M+H) + actual: 461.30.

¹ H NMR(400MHz,DMSO-d6)δ11.88(s,1H),9.30(d,J＝1.4Hz,1H),8.88(d,J＝5.2Hz,1H),8.39(s,1H),8.06(d,J＝5.1Hz,1H),7.62–7.53(m,2H),7.37(d,J＝5.0Hz,1H),7.19–7.13(m,1H),6.64(m,J＝8.3,6.0Hz,1H),6.50(m,J＝10.9,8.3,1.5Hz,1H),6.03(m,J＝8.2,1.3Hz,1H),5.53(s,2H),3.88(s,3H),3.46(m,2H),2.96(t,J＝6.8Hz,2H)。

example 31:2- [3- (1, 2, 3-Benzotriazol-1-ylmethoxy) pyridin-4-yl ] -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 479)

31.1: synthesis of 1- (chloromethyl) -1,2, 3-benzotriazole

To a stirred mixture of 1,2, 3-benzotriazol-1-yl-methanol (150.00 mg,1.006mmol,1.00 eq.) in thionyl chloride (2.00 mL) under nitrogen at room temperature was added a drop of DMF. The resulting mixture was stirred at room temperature under nitrogen for 30min. The resulting mixture was stirred overnight at 50 ℃ under nitrogen. The resulting mixture was concentrated under reduced pressure.

LC-MS (M+H) + actual: 168.00.

31.2: synthesis of 2- [3- (1, 2, 3-benzotriazol-1-ylmethoxy) pyridin-4-yl ] -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Stirring 3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (200.00 mg,0.543mmol,1.00 eq), 1- (chloromethyl) -1,2, 3-benzotriazole (136.49 mg,0.815mmol,1.50 eq) and Na ₂ CO ₃ (115.09 mg,1.086mmol,2.00 eq.) in DMF (5.00 mL) for 2h. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was diluted with DMF (2 mL). The crude product (30 mg) was purified by preparative HPLC and using the following conditions (column: XBridge Shield RP OBD column, 30 x 150mm,5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 15% B to 30% B,8 min; wavelength: 254nm; RT1 (min): 6.2;) to afford 2- [3- (1, 2, 3-benzotriazol-1-ylmethoxy) pyridin-4-yl)]-3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (15.4 mg, 5.68%) was a pale yellow solid.

LC-MS (M+H) + actual: 500.10.

¹ H NMR(400MHz,DMSO-d6)δ11.16(s,1H),8.68(s,1H),8.05(d,J＝5.1Hz,1H),7.99(dt,J＝8.5,0.9Hz,1H),7.90(dt,J＝8.3,1.0Hz,1H),7.53(m,1H),7.38(m,1H),7.30(s,1H),7.19(d,J＝5.1Hz,1H),7.11–7.06(m,1H),6.85(s,2H),6.49–6.39(m,2H),5.33–5.24(m,1H),3.86(d,J＝0.8Hz,3H),3.38–3.30(m,2H),2.78(t,J＝6.8Hz,2H)。

example 32:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- [ (2-methylpyrazol-3-yl) methoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 480)

Stirring 3- [ (3-fluoro-2-methoxyphenyl) amino group at 90℃under argon atmosphere]-2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A mixture of pyridin-4-one (150.00 mg,0.407mmol,1.00 eq), 2- (tributyl-. Lamda.5-phosphoranylidene) acetonitrile (393.13 mg, 1.6278 mmol,4.00 eq) and (2-methylpyrazol-3-yl) methanol (365.28 mg,3.256mmol,8.00 eq) in toluene (5.00 mL) for 4h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was diluted with DMF (2 mL). The crude product (30 mg) was purified by preparative HPLC and using the following conditions (column: XSelect CSH fluorophenyl, 30 x 150mm,5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 17% B to 20% B over 10 min; wavelength: 254nm; RT1 (min): 7.62) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- [3- [ (2-methylpyrazol-3-yl) methoxy group]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (14.8 mg, 4.52%) was a pale yellow solid.

LC-MS: M+Hactual: 463.10

¹ H NMR(400MHz,DMSO-d6)δ11.25(s,1H),8.54(s,1H),8.05(d,J＝5.0Hz,1H),7.39–7.34(m,2H),7.28(d,J＝5.0Hz,1H),7.10(d,J＝2.6Hz,1H),6.55(td,J＝8.2,6.0Hz,1H),6.44(m,J＝10.9,8.3,1.5Hz,1H),6.33(d,J＝1.9Hz,1H),5.87(m,J＝8.2,1.3Hz,1H),5.41(s,2H),3.84(s,3H),3.75(s,3H),3.50–3.35(m,2H),2.83(t,J＝6.8Hz,2H)。

Example 33:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- [ imidazo [1,2-a ] pyridin-2-ylmethoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 481)

Stirring bis (3- [ (3-fluoro-2-methoxyphenyl) amino) at 90℃under argon atmosphere]-2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one) (220.00 mg,0.299mmol,1.00 eq.) 2- (tributyl-. Lamda.5-phosphoranylidenyl) acetonitrile (288.29 mg,1.196mmol,4.00 eq.) and imidazo [1,2-a ]]A mixture of pyridin-2-yl-methanol (88.49 mg,0.598mmol,2.00 eq.) in toluene (5.00 mL) was stirred overnight. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC and using the following conditions (column: XSelect CSH fluorophenyl, 30 x 150mm,5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 17% B to 20% B over 10 min; wavelength: 254nm; RT1 (min): 7.62) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- [ imidazo [1, 2-a)]Pyridin-2-ylmethoxy]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (13.7 mg, 9.09%) was a yellow solid.

LC-MS (M+H) + actual: 499.10.

¹ H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.60(d,J＝6.0Hz,2H),8.07–7.98(m,2H),7.64(dd,J＝35.9,9.1Hz,1H),7.53(s,1H),7.33(dd,J＝8.3,5.4Hz,2H),7.15(d,J＝2.6Hz,1H),6.96(td,J＝6.8,1.2Hz,1H),6.62(td,J＝8.3,6.0Hz,1H),6.49(m,J＝10.0,8.4,1.5Hz,1H),6.04(d,J＝8.2Hz,1H),5.57(s,2H),3.91(s,3H),3.46(m,2H),3.00(t,J＝6.8Hz,2H)。

example 34:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- [ (1-methylimidazol-2-yl) methoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 482)

Stirring 3- [ (3-fluoro-2-methoxyphenyl) amino group at 90℃under argon atmosphere]-2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (300.00 mg,0.814mmol,1.00 eq.) 2A mixture of (393.13 mg,1.629mmol,2.00 eq.) and (1-methylimidazol-2-yl) methanol (182.64 mg,1.629mmol,2.00 eq.) in toluene (5.00 mL) was stirred overnight. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH 10:1) to give 3- [ (3-fluoro-2-methoxyphenyl) amino]-2- [3- [ (1-methylimidazol-2-yl) methoxy group]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (30 mg, 7.71%) was a black solid. The resulting mixture was diluted with DMF (2 mL). The crude product (30 mg) was purified by preparative HPLC and subjected to the following conditions (column: xselect CSH F-phenyl (F-phenyl) OBD column, 19X 250mm,5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25mL/min; gradient: 2% B to 18% B, within 9 min; wavelength: 254nm; RT1 (min): 8.77;) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- [3- [ (1-methylimidazol-2-yl) methoxy group]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (5 mg, 1.29%) was a pale yellow solid.

LC-MS (M+Na) + actual: 485.20.

¹ H NMR(400MHz,DMSO-d6)δ12.60(s,1H),8.58(s,1H),8.03(d,J＝5.1Hz,1H),7.48(s,1H),7.32(d,J＝5.0Hz,1H),7.22(d,J＝1.2Hz,1H),7.16–7.11(m,1H),7.00(d,J＝1.2Hz,1H),6.64(m,1H),6.50(m,1H),6.00(dt,J＝8.2,1.2Hz,1H),5.53(s,2H),3.91(d,J＝0.7Hz,3H),3.66(s,3H),3.44(td,J＝6.9,2.5Hz,2H),2.92(t,J＝6.8Hz,2H)。

example 35:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- [2- (furan-2-yl) ethoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 483)

35.1: synthesis of 3- [2- (furan-2-yl) ethoxy ] pyridine-4-carbonitrile

To 2- (furan-2-yl) ethanol (112 mg,1.00mmol, 1.00. Ang. At 0deg.C) Amount) in DMF (2 mL) was added NaH (48 mg,2.00mmol,2.00 eq.) and stirred for 0.5h. 3-chloropyridine-4-carbonitrile (139 mg,1.00mmol,1.00 eq.) was added to the mixture at room temperature under nitrogen and stirred for 2h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3X 15 mL). The combined organic layers were washed with brine (1×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH 20:1) to give 3- [2- (furan-2-yl) ethoxy]Pyridine-4-carbonitrile (172 mg, 80.03%) was a pale yellow solid.

LC-MS (M+H) + actual: 215.2.

35.2: synthesis of 1- [3- [2- (furan-2-yl) ethoxy ] pyridin-4-yl ] methylamine

Stirring 3- [2- (furan-2-yl) ethoxy group at room temperature under hydrogen atmosphere]Pyridine-4-carbonitrile (172 mg,0.80mmol,1.00 eq.) and Raney Ni (275 mg,3.21mmol,4.00 eq.) in NH ₃ (5 mL,7M in MeOH) and MeOH (5 mL) for 2h. The resulting mixture was filtered and the filter cake was washed with MeOH (1X 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH 1:1) to give 1- [3- [2- (furan-2-yl) ethoxy]Pyridin-4-yl]Methylamine (130 mg, 74.19%) as a pale yellow oil.

LC-MS (M+H) + actual: 219.1.

35.3: synthesis of tert-butyl 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl ] -4- [ ([ 3- [2- (furan-2-yl) ethoxy ] pyridin-4-yl ] methyl) amino ] -2-oxo-5, 6-dihydropyridine-1-carboxylate

Stirring 1- [3- [2- (furan-2-yl) ethoxy ] at room temperature under nitrogen]Pyridin-4-yl]Methylamine (120 mg,0.55mmol,1.00 eq.) and 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl]-4-hydroxy-2-oxo-5, 6-dihydropyridinesA solution of tert-butyl 1-carboxylate (217 mg,0.55mmol,1.00 eq.), pyBOP (375 mg,0.71mmol,1.30 eq.) and DIEA (213 mg,1.65mmol,3.00 eq.) in DMF (5 mL) was stirred overnight. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (1×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl]-4- [ ([ 3- [2- (furan-2-yl) ethoxy)]Pyridin-4-yl]Methyl) amino group]-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (75 mg, 22.86%) as a yellow oil.

LC-MS (M+H) + actual: 597.2.

35.4: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- [2- (furan-2-yl) ethoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Stirring 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl at 60℃under nitrogen atmosphere]-4- [ ([ 3- [2- (furan-2-yl) ethoxy)]Pyridin-4-yl]Methyl) amino group]-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (75 mg,0.12mmol,1.00 eq.) and H ₂ O ₂ (30%) (8 mg,0.25mmol,2.00 eq.) TFA (57 mg,0.50mmol,4.00 eq.) for 2 hours. The reaction was quenched with saturated aqueous NaHSO3 at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography and the following conditions were used: (MeCN/H) ₂ O=45%) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- [3- [2- (furan-2-yl) ethoxy ]]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (7.7 mg, 13.25%) was a yellow solid.

LC-MS (M+H) + actual: 463.1

¹ H NMR(300MHz,DMSO-d6)δ10.91(s,1H),8.39(s,1H),8.04(d,J＝5.0Hz,1H),7.58(d,J＝1.9Hz,1H),7.51(s,1H),7.31(d,J＝5.0Hz,1H),7.13(s,1H),6.61(td,J＝8.3,6.0Hz,1H),6.53–6.42(m,1H),6.40(dd,J＝3.2,1.9Hz,1H),6.26(d,J＝3.2Hz,1H),5.96(d,J＝8.2Hz,1H),4.39(t,J＝6.7Hz,2H),3.90(s,3H),3.42(dt,J＝6.5,4.0Hz,2H),3.21(t,J＝6.6Hz,2H),2.86(t,J＝6.8Hz,2H)。

Example 36:3- [ (3-fluoro-2-methylphenyl) amino ] -2- (3- [ [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 467)

36.1: synthesis of (2S) -2- [ [ (4-cyanopyridin-3-yl) oxy ] methyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

At 0 ℃, N ₂ To a solution/mixture of tert-butyl (2S) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (5.00 g,24.843mmol,1.00 eq.) in DMF (43.03 mL,588.651mmol,22.38 eq.) was added dropwise/portionwise NaH (1.19 g, 29.803 mmol,1.20 eq., 60%). The resulting mixture was stirred at 0℃for a further 0.5h. 3-chloropyridine-4-carbonitrile (4.13 g, 29.81mmol, 1.20 eq.) was then added to the mixture. The mixture was stirred at 25℃for 10h. By adding H at 0 ℃ ₂ O (100 mL) quenched the reaction. The resulting mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with ethanol (wine) (30 mL. Times.3), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EA (2:1-1:1) to provide (2S) -2- [ [ (4-cyanopyridin-3-yl) oxy]Methyl group]Pyrrolidine-1-carboxylic acid tert-butyl ester (3.4 mg, 0.04%) was a yellow oil.

LC-MS: M-56+H actual: 248.

36.2: synthesis of (2S) -2- ([ [4- (aminomethyl) pyridin-3-yl ] oxy ] methyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To (2S) -2- [ [ (4-cyanopyridin-3-yl) oxy]Methyl group]Pyrrolidine-1-carboxylic acid tert-butyl ester (3.00 g,9.889mmol,1.00 eq.) in MeOH (5000 mL) of NH3 (g) was added with Raney Ni (0.08 g,0.989mmol,0.1 eq.). By H ₂ The mixture is treated. The mixture was stirred at 25℃for 10h. The resulting mixture was filtered and the filter cake was washed with MeOH (20 ml x 3). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM: meOH (10:1-3:1) to provide (2S) -2- ([ [4- (aminomethyl) pyridin-3-yl)]Oxy group]Tert-butyl methyl-pyrrolidine-1-carboxylate (1.9 g, 62.50%) was a yellow oil.

LC-MS (M+H) + actual: 308.0.

36.3: synthesis of tert-butyl (2S) -2- [ ([ 4- [ ([ 3- [ (3-fluoro-2-methylphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydro-1H-pyridin-4-yl ] oxy) methyl ] pyridin-3-yl ] oxy) methyl ] pyrrolidine-1-carboxylate

N- (3-fluoro-2-methylphenyl) -4-hydroxy-2-oxo-5, 6-dihydro-1H-pyridin-3-thiocarboxamide (600.00 mg,2.140mmol,1.00 eq.) and (2S) -2- ([ [4- (aminomethyl) pyridin-3-yl) are stirred at 120 ℃]Oxy group]A stirred solution/mixture of tert-butyl methyl-pyrrolidine-1-carboxylate (986.92 mg,3.211mmol,1.50 eq.) in DMA (2.40 mL,27.549mmol,12.06 eq.) for 3h. The resulting mixture was extracted with EA (30 ml x 3). The combined organic layers were washed with ethanol (30 mL. Times.3), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM: meOH (20:1 to 10:1) to provide (2S) -2- [ ([ 4- [ ([ 3- [ (3-fluoro-2-methylphenyl) thiocarbamoyl)]-2-oxo-5, 6-dihydro-1H-pyridin-4-yl]Oxy) methyl]Pyridin-3-yl]Oxy) methyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 32.75%) was a yellow solid.

LC-MS (M+H) + actual: 570.

36.4: synthesis of tert-butyl (2S) -2- [ [ (4- [3- [ (3-fluoro-2-methylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl) oxy ] methyl ] pyrrolidine-1-carboxylate

To (2S) -2- [ ([ 4- [ ([ 3- [ (3-fluoro-2-methylphenyl) thiocarbamoyl)]-2-oxo-5, 6-dihydro-1H-pyridin-4-yl]Amino) methyl group]Pyridin-3-yl]Oxy) methyl]A stirred solution of pyrrolidine-1-carboxylic acid tert-butyl ester (400.00 mg,0.702mmol,1.00 eq.) in MeOH (20.00 mL,624.184mmol,703.55 eq.) was added dropwise H ₂ O ₂ (30%) (398.04 mg,3.510mmol,5.00 eq., 30%) and TFA (200.15 mg,1.755mmol,2.50 eq.). The mixture was stirred at 80℃for 3h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM: meOH (30:1-10:1) to provide (2S) -2- [ [ (4- [3- [ (3-fluoro-2-methylphenyl) amino group)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl) oxy]Methyl group]Pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 26.59%) was a yellow solid.

LC-MS (M+H) + actual: 536.

36.5: synthesis of 3- [ (3-fluoro-2-methylphenyl) amino ] -2- [3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 25 ℃, to (2S) -2- [ [ (4- [3- [ (3-fluoro-2-methylphenyl) amino group)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl) oxy]Methyl group]A stirred solution of pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg,1 eq.) in DCM (6 mL) was added TFA (2 mL) dropwise. The mixture was stirred at 25℃for 2h. The resulting mixture was concentrated in vacuo. With aqueous NaHCO ₃ (20 mL) the mixture/residue was acidified to pH 8-10. The aqueous layer was extracted with EA (30 mL. Times.3). The combined organic layers were concentrated in vacuo to afford 3- [ (3-fluoro-2-methylphenyl) amino group]-2- [3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (70 mg, 86.09%) was a yellow solid.

LC-MS (M+H) + actual: 436.

36.6: synthesis of 3- [ (3-fluoro-2-methylphenyl) amino ] -2- (3- [ [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0℃to 3- [ (3-fluoro-2-methylphenyl) amino group]-2- [3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100.00 mg,0.230mmol,1.00 eq.) in THF (5.00 mL, 61.015 mmol,109.44 eq.) and NaHCO ₃ The mixture in (5 mL) was added dropwise with acryloyl chloride (41.57 mg,0.459mmol,2 eq.). The mixture was stirred at 0℃for 1h. The resulting mixture was extracted with EA (30 ml x 3). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE: ea=10:1) to afford the crude product. The crude product was purified by preparative HPLC and using the following conditions (column: xselect CSH OBD column 30 x 150mm 5um, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 15B to 35B,8min, 35B to B, min, B to B; 254/220 nm) to afford 3- [ (3-fluoro-2-methylphenyl) amino group ]-2- (3- [ [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl]Methoxy group]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (14.8 mg, 12.51%) was a yellow solid.

LC-MS (M+H) + actual: 490.

¹ H NMR(400MHz,DMSO-d6)δ11.29(s,1H),8.37(s,1H),7.96(s,1H),7.29(d,J＝4.8Hz,1H),7.18(s,1H),6.84(s,1H),6.73(d,J＝7.6Hz,1H),6.63(dd,J＝16.7,10.4Hz,1H),6.44(t,J＝8.8Hz,1H),6.20(d,J＝17.2Hz,1H),6.11(d,J＝8.2Hz,1H),5.70(s,1H),4.65(s,1H),4.34(s,1H),4.18(s,1H),3.64(s,2H),3.49–3.44(m,2H),2.98(s,2H),2.21(s,3H),2.03(m,2H),1.93(m,3H)。

example 37:3- [ (3-fluoro-2-methylphenyl) amino ] -2- (3- [ [ (2R) -1- (prop-2-enoyl) piperidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 468)

37.1: synthesis of tert-butyl (2R) -2- [ [ (4-cyanopyridin-3-yl) oxy ] methyl ] piperidine-1-carboxylate

To a solution of 3-chloropyridine-4-carbonitrile (2.00 g,14.435mmol,1.00 eq.) and tert-butyl (2R) -2- (hydroxymethyl) piperidine-1-carboxylate (3.73 g,17.322mmol,1.2 eq.) in DMF (40.00 mL) was added NaH (692.82 mg,17.322mmol,1.2 eq., 60%). The mixture was stirred at room temperature for 12h. The reaction mixture was quenched with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 30 ml), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EA (1:1) to provide (2R) -2- [ [ (4-cyanopyridin-3-yl) oxy]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 54.57%) was a brown oil.

LC-MS: M+Hactual: 318.

37.2: synthesis of tert-butyl (2R) -2- ([ [4- (aminomethyl) pyridin-3-yl ] oxy ] methyl) piperidine-1-carboxylate

To a solution of tert-butyl (2R) -2- [ [ (4-cyanopyridin-3-yl) oxy ] methyl ] piperidine-1-carboxylate (2.50 g,7.877mmol,1.00 eq.) in MeOH (50.00 mL) in NH3 (g) was added Raney nickel (0.92 g,15.754mmol,2.00 eq.) under nitrogen. The mixture was hydrogenated using a hydrogen balloon at room temperature for 12h under a hydrogen atmosphere, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM: meOH (8:1) to give tert-butyl (2R) -2- ([ [4- (aminomethyl) pyridin-3-yl ] oxy ] methyl) piperidine-1-carboxylate (1.2 g, 47.40%) as a yellow solid.

LC-MS: M+Hactual: 322.

37.3: synthesis of tert-butyl (2R) -2- [ ([ 4- [ ([ 3- [ (3-fluoro-2-methylphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydro-1H-pyridin-4-yl ] oxy) methyl ] pyridin-3-yl ] oxy) methyl ] piperidine-1-carboxylate

Stirring (2R) -2- ([ [4- (aminomethyl) pyridin-3-yl) at 80 DEG C]Oxy group]A solution of tert-butyl methyl) piperidine-1-carboxylate (800.00 mg,2.489mmol,1.00 eq) and N- (3-fluoro-2-methylphenyl) -4-hydroxy-2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide (558.16 mg,1.991mmol,0.80 eq) in DMA (5.00 mL) was stirred for 2H. The reaction was quenched with water (50 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM: meoh=20:1) to afford (2R) -2- [ ([ 4- [ ([ 3- [ (3-fluoro-2-methylphenyl) thiocarbamoyl)]-2-oxo-5, 6-dihydro-1H-pyridin-4-yl]Oxy) methyl]Pyridin-3-yl]Oxy) methyl]Tert-butyl piperidine-1-carboxylate (580 mg, 32.88%) as a yellow oil.

LC-MS: M+Hactual: 585.

37.4: synthesis of tert-butyl (2R) -2- [ [ (4- [3- [ (3-fluoro-2-methylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl) oxy ] methyl ] piperidine-1-carboxylate

At room temperature, to (2R) -2- [ ([ 4- [ ([ 3- [ (3-fluoro-2-methylphenyl) thiocarbamoyl)]-2-oxo-5, 6-dihydro-1H-pyridin-4-yl]Oxy) methyl]Pyridin-3-yl]Oxy) methyl]A stirred solution of tert-butyl piperidine-1-carboxylate (580.00 mg,0.992mmol,1.00 eq.) in MeOH (6.00 mL) was added H ₂ O ₂ (30%) (57.36 mg,1.686mmol,1.70 eq.) and TFA (113.10 mg,0.992mmol,1 eq.). The resulting mixture was stirred at 80℃for 2h. The mixture was purified by preparative TLC (DCM: meoh=20:1) to afford (2R) -2- [ [ (4- [3- [ (3-fluoro-2-methylphenyl) amino group]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl ]Pyridin-3-yl) oxy]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (130)mg, 23.84%) as a yellow solid.

LC-MS: M+Hactual: 550

37.5: synthesis of 3- [ (3-fluoro-2-methylphenyl) amino ] -2- [3- [ (2R) -piperidin-2-ylmethoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a solution of tert-butyl (2R) -2- [ [ (4- [3- [ (3-fluoro-2-methylphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl) oxy ] methyl ] piperidine-1-carboxylate (240.00 mg) in DCM (6.00 mL) was added TFA (2.00 mL) and stirred for 2h. The resulting mixture was concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methylphenyl) amino ] -2- [3- [ (2R) -piperidin-2-ylmethoxy ] pyridin-4-yl ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (180 mg, crude) as a brown semisolid.

LC-MS: M+Hactual: 450

37.6: synthesis of 3- [ (3-fluoro-2-methylphenyl) amino ] -2- (3- [ [ (2R) -1- (prop-2-enoyl) piperidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0℃to 3- [ (3-fluoro-2-methylphenyl) amino group]-2- [3- [ (2R) -piperidin-2-ylmethoxy]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (70.00 mg,0.156mmol,1.00 eq.) in THF (4.00 mL) was added NaHCO3 (2.00 mL). The mixture was stirred for 5min. Acryloyl chloride (42.28 mg,0.467mmol,3.00 eq.) was added and the mixture was allowed to warm to RT and stirred for 1h. The reaction mixture was quenched with water (25 mL) and extracted with EA (3 x 25 mL). The residue was purified by preparative TLC (DCM: meOH 10:1) to give the crude product. The crude product was purified by preparative HPLC and using the following conditions (column: YMC-Actus Triart C18 ExRS,30 x 150mm,5 μm; mobile phase A: water (10 MMOL/LNH4HCO3+0.1% NH3. H) ₂ O) mobile phase B, ACN; the flow rate is 60mL/min; gradient 28% B to 61% B, within 7 min; wavelength of 254nm; RT1 (min) 6.88; ) To provide 3- [ (3-fluoro-2-methylphenyl) amino group]-2- (3- [ [ (2R) -1- (prop-2-enoyl) piperidin-2-yl]Methoxy group]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (10.1 mg, 12.78%) was a pale yellow solid.

LC-MS: M+Hactual: 504.

¹ H NMR(400MHz,DMSO-d6):δ10.82(s,1H),8.44(s,1H),7.98–7.93(m,1H),7.30(d,J＝12.9Hz,2H),6.99(s,1H),6.75(d,J＝8.4Hz,2H),6.46(t,J＝8.7Hz,1H),6.06(d,J＝8.3Hz,2H),5.72-5.56(m,,1H),5.39-5.11(m,,1H),4.72(m,1H),4.79-4.65(m,2H),3.44(dt,J＝7.4,4.3Hz,2H),3.05-2.90(m,3H),2.21(s,3H),1.89-1.78(m,1H),1.78–1.55(m,4H),1.52-1.37(m,1H)。

example 38:3- [ (3-fluoro-2-methylphenyl) amino ] -2- [3- [ (2S) -piperidin-2-ylmethoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 469)

38.1: synthesis of tert-butyl (2S) -2- [ [ (4-cyanopyridin-3-yl) oxy ] methyl ] piperidine-1-carboxylate

To a solution of 3-chloropyridine-4-carbonitrile (1.23 g,8.878mmol,1.00 eq.) and (2S) -tert-butyl 2- (hydroxymethyl) piperidine-1-carboxylate (2.29 g,10.653mmol,1.2 eq.) in DMF (30.00 mL) was added NaH (426.09 mg,10.653mmol,1.2 eq., 60%). After stirring overnight at room temperature, the aqueous layer was extracted with EA (3X 50 mL). The resulting mixture was washed with 2×30mL of saturated brine. The residue was purified by silica gel column chromatography eluting with pe:ea (1:1) to give tert-butyl (2S) -2- [ [ (4-cyanopyridin-3-yl) oxy ] methyl ] piperidine-1-carboxylate (2.3 g, 81.63%) as a pale orange oil.

LC-MS: M+Hactual: 318.10

38.2: synthesis of (2S) -2- ([ [4- (aminomethyl) pyridin-3-yl ] oxy ] methyl) piperidine-1-carboxylic acid tert-butyl ester

To a solution of Raney nickel (7.40 g,126.028mmol,10.00 eq.) in NH3 (g) in MeOH (100.00 mL) was added tert-butyl (2S) -2- [ [ (4-cyanopyridin-3-yl) oxy ] methyl ] piperidine-1-carboxylate (4.00 g,12.603mmol,1.00 eq.) under nitrogen. The mixture was hydrogenated overnight at room temperature under a hydrogen atmosphere using a hydrogen balloon. The precipitated solid was collected by filtration. The residue was purified by silica gel column chromatography eluting with DCM: meOH (7:1) to give tert-butyl (2S) -2- ([ [4- (aminomethyl) pyridin-3-yl ] oxy ] methyl) piperidine-1-carboxylate (2.04 g, 50.36%) as a pale yellow solid.

LC-MS: M+Hactual: 322

38.3: synthesis of tert-butyl (2S) -2- [ ([ 4- [ ([ 3- [ (3-fluoro-2-methylphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydro-1H-pyridin-4-yl ] oxy) methyl ] pyridin-3-yl ] oxy) methyl ] piperidine-1-carboxylate

A solution of (2S) -2- ([ [4- (aminomethyl) pyridin-3-yl ] oxy ] methyl) piperidine-1-carboxylic acid tert-butyl ester (997.56 mg,3.104mmol,1.50 eq.) and N- (3-fluoro-2-methylphenyl) -4-hydroxy-2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide (580.00 mg,2.069mmol,1.00 eq.) in DMA (6.00 mL) was stirred at 120deg.C for 2H. The aqueous layer was extracted with EA (3X 50 mL). The residue was washed with saturated brine (2×50 mL). The residue was purified by preparative TLC (DCM: meOH 20:1) to give tert-butyl (2S) -2- [ ([ 4- [ ([ 3- [ (3-fluoro-2-methylphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydro-1H-pyridin-4-yl ] oxy) methyl ] pyridin-3-yl ] oxy) methyl ] piperidine-1-carboxylate (570 mg, 47.12%) as a yellow solid.

LC-MS: M+Hactual: 585

38.4: synthesis of tert-butyl (2S) -2- [ [ (4- [3- [ (3-fluoro-2-methylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl) oxy ] methyl ] piperidine-1-carboxylate

Stirring (2S) -2- [ ([ 4- [ ([ 3- [ (3-fluoro-2-methylphenyl) thiocarbamoyl) at 80deg.C]-2-oxo-5, 6-dihydro-1H-pyridin-4-yl]Oxy) methyl]Pyridin-3-yl]Oxy) methyl]Piperidine-1-carboxylic acid tert-butyl ester (500.00 mg,0.855mmol,1.00 eq.) and H ₂ O ₂ (164.83 mg,1.454mmol,1.7 eq., 30%), TFA (97.50 mg,0.855mmol,1 eq.) in MeOH (6.00 mL) for 2h. The residue was purified by preparative TLC (DMC: meOH 15:1) to afford (2S) -2- [ [ (4- [3- [ (3-fluoro-2-methylphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl) oxy]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (150 mg, 31.91%) as an orange solid.

LC-MS: M+Hactual: 550

38.5: synthesis of 3- [ (3-fluoro-2-methylphenyl) amino ] -2- (3- [ [ (2S) -1- (prop-2-enoyl) piperidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

A solution of 3- [ (3-fluoro-2-methylphenyl) amino ] -2- [3- [ (2S) -piperidin-2-ylmethoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (150.00 mg) in TFA (1.00 mL) and DCM (3.00 mL) was stirred at room temperature for 2h. The resulting solid was dried under nitrogen atmosphere. This gave 3- [ (3-fluoro-2-methylphenyl) amino ] -2- (3- [ [ (2S) -1- (prop-2-enoyl) piperidin-2-yl ] methoxy ] pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (100 mg) as an orange solid.

LC-MS: M+Hactual: 450.10.

38.6: synthesis of 3- [ (3-fluoro-2-methylphenyl) amino ] -2- [3- [ (2S) -piperidin-2-ylmethoxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0 ℃, to (2S) -2- [ [ (4- [3- [ (3-fluoro-2-methylphenyl) amino group)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl) oxy]Methyl group]A solution of tert-butyl piperidine-1-carboxylate (60.00 mg,0.109mmol,1.00 eq.) in THF (4.00 mL) was added NaHCO ₃ (2.00 mL,0.024mmol,0.22 eq.). The mixture was stirred for 5min, acryloyl chloride (29.64 mg,0.327mmol,3.00 eq.) was added and the mixture was allowed to rise to RT and stirred for 1h. The reaction mixture was quenched with water (25 mL) and extracted with EA (3 x 25 mL). The residue was purified by preparative TLC (DCM: meOH 10:1) to give the crude product. The crude product was purified by preparative HPLC and using the following conditions (column: YMC-Actus Triart C18 ExRS,30 x 150mm,5 μm; mobile phase A: water (10 MMOL/L NH4HCO3+0.1% NH3. H) ₂ O) mobile phase B, ACN; the flow rate is 60mL/min; gradient 28% b to 61% b over 7 min; wavelength of 254nm; RT1 (min) 6.88; ) To provide 3- [ (3-fluoro-2-methylphenyl) amino group]-2- [3- [ (2S) -piperidin-2-ylmethoxy]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-one (4.7 mg, 9.58%) was a yellow solid.

LC-MS (M+H) + actual: 504.25

¹ H NMR(400MHz,DMSO-d6):δ10.76(s,1H),8.43(s,1H),7.95(d,J＝5.0Hz,1H),7.30(d,J＝5.0Hz,1H),7.22(s,1H),6.85(s,1H),6.75(q,J＝10.0,8.4Hz,2H),6.45(t,J＝8.9Hz,1H),6.08(d,J＝8.2Hz,1H),6.04(d,J＝16.7Hz,1H),5.62(d,J＝10.6Hz,1H),4.25-4.90(m,1H),4.66(s,1H),4.18-4.01(m,2H),3.49-3.42(m,3H),3.05-2.99(m,2H),2.21(s,3H),1.89-1.80(m,1H),1.71-1.61(m,4H),1.48-1.42(m,1H)。

Example 39:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [ [ (2S) -1- (prop-2-enoyl) azetidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 145 b)

39.1: synthesis of tert-butyl (2S) -2- { [ (4-cyanopyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

At 0 ℃ under nitrogen atmosphereA stirred solution of tert-butyl (2S) -2- (hydroxymethyl) azetidine-1-carboxylate (2.70 g, 14.433 mmol,1 eq.) in DMF was added NaH (415.69 mg,17.323mmol,1.2 eq.) in portions. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 0.5h. 3-chloropyridine-4-carbonitrile (1.80 g,12.992mmol,0.9 eq.) was added in portions to the above mixture at 0deg.C. The resulting mixture was stirred at room temperature for a further 16h. The reaction was quenched with water/ice at room temperature. The resulting mixture was extracted with DCM (4X 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ And (5) drying. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (1:1) to provide (2S) -2- { [ (4-cyanopyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (3.3 g, 79.01%) as a yellow oil.

LC-MS: M+Hactual: 290

39.2: synthesis of tert-butyl (2S) -2- ({ [4- (aminomethyl) pyridin-3-yl ] oxy } methyl) azetidine-1-carboxylate

To a solution of tert-butyl (2S) -2- { [ (4-cyanopyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (3.3 g,11.405mmol,1.00 eq.) in MeOH (50.00 mL) in NH3 (g) was added Raney nickel (9.77 g,114.050mmol,10 eq.) at room temperature under hydrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere overnight. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH 10:1) to give tert-butyl (2S) -2- ({ [4- (aminomethyl) pyridin-3-yl ] oxy } methyl) azetidine-1-carboxylate (2.7 g, 80.69%) as a yellow oil.

LC-MS: M+Hactual: 294

39.3: synthesis of tert-butyl (2S) -2- [ ({ 4- [ ({ 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydro-1H-pyridin-4-yl } amino) methyl ] pyridin-3-yl } oxy) methyl ] azetidine-1-carboxylate

(2S) -2- ({ [4- (aminomethyl) pyridin-3-yl) in DMA (3 mL,32.266mmol,11.21 eq.) was charged to an 8mL round bottom flask]Tert-butyl oxy } methyl) azetidine-1-carboxylate (1013.00 mg,3.454mmol,1.2 eq) and N- (3-chloro-2-methoxyphenyl) -4-hydroxy-2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide (900 mg,2.878mmol,1.00 eq). The resulting mixture was stirred at 120℃under nitrogen for 2h. The resulting mixture was treated with CH ₂ Cl ₂ Extraction and purification by preparative TLC (DCM/MeOH 10:1) provided (2S) -2- [ ({ 4- [ ({ 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl)]-2-oxo-5, 6-dihydro-1H-pyridin-4-yl } amino) methyl]Pyridin-3-yl } oxy) methyl]Azetidine-1-carboxylic acid tert-butyl ester (550 mg, 32.50%) was a yellow solid.

LC-MS: M+Hactual: 588

39.4: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

To (2S) -2- [ ({ 4- [ ({ 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl) under a nitrogen atmosphere at room temperature]-2-oxo-5, 6-dihydro-1H-pyridin-4-yl } amino) methyl]Pyridin-3-yl } oxy) methyl]A stirred solution of tert-butyl azetidine-1-carboxylate (300 mg,0.510mmol,1 eq.) in MeOH was added hydrogen peroxide (35%) (26.03 mg,0.765mmol,1.5 eq.). The resulting mixture was stirred at 80℃under nitrogen for 2h. The resulting mixture was treated with CH ₂ Cl ₂ (3X 10 mL) extraction. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ MeOH 10:1) purification to afford (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-2-yl } pyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (120 mg, 42.46%) as a yellow solid.

LC-MS: M+Hactual: 554

39.5: synthesis of 2- {3- [ (2S) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (110 mg,0.199mmol,1 eq.) in DCM (1 mL) was added TFA (0.50 mL). The resulting mixture was stirred at room temperature under an air atmosphere for 2h. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH 5:1) to give 2- {3- [ (2S) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (85 mg, 94.31%) as a yellow oil.

LC-MS: M+Hactual: 454.

39.6: synthesis of [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [ [ (2S) -1- (prop-2-enoyl) azetidin-2-yl ] methoxy ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- [3- [ (2S) -azetidin-2-ylmethoxy at room temperature ]Pyridin-4-yl]-3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (100.00 mg,0.220mmol,1.00 eq.) in THF (1.00 mL) was added saturated NaHCO3 (1 mL) and acryloyl chloride (29.91 mg,0.330mmol,1.50 eq.) which were added in portions over 10 minutes. The resulting mixture was extracted with EA (3×10 ml). The combined organic layers were washed with EA (3×5 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative HPLC and using the following conditions (column: porosill HPH C18.0.50 mm,2.7um; mobile phase A: water6.5mM NH ₄ HCO ₃ (ph=10); mobile phase B, ACN; the flow rate is 1.2mL/min; gradient from 10% B to 95% B, for 1.1min, for 0.6min;254 nm) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- [ [ (2S) -1- (prop-2-enoyl) azetidin-2-yl]Methoxy group]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (24.8 mg, 22.16%) was a yellow solid.

LC-MS: M+Hactual: 508

¹ H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.38(s,1H),7.98(d,J＝5.1Hz,1H),7.39(s,1H),7.34(d,J＝5.0Hz,1H),6.78(s,1H),6.71–6.58(m,2H),6.33(dd,J＝16.9,10.3Hz,1H),6.17(dd,J＝6.8,2.8Hz,2H),5.68(s,1H),4.84(d,J＝7.4Hz,1H),4.56–4.45(m,1H),4.42(dd,J＝10.7,2.9Hz,1H),4.15(s,2H),3.91(s,3H),3.44(td,J＝6.9,2.5Hz,2H),2.94(s,2H),2.52(m,1H),2.15(m,1H)。

Example 40:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- (2-methylsulfonylethoxy) pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 137)

40.1: synthesis of 3- [2- (trimethylsilyl) ethoxy ] pyridine-4-carbonitrile

To a solution of 2- (trimethylsilyl) ethanol (6.83 g,57.741mmol,2.00 eq.) in THF (100.00 mL) at 0deg.C was added NaH (2.31 g,57.741mmol,2.00 eq., 60%). The mixture was stirred for 1h. 3-chloropyridine-4-carbonitrile (4.00 g, 28.87mmol, 1.00 eq.) was added and the mixture was allowed to warm to 50℃and stirred for 16h. The reaction mixture was quenched with water (100 mL) and extracted with EA (3 x100 mL). The combined organic layers were washed with (1×50 mL) brine, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE:EA (2:1) to provide 3- [2- (trimethylsilyl) ethoxy]Pyridine-4-carbonitrile (4.3 g, 67.59%) was a yellow oil.

LC-MS: M+Hactual: 221

40.2: synthesis of 3-hydroxypyridine-4-carbonitrile

At 0℃to 3- [2- (trimethylsilyl) ethoxy]A stirred solution of pyridine-4-carbonitrile (4.30 g,19.515mmol,1.00 eq.) in THF (50.00 mL) was added dropwise TBAF (10.20 g,39.029mmol,2 eq.). The resulting mixture was stirred at room temperature for 2h. The resulting mixture was diluted with H ₂ O (100 mL). The resulting mixture was extracted with EA (3X 100 mL). The combined organic layers were washed with (1×50 mL) brine, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM: meOH (10:1) to give 3-hydroxypyridine-4-carbonitrile (2 g, 85.33%) as a white solid.

LC-MS: M+Hactual: 121.

40.3: synthesis of 4- (aminomethyl) pyridin-3-ol

To a solution of Raney nickel (1.03 g, 17.284 mmol,1.00 eq.) in MeOH (100.00 mL) in NH3 (g) under nitrogen was added 3-hydroxypyridine-4-carbonitrile (2.10 g, 17.284 mmol,1.00 eq.). The mixture was hydrogenated at room temperature under a hydrogen atmosphere using a hydrogen balloon for 16h, filtered through a celite pad and concentrated under reduced pressure to provide 4- (aminomethyl) pyridin-3-ol (1.8 g, 82.93%) as a gray solid.

LC-MS: M+Hactual: 125.

40.4: synthesis of N- (3-chloro-2-methoxyphenyl) -4- [ [ (3-hydroxypyridin-4-yl) methyl ] amino ] -2-oxo-5, 6-dihydro-1H-pyridin-3-thiocarboxamide

N- (3-chloro-2-methoxyphenyl) -4-hydroxy-2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide (0.80 g, 2.558) was stirred at room temperaturemmol,1.00 eq.) and 4- (aminomethyl) pyridin-3-ol (0.63 g,5.090mmol,1.99 eq.) in DMA (10.00 mL). The resulting mixture was stirred at 120℃for 2h. The mixture obtained is treated with H ₂ O (100 mL) dilution. The resulting mixture was extracted with EA (3X 100 mL). The combined organic layers were washed with brine (1×50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM: meoh=15:1) to provide N- (3-chloro-2-methoxyphenyl) -4- [ (3-hydroxypyridin-4-yl) methyl ]Amino group]-2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide (600 mg, 56.00%) as a brown oil.

LC-MS: M+Hactual: 419.

40.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To N- (3-chloro-2-methoxyphenyl) -4- [ [ (3-hydroxypyridin-4-yl) methyl at room temperature]Amino group]A stirred solution of (E) -2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide (600.00 mg,1.432mmol,1.00 eq.) in MeOH (8.00 mL) was added dropwise H ₂ O ₂ (82.82 mg,2.435mmol,1.7 eq.) and TFA (163.32 mg,1.432mmol,1 eq.). The resulting mixture was stirred at 80℃for 2h. The mixture obtained is treated with H ₂ O (100 mL) dilution. The resulting mixture was extracted with EA (3X 100 mL). The combined organic layers were washed with brine (1×50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM: meoh=10:1) to afford 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (300 mg, 54.43%) was a brown solid.

LC-MS: M+Hactual: 385

40.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- (2-methylsulfonylethoxy) pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At room temperature, N ₂ To 3- [ (3-chloro-2-methoxyphenyl) amino group under an atmosphere]-2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (100.00 mg,0.260mmol,1.00 eq.) and 2-methanesulfonylethanol (64.52 mg,0.520mmol,2.00 eq.) in toluene (2.00 mL) was added dropwise 2- (tributyl-l [5 ]]Phosphoranylidene) acetonitrile (125.44 mg,0.520mmol,2 eq.). The resulting mixture was stirred at 100deg.C under N2 atmosphere for two days. The mixture obtained is treated with H ₂ O (30 mL) dilution. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (1×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM: meoh=5:1) to provide the crude product. The crude product (30 mg) was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18,30 x 150mm,5 μm; mobile phase A: water (10 MMOL/L NH4HCO3+0.1% NH3. H) ₂ O) mobile phase B, ACN; the flow rate is 60mL/min; gradient from 25% b to 35% b,8 min; wavelength of 254nm; RT1 (min) 8.05; ) To provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- [3- (2-methylsulfonylethoxy) pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (8.4 mg, 6.54%) was a yellow solid.

LC-MS: M+Hactual: 491

¹ H NMR(400MHz,DMSO-d6):δ14.06(s,1H),7.68(s,2H),7.49(d,J＝6.4Hz,1H),7.26–7.07(m,2H),6.96–6.70(m,2H),6.19(dd,J＝7.3,2.4Hz,1H),4.55(t,J＝7.1Hz,2H),3.92(s,3H),3.85(t,J＝6.9Hz,2H),3.39(t,J＝6.9Hz,2H),3.02(s,3H),2.91(t,J＝6.9Hz,2H)。

Example 41:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- (furan-2-ylmethoxy) pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 471)

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under N2 atmosphere]-2- (3-hydroxypyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (100.00 mg,0.260mmol,1.00 eq.) and furanmethanol (50.99 mg,0.520mmol,2.00 eq.) in toluene (2.00 mL,18.798mmol,72.34 eq.) was added dropwise 2- (tributyl-l [5 ]]Phosphoranylidene) acetonitrile (125.44 mg,0.520mmol,2 eq.). The resulting mixture was stirred at 100deg.C under N2 atmosphere for two days. The mixture obtained is treated with H ₂ O (30 mL) dilution. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (1×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM: meoh=10:1) to provide the crude product. The crude product (60 mg) was purified by preparative HPLC using the following conditions (column: XBridge Shield RP OBD column, 30 x 150mm,5 μm; mobile phase A: water (10 MMOL/LNH4HCO3+0.1% NH3. H) ₂ O) mobile phase B, ACN; the flow rate is 60mL/min; gradient from 31% b to 41% b,8 min; wavelength of 254nm; RT1 (min) 7.13; ) To provide 3- [ (3-chloro-2-methoxyphenyl) amino group ]-2- [3- (furan-2-ylmethoxy) pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (14.3 mg, 11.60%) was a yellow solid. LC-MS: M+Hactual: 465

¹ H NMR(400MHz,DMSO-d6):δ14.04(s,1H),7.71(d,J＝1.8Hz,1H),7.65(s,1H),7.56(d,J＝1.9Hz,1H),7.51–7.41(m,1H),7.21–7.09(m,2H),6.86–6.73(m,2H),6.68(d,J＝3.3Hz,1H),6.53–6.46(m,1H),6.19(dd,J＝7.6,2.1Hz,1H),5.39(s,2H),3.92(s,3H),3.48–3.39(t,2H),2.90(t,J＝6.8Hz,2H).

Example 42:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- [ (1-methylpyrazol-4-yl) oxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 484)

42.1: synthesis of 2- [ (3-bromopyridin-4-yl) methyl ] isoindole-1, 3-dione

To (3-bromopyridin-4-yl) methanol (2000 mg, 1)0.637mmol,1.00 eq.) and phthalimide (2347.57 mg,15.956mmol,1.5 eq.) in THF (15 mL) were added dropwise PPh ₃ (6974.79 mg,26.593mmol,2.5 eq.) and DIAD (3226.31 mg,15.955mmol,1.50 eq.) for 5h. By adding H at 0 ℃ ₂ The reaction was quenched with O (15 ml). The resulting mixture was extracted with EA (3×50 ml). The combined organic layers were washed with NaCl (3X 2 30 ml), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM: meoh=18:1) to provide 2- [ (3-bromopyridin-4-yl) methyl]Isoindole-1, 3-dione (1.5 g, 84.47%) as an off-white solid.

LC-MS (M+H) + actual: 318.90.

42.2: synthesis of 1- (3-iodopyridin-4-yl) methylamine

To 2- [ (3-iodopyridin-4-yl) methyl at 50℃under N2 atmosphere]Isoindole-1, 3-dione (1500 mg,4.119mmol,1.00 eq.) in CH ₃ The stirred solution in OH (15 mL) was added CH in portions ₃ ONa (778.88 mg,14.416mmol,3.5 eq.). The resulting mixture was extracted with EA (3 x100 ml). The combined organic layers were washed with NaCl (3X 1 20 ml), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM: meoh=10:1) to give 1- (3-iodopyridin-4-yl) methylamine (500 mg, 61.86%) as a white solid.

LC-MS (M+H) + actual: 187.62.

42.3: synthesis of 4- { [ (3-bromopyridin-4-yl) methyl ] amino } -N- (3-fluoro-2-methoxyphenyl) -2-oxo-5, 6-dihydro-1H-pyridin-3-thiocarboxamide

Stirring N- (3-fluoro-2-methoxyphenyl) -4-hydroxy-2-oxo-5, 6-dihydro-1H at 110deg.C under N2 atmosphereA stirred solution of pyridine-3-thiocarboxamide (400 mg,1.350mmol,1.00 eq.) and 1- (3-bromopyridin-4-yl) methylamine (302.98 mg,1.620mmol,1.20 eq.) in DMA (2 mL). The resulting mixture was extracted with EA (3×20 ml). The combined organic layers were washed with NaCl (3X 230 ml), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM: meoh=15:1) to give 4- { [ (3-bromopyridin-4-yl) methyl ]Amino } -N- (3-fluoro-2-methoxyphenyl) -2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide (200 mg, 70.84%) as a brown solid.

LC-MS (M+H) + actual: 467.20.

42.4: synthesis of 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 4- { [ (3-bromopyridin-4-yl) methyl at 50℃under N2 atmosphere]A stirred solution of amino } -N- (3-fluoro-2-methoxyphenyl) -2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide (500 mg,1.074mmol,1.00 eq.) in methanol (8 mL,1.074mmol,1.00 eq.) was added dropwise H ₂ O ₂ (7.31 mg,0.215mmol,0.2 eq.) for 8h. The residue was purified by preparative TLC (DCM: meoh=15:1) to give 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (150 mg, 50.57%) was an off-white solid.

LC-MS (M+H) + actual: 432.95.

42.5: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- [ (1-methylpyrazol-4-yl) oxy ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino group at 80℃under N2 atmosphere]-1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-onesA stirred solution of (100.00 mg,0.23mmol,1.00 eq.) and 1-methylpyrazol-4-ol (25.0 mg,0.25mmol,1.10 eq.) in DMF (3.5 mL) was added in portions 2, 6-tetramethylheptane-3, 5-dione (8.5 mg,0.005mmol,0.20 eq.), cuI (8.8 mg,0.005mmol,0.20 eq.) and Cs ₂ CO ₃ (377.7 mg,0.116mmol,5.00 eq.) for 2h. The resulting mixture was extracted with EA (3×10 ml). The combined organic layers were washed with NaCl (3X 25 ml), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH4HCO3+0.1% NH3. H) ₂ O) mobile phase B, ACN; the flow rate is 60mL/min; gradient 20% B to 45% B, 45% B over 10 min; wavelength is 254/220nm; RT1 (min) 9.82; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- [3- [ (1-methylpyrazol-4-yl) oxy ]]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (8.6 mg, 97.80%) was a white solid.

LC-MS (M+H) + actual: 449.1.

¹ H NMR(400MHz,DMSO-d6)δ11.41(s,1H),8.67–7.94(m,2H),7.64(s,1H),7.53(d,J＝0.8Hz,1H),7.41(d,J＝5.1Hz,1H),7.14(s,2H),7.11(d,J＝1.0Hz,1H),6.62(d,J＝6.2Hz,1H),6.50(s,1H),6.21–5.89(m,1H),3.79(d,J＝1.5Hz,6H),3.41(dt,J＝6.7,3.4Hz,2H),2.86(t,J＝6.8Hz,2H)。

example 43:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (3R) -4- (prop-2-enoyl) morpholin-3-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 522)

43.1: synthesis of tert-butyl (3R) -3- { [ (4-cyanopyridin-3-yl) oxy ] methyl } morpholine-4-carboxylate

Cs was added portionwise to a stirred solution of tert-butyl (3S) -3- (hydroxymethyl) morpholine-4-carboxylate (3.56 g,16.38mmol,1.00 eq.) and 3-fluoropyridine-4-carbonitrile (2.00 g,16.38mmol,1.00 eq.) in DMF (10 mL) at room temperature under argon ₂ CO ₃ (16.06 g,49.29mmol,3.0 eq.). The resulting mixture was stirred overnight at 60℃under argon. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with water (3×100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (1:1) to provide (3R) -3- { [ (4-cyanopyridin-3-yl) oxy]Tert-butyl methyl } morpholine-4-carboxylate (4.2 g, 80.29%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 320.05

43.2: synthesis of tert-butyl (3R) -3- ({ [4- (aminomethyl) pyridin-3-yl ] oxy } methyl) morpholine-4-carboxylate

(3R) -3- { [ (4-cyanopyridin-3-yl) oxy was stirred at room temperature under a hydrogen atmosphere]A stirred mixture of tert-butyl methyl } morpholine-4-carboxylate (4.20 g,13.15mmol,1.00 eq.) and ammonia (7.0M in MeOH, 20mL,140.00 mmol) in MeOH (40 mL) and Raney Ni (2.25 g,54 w/w%) was stirred overnight. The resulting mixture was filtered and the filter cake was washed with methanol (3 x30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford (3R) -3- ({ [4- (aminomethyl) pyridin-3-yl)]Tert-butyl oxy } methyl) morpholine-4-carboxylate (4.20 g, 98.75%) as a yellow oil.

LC-MS:(M+H) ⁺ Actual: 324.05.

43.3: synthesis of tert-butyl (3R) -3- ({ [4- ({ [1- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydropyridin-4-yl ] amino } methyl) pyridin-3-yl ] oxy } methyl) morpholine-4-carboxylate

At room temperature under argon atmosphere to 3- [ (3)-chloro-2-methoxyphenyl) thiocarbamoyl]-4-hydroxy-2-oxo-5, 6-dihydropyridin-1-carboxylate (5.36 g,12.99mmol,1.00 eq.) and (3R) -3- ({ [4- (aminomethyl) pyridin-3-yl)]A stirred mixture of tert-butyl oxy } methyl) morpholine-4-carboxylate (4.20 g,12.99mmol,1.00 eq.) in DMF (40 mL) was added DIEA (5.04 g,38.96mmol,3.00 eq.) and PyBOP (10.14 g,19.48mmol,1.50 eq.). The resulting mixture was stirred overnight at room temperature under argon. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (1:2) to provide (3R) -3- ({ [4- ({ [1- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl) ]-2-oxo-5, 6-dihydropyridin-4-yl]Amino } methyl) pyridin-3-yl]Tert-butyl oxy } methyl) morpholine-4-carboxylate (6.50 g, 69.68%) as an orange solid.

LC-MS:(M+H) ⁺ Actual: 718.0.

43.4: synthesis of tert-butyl (3R) -3- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl } oxy) methyl ] morpholine-4-carboxylate

To (3R) -3- ({ [4- ({ [1- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl) under argon at room temperature]-2-oxo-5, 6-dihydropyridin-4-yl]Amino } methyl) pyridin-3-yl]A stirred mixture of tert-butyl oxy } methyl) morpholine-4-carboxylate (500 mg,0.70mmol,1.00 eq.) in methanol (5 mL) was added hydrogen peroxide (30 w/w%,103mg,0.91mmol,1.30 eq.). The resulting mixture was stirred at 80℃under argon for 4h. The mixture was cooled to room temperature. The reaction was carried out by adding saturated Na at room temperature ₂ SO ₃ The aqueous solution (0.1 mL) was quenched. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ Purification to afford (3R)) -3- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl } oxy) methyl ]Morpholine-4-carboxylic acid tert-butyl ester (200 mg, 41.99%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 684.1.

43.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ (3R) -morpholin-3-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (3R) -3- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl } oxy) methyl ] morpholine-4-carboxylate (140 mg,0.20mmol,1.00 eq.) in DCM (5 mL) at 0 ℃ under argon atmosphere was added TFA (1 mL). The resulting mixture was stirred at room temperature under argon for 12h. The resulting mixture was concentrated under reduced pressure. This gave 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ (3R) -morpholin-3-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (120 mg, crude) as a yellow solid. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 484.05.

43.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (3R) -4- (prop-2-enoyl) morpholin-3-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group at 0℃under argon atmosphere ]-2- {3- [ (3R) -morpholin-3-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (110 mg,0.23mmol,1.00 eq.) in CH ₂ Cl ₂ Triethylamine (93 mg,0.92mmol,5.00 eq.) was added to a stirred mixture of (4 mL)) To-30 ℃. To the above mixture was added in portions at-30℃acryloyl chloride (14.98 mg,0.17mmol,0.90 eq.). The resulting mixture was stirred at room temperature for 1h. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Shield RP OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 38% B to 50% B, 50% B over 10 min; wavelength is 220/254nm; RT1 (min) 7.43; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (3R) -4- (prop-2-enoyl) morpholin-3-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (19.8 mg, 16.21%) was a white solid.

LC-MS:(M+H) ⁺ Actual: 537.95.

¹ H NMR(300MHz,DMSO-d ₆ )δ10.93(s,1H),8.47(s,1H),8.14–7.94(m,1H),7.60–7.43(m,1H),7.42–7.25(m,1H),7.17(t,1H),6.96–6.79(m,1H),6.76–6.58(m,2H),6.26–5.96(m,2H),5.83–5.47(m,1H),5.06–4.66(m,1H),4.54–4.14(m,2H),4.11–3.79(m,6H),3.72–3.37(m,5H),3.07–2.78(m,2H)。

example 44:2- (3- { [ (2S) -4-Acetylmorpholin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 195)

44.1: synthesis of tert-butyl (2S) -2- { [ (4-cyanopyridin-3-yl) oxy ] methyl } morpholine-4-carboxylate

To a stirred mixture of tert-butyl (2S) -2- (hydroxymethyl) morpholine-4-carboxylate (1.96 g,9.01mmol,1.10 eq.) in DMF (20.00 mL) was added NaH (0.49 g,12.29mmol,1.50 eq., 60% in oil) in portions under argon at 0deg.C. The resulting mixture was stirred at 0℃under argon for 30min. 3-Fluoropyridine-4-carbonitrile (1.00 g,8.19mmol,1.00 eq.) was added in portions to the above mixture at 0deg.C over 5 min. The resulting mixture was stirred at room temperature for an additional 2h. The reaction was monitored by LCMS. The expectation can be detected by LCMSIs a product of (a). The reaction was quenched with water at 0 ℃. The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (4:1) to provide (2S) -2- { [ (4-cyanopyridin-3-yl) oxy]Methyl } morpholine-4-carboxylic acid tert-butyl ester (1.20 g, 45.42%) was a colorless oil.

LC-MS: M+Na actual: 341.95.

44.2: (2S) -2- ({ [4- (aminomethyl) pyridin-3-yl ] oxy } methyl) morpholine-4-carboxylic acid tert-butyl ester

To (2S) -2- { [ (4-cyanopyridin-3-yl) oxy at room temperature under nitrogen atmosphere]A stirred mixture of tert-butyl methyl } morpholine-4-carboxylate (1.00 g,3.13mmol,1.00 eq.) and ammonia (7.0M in MeOH, 12.50mL,87.50 mmol) in MeOH (25.00 mL) was added Raney Ni (1.00 g,100 w/w%). The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 150 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) elution to afford (2S) -2- ({ [4- (aminomethyl) pyridin-3-yl)]Tert-butyl oxy } methyl) morpholine-4-carboxylate (1.00 g, 95.79%) as a pale yellow oil.

LC-MS: M+Hactual: 324.05.

44.3: synthesis of tert-butyl (2S) -2- [ ({ 4- [ ({ 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydro-1H-pyridin-4-yl } amino) methyl ] pyridin-3-yl } oxy) methyl ] morpholine-4-carboxylate

To a stirred mixture of (2S) -2- ({ [4- (aminomethyl) pyridin-3-yl ] oxy } methyl) morpholine-4-carboxylate (1.10 g,3.40mmol,1.00 eq) and N- (3-chloro-2-methoxyphenyl) -4-hydroxy-2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide (1.06 g,3.40mmol,1.00 eq) in DMF (12.00 mL) was added PyBOP (2.66 g,5.10mmol,1.50 eq) and DIEA (1.32 g,10.20mmol,3.00 eq) in portions at 0deg.C under nitrogen. The resulting mixture was stirred overnight at room temperature under nitrogen. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting PE/EA (5:1) to give tert-butyl (2S) -2- [ ({ 4- [ ({ 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydro-1H-pyridin-4-yl } amino) methyl ] pyridin-3-yl } oxy) methyl ] morpholine-4-carboxylate (800 mg, 34.62%) as a yellow solid.

LC-MS: M+Hactual: 618.10.

44.4: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } morpholine-4-carboxylate

Stirring (2S) -2- [ ({ 4- [ ({ 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl) at 80deg.C under nitrogen atmosphere]-2-oxo-5, 6-dihydro-1H-pyridin-4-yl } amino) methyl]Pyridin-3-yl } oxy) methyl]Morpholine-4-carboxylic acid tert-butyl ester (800 mg,1.29mmol,1.00 eq.) and H ₂ O ₂ (30 w/w%,190mg,1.68mmol,1.30 eq.) in MeOH (8.00 mL) for 4h. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The reaction was quenched with saturated aqueous sodium thiosulfate at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography and the following conditions were used: column, C18 sphere column; mobile phase, meCN in water, gradient 10% to 50%, within 30 min; a detector: UV 254nm to provide (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } morpholine-4-carboxylic acid tert-butyl ester (300 mg, 35.72%) asPale yellow solid.

LC-MS: M+Hactual: 584.20.

44.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ (2S) -morpholin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under an air atmosphere]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } morpholine-4-carboxylate (250 mg,0.43mmol,1.00 eq.) and DCM (5.00 mL) was added TFA (1.00 mL) in portions. The resulting mixture was stirred at room temperature under an air atmosphere for 1h. The desired product was detectable by LCMS. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. With saturated NaHCO ₃ The mixture was neutralized to pH 7 with aqueous solution. CH for aqueous layer ₂ Cl ₂ (3X 10 mL) extraction. Concentrating the organic phase under reduced pressure to afford 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- {3- [ (2S) -morpholin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (220 mg, 84.96%) was a pale yellow solid.

LC-MS: M+Hactual: 484.10.

44.6: synthesis of 2- (3- { [ (2S) -4-acetylmorpholin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

at-30deg.C under argon atmosphere to 3- [ (3-chloro-2-methoxyphenyl) amino group ]-2- {3- [ (2S) -morpholin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (65 mg,0.13mmol,1.00 eq.) Et was added in portions in DCM (1.00 mL) ₃ N (54 mg,0.52mmol,4.00 eq.) and acetic anhydride (14 mg,0.13mmol,1.00 eq.). The resulting mixture was stirred at 0℃under argon for 1h. Monitoring of the reaction by LCMSShould be. The desired product was detectable by LCMS. The reaction was quenched with MeOH at 0 ℃. The resulting mixture was concentrated under reduced pressure. The crude product (65 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 20% B to 50% B, over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number 0) to provide 2- (3- { [ (2S) -4-acetylmorpholin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (34.6 mg, 48.29%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 525.95.

¹ H NMR(300MHz,DMSO-d ₆ )δ11.06(s,1H),8.42(s,1H),8.06-8.02(m,1H),7.53(s,1H),7.31-7.27(m,1H),7.16(s,1H),6.70-6.68(m,2H),6.20-5.97(m,1H),4.43-4.15(m,3H),4.00-3.96(m,1H),3.88(s,4H),3.80-3.48(m,2H),3.42–3.99(m,2H),3.29-3.04(m,1H),2.90-2.83(m,2H),2.79-2.57(m,1H),2.03(s,3H)。

example 45:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -4-methylsulfonylmelin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 193)

at-30deg.C under argon atmosphere to 3- [ (3-chloro-2-methoxyphenyl) amino group ]-2- {3- [ (2S) -morpholin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (100 mg,0.21mmol,1.00 eq.) in DCM (1.50 mL) was added Et in portions ₃ N (84 mg,0.84mmol,4.00 eq.) and methanesulfonyl chloride (24 mg,0.21mmol,1.00 eq.). The resulting mixture was stirred at 0℃under argon for 1h. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The reaction was quenched with MeOH at 0 ℃. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/LNH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 23% b to 43% b, 43% b over 10 min; wavelength is 254/220nm; RT1 (min) 9.67; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (2S) -4-methanesulfonylmorpholin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (41.3 mg, 34.49%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 561.90.

¹ H NMR(300MHz,DMSO-d ₆ )δ11.05(s,1H),8.42(s,1H),8.05(d,1H),7.51(s,1H),7.28(d,1H),7.16(t,J＝2.5Hz,1H),6.76-6.63(m,2H),6.21-6.09(m,1H),4.37-4.32(m,1H),4.29-4.24(m,1H),4.13-4.00(m,2H),3.88(s,3H),3.80-3.61(m,2H),3.48-3.38(m,3H),2.94-2.76(m,7H)。

example 46.3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (3R) -4- [ (2E) -4- (dimethylamino) but-2-enoyl ] morpholin-3-yl ] methoxy } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one; trifluoroacetate salt (Compound 197)

46.1: (E) Synthesis of (E) -4- (dimethylamino) but-2-enoyl chloride

To a stirred mixture of (2E) -4- (dimethylamino) but-2-enoic acid (70 mg,0.54mmol,1.00 eq.) in THF (6 mL) at 0deg.C under argon atmosphere was added dropwise (COCl) ₂ (76 mg,0.60mmol,1.10 eq.). The resulting mixture was stirred at room temperature under argon atmosphere for 30min. By TLC (CH) ₂ Cl ₂ Meoh=5:1) was monitored for reaction. The resulting mixture was used directly in the next step without further purification.

46.2:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (3R) -4- [ (2E) -4- (dimethylamino) but-2-enoyl ] morpholin-3-yl ] methoxy } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one; synthesis of trifluoroacetate salt

To a stirred mixture of (2E) -4- (dimethylamino) but-2-enoyl chloride (21 mg,0.14mmol,1.0 eq.) in THF (0.5 mL) at 0deg.C under nitrogen was added dropwise a solution of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ (3R) -morpholin-3-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (70 mg,0.14mmol,1.00 eq.) in NMP (0.5 mL). The resulting mixture was stirred at room temperature for 1.5h. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC and using the following conditions (column: xcell CSH F-phenyl OBD column, 19X 250mm,5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25mL/min; gradient: 14% B to 21% B over 10min, 21% B; wavelength: 254nm; RT1 (min): 7.68; running number: 0) to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (3R) -4- [ (2E) -4- (dimethylamino) but-2-enoyl ] morpholin-3-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one; trifluoroacetic acid (14.4 mg, 14.04%) as a yellow solid.

LC-MS:(M+Na) ⁺ Actual: 617.05

¹ H NMR(400MHz,DMSO-d ₆ )δ11.16(s,1H),9.98(s,1H),8.63(s,1H),8.21(d,1H),7.99(s,1H),7.55–7.30(m,2H),7.02–6.87(m,1H),6.85–6.70(m,2H),6.67–6.49(m,1H),6.20–6.10(m,1H),5.04–4.85(m,1H),4.85(t,1H),4.65–4.45(m,1H),4.23–4.20(m,1H),4.11–3.79(m,7H),3.77–3.59(m,2H),3.57–3.36(m,3H),3.25–3.04(m,1H),2.97–2.64(m,6H)。

Example 47:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (3R) -4- (prop-2-enoyl) morpholin-3-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 189)

47.1: synthesis of tert-butyl (3R) -3- { [ (4-cyanopyridin-3-yl) oxy ] methyl } morpholine-4-carboxylate

3-fluoropyridine-4-carbonitrile (1.95 g,15.97mmol,1.00 g) was stirred at 80deg.C under nitrogen atmosphereAmount) and (3S) -3- (hydroxymethyl) morpholine-4-carboxylic acid tert-butyl ester (3.47 g,15.97mmol,1.00 eq.) and Cs ₂ CO ₃ (15.61 g,47.91mmol,3.00 eq.) in DMF (8 mL) for 2h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (3×5 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (2:1) to provide (3R) -3- { [ (4-cyanopyridin-3-yl) oxy]Methyl } morpholine-4-carboxylic acid tert-butyl ester (5 g, 98.03%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 320.05.

47.2: synthesis of tert-butyl (3R) -3- ({ [4- (aminomethyl) pyridin-3-yl ] oxy } methyl) morpholine-4-carboxylate

To (3R) -3- { [ (4-cyanopyridin-3-yl) oxy in a 50mL round bottom flask under nitrogen atmosphere ]A solution of tert-butyl methyl } morpholine-4-carboxylate (500 mg,1.57mmol,1.00 eq.) in MeOH (5.00 mL) and ammonia (7.0M in MeOH, 5.00mL,35 mmol) was added Raney Ni (500 mg,100 w/w%). The mixture was hydrogenated overnight at room temperature using a hydrogen balloon under a hydrogen atmosphere, filtered through a celite pad and concentrated under reduced pressure. The reaction was monitored by LCMS. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) elution to afford (3R) -3- ({ [4- (aminomethyl) pyridin-3-yl)]Tert-butyl oxy } methyl) morpholine-4-carboxylate (490 mg, 96.78%) as a yellow oil.

LC-MS: M+Hactual: 324.00.

47.3: synthesis of tert-butyl (3R) -3- ({ [4- ({ [1- (tert-butoxycarbonyl) -3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydropyridin-4-yl ] amino } methyl) pyridin-3-yl ] oxy } methyl) morpholine-4-carboxylate

(3R) -3- ({ [4- (aminomethyl) pyridin-3-yl) was added to a 50mL round bottom flask at room temperature]Tert-butyl oxy } methyl) morpholine-4-carboxylate (490 mg,1.50mmol,1.00 eq.) and 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl]-4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (600 mg,1.50mmol,1.00 eq.) and PyBOP (1.18 g,2.30mmol,1.50 eq.) and DIEA (587 mg,4.50mmol,3.00 eq.) and DMF (15 mL). The resulting mixture was stirred at room temperature under nitrogen for 5h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (1:1) to provide (3R) -3- ({ [4- ({ [1- (tert-butoxycarbonyl) -3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl)]-2-oxo-5, 6-dihydropyridin-4-yl]Amino } methyl) pyridin-3-yl]Tert-butyl oxy } methyl) morpholine-4-carboxylate (970 mg, 91.22%) as a yellow solid.

LC-MS: M+Hactual: 702.2.

47.4: synthesis of tert-butyl (3R) -3- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl } oxy) methyl ] morpholine-4-carboxylate

Stirring (3R) -3- ({ [4- ({ [1- (tert-butoxycarbonyl) -3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl) at 80℃under an air atmosphere]-2-oxo-5, 6-dihydropyridin-4-yl]Amino } methyl) pyridin-3-yl]Tert-butyl oxy } methyl) morpholine-4-carboxylate (970 mg,1.38mmol,1.00 eq.) and H ₂ O ₂ (30 w/w%,204mg,1.80mmol,1.30 eq.) in MeOH (15 mL) for 4h. The reaction was monitored by LCMS. The reaction was carried out by adding saturated Na at 0 ℃ ₂ SO ₃ (saturated) (0.1 mL) quench. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatographyPurification by CH ₂ Cl ₂ MeOH (50:1) to afford (3R) -3- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl } oxy) methyl]Morpholine-4-carboxylic acid tert-butyl ester (600 mg, 39.01%) as a yellow solid.

LC-MS: M+Hactual: 668.2.

47.5: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (3R) -morpholin-3-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

(3R) -3- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] was stirred at room temperature under a nitrogen atmosphere]-4-oxo-1H, 6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl } oxy) methyl]A solution of tert-butyl morpholine-4-carboxylate (300 mg,0.45mmol,1.00 eq.) in TFA (1.5 mL) and DCM (4.5 mL) for 20min. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ MeOH 10:1) purification to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- {3- [ (3R) -morpholin-3-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (150 mg, 49.28%) was a yellow solid.

LC-MS:M+H ⁺ Actual: 468.1.

47.6: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (3R) -4- (prop-2-enoyl) morpholin-3-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

In an 8mL vial, 3- [ (3-fluoro-2-methoxyphenyl) amino was added at 0deg.C]-2- {3- [ (3R) -morpholin-3-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (70 mg,0.15mmol,1.00 eq.) and acryloyl chloride (12 mg,0.14mmol,0.90 eq.) and TEA (45 mg,0.45 eq.)mmol,3.00 eq) and DCM (1.5 mL). The resulting mixture was stirred at room temperature under nitrogen for 1h. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The crude product (80 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 18% b to 33% b, 33% b in 11 min; wavelength is 254/220nm; RT1 (min) 10.38; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- { [ (3R) -4- (prop-2-enoyl) morpholin-3-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (16.3 mg, 20.29%) was a yellow solid.

LC-MS:M+H ⁺ Actual: 522.00.

¹ H NMR(300MHz,DMSO-d ₆ )δ10.91(s,1H),8.46(s,1H),8.11–7.91(m,1H),7.51(s,1H),7.44–7.21(m,1H),7.12(s,1H),7.00–6.34(m,3H),6.26–5.87(m,2H),5.76(s,1H),5.14–4.61(m,1H),4.55–4.12(m,2H),4.11–3.79(m,6H),3.62-3.59(m,2H),3.48-3.40(m,3H),3.24–2.70(m,2H)。

example 48:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -4- (prop-2-enoyl) morpholin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 201)

48.1: synthesis of (3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ (2R) -morpholin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

A solution of tert-butyl (2R) -2- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl } oxy) methyl ] morpholine-4-carboxylate (100 mg,0.15mmol,1.00 eq.) in DCM (1.5 mL) and TFA (0.5 mL) was stirred at room temperature under a nitrogen atmosphere for 20min. The resulting mixture was concentrated under reduced pressure to afford (3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ (2R) -morpholin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (65 mg, 91.89%) as a brown oil which was used directly in the next step without further purification.

LC-MS:M+H ⁺ Actual: 484.05.

48.2: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -4- (prop-2-enoyl) morpholin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ (2R) -morpholin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (50 mg,0.10mmol,1.00 eq.) and DIEA (80 mg,0.62mmol,6.00 eq.) in DCM (1 mL) at 0 ℃ under nitrogen was added dropwise acryloyl chloride (8 mg,0.09mmol,0.9 eq.). The resulting mixture was stirred at room temperature under nitrogen for 10min. The reaction was quenched by the addition of MeOH (0.5 mL) at 0deg.C. The resulting mixture was concentrated under reduced pressure to provide a crude product. The crude product (60 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH C18OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 8% B to 38% B over 7min, 38% B; wavelength: 254/220nm; RT1 (min): 6.53; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -4- (prop-2-enoyl) morpholin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-C ] pyridin-4-one (14.2 mg, 24.45%) as a yellow solid.

LC-MS:M+H ⁺ Actual: 537.95.

¹ H NMR(300MHz,DMSO-d ₆ )δ11.12(s,1H),8.48(s,1H),8.13(d,1H),7.70(s,1H),7.40(d,1H),7.23(t,1H),6.88–6.66(m,3H),6.25–6.08(m,2H),5.75–5.71(m,1H),4.54–4.38(m,1H),4.36–4.23(m,2H),4.18–3.93(m,3H),3.90(s,3H),3.51(s,1H),3.45(t,2H),3.35–3.07(m,1H),2.98–2.74(m,3H)。

example 49: (6S) -6- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } morpholin-3-one (compound 194)

49.1: synthesis of 3- { [ (2S) -5-oxomorpholin-2-yl ] methoxy } pyridine-4-carbonitrile

3-Fluoropyridine-4-carbonitrile (126 mg,1.03mmol,1.00 eq.) and (6S) -6- (hydroxymethyl) morpholin-3-one (788 mg,1.24mmol,1.20 eq.) were stirred at 60℃under N2 atmosphere ₂ CO ₃ (588 mg,3.10mmol,3.00 eq.) in DMF (3.00 mL) for 1h. The mixture was cooled to room temperature. The residue was dissolved in EA (20.00 ml). The resulting mixture was washed with saturated salt solution. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography DCM/meoh=10/1 to provide 3- { [ (2S) -5-oxomorpholin-2-yl]Methoxy } pyridine-4-carbonitrile (150 mg, 61.98%) as a white solid.

LC-MS: M+Hactual: 233.90.

49.2: synthesis of (S) -6- (((4- (aminomethyl) pyridin-3-yl) oxy) methyl) morpholin-3-one

At room temperature, H ₂ Stirring 3- { [ (2S) -5-oxomorpholin-2-yl under an atmosphere]A solution of methoxy } pyridine-4-carbonitrile (1.02 g,4.38mmol,1.00 eq.) and Raney Ni (1.02 g,100 w/w%) in ammonia (7.0M in MeOH, 5.00mL,35.00 mmol) in MeOH (10.00 mL) for 1h. The reaction was monitored by LCMS. The crude product (1.00 g) was used directly in the next step without further purification.

LC-MS: M+Hactual: 238.27.

49.3: synthesis of tert-butyl 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-4- { [ (3- { [ (2S) -5-oxomorpholin-2-yl ] methoxy } pyridin-4-yl) methyl ] amino } -5, 6-dihydropyridine-1-carboxylate

To (6S) -6- ({ [4- (aminomethyl) pyridin-3-yl) at room temperature under N2 atmosphere]Oxy } methyl) morpholin-3-one (400 mg,1.68mmol,1.00 eq.) and 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl]A stirred solution of tert-butyl 4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylate (696 mg,1.68mmol,1.00 eq.) in DMF (16.00 mL) was added dropwise DIEA (264 mg,5.06mmol,3.00 eq.) and PyBoP (1.31 g,2.53mmol,1.50 eq.). The resulting mixture was stirred at room temperature under an N2 atmosphere for 2h. The reaction was monitored by LCMS. The resulting mixture was extracted with EA (10.00 mL). The combined organic layers were washed with saturated saline (10.00 mL) and dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with MeOH/DCM (10%) to provide 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl]-2-oxo-4- { [ (3- { [ (2S) -5-oxomorpholin-2-yl]Methoxy } pyridin-4-yl) methyl]Amino } -5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (450 mg, 38.00%) as a dark yellow solid.

LC-MS: M+Hactual: 633.14.

49.4: synthesis of tert-butyl 3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-2- (3- { [ (2S) -5-oxomorpholin-2-yl ] methoxy } pyridin-4-yl) -1H,6H, 7H-pyrrolo [3,2-c ] pyridine-5-carboxylate

To MeOH (10.00 mL) was added 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl at room temperature]-2-oxo-4- { [ (3- { [ (2S) -5-oxomorpholin-2-yl]Methoxy } pyridin-4-yl) methyl]Amino } -5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (400 mg,0.63mmol,1.00 eq.) and H ₂ O ₂ Solution (30 w/w%,70mg,0.63mmol,1.00 eq.). The resulting mixture was stirred at 80℃for 1h. The reaction was monitored by LCMS. The residue was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with MeOH/DCM (10%) to afford 3- [ (3-chloro-2-methoxyphenyl) amino]-4-oxo-2- (3- { [ (2S) -5-oxomorpholin-2-yl]Methoxy groupPyridin-4-yl) -1H,6H, 7H-pyrrolo [3,2-c]Pyridine-5-carboxylic acid tert-butyl ester (120 mg, 28.54%) as a yellow oil.

LC-MS: M+Hactual: 599.06.

49.5: synthesis of (6S) -6- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } morpholin-3-one

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To a stirred solution of 3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-2- (3- { [ (2S) -5-oxomorpholin-2-yl ] methoxy } pyridin-4-yl) -1h,6h,7 h-pyrrolo [3,2-c ] pyridine-5-carboxylic acid tert-butyl ester (120 mg,0.20mmol,1.00 eq.) in DCM (1.00 mL) was added TFA (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 1h. The reaction was monitored by LCMS. The crude product was purified by preparative HPLC and using the following conditions (column: xselect CSH F-phenyl OBD column, 19X 250mm,5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25mL/min; gradient: 21% B to 32% B over 10min, 32% B; wavelength: 254nm; R1 (min): 8.75; running number: 0) to afford (6S) -6- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } morpholin-3-one (19.0 mg, 18.35%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 497.90.

¹ H NMR(400MHz,DMSO-d6)δ11.29(s,1H),8.53(s,1H),8.22(d,1H),8.12(d,1H),7.89(s,1H),7.48(d,1H),7.32(s,1H),6.83-6.71(m,2H),6.16(d,1H),4.52-4.41(m,1H),4.38-4.25(m,2H),4.18(s,2H),3.39(s,3H),3.29-3.26(m,4H),2.96-2.88(m,2H)。

example 50:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1-methanesulfonylazetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 191)

50.1: synthesis of tert-butyl (2R) -2- { [ (4-cyanopyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

To a stirred solution of tert-butyl (2R) -2- (hydroxymethyl) azetidine-1-carboxylate (0.74 g,3.93mmol,1.00 eq.) in THF (7.00 mL) at 0deg.C was added NaH (0.24 g,5.90mmol,1.50 eq., 60%) and stirred for 20 min. A solution of 3-fluoropyridine-4-carbonitrile (0.48 g,3.93mmol,1.00 eq.) in THF (7.00 mL) was added dropwise to the above mixture at 0deg.C. The resulting mixture was stirred at 0℃for a further 0.5h. The resulting mixture was quenched with water and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE/ea=3:1 to provide tert-butyl (2R) -2- { [ (4-cyanopyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (1.09 g, 95.83%) as a colorless oil.

LC-MS:(M+H) ⁺ Actual: 290.2.

50.2: synthesis of tert-butyl (2R) -2- ([ [4- (aminomethyl) pyridin-3-yl ] oxy ] methyl) azetidine-1-carboxylate

To (2R) -2- [ [ (4-cyanopyridin-3-yl) oxy at room temperature ]Methyl group]Azetidine-1-carboxylic acid tert-butyl ester (1.39 g,4.81mmol,1.00 eq.) in 7M NH ₃ (g) A solution in MeOH (2.00 mL) was added with Raney Ni (618 mg,44 w/w%). The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ MeOH 10:1) purification to afford (2R) -2- ([ [4- (aminomethyl) pyridin-3-yl)]Oxy group]Tert-butyl methyl-azetidine-1-carboxylate (1.40 g, 90%) as a yellow oil.

LC-MS:(M+H) ⁺ Actual: 294.2.

50.3: synthesis of tert-butyl 4- { [ (3- { [ (2R) -1- (tert-butoxycarbonyl) azetidin-2-yl ] methoxy } pyridin-4-yl) methyl ] amino } -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydropyridine-1-carboxylate

To a stirred solution of tert-butyl (2R) -2- ({ [4- (aminomethyl) pyridin-3-yl ] oxy } methyl) azetidine-1-carboxylate (630 mg,2.15mmol,1.00 eq) and tert-butyl 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylate (975 mg,2.36mmol,1.10 eq) and PyBOP (1676 mg,3.22mmol,1.50 eq) in DMF (15.00 mL) was added dropwise a solution of DIEA (833 mg,6.44mmol,3.00 eq) in DMF (15.00 mL) at room temperature under Ar atmosphere for 2h. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with DCM/meoh=100/1 to give tert-butyl 4- { [ (3- { [ (2R) -1- (tert-butoxycarbonyl) azetidin-2-yl ] methoxy } pyridin-4-yl) methyl ] amino } -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydropyridine-1-carboxylate (1.4954 g, 101.08%) as a yellow oil.

LC-MS:(M+H) ⁺ Actual: 688.2

50.4: synthesis of tert-butyl (2R) -2- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl } oxy) methyl ] azetidine-1-carboxylate

At 80 ℃ N ₂ 4- { [ (3- { [ (2R) -1- (tert-butoxycarbonyl) azetidin-2-yl was stirred under an atmosphere]Methoxy } pyridin-4-yl) methyl]Amino } -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl]-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (500 mg,0.73mmol,1.00 eq.) and H ₂ O ₂ (82 mg,0.73mmol,1.00 eq., 30%) in MeOH (10.00 mL) for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, C18 silica gel; mobile phase A.H ₂ O(0.05％NH ₄ HCO ₃ ) Mobile phase b.ch ₃ A CN; the flow rate is 60mL/min; gradient from 40B to 55B,8 min; 254nm; RT:6 to provide (2R) -2- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl } oxy) methyl]Azetidine-1-carboxylic acid tert-butyl ester (200 mg, 42.08%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 654.3

50.5: synthesis of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

A solution of tert-butyl (2R) -2- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl } oxy) methyl ] azetidine-1-carboxylate (200 mg,0.31mmol,1.00 eq.) and TFA (0.45 mL) in DCM (3.00 mL) was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. This gave the crude product 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (120 mg) as a colorless oil.

LC-MS:(M+H) ⁺ Actual: 454.0

50.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1-methanesulfonylazetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At room temperature, N ₂ Under an atmosphere, (2R) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] amino group was stirred]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (120 mg,0.22mmol,1.00 eq.) and MsCl (25 mg,0.22 mmol)A solution of TEA (109 mg,1.10mmol,5.00 eq.) in DCM (3.00 mL) for 1h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 30% B to 60% B, 60% B over 10 min; wavelength is 254/220nm; RT1 (min) 9.67; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (2R) -1-methanesulfonylazetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (20.8 mg, 17.89%) was a yellow solid.

LC-MS:(M) ⁺ Actual: 531.90

¹ H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.44(s,1H),8.04(d,1H),7.54(s,1H),7.33(d,1H),7.16(s,1H),6.74-6.65(m,2H),6.20-6.12(m,1H),4.86-4.75(m,1H),4.54-4.44(m,1H),4.32-4.23(m,1H),4.09-3.98(m,1H),3.89(s,3H),3.76-3.66(m,1H),3.45-3.36(m,2H),3.12(s,3H),2.88(t,2H),2.43-2.20(m,2H)。

Example 51:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -4- (prop-2-enoyl) morpholin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 200)

51.1: synthesis of (S) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (morpholin-2-ylmethoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } morpholine-4-carboxylate (50 mg,0.09mmol,1.00 eq.) in DCM (0.9 mL) at 0deg.C under nitrogen was added TFA (0.4 mL). The resulting mixture was stirred at room temperature under nitrogen for 1h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 484.05.

51.2: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -4- (prop-2-enoyl) morpholin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group at 0℃under argon atmosphere]-2- {3- [ (2S) -morpholin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (50 mg,0.10mmol,1.00 eq.) and Et ₃ A stirred mixture of N (52 mg,0.50mmol,5.00 eq.) in DCM (1.00 mL) was added dropwise acryloyl chloride (2 mg,0.02mmol,0.15 eq.). The resulting mixture was stirred at 0℃under argon for 10min. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by preparative HPLC and using the following conditions (column: xselect Peptide CSH C1819 x 150mm 5 μm,1; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 15% B to 45% B over 7 min; wavelength: 254nm; RT1 (min): 6.5; running number: 0) to afford 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (2S) -4- (prop-2-enoyl) morpholin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (8.7 mg, 15.17%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 538.30.

¹ H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.43(s,1H),8.04(s,1H),7.52(d,1H),7.29(s,1H),7.15(s,1H),6.75-6.90(m,1H),6.68(d,2H),6.20-6.09(m,2H),5.80-5.70(m,1H),4.50-4.35(m,1H),4.35-4.20(m,2H),4.20-3.95(m,2H),3.90-3.75(m,4H),3.65-3.50(m,1H),3.50-3.40(m,2H),3.20-3.05(m,1H),2.96-2.71(m,3H)。

example 52:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1-methanesulfonylazetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 192)

52.1: synthesis of tert-butyl (2S) -2- { [ (4-cyanopyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

To a stirred mixture of tert-butyl (2S) -2- (hydroxymethyl) azetidine-1-carboxylate (1533 mg,8.19mmol,1.00 eq.) in THF (14.00 mL) at 0deg.C under nitrogen was added NaH (60% in oil, 491mg,12.29mmol,1.50 eq.) in portions. The resulting mixture was stirred at 0℃under nitrogen for 30min. 3-Fluoropyridine-4-carbonitrile (1000 mg,8.19mmol,1.00 eq.) was added in portions to the above mixture at 0deg.C over 1 min. The resulting mixture was stirred overnight at room temperature under nitrogen. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (1:1) to provide tert-butyl (2S) -2- { [ (4-cyanopyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (180 mg, 75.96%) as a white solid.

LC-MS:(M+H) ⁺ Actual: 290.15

52.2.: synthesis of tert-butyl (2S) -2- ({ [4- (aminomethyl) pyridin-3-yl ] oxy } methyl) azetidine-1-carboxylate

To (2S) -2- { [ (4-cyanopyridin-3-yl) oxy at room temperature under argon atmosphere]Tert-butyl methyl } azetidine-1-carboxylate (1.00 g,3.46mmol,1.00 eq.) and NH in methanol ₃ (g) (7M in methanol, 20mL,140.00 mmol) and Raney Nickel (0.60 g,60 w/w%) were added in portions. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 2.5h. The desired product was detectable by LCMS. Filtering the resulting mixture; the filter cake was washed with methanol (3×100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (15:1) elution to afford (2S) -2- ({ [4- (aminomethyl) pyridin-3-yl)]Oxy } methyl) azetidinesTert-butyl alkyl-1-carboxylate (1.1 g, 90.41%) as a clear oil.

LC-MS:(M+H) ⁺ Actual: 294.20

52.3: synthesis of tert-butyl 2- [ ({ 4- [ ({ 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydro-1H-pyridin-4-yl } amino) methyl ] pyridin-3-yl } oxy) methyl ] azetidine-1-carboxylate

To a stirred mixture of tert-butyl (2S) -2- ({ [4- (aminomethyl) pyridin-3-yl ] oxy } methyl) azetidine-1-carboxylate (1.00 g,3.41mmol,1.00 eq.) and tert-butyl 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylate (1.40 g,3.41mmol,1.00 eq.) and PyBOP (2.66 g,5.11mmol,1.50 eq.) in DMF (20.00 mL) was added in portions DIEA (1.32 g,10.23mmol,3.00 eq.) at room temperature under nitrogen. The resulting mixture was stirred overnight at room temperature under nitrogen. The desired product was detectable by LCMS. Filtering the resulting mixture; the filter cake was washed with ethyl acetate (3×40 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, silica gel; mobile phase, meCN in water, gradient 10% to 50% within 10 min; a detector: UV 254nm. This gave tert-butyl 2- [ ({ 4- [ ({ 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydro-1H-pyridin-4-yl } amino) methyl ] pyridin-3-yl } oxy) methyl ] azetidine-1-carboxylate (1.1 g, 54.87%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 688.20

52.4: synthesis of tert-butyl (2S) -2- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl } oxy) methyl ] azetidine-1-carboxylate

A stirred mixture of tert-butyl 4- { [ (3- { [1- (tert-butoxycarbonyl) azetidin-2-yl ] methoxy } pyridin-4-yl) methyl ] amino } -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydropyridine-1-carboxylate (1.60 g,2.32mmol,1.00 eq.) and hydrogen peroxide (30 w/w%,0.34g,3.00mmol,1.30 eq.) added in portions in MeOH (30.0 mL) was stirred at room temperature under nitrogen. The resulting mixture was stirred at 80℃under nitrogen for 2h. The desired product was detectable by LCMS. The residue was purified by reverse phase flash chromatography using column, silica gel; mobile phase, meCN in water, gradient 10% to 50% within 10 min; a detector: UV 254nm. This gave (2S) -2- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl } oxy) methyl ] azetidine-1-carboxylic acid tert-butyl ester (0.56 g, 36.82%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 688.2

52.5: synthesis of (S) -2- (3- (azetidin-2-ylmethoxy) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl } oxy) methyl ] azetidine-1-carboxylate (50 mg,0.08mmol,1.00 eq.) in DCM (1.40 mL) at 0 ℃ under nitrogen atmosphere was added TFA (1.40 mL). The resulting mixture was stirred at room temperature under nitrogen for 1h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 454.1

52.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1-methanesulfonylazetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- {3- [ (2S) -azetidin-2-ylmethoxy at 0℃under argon atmosphere]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (135 mg,0.30mmol,1.00 eq.) and Et ₃ A stirred mixture of N (150 mg,1.50mmol,5.00 eq.) in DCM (2.90 mL) was added MsCl (34 mg,0.30mmol,1.00 eq.) in portions. The resulting mixture was stirred at 0℃under argon for 10min. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 20% B to 50% B, 50% B over 10 min; wavelength is 254/220nm; RT1 (min) 6.32; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (2S) -1-methanesulfonylazetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (27.7 mg, 17.33%) was a white solid.

LC-MS:(M+H) ⁺ Actual: 531.9.

¹ H NMR(300MHz,DMSO-d6)δ10.99(s,1H),8.44(s,1H),8.04(d,1H),7.54(s,1H),7.34(d,1H),7.18(d,1H),6.75-6.62(m,2H),6.21-6.08(m,1H),4.79(d,1H),4.51-4.39(m,1H),4.30-4.17(m,1H),4.07-3.90(m,1H),3.89(s,3H),3.79-3.60(m,1H),3.49-3.32(m,2H),3.13(s,3H),2.90-2.68(m,2H),2.39-2.21(m,2H)。

example 53:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (3S) -4- (prop-2-enoyl) morpholin-3-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 521)

53.1: synthesis of tert-butyl (3S) -3- { [ (4-cyanopyridin-3-yl) oxy ] methyl } morpholine-4-carboxylate

Cs was added portionwise to a stirred solution of 3-fluoropyridine-4-carbonitrile (5.87 g,27.05mmol,1.10 eq.) and (3R) -tert-butyl 3- (hydroxymethyl) morpholine-4-carboxylate (3.00 g,24.59mmol,1.00 eq.) in DMF (6 mL) at room temperature under nitrogen ₂ CO ₃ (5.40 g,16.57mmol,1.20 eq.). The resulting mixture was stirred at 60℃under nitrogen for 2h. The desired product can be detected in LC-MS. The reaction was diluted with water (20 mL) at room temperature. The aqueous layer was extracted with EtOAc (3×30 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with PE/EA (1:1) to provide (3S) -3- { [ (4-cyanopyridin-3-yl) oxy ]Tert-butyl methyl } morpholine-4-carboxylate (8.5 g, crude) as an off-white solid.

LC-MS (M+H) + actual: 320.00.

53.2: synthesis of tert-butyl (3S) -3- ({ [4- (aminomethyl) pyridin-3-yl ] oxy } methyl) morpholine-4-carboxylate

To a stirred solution of tert-butyl (3S) -3- { [ (4-cyanopyridin-3-yl) oxy ] methyl } morpholine-4-carboxylate (8.40 g,26.30mmol,1.00 eq.) and Raney nickel (4.2 g,50 w/w%) in MeOH (30 mL) was added ammonia (7.0M in MeOH, 15.00mL,105.00 mmol) dropwise at room temperature under nitrogen. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3h. The desired product was detected by LCMS. Filtering the resulting mixture; the filter cake was washed with MeOH (3X 30 mL). The filtrate was concentrated under reduced pressure to give tert-butyl (3S) -3- ({ [4- (aminomethyl) pyridin-3-yl ] oxy } methyl) morpholine-4-carboxylate (7.6 g, 66.12%) as a brown oil.

LC-MS:(M+H) ⁺ Actual: 324.05.

53.3: synthesis of tert-butyl (3S) -3- ({ [4- ({ [1- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydropyridin-4-yl ] amino } methyl) pyridin-3-yl ] oxy } methyl) morpholine-4-carboxylate

To (3S) -3- ({ [4- (aminomethyl) pyridin-3-yl) at room temperature under argon atmosphere]Tert-butyl oxy } methyl) morpholine-4-carboxylate (7.50 g,23.19mmol,1.00 eq.) and 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ]A stirred solution of tert-butyl 4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylate (11.49 g,27.83mmol,1.20 eq.) in DMF (70 mL) was added in portions DIEA (8.99 g,69.58mmol,3.00 eq.) and PyBOP (14.48 g,27.83mmol,1.20 eq.). The resulting mixture was stirred at room temperature under argon for 3h. The desired product can be detected by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) to afford (3S) -3- ({ [4- ({ [1- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl)]-2-oxo-5, 6-dihydropyridin-4-yl]Amino } methyl) pyridin-3-yl]Tert-butyl oxy } methyl) morpholine-4-carboxylate (9.60 g, 43.22%) as a yellow-green oil.

LC-MS:(M+H) ⁺ Actual: 718.2.

53.4: synthesis of tert-butyl (3S) -3- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl } oxy) methyl ] morpholine-4-carboxylate

To (3S) -3- ({ [4- ({ [1- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl) under a nitrogen atmosphere at room temperature]-2-oxo-5, 6-dihydropyridin-4-yl]Amino } methyl) pyridin-3-yl]A stirred mixture of tert-butyl oxy } methyl) morpholine-4-carboxylate (9.00 g,12.55mmol,1.00 eq.) in MeOH (90 mL) was added dropwise H ₂ O ₂ (30%) (2.13 g,18.80mmol,1.50 eq.). The resulting mixture was stirred at 80℃under nitrogen for 2h. The desired product can be detected by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) to afford (3S) -3- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl } oxy) methyl]Morpholine-4-carboxylic acid tert-butyl ester (8.00 g, 55.99%) as a tan oil.

LC-MS (M+H) + actual: 684.1.

53.5: synthesis of (S) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (morpholin-3-ylmethoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (3S) -3- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } morpholine-4-carboxylate (100 mg,0.17mmol,1.00 eq.) in DCM (3 mL) was added TFA (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 1h. The desired product can be detected by LCMS. The resulting mixture was concentrated in vacuo. The residue was used directly in the next step without any further purification.

LC-MS:(M+H) ⁺ Actual: 484.05.

53.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (3S) -4- (prop-2-enoyl) morpholin-3-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0℃to 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- {3- [ (3S) -morpholin-3-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (100 mg,0.21mmol,1.00 eq.) in DCM (3.00 mL) was added dropwise TEA (209 mg,2.07mmol,10.00 eq.) and acryloyl chloride (13 mg,0.15mmol,0.70 eq.). The resulting mixture was stirred at 0℃under nitrogen for 1h. The reaction was quenched with MeOH at 0 ℃. The resulting mixture was concentrated in vacuo. The crude product (150 mg) was purified by preparative HPLCThe following conditions (column: XBridge Prep OBD C, column: 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient from 22% b to 55% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (3S) -4- (prop-2-enoyl) morpholin-3-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (9.0 mg, 7.89%) was a white solid.

LC-MS:(M+H) ⁺ Actual: 537.95.

¹ H NMR(300MHz,DMSO-d6)δ11.01(s,1H),8.46(s,1H),8.11-7.93(m,1H),7.61-7.04(m,3H),6.85(m,1H),6.75 -6.56(m,2H),6.26-5.94(m,2H),5.82-5.39(m,1H),5.10-4.70(m,1H),4.55-4.11(m,2H),4.08-3.72(m,6H),3.71-3.33(m,5H),3.11-2.72(m,2H)。

Example 54:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 199)

54.1: (E) Synthesis of (E) -4- (dimethylamino) but-2-enoyl chloride

Oxalyl chloride (108 mg,0.85mmol,1.10 eq.) and DMF (3 mg,0.04mmol,0.05 eq.) are added dropwise to a stirred solution of (2E) -4- (dimethylamino) but-2-enoic acid (100 mg,0.78mmol,1.00 eq.) in THF (4 mL) at 0deg.C under nitrogen. The resulting mixture was stirred at 0℃under nitrogen for 1h. The desired product can be detected by TLC. The reaction was used directly in the next step without work-up.

54.2: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- {3- [ (2R) -azetidin-2-ylmethoxy at 0℃under argon atmosphere]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (80 mg,0.18mmol,1.00 eq.) in NMP (4 mL) was added dropwise (2E) -4- (dimethylamino) but-2-enoyl chloride (78 mg,0.53mmol,3.00 eq.). The resulting mixture was stirred at 0℃under argon for 1h. The desired product can be detected in LC-MS. The reaction was quenched by the addition of MeOH (5 mL) at 0deg.C. The resulting mixture was concentrated in vacuo. The crude product (40 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 21% b to 51% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl]Azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (8.3 mg, 8.33%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 565.35

¹ H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.39(s,1H),7.98(d,1H),7.56(s,1H),7.36(d,1H),7.15(t,1H),6.77-6.63(m,3H),6.19-6.08(m,2H),4.85(q,1H),4.56-4.51(m,1H),4.41-4.38(m,1H),4.23-4.17(m,2H),3.91(s,3H),3.45-3.41(m,2H),3.12-2.90(m,4H),3.33-2.96(m,3H),2.52-1.94(m,5H)。

Example 55:3- [ (3-fluoro-2-methylphenyl) amino ] -2- (3- { [ (2S) -1- (2-fluoroprop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 218)

55.1: synthesis of 3- [ (3-fluoro-2-methylphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (40 mg,0.075mmol,1 eq.) in DCM (1 mL) at room temperature under nitrogen was added TFA (0.3 mL). The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methylphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (32 mg, crude) as a red-brown yellow oil.

LC-MS:(M+H) ⁺ Actual: 436.0

55.2: synthesis of 3- [ (3-fluoro-2-methylphenyl) amino ] -2- (3- { [ (2S) -1- (2-fluoroprop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (3-fluoro-2-methylphenyl) amino group was cleaved by DIEA]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (32 mg,0.073mmol,1 eq.) in THF (3 mL) was basified to pH 8. 2-Fluoroprop-2-enoic acid (9.9 mg,0.109mmol,1.5 eq.) was added to the above mixture at 0deg.C under nitrogen atmosphere followed by dropwise addition of T ₃ P (46.8 mg,0.145mmol,2.0 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (40 mg) which was purified by preparative HPLC under the following conditions (YMC-acts three C18 ExRS,30 x 150mm,5 μm; mobile phase a: water (10 mmol/LNH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 30% B to 54% B, 54% B over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to give 3- [ (3-fluoro-2-methylphenyl) amino group ]-2- (3- { [ (2S) -1- (2-fluoroprop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (10.3 mg, 27.6%) as a pale yellow solid。

LC-MS:(M+H) ⁺ Actual: 508.15

¹ H NMR (400 MHz, chloroform-d) δ11.16 (s, 1H), 8.21 (s, 1H), 7.91 (d, 1H), 7.44 (s, 1H), 7.31 (d, 1H), 6.76-6.71 (m, 1H), 6.50 (t, 1H), 6.17 (d, 1H), 5.57-5.44 (m, 1H), 5.33-5.18 (m, 2H), 5.06 (s, 1H), 4.27 (t, 1H), 4.17-4.14 (m, 1H), 3.92-3.77 (m, 2H), 3.75-3.55 (m, 2H), 3.14 (t, 2H), 2.34 (s, 3H), 2.29-2.01 (m, 3H), 1.85-1.78 (m, 1H).

Example 56:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 523)

56.1: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a solution of tert-butyl (2R) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] pyrrolidine-1-carboxylate (100 mg,0.178mmol,1 eq.) in DCM (2 mL) was added TFA (0.7 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (100 mg, crude) as a red oil.

LCMS:(M+H) ⁺ Actual: 462.

56.2: (2E) Synthesis of (E) -4- (dimethylamino) but-2-enoyl chloride

To a stirred solution of (2E) -4- (dimethylamino) but-2-enoic acid (100 mg,0.774mmol,1 eq.) in THF (6 mL) at 0deg.C under nitrogen was added (COCl) ₂ (108 mg,0.851mmol,1.1 eq.) and DMF (0.1 mL). The resulting mixture was stirred at 0℃under nitrogen for 1h. TLC (PE/ea=2:1) showed that a new spot was detected. The resulting mixture was concentrated under reduced pressure to give (2E) -4- (dimethylamino) but-2-enoyl chloride (80 mg, crude) as a brown oil.

56.3: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

A mixture of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (100 mg,0.216mmol,1.00 eq.) in NMP (2 mL) was basified with DIEA to pH 8. (2E) -4- (dimethylamino) but-2-enoyl chloride (47.9 mg,0.324mmol,1.5 eq.) was added dropwise to the above mixture at 0℃under argon. The resulting mixture was stirred at 0℃for 30min. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC using the following conditions (column: xselect CSH C18 OBD column 30 x 150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 9%B to 25% B, 25% B over 10 min; wavelength: 254/220 nm) to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-C ] pyridin-4-one (31.7 mg, 25.3%) as a light brown solid.

LCMS:(M+H) ⁺ Actual: 573.35.

¹ h NMR (300 MHz, chloroform-d) δ11.09 (s, 1H), 8.54 (s, 1H), 8.19-8.10 (m, 1H), 7.69 (s, 1H), 7.42 (d, 1H), 6.93-6.73 (m, 1H), 6.71-6.65 (m, 1H), 6.60 (t, 1H), 6.51-6.42 (m, 1H), 6.25-6.12 (m, 1H), 5.58 (s, 1H), 4.89 (t, 1H), 4.06 (s, 3H), 3.88-3.74 (m, 1H), 3.72-3.31 (m, 5H), 3.29-3.20 (m, 2H), 2.49 (s, 6H), 2.39-2.21 (m, 3H), 2.15-2.05 (m, 1H).

Example 57:2- (3- {2- [1- (difluoromethyl) cyclopropyl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 558)

57.1: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (500 mg,1.16mmol,1.00 eq), cuI (22 mg,0.116mmol,0.10 eq.) and NaI (347mg, 2.32mmol,2.00 eq.) in dioxane (5 mL) was added dropwise DMEDA (51 mg,0.580mmol,0.50 eq.). The resulting mixture was stirred overnight at 110℃under argon. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) elution to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (320 mg, 57.71%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 478.95.

57.2: synthesis of 2- (3- {2- [1- (difluoromethyl) cyclopropyl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (80 mg,0.162mmol,1.00 eq.), cuI (4 mg,0.02mmol,0.10 eq.), pd (dppf) Cl ₂ .CH ₂ Cl ₂ A stirred mixture of (17 mg,0.02mmol,0.10 eq.) and DIEA (108 mg, 0.336 mmol,4.00 eq.) in DMF (1 mL) was added 1- (difluoromethyl) -1-ethynylcyclopropane (48 mg,0.418mmol,2 eq.). Stirring at 50deg.C under argon atmosphereThe resulting mixture was allowed to stand for 4h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC and using the following conditions (column: xselect CSH OBD column 30 x 150mm 5um, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 28% B to 47% B,8min, 47% B; wavelength: 254/220nm; RT1 (min): 8; running number: 0) to provide 2- (3- {2- [1- (difluoromethyl) cyclopropyl) ]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (42.9 mg, 43.33%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 466.95.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.40(s,1H),8.86-8.21(m,2H),7.42-7.29(m,2H),7.13(t,1H),6.61-6.54(m,1H),6.46-6.39(m,1H),5.98-5.67(m,2H),3.87(s,3H),3.47-3.41(m,2H),2.82(t,2H),1.32-1.18(m,4H)。

example 58:2- (3- {2- [1- (difluoromethyl) cyclopropyl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methylphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 557)

58.1: synthesis of 3- [ (3-fluoro-2-methylphenyl) amino ] -2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methylphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (500 mg,1.20mmol,1.00 eq), cuI (23 mg,0.12mmol,0.10 eq.) and NaI (361 mg,2.40mmol,2.00 eq.) in dioxane (5 mL) was added dropwise DMEDA (53 mg,0.602mmol,0.50 eq.). The resulting mixture was stirred overnight at 110℃under argon. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) elution to afford 3- [ (3-fluoro-2-methylphenyl) amino group]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (300 mg, 53.90%) It is a yellow solid.

LC-MS:(M+H) ⁺ Actual: 463.0.

58.2: synthesis of 2- (3- {2- [1- (difluoromethyl) cyclopropyl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methylphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (80 mg,0.162mmol,1.00 eq.), cuI (3 mg,0.02mmol,0.10 eq.), pd (dppf) Cl ₂ .CH ₂ Cl ₂ A stirred mixture of (14 mg,0.02mmol,0.10 eq.) and DIEA (89 mg,0.692mmol,4.0 eq.) in DMF (1 mL) was added 1- (difluoromethyl) -1-ethynylcyclopropane (40 mg, 0.348 mmol,2.0 eq.). The resulting mixture was stirred at 50℃under argon for 4h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC and using the following conditions (column: xselect CSH OBD column 30X 150mm 5um, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 28% B to 47% B,8min, 47% B; wavelength: 254/220nm; RT1 (min): 8; running number: 0) to provide 2- (3- {2- [1- (difluoromethyl) cyclopropyl)]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methylphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-one (14.7 mg, 18.67%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 451.00.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.32(s,1H),8.53(s,1H),8.31(d,1H),7.23(d,1H),7.20-7.14(m,2H),6.74-6.67(m,1H),6.40(t,1H),6.02(d,1H),5.98-5.65(m,1H),3.47-3.40(m,2H),2.83(t,2H),2.14(s,3H),1.29-1.17(m,4H)。

example 59:2- (3- { [ (2S) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methylphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 217)

59.1: synthesis of 3- [ (3-fluoro-2-methylphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one

To a solution of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (40 mg,0.075mmol,1 eq.) in DCM (1 mL) was added TFA (0.3 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methylphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (32 mg, crude) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 436.0

59.2: synthesis of 2- (3- { [ (2S) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methylphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (3-fluoro-2-methylphenyl) amino group in THF (1 mL) was cleaved with DIEA]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (32 mg,0.073mmol,1 eq.) was basified to pH8. (2E) -4- (dimethylamino) but-2-enoic acid (14.2 mg,0.11mmol,1.50 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (46.7 mg,0.146mmol,2.00 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. At 0 ℃, naHCO is added ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (60 mg), which was purified by preparative HPLC under the following conditions (column: Xselect CSH C18 OBD column 30 x 150mm 5 μm, n; mobile phase A water (0.1% FA), mobile phase B ACN; the flow rate is 60mL/min; gradient 9%B to 19% b, 19% b over 7 min; wavelength 254/220 nm) to provide 2- (3- { [ (2S) -1- [ (2E) -4- (dimethylamino) but-2-enoyl]Pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methylphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (10.9 mg, 26.8%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 547.15

¹ H NMR (300 MHz, chloroform-d) δ11.49 (s, 1H), 8.20 (s, 1H), 7.91 (d, 1H), 7.38-7.31 (m, 2H), 6.94-6.80 (m, 1H), 6.78-6.63 (m, 1H), 6.55-6.42 (m, 2H), 6.17 (d, 1H), 5.47 (s, 1H), 5.11-4.93 (m, 1H), 4.26 (t, 1H), 4.09-3.85 (m, 1H), 3.76 (t, 2H), 3.69-3.54 (m, 2H), 3.37-3.26 (m, 2H), 3.24-3.16 (m, 2H), 2.42 (s, 6H), 2.34 (s, 3H), 2.21-2.05 (m, 3H), 1.96-1.84 (m, 1H).

Example 60:3- [ (3-chloro-2-ethylphenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 216)

60.1: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-ethylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

(2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) was reacted at room temperature under argon atmosphere]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (90 mg,0.167mmol,1 eq.) and Cs ₂ CO ₃ A stirred solution of (108 mg, 0.336 mmol,2 eq.) in DMF (1 mL) was added EPhos Pd G4 (15.3 mg,0.017mmol,0.1 eq.) and 3-chloro-2-ethylaniline (26 mg,0.167mmol,1 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to provide (2S) -2- { [ (4- {3- [ (3-chloro-2-ethylphenyl) amino)]-4-oxo-1H, 5H,6H7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (90 mg, 95.1%) was a yellow solid.

LC-MS: M+Hactual: 566.0.

60.2: synthesis of 3- [ (2-ethylphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-ethylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (90 mg,0.159mmol,1 eq.) in DCM (0.9 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (2-ethylphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (130 mg, crude) as a red oil.

LC-MS: M+Hactual: 466.0.

60.3: synthesis of 3- [ (3-chloro-2-ethylphenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With NaHCO ₃ 3- [ (2-ethylphenyl) amino ] in THF (2 mL)]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (130 mg,0.181mmol,1 eq.) was basified to pH8. To the above mixture was added acryloyl chloride (18.8 mg,0.208mmol,1.15 eq.) at 0deg.C under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 1h. For mixtures CH ₂ Cl ₂ (3X 3 mL) extraction. The combined organic layers were washed with saturated NaCl (aq) (10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. Passing throughAfter filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 33% b to 50% b, 50% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 3- [ (3-chloro-2-ethylphenyl) amino group]-2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (5.9 mg, 6.18%) was a yellow solid.

LC-MS: M+Hactual: 520.00.

¹ h NMR (300 MHz, chloroform-d) δ11.60 (s, 1H), 8.16 (s, 1H), 7.83 (d, 1H), 7.73 (s, 1H), 7.23 (s, 1H), 6.84 (d, 1H), 6.69 (t, 1H), 6.56-6.45 (m, 1H), 6.42 (d, 1H), 6.38-6.31 (m, 1H), 5.83-5.79 (m, 1H), 5.23 (s, 1H), 5.13-4.96 (m, 1H), 4.24 (t, 1H), 4.15-4.08 (m, 1H), 3.76 (t, 2H), 3.68-3.54 (m, 2H), 3.32-3.18 (m, 2H), 3.07-2.91 (m, 2H), 2.25-2.06 (m, 4H), 1.37 (t, 3H).

Example 61:3- [ (2-Ethyl-3-fluorophenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 211)

61.1: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (2-ethyl-3-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

To (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) under argon at room temperature]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (90 mg,0.167mmol,1 eq.) and Cs ₂ CO ₃ A stirred solution of (109 mg, 0.336 mmol,2 eq.) in DMF (1 mL) was added EPhos Pd G4 (15.4 mg,0.017mmol,0.1 eq.) and 2-ethyl-3-fluoroaniline (27.9 mg,0.200mmol,1.2 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed completion of the reaction and observed the desired yieldAnd (3) an object. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (10:1) elution to provide (2S) -2- { [ (4- {3- [ (2-ethyl-3-fluorophenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (90 mg, 97.95%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 550.30.

61.2: synthesis of 3- [ (2-ethyl-3-fluorophenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2S) -2- { [ (4- {3- [ (2-ethyl-3-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (90 mg,0.164mmol,1 eq.) in DCM (0.9 mL) was added TFA (0.3 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (2-ethyl-3-fluorophenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (90 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 450.20.

61.3: synthesis of 3- [ (2-ethyl-3-fluorophenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With NaHCO ₃ Aqueous solution 3- [ (2-ethyl-3-fluorophenyl) amino group in THF (0.5 mL)]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ]Stirring solution base of pyridin-4-one (90 mg,0.160mmol,1 eq.) in waterAnd (3) the solution is converted to pH 8. To the above mixture was added acryloyl chloride (16.6 mg,0.184mmol,1.15 eq.) at 0deg.C under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 1h. For mixtures CH ₂ Cl ₂ (3X 3 mL) extraction. The combined organic layers were washed with saturated NaCl (aq) (10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 30% B to 60% B, over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number 0) to provide 3- [ (2-ethyl-3-fluorophenyl) amino group]-2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (11.6 mg, 13.96%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 504.15.

¹ h NMR (300 MHz, chloroform-d) δ11.53 (s, 1H), 8.17 (s, 1H), 7.86 (d, 1H), 7.60 (s, 1H), 7.29 (d, 1H), 6.76-6.33 (m, 4H), 6.21 (d, 1H), 5.85-5.79 (m, 1H), 5.22 (s, 1H), 5.14-4.98 (m, 1H), 4.24 (t, 1H), 4.16-4.10 (m, 1H), 3.76 (t, 2H), 3.67-3.50 (m, 2H), 3.23 (t, 2H), 2.95-2.78 (m, 2H), 2.25-2.05 (m, 4H), 1.45-1.31 (m, 3H).

Example 62:2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 227)

62.1: synthesis of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2S) -2- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl } oxy) methyl ] azetidine-1-carboxylate (640 mg,1.02mmol,1 eq.) in DCM (6 mL) was added TFA (2 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (1.2 g, crude) as a red oil.

LC-MS: M+Hactual: 454.1.

62.2: synthesis of 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- {3- [ (2R) -azetidin-2-ylmethoxy ] with DIEA ]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A mixture of pyridin-4-one (230 mg,0.220mmol,1 eq.) in THF (1 mL) was basified to pH 8. 2-butynoic acid (27.7 mg,0.330mmol,1.5 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (209 mg,0.330mmol,1.5 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (100 mg) which was purified by preparative HPLC (column XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/LNH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 27% b to 57% b, 57% b over 7 min; wavelength of 254nm; RT1 (min) 5.57; running number 0) to provide 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (16.3 mg, 14.0%) was a yellow solid.

LC-MS: M+Hactual: 519.95.

¹ h NMR (400 MHz, chloroform-d) δ11.40 (s, 1H), 8.25 (s, 1H), 7.98 (d, 1H),7.53(s,1H),7.44(d,1H),6.80-6.70(m,1H),6.60(t,1H),6.20-6.18(m,1H),5.19(s,1H),5.01-4.87(m,1H),4.49(t,1H),4.31-4.19(m,3H),4.07(s,3H),3.64-3.51(m,2H),3.11-3.00(m,2H),2.72-2.49(m,1H),2.20-2.10(m,1H),2.03(s,3H)。

Example 63:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 226)

2- {3- [ (2R) -azetidin-2-ylmethoxy in THF (1 mL) was treated with DIEA]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (230 mg,0.220mmol,1 eq.) was basified to pH 8. 2-Fluoroprop-2-enoic acid (29.7 mg,0.330mmol,1.5 eq.) was added to the above mixture at 0deg.C under nitrogen atmosphere followed by dropwise addition of T ₃ P (210 mg,0.330mmol,1.5 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (100 mg) which was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/LNH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 28% b to 52% b, 52% b over 9 min; wavelength is 254/220nm; RT1 (min) 7.53; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group ]-2- (3- { [ (2R) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (25.2 mg, 21.55%) was a yellow solid.

LC-MS: M+Hactual: 525.90.

¹ H NMR(300MHz,DMSO-d ₆ )δ11.53(s,1H),8.40(s,1H),8.01(d,1H),7.49(s,1H),7.35(d,1H),7.12(s,1H),6.75-6.57(m,2H),6.19-6.04(m,1H),5.65-5.26(m,2H),4.98-4.72(m,1H),4.64-4.40(m,2H),4.32(s,2H),3.89(s,3H),3.45-3.39(m,2H),2.99-2.81(m,2H),2.62-2.52(m,1H),2.26-2.02(m,1H)。

example 64:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S, 5S) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 240)

64.1: synthesis of (2S, 5S) -2- (hydroxymethyl) -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

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At 0 ℃, N ₂ To a stirred solution of (2S, 5S) -1- (tert-butoxycarbonyl) -5-methylpyrrolidine-2-carboxylic acid (3.00 g,13.1mmol,1 eq.) in THF (30 mL) under an atmosphere was added BH ₃ THF (1.35 g,15.7mmol,1.20 eq.). The resulting mixture was stirred at 25℃for 1h. The resulting solution was quenched by the addition of MeOH (100 mL). The mixture was concentrated in vacuo to afford (2 s,5 s) -2- (hydroxymethyl) -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (3 g, crude) as a white oil.

64.2: synthesis of (2S, 5S) -2-formyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

At 0 ℃, N ₂ To a stirred solution of (2S, 5S) -2- (hydroxymethyl) -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (3 g,13.9mmol,1 eq.) in DCM (30 mL) was added Dess-Martin (Dess-Martin) reagent (8.88 g,20.9mmol,1.5 eq.) under atmosphere. The resulting mixture was stirred at 25℃for 1h. By addition of Na ₂ SO ₃ (5 mL) quench the resulting solution. With Na ₂ CO ₃ The mixture was neutralized to pH 7. The mixture was extracted with DCM (3X 20 mL). The combined organic layers were washed with NaCl (3X 50 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE/EA (20/1) to give (2S, 5S) -2-formyl-5-methylpyrrolidine-1-Tert-butyl carboxylate (2.33 g, 80.5%) as a white oil.

64.3: synthesis of (2S, 5S) -2-ethynyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

At 0 ℃, N ₂ To (2S, 5S) -2-formyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (2 g,9.37mmol,1.00 eq.) and K under an atmosphere ₂ CO ₃ A stirred solution of (2.59 g,18.7mmol,2.00 eq.) in MeOH (30 mL) was added Bestmann-Ohira reagent (2.16 g,11.2mmol,1.20 eq.). The resulting mixture was stirred at 25℃for 2h. The resulting solution was quenched with saturated sodium potassium tartrate (aq) (5 mL) at 0 ℃. The mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with aqueous NaCl (3X 50 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE/EA (20/1) to give (2 s,5 s) -2-ethynyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 68.79%) as a white oil.

64.4: synthesis of (2S, 5S) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

Under the argon atmosphere at room temperature, 3- [ (3-chloro-2-methoxyphenyl) amino is obtained]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (200 mg,0.404mmol,1.00 eq), (2S, 5S) -2-ethynyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (254 mg,1.21mmol,3 eq.), cuI (38.5 mg,0.202mmol,0.5 eq.), DIEA (261 mg,2.02mmol,5 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (82.3 mg,0.101mmol,0.25 eq.) in DMF (5 mL). The resulting mixture was stirred overnight at 50℃under argon. The resulting mixture was concentrated in vacuo. The residue was taken up in silica gelPurification by column chromatography using CH ₂ Cl ₂ MeOH (25:1) to afford (2 s,5 s) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 51.53%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 576.25

64.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S, 5S) -5-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of (2 s,5 s) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (100 mg,0.174mmol,1 eq.) in DCM (3 mL) at room temperature under nitrogen atmosphere was added TFA (1 mL). The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2 s,5 s) -5-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (120 mg, crude) as a yellow oil.

LC-MS:(M+H) ⁺ Actual: 476.20

64.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2 s,5 s) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one

With saturated NaHCO ₃ (aqueous solution) 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2S, 5S) -5-methylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (100 mg,0.210mmol,1 eq.) in THF (3 mL) was basified to pH 8. At 0 ℃, toAcryloyl chloride (38 mg,0.420mmol,2 eq.) was added dropwise to the above mixture. The resulting mixture was stirred at room temperature for 30min. The reaction was quenched with MeOH (0.5 mL) at 0deg.C. For mixtures CH ₂ Cl ₂ MeOH (10/1) (2X 10 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (100 mg) which was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 34% b to 53% b, 53% b over 8 min; wavelength is 254/220nm; RT1 (min): 8) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2 s,5 s) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (34.9 mg, 31.18%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 530.10.

¹ h NMR (400 MHz, chloroform-d) δ11.25 (s, 1H), 8.55 (s, 1H), 8.12 (d, 1H), 7.80 (s, 1H), 7.42 (d, 1H), 6.73-6.71 (m, 1H), 6.62-6.57 (m, 1H), 6.54-6.50 (m, 1H), 6.45-6.40 (m, 1H), 6.23-6.21 (m, 1H), 5.79-5.76 (m, 1H), 5.25 (s, 1H), 4.89-4.80 (m, 1H), 4.38-4.25 (m, 1H), 4.07 (s, 3H), 3.68-3.52 (m, 2H), 3.32-3.21 (m, 2H), 2.49-2.30 (m, 2H), 2.22-2.10 (m, 1H), 1.98-1.90 (m, 1H), and 1.42 (d, 1H).

Example 65:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S, 5R) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 239)

65.1: synthesis of (2S, 5R) -2- (hydroxymethyl) -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of (2S, 5R) -1- (tert-butoxycarbonyl) -5-methylpyrrolidine-2-carboxylic acid (900 mg,3.925mmol,1 eq.) in THF (9 mL) at 0deg.C under nitrogen atmosphere was added BH ₃ THF (506 mg,5.89mmol,1.5 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. By passing throughThe resulting solution was quenched by the addition of MeOH (20 mL). The mixture was concentrated in vacuo to afford (2 s,5 r) -2- (hydroxymethyl) -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (850 mg, crude) as a yellow oil.

LC-MS: M+Hactual: 216.0.

65.2: synthesis of (2S, 5R) -2-formyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred mixture of (2S, 5R) -2- (hydroxymethyl) -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (870 mg,4.04mmol,1 eq.) in dichloromethane (9 mL) at 0deg.C under nitrogen was added the Dess-Martin reagent (2.06 g,4.85mmol,1.2 eq.) in portions. The resulting mixture was stirred at room temperature under nitrogen for 1h. At 0℃with saturated NaHCO ₃ The reaction was quenched (in water). For mixtures CH ₂ Cl ₂ (3X 10 mL) extraction. The combined organic layers were washed with saturated aqueous NaCl solution (20 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE/EA (30:1) to give (2 s,5 r) -2-formyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (700 mg, 81.22%) as a white oil.

LC-MS: M+Hactual: 214.0.

65.3: synthesis of (2S, 5R) -2-ethynyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To (2S, 5R) -2-formyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (650 mg,3.05mmol,1 eq.) and K at 0deg.C under nitrogen atmosphere ₂ CO ₃ A stirred solution of (842 mg,6.10mmol,2 eq.) in MeOH (10 mL) was added in portions dimethyl (1-diazo-2-oxopropyl) phosphonate (878 mg,4.57mmol,1.5 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting solution was quenched with saturated sodium potassium tartrate (aq) (10 mL) at 0 ℃. For mixturesEA (3X 20 mL) extraction. The combined organic layers were washed with saturated aqueous NaCl solution (20 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE/EA (30:1) to give (2 s,5 r) -2-ethynyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (450 mg, 70.55%) as a white oil.

LC-MS: M+Hactual: 210.0.

65.4: synthesis of- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2 s,5 r) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere ]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (200 mg,0.404mmol,1.00 eq.) and CuI (38.5 mg,0.202mmol,0.5 eq.) in DMF (3 mL) was added Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (164 mg,0.202mmol,0.5 eq.) and DIEA (157 mg,1.21mmol,3 eq.) and (2 s,5 r) -2-ethynyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (211 mg,1.01mmol,2.50 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using column, silica gel; mobile phase, meCN in water, gradient 10% to 50% within 10 min; a detector: UV 254nm to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2 s,5 r) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (150 mg, 70.00%) was a yellow solid.

LC-MS: M+Hactual: 576.0.

65.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S, 5R) -5-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2 s,5 r) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (140 mg,0.264mmol,1 eq) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2 s,5 r) -5-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (180 mg, crude) as a red oil.

LC-MS: M+Hactual: 476.0.

65.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2 s,5 r) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one

With saturated NaHCO ₃ (aqueous solution) 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2S, 5R) -5-methylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (180 mg,0.265mmol,1 eq.) in THF (2 mL) was basified to pH 8. To the above mixture was added acryloyl chloride (27.5 mg,0.305mmol,1.15 eq.) at 0deg.C under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 1h. MeOH (1 mL) was added to the reaction mixture at 0deg.C and used with CH ₂ Cl ₂ (3X 5 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (130 mg) which was purified by preparative HPLC (column XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 38% B to 54% B, 54% B over 8 min; wavelength is 254/220nm; RT1 (min) 8; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group ]-2-(3-{2-[(2S,5R) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (14.2 mg, 10.05%) was a yellow solid.

LC-MS: M+Hactual: 530.10.

¹ h NMR (300 MHz, chloroform-d) δ11.06 (s, 1H), 8.53 (s, 1H), 8.15 (s, 1H), 7.72 (s, 1H), 7.44 (s, 1H), 6.78-6.71 (m, 1H), 6.65-6.38 (m, 3H), 6.27-6.12 (m, 1H), 5.83-5.67 (m, 1H), 5.26 (s, 1H), 5.01 (d, 1H), 4.46-4.28 (m, 1H), 4.07 (s, 3H), 3.77-3.49 (m, 2H), 3.38-3.14 (m, 2H), 2.58-2.22 (m, 3H), 1.95-1.86 (m, 1H), 1.30 (d, 3H).

Example 66:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R, 5R) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 238)

66.1: synthesis of (2R, 5R) -2- (hydroxymethyl) -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

BH was added dropwise to a stirred solution of (2R, 5R) -1- (tert-butoxycarbonyl) -5-methylpyrrolidine-2-carboxylic acid (1 g,4.36mmol,1 eq.) in THF (10 mL) at 0deg.C under nitrogen ₃ THF (6.6 mL,1.5 eq.). The resulting mixture was stirred at 75℃under nitrogen for 1h. The reaction was quenched with MeOH (5 mL) at 0deg.C. The mixture was concentrated in vacuo to afford (2 r,5 r) -2- (hydroxymethyl) -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (900 mg, crude) as a colorless oil.

66.2: synthesis of (2R, 5R) -2-formyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of (2R, 5R) -2- (hydroxymethyl) -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (900 mg,4.18mmol,1 eq.) in DCM (20 mL) at 0deg.C under nitrogen was added the Dess-Martin reagent (1.95 g,4.60mmol,1.1 eq.) in portions. At room temperature,The resulting mixture was stirred under nitrogen for 1h. The reaction was quenched with saturated aqueous sodium sulfite (5 mL) at 0 ℃. For mixtures CH ₂ Cl ₂ (2X 20 mL) extraction. The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE/EA (30:1) to give (2 r,5 r) -2-formyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (79mg, 88.6%) as a colorless oil.

66.3: synthesis of (2R, 5R) -2-ethynyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To (2R, 5R) -2-formyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (79mg, 3.70mmol,1 eq.) and K at 0deg.C under nitrogen atmosphere ₂ CO ₃ (1.02 g,7.41mmol,2 eq.) A stirred solution of Bestmann-Ohira reagent (254 mg,4.45mmol,1.2 eq.) in MeOH (30 mL) was added dropwise. The resulting mixture was stirred at room temperature under nitrogen for 1h. The reaction was quenched with saturated sodium potassium tartrate (aq) (5 mL) at 0deg.C. The mixture was extracted with EtOAc (2X 30 mL). The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE/EA (20:1) to give (2 r,5 r) -2-ethynyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (610 mg, 78.7%) as a colorless oil.

66.4: synthesis of (2R, 5R) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

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Stirring 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100 mg,0.202mmol,1.00 eq.), cuI (19.3 mg,0.101mmol,0.5 eq.), DIEA (131 mg,1.01mmol,5 eq.), pd (dppf) Cl ₂ CH ₂ Cl ₂ (91 mg,0.11mmol,0.25 eq.) and (2R, 5R) -2-ethynyl-5-A mixture of tert-butyl methylpyrrolidine-1-carboxylate (84.6 mg,0.404mmol,2 eq.) in DMF (3 mL). The resulting mixture was stirred at 50℃under argon for 4h. The mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 80% within 10 min; a detector: UV 254nm. This gives (2R, 5R) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 85.8%) as a yellow oil.

LC-MS:(M+H) ⁺ Actual: 576.10

66.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R, 5R) -5-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2 r,5 r) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -5-methylpyrrolidine-1-carboxylate (90.0 mg,0.156mmol,1 eq.) in DCM (3 mL) was added TFA (1 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2 r,5 r) -5-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (120 mg, crude) as a yellow oil.

LC-MS:(M+H) ⁺ Actual: 476.0

66.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R, 5R) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With saturated NaHCO ₃ Aqueous solution 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2R, 5R) -5-methylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A mixture of pyridin-4-one (120 mg,0.252mmol,1 eq.) in THF (2 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (41.1 mg,0.454mmol,1.8 eq.) at 0deg.C. The resulting mixture was stirred at room temperature for 30min. The reaction was quenched with MeOH (0.5 mL) at 0deg.C. For mixtures CH ₂ Cl ₂ MeOH (10/1) (2X 10 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (100 mg) which was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 33% b to 49% b, 49% b over 8 min; wavelength is 254/220nm; RT1 (min) 8; ) To provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2 r,5 r) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (28.7 mg, 21.1%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 530.10

¹ H NMR (400 MHz, chloroform-d) δ11.25 (s, 1H), 8.56 (s, 1H), 8.13 (s, 1H), 7.80 (s, 1H), 7.44 (s, 1H), 6.76-6.69 (m, 1H), 6.61 (t, 1H), 6.49-6.57 (m, 1H), 6.47-6.39 (m, 1H), 6.22 (d, 1H), 5.82-5.75 (m, 1H), 5.22 (s, 1H), 4.83 (t, 1H), 4.33-4.21 (m, 1H), 4.07 (s, 3H), 3.66-3.56 (m, 2H), 3.34-3.19 (m, 2H), 2.52-2.29 (m, 2H), 2.23-2.09 (m, 1H), 1.97-1.88 (m, 1H), 1.42 (d, 1.42).

Example 67:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1S, 3R, 4R) -2- (prop-2-enoyl) -2-azabicyclo [2.2.1] hept-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 236)

67.1: synthesis of tert-butyl (1S, 3R, 4R) -3- (hydroxymethyl) -2-azabicyclo [2.2.1] heptane-2-carboxylate

At 0 ℃, N ₂ To (1S, 3R, 4R) -2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1 under an atmosphere]A stirred solution of heptane-3-carboxylic acid (1 g,4.14mmol,1 eq.) in THF (10 mL) was added drop wise to BH ₃ THF (0.43 g,4.97mmol,1.2 eq.). At N ₂ The resulting mixture was stirred at room temperature for 2h under an atmosphere. By addition of saturated NaHCO at 0deg.C ₃ The reaction was quenched with water and extracted with EA (50 mL). The organic layer was washed with saturated aqueous NaCl solution (50 mL) and concentrated under reduced pressure. This gives (1S, 3R, 4R) -3- (hydroxymethyl) -2-azabicyclo [2.2.1]Tert-butyl heptane-2-carboxylate (0.94 g, crude) as a colorless oil.

67.2: synthesis of tert-butyl (1S, 3R, 4R) -3-formyl-2-azabicyclo [2.2.1] heptane-2-carboxylate

At 0 ℃, N ₂ To (1S, 3R, 4R) -3- (hydroxymethyl) -2-azabicyclo [2.2.1 under an atmosphere]A stirred solution of tert-butyl heptane-2-carboxylate (0.94 g,4.13mmol,1 eq.) in dichloromethane (10 mL) was added Dess-Martin reagent (1.93 g,4.54mmol,1.1 eq.). At room temperature, N ₂ The resulting mixture was stirred for 2h under an atmosphere. The reaction was quenched by addition of saturated NaHCO at 0deg.C ₃ The aqueous solution was quenched and extracted with DCM (10 mL). The organic layer was washed with saturated aqueous NaCl solution (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/ea=8:1 to provide (1 s,3r,4 r) -3-formyl-2-azabicyclo [2.2.1 ]Heptane-2-carboxylic acid tert-butyl ester (879 mg, 94.3%) was a colorless oil.

67.3: synthesis of tert-butyl (1S, 3R, 4R) -3-ethynyl-2-azabicyclo [2.2.1] heptane-2-carboxylate

At 0 ℃, N ₂ To (1S, 3R, 4R) -3-formyl-2-azabicyclo [2.2.1 under an atmosphere]Heptane-2-carboxylic acid tert-butyl ester (800 mg,3.55mmol,1 eq.) and K ₂ CO ₃ (981mg,7.10mmol,2 eq.) of dimethyl (1-diazo-2-oxopropyl) phosphonate (818 mg,4.26mmol,1.2 eq.) is added dropwise in MeOH (20 mL). At room temperature, N ₂ The resulting mixture was stirred under an atmosphere for 1h. By adding potassium sodium tartrate and NaHCO ₃ The reaction was quenched with saturated aqueous solution (2 mL). The mixture was extracted with EA (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/ea=2:1 to provide (1 s,3r,4 r) -3-ethynyl-2-azabicyclo [2.2.1]Tert-butyl heptane-2-carboxylate (625 mg, 79.5%) as a white solid.

67.4: synthesis of tert-butyl (1S, 3R, 4R) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [2.2.1] heptane-2-carboxylate

To a stirred solution of tert-butyl (1S, 3R, 4R) -3-ethynyl-2-azabicyclo [2.2.1] heptane-2-carboxylate (134 mg, 0.602 mmol,3 eq.) and 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (100 mg,0.202mmol,1.00 eq.) and CuI (19 mg,0.101mmol,0.5 eq.) and 1,1' -bis (diphenylphosphine) ferrocene-palladium (II) dichloride dichloromethane complex (41 mg,0.051mmol,0.25 eq.) in DMF (2.5 mL) under argon was added DIEA (130 mg,1.01mmol,5 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, meCN in water, 60% to 70% gradient, within 10 min; detector: UV 254 nm). This gave (1S, 3R, 4R) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (101 mg, 84.9%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 588.

67.5: synthesis of 2- (3- {2- [ (1S, 3R, 4R) -2-azabicyclo [2.2.1] hept-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (1 s,3r,4 r) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [2.2.1] heptane-2-carboxylate (100 mg,0.170mmol,1 eq) in DCM (2 mL) was added TFA (0.7 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to give 2- (3- {2- [ (1 s,3r,4 r) -2-azabicyclo [2.2.1] hept-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (50 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 488.

67.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1S, 3R, 4R) -2- (prop-2-enoyl) -2-azabicyclo [2.2.1] hept-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With NaHCO ₃ Saturated solution will be 2- (3- {2- [ (1S, 3R, 4R) -2-azabicyclo [ 2.2.1)]Hept-3-yl]Ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ]-1H,5H,6H, 7H-pyrrolo [3,2-c]A mixture of pyridin-4-one (50 mg,0.102mmol,1 eq.) in THF (2 mL) was basified to pH8. To the above mixture was added dropwise acryloyl chloride (8.35 mg,0.092mmol,0.9 eq.) at 0deg.C. The resulting mixture was stirred at room temperature for 2h. MeOH (1 mL) was added to the reaction mixture at 0deg.C and used with CH ₂ Cl ₂ (3X 5 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (130 mg) which was purified by preparative HPLC under the following conditions (column: aers PEPTIDE 5um XB-C18 Axia,21.2mm X250 mm,5 μm;mobile phase A THF-HPLC, mobile phase B Hex-HPLC; the flow rate is 25mL/min; gradient 32% b to 62% b, 62% b over 10 min; wavelength is 254/220nm; RT1 (min) 9.32; running number: 0). This gives 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (1S, 3R, 4R) -2- (prop-2-enoyl) -2-azabicyclo [2.2.1]Hept-3-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (25 mg, 43.7%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 542.40.

¹ h NMR (400 MHz, chloroform-d) δ11.02 (s, 1H), 8.53 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.41 (s, 1H), 6.79-6.71 (m, 1H), 6.62 (t, 1H), 6.57-6.48 (m, 1H), 6.43-6.34 (m, 1H), 6.24-6.15 (m, 1H), 5.81-5.72 (m, 1H), 5.63-5.52 (m, 1H), 5.28 (s, 1H), 4.48 (s, 1H), 4.43 (s, 1H), 4.07 (s, 3H), 4.00-3.91 (m, 2H), 3.70-3.56 (m, 2H), 3.37-3.23 (m, 2H), 2.87 (s, 1H), 2.31-5.52 (m, 1H), 5.28 (m, 1H), 4.48 (s, 1H).

Example 68:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -4, 4-dimethyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 235)

68.1: synthesis of (2R) -2- (hydroxymethyl) -4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

At 0 ℃, N ₂ To a stirred solution of (2R) -1- (tert-butoxycarbonyl) -4, 4-dimethylpyrrolidine-2-carboxylic acid (1.00 g,4.11mmol,1.00 eq.) in THF (10.0 ml) under an atmosphere was added BH ₃ THF (423 mg,4.93mmol,1.02 eq.). The resulting mixture was stirred at 25℃for 1h. The resulting solution was quenched by the addition of MeOH (10 mL). The mixture was concentrated in vacuo to afford (2R) -2- (hydroxymethyl) -4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (1.01 g, crude) as a colorless oil.

LC-MS: M+H-56 actual: 174.00.

68.2: synthesis of (2R) -2-formyl-4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

At 0 ℃, N ₂ To a stirred solution of tert-butyl (2R) -2- (hydroxymethyl) -4, 4-dimethylpyrrolidine-1-carboxylate (700 mg,3.05mmol,1.00 eq.) in DCM (7.00 mL) was added Dess-Martin reagent (1.94 g,4.57mmol,1.50 eq.) under atmosphere. The resulting mixture was stirred at 25℃for 1h. By addition of Na ₂ SO ₃ The resulting solution was quenched. With Na ₂ CO ₃ The mixture was neutralized to pH 7 and extracted with DCM (3×20 mL). The combined organic layers were washed with NaCl (3X 50 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE/EA (20/1) to give tert-butyl (2R) -2-formyl-4, 4-dimethylpyrrolidine-1-carboxylate (600 mg, 86.5%) as a colorless oil.

68.3: synthesis of (2R) -2-ethynyl-4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

At 0 ℃, N ₂ To (2R) -2-formyl-4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (540 mg,2.37mmol,1.00 eq.) and K under an atmosphere ₂ CO ₃ A stirred solution of (650 mg,4.75mmol,2.00 eq.) in MeOH (2 mL) was added Bestmann-Ohira reagent (547 mg,2.85mmol,1.20 eq.). The resulting mixture was stirred at 25℃for 2h. The resulting solution was quenched by addition of Rochelle salt. The mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE/EA (50/1) to give tert-butyl (2R) -2-ethynyl-4, 4-dimethylpyrrolidine-1-carboxylate (440 mg, 74.64%) as a colorless oil.

68.4: synthesis of (2R) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

To 3- [ (3-chloro-2-methoxyphenyl) amino group under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (200 mg,0.40mmol,1.00 eq.), cuI (38 mg,0.20mmol,0.5 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (91 mg,0.11mmol,0.25 eq.) in DMF (4 mL) was added (2R) -2-ethynyl-4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (90 mg,0.40mmol,1.00 eq.) and DIEA (261 mg,2.020mmol,5 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. The desired product was detectable by LCMS. The precipitated solid was collected by filtration and used as H ₂ O (3X 10 mL) was washed. The residue was purified by column chromatography on silica gel eluting with PE/EA (1/1) to provide (2R) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (130 mg, 53.95%) as a yellow solid.

LC-MS: M+Hactual: 590.15.

68.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -4, 4-dimethylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a solution of tert-butyl (2S) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate (60 mg,0.10mmol,1.00 eq) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -4, 4-dimethylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (70 mg, crude) as a red oil.

LC-MS: M+Hactual: 490.20.

68.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -4, 4-dimethyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With saturated NaHCO ₃ (aqueous solution) 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2R) -4, 4-dimethylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (70 mg,0.14mmol,1.00 eq.) in THF (3 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (14 mg,0.15mmol,1.10 eq.) at 0deg.C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen for 2h. MeOH (1 mL) was added to the reaction mixture at 0deg.C and used with CH ₂ Cl ₂ (3X 5 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (50 mg) which was purified by preparative HPLC (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 33% B to 56% B,8min, 56% B; wavelength: 254/220nm; RT1 (min): 8; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2R) -4, 4-dimethyl-1- (prop-2-enoyl) pyrrolidin-2-yl ]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (22.3 mg, 28.41%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 544.50.

¹ h NMR (400 MHz, chloroform-d) δ11.21 (s, 1H), 8.54 (s, 1H), 8.13 (s, 1H), 7.74 (s, 1H), 7.47-7.36 (m, 1H), 6.71-6.61 (m, 1H), 6.60 (t, 1H), 6.51-6.36 (m, 2H), 6.22-6.10 (m, 1H), 5.76-5.65 (m, 1H), 5.34 (s, 1H), 4.93 (t, 1H), 4.07 (s, 3H), 3.67-3.56 (m, 2H), 3.55-3.41 (m, 2H), 3.40-3.21 (m, 2H), 2.25-2.18 (m, 1H), 2.12-2.06 (m, 1H), 1.33 (s, 3H), 1.15 (s, 3H).

Example 69:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R, 5R) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 256)

69.1: synthesis of (2R, 5R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

Stirring 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100 mg,0.232mmol,1 eq), (2R, 5R) -2-ethynyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (97.1 mg, 0.460 mmol,2 eq), pd (dppf) Cl ₂ .CH ₂ Cl ₂ (47.2 mg,0.058mmol,0.25 eq.) CuI (22.1 mg,0.116mmol,0.5 eq.) and DIEA (149 mg,1.160mmol,5 eq.) in DMF (2 mL). The resulting mixture was stirred overnight at 50℃under argon. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 80%, within 20 min; a detector: UV 254nm. This gives (2R, 5R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 77.0%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 560.35

69.2: synthesis of (3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R, 5R) -5-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2 r,5 r) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -5-methylpyrrolidine-1-carboxylate (100 mg, 0.178 mmol,1 eq) in DCM (3 mL) at room temperature under nitrogen atmosphere was added TFA (1 mL). The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford (3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2 r,5 r) -5-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (100 mg, crude) as a yellow oil.

LC-MS:(M+H) ⁺ Actual: 460.1

69.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R, 5R) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With saturated NaHCO ₃ Aqueous solution 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2R, 5R) -5-methylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A mixture of pyridin-4-one (100 mg,0.218mmol,1 eq.) in THF (2 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (29.5 mg,0.327mmol,1.5 eq.) at 0deg.C. The resulting mixture was stirred at 0℃for 30min. The reaction was quenched with MeOH (0.5 mL) at 0deg.C. For mixtures CH ₂ Cl ₂ MeOH 10:1 (2X 10 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (110 mg) which was purified by preparative HPLC (column XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 28% b to 58% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; ) To provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2 r,5 r) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (31.5 mg, 28.1%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 514.15。

¹ H NMR (400 MHz, chloroform-d) δ11.26 (s, 1H), 8.54 (s, 1H), 8.11 (d, 1H), 7.84 (s, 1H), 7.47 (d, 1H), 6.63-6.38 (m, 4H), 6.09-6.07 (m, 1H), 5.80-5.77 (m, 1H), 5.22 (s, 1H), 4.84-4.80 (m, 1H), 4.26-4.25 (m, 1H), 4.10 (d, 3H), 3.62-3.58 (m, 2H), 3.33-3.24 (m, 2H), 2.53-2.41 (m, 1H), 2.41-2.30 (m, 1H), 2.16 (t, 1H), 1.95-1.93 (m, 1H), 1.42 (d, 3H).

Example 70:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S, 5S) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 255)

70.1: synthesis of- (3- (((2S, 5S) -1-propenoyl-5-methylpyrrolidin-2-yl) ethynyl) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To 2- (3-bromopyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] under an argon atmosphere]Pyridin-4-one (200 mg,0.47mmol,1.00 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ A stirred mixture of (95 mg,0.11mmol,0.25 eq.) in DMF (4 mL) was added (2S, 5S) -2-ethynyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (4816 mg,2.25mmol,5.00 eq.), cuI (44 mg,0.23mmol,0.50 eq.) and DIEA (300 mg,2.25mmol,5.00 eq.). The resulting suspension was re-aerated three times with argon and stirred overnight at 50 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, silica gel; mobile phase, meCN in water, gradient 20% to 100%, within 10 min; a detector: UV 254 nm to provide 2- (3- (((2S, 5S) -1-propenoyl-5-methylpyrrolidin-2-yl) ethynyl) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3, 2-c) ]Pyridin-4-one (260 mg, 86%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 560.50.

70.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S, 5S) -5-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of (2 s,5 s) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (23 mg,0.041mmol,1 eq.) in DCM (0.9 mL) was added TFA (0.3 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2 s,5 s) -5-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (80 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 460.10.

70.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2 s,5 s) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one

With saturated NaHCO ₃ (aqueous solution) 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2S, 5S) -5-methylpyrrolidin-2-yl) ]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (82 mg,0.178mmol,1 eq.) in THF (2 mL) was basified to pH 8. To the above mixture was slowly added acryloyl chloride (16.2 mg,0.178mmol,1.00 eq). The resulting mixture was stirred at 0℃for 0.5h. MeOH (1 mL) was added to the reaction mixture at 0deg.C and used with CH ₂ Cl ₂ (3X 5 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (120 mg) which was purified by preparative HPLC under the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/LNH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 38% b to 52% b, 52% b over 10 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2 s,5 s) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (36.6 mg, 39.62%) was a yellow solid.

.LC-MS:(M+H) ⁺ Actual: 514.15.

¹ h NMR (400 MHz, chloroform-d) δ11.12 (s, 1H), 8.60-7.9 (m, 2H), 7.64 (s, 1H), 7.58-7.34 (m, 1H), 6.58-6.26 (m, 4H), 6.02 (d, 1H), 5.78-5.65 (m, 1H), 5.19 (s, 1H), 4.77 (t, 1H), 4.34-4.11 (m, 1H), 4.03 (s, 3H), 3.65-3.42 (m, 2H), 3.33-3.06 (m, 2H), 2.52-2.20 (m, 2H), 2.18-1.99 (m, 1H), 1.92-1.79 (m, 1H), 1.35 (d, 3H).

Example 71:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1S, 3R, 4R) -2- (prop-2-enoyl) -2-azabicyclo [2.2.1] hept-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 252)

71.1: synthesis of tert-butyl (1S, 3R, 4R) -3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [2.2.1] heptane-2-carboxylate

To (1S, 3R, 4R) -3-ethynyl-2-azabicyclo [2.2.1 under argon atmosphere]Heptane-2-carboxylic acid tert-butyl ester (154 mg,0.696mmol,3 eq.) and 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100 mg,0.232mmol,1.00 eq.) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ A stirred solution of (47.2 mg,0.058mmol,0.25 eq.) and CuI (22.1 mg,0.116mmol,0.5 eq.) in DMF (1 mL) was added DIEA (149 mg,1.16mmol,5 eq.). The resulting suspension was re-aerated three times with argon and stirred overnight at 50 ℃. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using (column, C1)8, silica gel; mobile phase, meCN in water, gradient 60% to 70% within 10 min; a detector: UV 254 nm). This gives (1S, 3R, 4R) -3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (80 mg, 60.35%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 572.

71.2: synthesis of 2- (3- {2- [ (1S, 3R, 4R) -2-azabicyclo [2.2.1] hept-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (1 s,3r,4 r) -3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [2.2.1] heptane-2-carboxylate (80 mg,0.140mmol,1 eq) in DCM (2 mL) was added TFA (0.7 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to give 2- (3- {2- [ (1 s,3r,4 r) -2-azabicyclo [2.2.1] hept-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (80 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 472.

71.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1S, 3R, 4R) -2- (prop-2-enoyl) -2-azabicyclo [2.2.1] hept-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With NaHCO ₃ Saturated solution will be 2- (3- {2- [ (1S, 3R, 4R) -2-azabicyclo [ 2.2.1)]Hept-3-yl]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-ones(80 mg,0.170mmol,1 eq.) in THF (2 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (13.82 mg,0.153mmol,0.9 eq.) at 0deg.C. The resulting mixture was stirred at room temperature for 2h. MeOH (1 mL) was added to the reaction mixture at 0deg.C and used with CH ₂ Cl ₂ (3X 5 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (80 mg) which was purified by preparative HPLC (column: xselect CSH C18 OBD column 30 x 150mm 5 μm, n mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min: gradient: 24% B to 47% B,8min, 47% B; wavelength; 254/220nm; RT1 (min); 8; running number; 0). This gives 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- {2- [ (1S, 3R, 4R) -2- (prop-2-enoyl) -2-azabicyclo [2.2.1]Hept-3-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (42 mg, 46.6%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 526.45.

¹ h NMR (300 MHz, chloroform-d) δ11.00 (s, 1H), 8.53 (s, 1H), 8.09 (s, 1H), 7.88 (s, 1H), 7.47 (s, 1H), 6.63-6.28 (m, 5H), 6.07 (d, 1H), 5.81-5.69 (m, 1H), 5.28 (s, 1H), 4.47 (s, 1H), 4.42 (s, 1H), 4.10 (s, 3H), 3.68-3.55 (m, 2H), 3.353.24 (m, 2H), 2.87 (s, 1H), 2.32-2.21 (m, 1H), 1.97-1.50 (m, 4H).

Example 72: n- {3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] oxetan-3-yl } prop-2-enamide (compound 264)

72.1: synthesis of N- {3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] oxetan-3-yl } prop-2-enamide

To 3- [ (3-chloro-2-methoxyphenyl) amino group under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (120 mg,0.24mmol,1.00 eq.) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ A stirred solution of (49 mg,0.061mmol,0.25 eq.) and CuI (23 mg,0.12mmol,0.50 eq.) in DMF (2 mL) was added tert-butyl N- (3-ethynyloxetan-3-yl) carbamate (239 mg,1.21mmol,5.00 eq.) and DIEA (156 mg,1.21mmol,5.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using (column, C18 silica gel; mobile phase, meCN in water, 60% to 70% gradient over 10 min; detector: UV 254 nm) to afford (6R) -6- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-5-azaspiro [2.4 ]]Heptane-5-carboxylic acid tert-butyl ester (150 mg, 84.12%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 564.10.

72.2: synthesis of 2- {3- [2- (3-amino-oxetan-3-yl) ethynyl ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl N- {3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] oxetan-3-yl } carbamate (100 mg,0.17mmol,1.00 eq.) in DCM (3 mL) was added TFA (1 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- {3- [2- (3-aminooxetan-3-yl) ethynyl ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (100 mg, crude) as a red oil.

LC-MS:(M+Na) ⁺ Actual: 486.15.

72.3: synthesis of N- {3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] oxetan-3-yl } prop-2-enamide

With NaHCO ₃ Aqueous solution 2- {3- [2- (3-Aminooxetan-3-yl) ethynyl ] ]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (100 mg,0.21mmol,1.00 eq.) in THF (1.5 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (23 mg,0.25mmol,1.20 eq.) at 0deg.C. The resulting mixture was stirred at room temperature under nitrogen for 1.5h. MeOH (1 mL) was added to the reaction mixture at 0deg.C and used with CH ₂ Cl ₂ (3X 5 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (130 mg) which was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 23% b to 38% b, 38% b over 10 min; wavelength is 254/220nm; RT1 (min) 10.38; running number 0) to provide N- {3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Oxetan-3-yl } prop-2-enamide (9.9 mg, 8.87%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 518.10.

¹ H NMR(300MHz,DMSO-d6)δ11.30(s,1H,),9.45(s,1H),8.59(s,1H),8.32(d,1H),7.50(s,1H),7.35(d,1H),7.16(s,1H),6.72-6.63(m,2H),6.36-6.17(m,2H),6.14-6.12(m,1H),5.76-5.72(m,1H),4.90(d,2H,),4.74(d,2H),3.86(s,3H),3.47-3.38(m,2H,),2.93(t,2H)。

example 73: n- {1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclobutyl } prop-2-enamide (compound 262)

73.1: synthesis of 2- {3- [2- (1-aminocyclobutyl) ethynyl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Obtaining 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100 mg,0.232mmol,1 eq.) 1-ethynyl cyclobutan-1-amine (55 mg,0.580mmol,2.5 eq.) Pd (dppf) Cl ₂ (84.8 mg,0.116mmol,0.5 eq.) CuI (22 mg,0.116mmol,0.5 eq.) and DIEA (89.9 mg,0.696mmol,3 eq.) in DMF (2 mL). The resulting mixture was stirred at 50℃under argon for 1h. The resulting mixture was diluted with water and with CH ₂ Cl ₂ Extracting with anhydrous Na ₂ SO ₄ Drying and filtering. Concentrating the filtrate under reduced pressure to provide 2- {3- [2- (1-aminocyclobutyl) ethynyl } -]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100 mg, crude) was a light brown oil.

LC-MS:(M+H) ⁺ Actual: 446.0

73.2: synthesis of N- {1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclobutyl } prop-2-enamide

With saturated NaHCO ₃ (aqueous solution) 2- {3- [2- (1-aminocyclobutyl) ethynyl ] ]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (100 mg,0.224mmol,1 eq.) in THF (2 mL) was basified to pH 8. To the above mixture was added acryloyl chloride (23.3 mg,0.258mmol,1.15 eq.) at 0deg.C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 30min. MeOH (1 mL) was added to the reaction mixture at 0deg.C and used with CH ₂ Cl ₂ (3X 5 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (50 mg) which was purified by preparative HPLC under the following conditions (column: XBRID Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/LNH) ₄ HCO ₃ ),Mobile phase B, ACN; the flow rate is 60mL/min; gradient 28% B to 48% B, 48% B over 10 min; wavelength 254/220 nm) to provide N- {1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Cyclobutyl } prop-2-enamide (8.4 mg, 7.23%) as a light brown solid.

LC-MS:(M+H) ⁺ Actual: 500.15

¹ H NMR(400MHz,DMSO-d ₆ )δ11.44(s,1H),9.11(s,1H),8.55(s,1H),8.29-8.21(m,1H),7.59(s,1H),7.37(d,1H),7.20(s,1H),6.69-6.61(m,1H),6.52(t,1H),6.35-6.17(m,2H),6.02(d,1H),5.74-5.65(m,1H),3.92(s,3H),3.48-3.39(m,2H),2.98(t,2H),2.62-2.53(m,2H),2.45-2.38(m,2H),2.11-1.96(m,2H)。

Example 74: n- {1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclobutyl } prop-2-enamide (compound 261)

74.1: synthesis of 2- {3- [2- (1-aminocyclobutyl) ethynyl ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (200 mg,0.404mmol,1 eq.) and 1-ethynyl cyclobutan-1-amine (96.2 mg,1.010mmol,2.5 eq.) in DMF (2 mL) was added CuI (38.50 mg,0.202mmol,0.5 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (165 mg,0.202mmol,0.5 eq.) and DIEA (156 mg,1.21mmol,3 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 1h. The resulting mixture was diluted with water and with CH ₂ Cl ₂ And (5) extracting. The organic layer was treated with anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to provide 2- {3- [2- (1-aminocyclobutyl) ethynyl group]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100 mg, crude) as a yellow oil.

LC-MS: M+Hactual: 462.0.

74.2: synthesis of N- {1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclobutyl } prop-2-enamide

With saturated NaHCO ₃ (aqueous solution) 2- {3- [2- (1-aminocyclobutyl) ethynyl ]]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (100 mg,0.216mmol,1 eq.) in THF (2 mL) was basified to pH 8. To the above mixture was added acryloyl chloride (22.5 mg,0.248mmol,1.15 eq.) at 0deg.C under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 1h. MeOH (1 mL) was added to the reaction mixture at 0deg.C and used with CH ₂ Cl ₂ (3X 5 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (60 mg) which was purified by preparative HPLC (column: XBridge Shield RP OBD column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 28% b to 58% b, 58% b over 10 min; wavelength is 220/254nm; RT1 (min) 10.37; running number 0) to provide N- {1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Cyclobutyl } prop-2-enamide (9.4 mg, 8.36%) as a white solid.

LC-MS: M+Hactual: 516.10.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.46(s,1H),9.10(s,1H),8.55(s,1H),8.27(d,1H),7.57(s,1H),7.36(d,1H),7.19(d,1H),6.82-6.59(m,2H),6.36-6.07(m,3H),5.79-5.60(m,1H),3.88(s,3H),3.48-3.42(m,2H),2.97(t,2H),2.63-2.54(m,2H),2.46-2.35(m,2H),2.04-1.86(m,2H)。

example 75:2- (3- { [ (3R) -4- (but-2-ynyl) morpholin-3-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 293)

75.1: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (3R) -morpholin-3-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (3R) -3- [ ({ 4- [5- (tert-butoxycarbonyl) -4-oxo-1H, 6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl } oxy) methyl ] morpholine-4-carboxylate (75 mg,0.142mmol,1 eq.) in DCM (1 mL) at room temperature under nitrogen was added TFA (0.3 mL). The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (3R) -morpholin-3-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (90 mg, crude) as a red oil.

LC-MS: M+Hactual: 468.0.

75.2: synthesis of 2- (3- { [ (3R) -4- (but-2-ynyl) morpholin-3-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (3-fluoro-2-methoxyphenyl) amino group was cleaved with DIEA]-2- {3- [ (3R) -morpholin-3-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (75 mg,0.160mmol,1 eq.) in THF (1 mL) was basified to pH 8. 2-butynoic acid (20.2 mg,0.240mmol,1.5 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (102 mg,0.320mmol,2.0 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. At 0 ℃, naHCO is added ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. Reduced pressure concentration filterThe solution was purified by preparative HPLC under the following conditions (column XBridge Prep OBD C18, 30X 150mm,5 μm; mobile phase A: water (10 mmol/LNH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 23% b to 39% b, 39% b over 8 min; wavelength is 254/220nm; RT1 (min) 8; running number 0) to provide 2- (3- { [ (3R) -4- (but-2-ynyl) morpholin-3-yl]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (27.8 mg, 32.19%) was a yellow solid.

LC-MS: M+Hactual: 534.10.

¹ h NMR (400 MHz, chloroform-d) δ10.30 (s, 1H), 8.32 (s, 1H), 8.01 (d, 1H), 7.72-7.42 (m, 2H), 6.62-6.58 (m, 1H), 6.52-6.47 (m, 1H), 6.06-6.02 (m, 1H), 5.28-5.01 (m, 2H), 4.80 (t, 1H), 4.35-4.18 (m, 2H), 4.16-3.93 (m, 5H), 3.76-3.72 (m, 1H), 3.70-3.48 (m, 4H), 3.39-3.03 (m, 2H), 2.03 (s, 3H).

Example 76:3- [ (3-fluoro-2-methylphenyl) amino ] -2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 304)

76.1: synthesis of 1-fluoro-3-isothiocyanato-2-methylbenzene

To 3-fluoro-2-methyl-aniline (10 g,79.9mmol,1.00 eq.) in NaHCO at 0deg.C ₃ A stirred solution of thiophosgene (9.2 g,79.9mmol,1.00 eq.) was added dropwise to (60 mL) and DCM (60 mL). The resulting mixture was stirred at room temperature for 2h. The resulting mixture was extracted with DCM (3X 60 mL). The combined organic layers were washed with brine (180 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE to give 1-fluoro-3-isothiocyanato-2-methylbenzene (11.3 g, 84.58%) as a yellow oil.

LC-MS:(M+H) ⁺ Actual: 168.00.

76.2: synthesis of N- (3-fluoro-2-methylphenyl) -4-hydroxy-2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide

DBU (15.1 mL,101mmol,1.50 eq.) was added dropwise to a stirred solution of 1-fluoro-3-isothiocyanato-2-methylbenzene (11.3 g,67.5mmol,1.00 eq.) and piperidine-2, 4-dione (7.6 g,67.5mmol,1.00 eq.) in ACN (100 mL) at 0deg.C. The resulting mixture was stirred at room temperature overnight. The desired product was detectable by LCMS. The mixture was acidified to pH 3 with 1N HCl. The precipitated solid was collected by filtration and washed with MeCN (3 x15 mL), and the resulting solid was dried in vacuo to afford N- (3-fluoro-2-methylphenyl) -4-hydroxy-2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide (17.1 g, crude) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 280.95.

76.3: synthesis of 4- { [ (3-bromopyridin-4-yl) methyl ] amino } -N- (3-fluoro-2-methylphenyl) -2-oxo-5, 6-dihydro-1H-pyridin-3-thiocarboxamide

To a stirred solution of N- (3-fluoro-2-methylphenyl) -4-hydroxy-2-oxo-5, 6-dihydro-1H-pyridin-3-thiocarboxamide (17.1 g,61.0mmol,1.00 eq.) and 1- (3-bromopyridin-4-yl) methylamine (12.5 g,67.1mmol,1.10 eq.) in DMF (171 mL) was added DIEA (23.6 g,183mmol,3.00 eq.) and PyBOP (47.6 g,91.5mmol,1.50 eq.) in portions at 0deg.C. The resulting mixture was stirred at room temperature overnight. The desired product was detectable by LCMS. The resulting mixture was diluted with water (400 mL). The precipitated solid was collected by filtration and washed with water (3×20 mL) and MeOH (3×20 mL). The resulting solid was dried in vacuo to afford 4- { [ (3-bromopyridin-4-yl) methyl ] amino } -N- (3-fluoro-2-methylphenyl) -2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide (15 g, crude) as an off-white solid.

LC-MS:(M+H) ⁺ Actual: 448.85.

76.4: synthesis of 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methylphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Preparation of 4- { [ (3-bromopyridin-4-yl) methyl]Amino } -N- (3-fluoro-2-methylphenyl) -2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide (15.0 g,33.3mmol,1.00 eq.) and H ₂ O ₂ (30%) (2.59 mL,33.3mmol,1.00 eq., 30%) in MeOH (150 mL). The resulting mixture was stirred overnight at 80 ℃ under nitrogen. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, C18; mobile phase, meCN in water, gradient 40% to 45% within 10 min; a detector: UV 254nm to provide 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methylphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (2.5 g, 18.03%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 414.85.

76.5: synthesis of (2R) -2-formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred mixture of tert-butyl (2R) -2- (hydroxymethyl) -2-methylpyrrolidine-1-carboxylate (0.74 g,3.43mmol,1.00 eq.) in DCM (10 mL) was added the Dess-Martin reagent (2.19 g,5.16mmol,1.50 eq.) in portions at 0deg.C. The resulting mixture was stirred at room temperature for 2h. The reaction was carried out by adding saturated Na at 0 ℃ ₂ SO ₃ The aqueous solution (10 mL) was quenched. The mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE/EA (8:1) to provide tert-butyl (2R) -2-formyl-2-methylpyrrolidine-1-carboxylate (640 mg, 87.30%) as a colorless oil.

76.6. Synthesis of (2R) -2-ethynyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To (2R) -2-formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (640 mg,3.00mmol,1.00 eq.) and K at 0deg.C ₂ CO ₃ (829 mg,6.00mmol,2.00 eq.) Bestmann-Ohira reagent (691 mg,3.60mmol,1.20 eq.) was added dropwise to a stirred mixture of MeOH (10 mL). The resulting mixture was stirred at room temperature for 2h. The reaction was quenched with water at 0deg.C and extracted with EtOAc (3X 10 mL) over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE/EA (8:1) to provide tert-butyl (2R) -2-ethynyl-2-methylpyrrolidine-1-carboxylate (450 mg, 71.65%) as a colorless oil.

76.7: synthesis of tert-butyl (2R) -2- [2- (4- {3- [ (3-fluoro-2-methylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate

To (2R) -2-ethynyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (226 mg,1.08mmol,3.00 eq.) CuI (6 mg,0.036mmol,0.10 eq.), DIEA (186 mg,1.44mmol,4.00 eq.) and 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methylphenyl) amino group under argon atmosphere]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (150 mg,0.36mmol,1.00 eq.) in DMF (2.5 mL) was added Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (29 mg,0.036mmol,0.10 eq.). The resulting mixture was stirred overnight at 50℃under argon. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was diluted with water (12.5 mL). The precipitated solid was collected by filtration and washed with water (3×5 mL). The crude product was purified by using Et ₂ O (10 mL) was triturated and purified to provide (2R) -2- [2- (4- {3- [ (3-fluoro-2-methylphenyl) ammonia)Base group]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (80 mg, crude) as yellow solid.

LC-MS:(M+H) ⁺ Actual: 544.15.

76.8: synthesis of 3- [ (3-fluoro-2-methylphenyl) amino ] -2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2R) -2- [2- (4- {3- [ (3-fluoro-2-methylphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate (80 mg,0.15mmol,1.00 eq.) in DCM (1 mL) was added TFA (0.3 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methylphenyl) amino ] -2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (160 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 444.10.

76.9: synthesis of 3- [ (3-fluoro-2-methylphenyl) amino ] -2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With NaHCO ₃ Aqueous solution 3- [ (3-fluoro-2-methylphenyl) amino group]-2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (80 mg,0.180mmol,1.00 eq.) in THF (1 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (16 mg,0.18mmol,1.00 eq.) at 0deg.C under nitrogen atmosphere. The resulting mixture was stirred at 0℃under nitrogen for 30min. MeOH at 0 ℃(1 mL) was added to the reaction mixture and used with CH ₂ Cl ₂ (3X 5 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (50 mg) which was purified by preparative HPLC under the following conditions (column: XBRID Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 38% b to 52% b, 52% b over 10 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 3- [ (3-fluoro-2-methylphenyl) amino group]-2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (5.3 mg, 5.87%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 498.20.

¹ h NMR (300 MHz, chloroform-d) δ11.39 (s, 1H), 8.67-7.80 (m, 2H), 7.44 (s, 1H), 7.20-7.10 (m, 1H), 6.71-6.59 (m, 1H), 6.47-6.25 (m, 3H), 6.16 (d, 1H), 5.71-5.63 (m, 1H), 5.15 (s, 1H), 3.78-3.61 (m, 2H), 3.59-3.45 (m, 2H), 3.27-3.10 (m, 2H), 2.54-2.37 (m, 1H), 2.26 (s, 3H), 2.17-1.94 (m, 3H), 1.71 (s, 3H).

Example 77:2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 303)

77.1: synthesis of tert-butyl (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] pyrrolidine-1-carboxylate

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Preparation of 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (150 mg,0.348mmol,1 eq.) tert-butyl (2R) -2-ethynyl-pyrrolidine-1-carboxylate (135.83 mg,0.696mmol,2 eq.) Pd (dppf) Cl ₂ CH ₂ Cl ₂ (70.8 mg,0.087mmol,0.25 eq.) CuI (33.1 mg,0.174mmol,0.5 eq.) And DIEA (225 mg,1.74mmol,5 eq.) in DMF (5 mL). The resulting mixture was stirred overnight at 50℃under argon. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 70%, within 40 min; a detector: UV 254nm. This gives (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 63.23%) was a yellow oil.

LC-MS:(M+H) ⁺ Actual: 546.30.

77.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] pyrrolidine-1-carboxylate (100 mg,0.183mmol,1 eq) in DCM (3 mL) at room temperature under nitrogen atmosphere was added TFA (1 mL). The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (120 mg, crude) as a yellow oil.

LC-MS:(M+H) ⁺ Actual: 446.05.

77.3: synthesis of 2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (3-fluoro-2-methoxyphenyl) amino group was cleaved with DIEA]-2-(3- {2- [ (2R) -pyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (110 mg,0.247mmol,1 eq.) in THF (2 mL) was basified to pH 8. (2E) -4- (dimethylamino) but-2-enoic acid (47.9 mg,0.371mmol,1.5 eq.) was added to the above mixture at 0deg.C under nitrogen atmosphere followed by dropwise addition of T ₃ P (157 mg,0.494mmol,2.0 eq, 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (100 mg) which was purified by preparative HPLC (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 10% B to 24% B,8min, 24% B; wavelength: 254/220nm; RT1 (min): 8;) to provide 2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl) ]Pyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (44 mg, 31.9%) was a yellow solid.

.LC-MS:(M+H) ⁺ Actual: 557.6.

¹ h NMR (400 MHz, chloroform-d) δ11.05 (s, 1H), 8.53 (s, 1H), 8.15 (s, 1H), 7.70 (s, 1H), 7.47 (s, 1H), 6.94-6.88 (m, 1H), 6.59-6.53 (m, 2H), 6.48-6.43 (m, 1H), 6.09-6.07 (m, 1H), 5.30 (s, 1H), 4.89 (t, 1H), 4.09 (s, 3H), 3.85-3.75 (m, 1H), 3.71-3.64 (m, 1H), 3.56-3.64 (m, 2H), 3.54-3.49 (m, 2H), 3.23 (t, 2H), 2.60 (s, 6H), 2.35-2.31 (m, 1H), 2.29-2.12 (m, 2H), 2.10-2.09 (m, 1H).

Example 78:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (1S) -1- [ (2R) -1- (prop-2-enoyl) azetidin-2-yl ] ethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 310)

78.1: synthesis of tert-butyl (2S) -2- [ methoxy (methyl) carbamoyl ] azetidine-1-carboxylate

To a stirred solution of (2S) -1- (tert-butoxycarbonyl) azetidine-2-carboxylic acid (10 g,49.7mmol,1 eq.) and methoxy (meth) amine hydrochloride (5.82 g,59.6mmol,1.2 eq.) in DMF (200 mL) was added N-methylmorpholine (6.03 g,59.6mmol,1.2 eq.), HOBT (8.06 g,59.6mmol,1.2 eq.) and EDCI (11.4 g,59.6mmol,1.2 eq.) at 0deg.C under nitrogen. The resulting mixture was stirred at 0℃under nitrogen for 2h. Then stirred overnight at room temperature under nitrogen. The resulting mixture was diluted with ethyl acetate (500 mL). The mixture was washed with 1N HCl (2X 100 mL) and 2N NaOH (2X 200 mL) and brine (3X 100 mL). The organic layer was concentrated in vacuo to afford tert-butyl (2S) -2- [ methoxy (methyl) carbamoyl ] azetidine-1-carboxylate (7.9 g, crude) as a colorless oil.

LC-MS:(M+H) ⁺ Actual: 245.2

78.2: synthesis of (2S) -2-acetylazetidine-1-carboxylic acid tert-butyl ester

To (2S) -2- [ methoxy (methyl) carbamoyl at-78℃under nitrogen atmosphere]A stirred solution of tert-butyl azetidine-1-carboxylate (7.4 g,30.3mmol,1 eq.) in THF (150 mL) was added dropwise to 1M CH in THF ₃ MgBr (60 mL,2 eq). The resulting mixture was stirred at-78℃under nitrogen for 2h. Saturated NH at 0deg.C ₄ The reaction was quenched with aqueous Cl (300 mL). The mixture was extracted with EtOAc (3×100 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE/EA (30:1) to provide tert-butyl (2S) -2-acetylazetidine-1-carboxylate (5 g, 82.84%) as an off-white oil.

LC-MS:(M-H) ^- Actual: 198.0

78.3: synthesis of tert-butyl (2S) -2- [ (1R) -1-hydroxyethyl ] azetidine-1-carboxylate

To a stirred solution of tert-butyl (2S) -2-acetylazetidine-1-carboxylate (4.5 g,22.6mmol,1 eq.) in MeOH (80 mL) at 0deg.C under nitrogen was added NaBH in portions ₄ (1.03 g,27.1mmol,1.2 eq.). The resulting mixture was stirred at room temperature under nitrogen for 30min. The reaction is carried out by adding saturated NH at 0 DEG C ₄ Aqueous Cl (80 mL) was quenched. The mixture was extracted with EtOAc (3X 50 mL). The organic layer was washed with brine (50 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with PE/EA (30:1) to provide (2S) -2- [ (1R) -1-hydroxyethyl ]Azetidine-1-carboxylic acid tert-butyl ester (2.5 g, 55.0%) was a colorless oil.

LC-MS:(M+H) ⁺ Actual: 202.0.

78.4: synthesis of tert-butyl 2- [ (1S) -1- [ (4-bromopyridin-3-yl) oxy ] ethyl ] azetidine-1-carboxylate

To (2S) -2- [ (1R) -1-hydroxyethyl at 0℃under nitrogen atmosphere]Azetidine-1-carboxylic acid tert-butyl ester (1 g,4.97mmol,1 eq.) 4-bromopyridin-3-ol (0.86 g,4.97mmol,1 eq.) and PPh ₃ (1.95 g,7.454mmol,1.5 eq.) of DEAD (1.30 g,7.46mmol,1.50 eq.) is added dropwise to a stirred solution of DEAD in THF (15 mL). The resulting mixture was stirred overnight at room temperature under nitrogen. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 50%, within 20 min; a detector: UV 254nm. This gives 2- [ (1S) -1- [ (4-bromopyridin-3-yl) oxy]Ethyl group]Azetidine-1-carboxylic acid tert-butyl ester (1.2 g, 67.6%) was a colorless oil.

LC-MS:(M+H) ⁺ Actual: 357.0.

78.5: synthesis of tert-butyl (2R) -2- [ (1S) -1- [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] ethyl ] azetidine-1-carboxylate

Preparation of 2- [ (1S) -1- [ (4-bromopyridin-3-yl) oxy) at room temperature under nitrogen atmosphere ]Ethyl group]Azetidine-1-carboxylic acid tert-butyl ester (500 mg,1.40mmol,1 eq.) 2- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]]Pyridin-4-one (734 mg,2.80mmol,2 eq.) Na ₂ CO ₃ (445 mg,4.20mmol,3 eq.) and a 2 nd generation XPhos pre-catalyst (110 mg,0.140mmol,0.1 eq.) in dioxane (10 mL) and H ₂ Mixtures in O (1 mL). The resulting mixture was stirred at 80℃under nitrogen for 5h. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CH ₂ Cl ₂ 1:1) purification to afford (2R) -2- [ (1S) -1- [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]Ethyl group]Azetidine-1-carboxylic acid tert-butyl ester (450 mg, 77.9%) was a yellow oil.

LC-MS:(M+H) ⁺ Actual: 413.10.

78.6: synthesis of tert-butyl (2R) -2- [ (1S) -1- [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] ethyl ] azetidine-1-carboxylate

To (2R) -2- [ (1S) -1- [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] at 0℃under nitrogen atmosphere]Pyridin-2-yl } pyridin-3-yl) oxy]Ethyl group]A stirred solution of tert-butyl azetidine-1-carboxylate (410 mg,0.994mmol,1 eq.) in DMF (5 mL) was added NIS (268 mg,1.19mmol,1.2 eq.) in portions. The resulting mixture was stirred at room temperature under nitrogen for 1h. The reaction was quenched with saturated aqueous sodium sulfite (1 mL) at 0 ℃. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2R) -2- [ (1S) -1- [ (4- { 3-iodo-4-oxo-1 h,5h,6h,7 h-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]Ethyl group]Azetidine-1-carboxylic acid tert-butyl ester (520 mg, 97.1%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 539.05.

78.7: synthesis of tert-butyl (2R) -2- [ (1S) -1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] ethyl ] azetidine-1-carboxylate

To (2R) -2- [ (1S) -1- [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] under argon atmosphere]Pyridin-2-yl } pyridin-3-yl) oxy]Ethyl group]A stirred mixture of tert-butyl azetidine-1-carboxylate (470 mg,0.873mmol,1 eq.) and 3-fluoro-2-methoxyaniline (246 mg,1.74mmol,2 eq.) in DMF (8 mL) was added Cs ₂ CO ₃ (618 mg,1.74mmol,2 eq.) and EPhos Pd G4 (80.2 mg,0.087mmol,0.1 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (20:1) elution to afford (2R) -2- [ (1S) -1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Ethyl group]Azetidine-1-carboxylic acid tert-butyl ester (480 mg, 99.6%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 552.20.

78.8: synthesis of 2- {3- [ (1S) -1- [ (2R) -azetidin-2-yl ] ethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2R) -2- [ (1S) -1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] ethyl ] azetidine-1-carboxylate (100 mg,0.181mmol,1 eq.) in DCM (3 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- {3- [ (1S) -1- [ (2R) -azetidin-2-yl ] ethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (120 mg, crude) as a yellow oil.

LC-MS:(M+H) ⁺ Actual: 452.20.

78.9: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (1S) -1- [ (2R) -1- (prop-2-enoyl) azetidin-2-yl ] ethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With saturated NaHCO ₃ Aqueous solution 2- {3- [ (1S) -1- [ (2R) -azetidin-2-yl]Ethoxy group]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A mixture of pyridin-4-one (150 mg,0.332mmol,1 eq.) in THF (3 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (45.1 mg,0.498mmol,1.5 eq.) at 0deg.C. The resulting mixture was stirred at room temperature for 30min. Quench the reaction with MeOH (2 mL) at 0deg.C and use CH ₂ Cl ₂ MeOH (10/1) (2X 10 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (120 mg) which was purified by preparative HPLC under the following conditions (column: XBRID Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient from 22% b to 42% b, 42% b over 9 min; wavelength is 254/220nm; RT1 (min) 7.53; ) To provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- {3- [ (1S) -1- [ (2R) -1- (prop-2-enoyl) azetidin-2-yl]Ethoxy group]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (22.3 mg, 13.2%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 506.15.

¹ h NMR (400 MHz, chloroform-d) δ11.80 (s, 1H), 8.26 (s, 1H), 7.94(d,1H),7.62(s,1H),7.57(d,1H),6.65-6.56(m,1H),6.50-6.28(m,3H),6.12-6.07(m,1H),5.85-5.78(m,1H),5.22(s,1H),5.02-4.98(m,1H),4.78-4.69(m,1H),4.30-4.18(m,2H),4.13(d,3H),3.64-3.52(m,2H),3.24-3.07(m,2H),2.65-2.54(m,1H),2.19-2.07(m,1H),1.60(d,3H)。

Example 79:2- {3- [ (1S) -1- [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] ethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 313)

79.1: synthesis of 2- {3- [ (1S) -1- [ (2R) -azetidin-2-yl ] ethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

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LC-MS:(M+H) ⁺ Actual: 452.20.

79.2: synthesis of 2- {3- [ (1S) -1- [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] ethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- {3- [ (1S) -1- [ (2R) -azetidin-2-yl using DIEA]Ethoxy group]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100 mg,0.221 mm)ol,1 equivalent) in THF (3 mL) to pH 8. 2-butynoic acid (27.9 mg, 0.336 mmol,1.5 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (282 mg,0.442mmol,3 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. At 0 ℃, naHCO is added ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (120 mg) which was purified by preparative HPLC (column: XBridge Shield RP OBD column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/LNH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient from 20% b to 50% b, 50% b over 8 min; wavelength is 220/254nm; RT1 (min) 8.00; ) To provide 2- {3- [ (1S) -1- [ (2R) -1- (but-2-ynyl) azetidin-2-yl]Ethoxy group]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (31.4 mg, 27.09%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 518.15.

¹ h NMR (400 MHz, chloroform-d) δ11.47 (s, 1H), 8.26 (s, 1H), 7.93 (d, 1H), 7.69 (s, 1H), 7.54 (d, 1H), 6.62-6.58 (m, 1H), 6.56-6.46 (m, 1H), 6.06-6.04 (m, 1H), 5.23 (s, 1H), 4.95-4.91 (m, 1H), 4.74-4.69 (m, 1H), 4.27-4.21 (m, 1H), 4.19-4.09 (m, 4H), 3.59-3.53 (m, 2H), 3.17-3.04 (m, 2H), 2.62-2.51 (m, 1H), 2.09-2.02 (m, 4H), 1.59 (d, 3H).

Example 80:2- (3- { [ (2S) -4, 4-dimethyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 327)

80.1: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -4, 4-dimethylpyrrolidine-1-carboxylate

In the presence of argon gas in the atmosphere,to (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (170 mg,0.300mmol,1 eq.) and Cs ₂ CO ₃ A stirred solution of (196 mg,0.600mmol,2 eq.) in DMF (2 mL) was added EPhos Pd G4 (27.6 mg,0.030mmol,0.1 eq.) and 3-fluoro-2-methoxyaniline (50.8 mg,0.360mmol,1.2 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (20:1) elution to afford (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 86.22%) as a yellow solid.

LC-MS: M+Hactual: 580.0.

80.2: synthesis of 2- (3- { [ (2S) -4, 4-dimethylpyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (120 mg,0.207mmol,1 eq.) in DCM (1 mL) was added TFA (0.3 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- (3- { [ (2S) -4, 4-dimethylpyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (150 mg, crude) as a red oil.

LC-MS: M+Hactual: 480.

80.3: synthesis of 2- (3- { [ (2S) -4, 4-dimethyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With saturated NaHCO ₃ (aqueous solution) 2- (3- { [ (2S) -4, 4-dimethylpyrrolidin-2-yl)]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c ]A stirred solution of pyridin-4-one (150 mg,0.250mmol,1 eq.) in THF (1.5 mL) was basified to pH 8. To the above mixture was added acryloyl chloride (26.1 mg,0.287mmol,1.15 eq.) at 0deg.C under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 1h. MeOH (1 mL) was added to the reaction mixture at 0deg.C and used with CH ₂ Cl ₂ (3X 5 mL) extraction over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (130 mg) which was purified by preparative HPLC (column: XBridge Shield RP OBD column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 28% b to 58% b, 58% b over 10 min; wavelength is 220/254nm; RT1 (min) 10.37; running number 0) to provide 2- (3- { [ (2S) -4, 4-dimethyl-1- (prop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (25.1 mg, 18.67%) was a yellow solid.

LC-MS: M+Hactual: 534.15.

¹ h NMR (400 MHz, chloroform-d) δ11.67 (s, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.72-7.47 (m, 2H), 6.70-6.44 (m, 3H), 6.38-4.35 (m, 1H), 6.11-6.08 (m, 1H), 5.78-5.72 (m, 1H), 5.28 (s, 1H), 5.07-4.98 (m, 1H), 4.26 (t, 1H), 4.26-4.03 (m, 4H), 3.78-3.47 (m, 3H), 3.35 (d, 1H), 3.30-3.12 (m, 2H), 2.31-1.92 (m, 1H), 1.62-1.39 (m, 1H), 1.25 (s, 3H), 1.07 (s, 3H).

Example 81:2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] -4, 4-dimethylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 344)

81.1: synthesis of 2- (3- {2- [ (2R) -4, 4-dimethylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (70 mg,0.122mmol,1.0 eq.) in DCM (1 mL) was added TFA (0.3 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- (3- {2- [ (2R) -4, 4-dimethylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (70 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 474.10.

81.2: synthesis of 2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] -4, 4-dimethylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- (3- {2- [ (2R) -4, 4-dimethylpyrrolidin-2-yl) with DIEA]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (70 mg,0.148mmol,1.00 eq.) in THF (1 mL) was basified to pH 8. (2E) -4- (dimethylamino) but-2-enoic acid (28.5 mg,0.222mmol,1.50 eq.) and T were added dropwise to the above mixture ₃ P (93.3 mg, 0.298 mmol,2.00 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (60 mg) which was purified by preparative HPLC (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 17% B to 34% B, 34% B over 7 min; wavelength: 254/220nm; RT1 (min): 7; running number: 0) to afford 2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl)]-4, 4-dimethylpyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (46.1 mg, 52.64%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 585.15.

¹ h NMR (400 MHz, chloroform-d) δ11.18 (s, 1H), 8.51 (s, 1H), 8.13 (d, 1H), 7.67 (s, 1H), 7.46 (d, 1H), 6.98-6.85 (m, 1H), 6.58-6.32 (m, 3H), 6.11-6.03 (m, 1H), 5.33 (s, 1H), 4.90 (t, 1H), 4.07 (s, 3H), 3.66-3.37 (m, 4H), 3.27-3.14 (m, 4H), 2.35 (s, 6H), 2.21-2.15 (m, 1H), 2.09-2.03 (m, 1H), 1.32 (s, 3H), 1.13 (s, 3H).

Example 82:2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3, 4-difluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 351)

82.1: synthesis of tert-butyl (2R) -2- { [ (4- {3- [ (3, 4-difluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

Under argon atmosphere, to (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (240 mg,0.46mmol,1.00 eq.) and 3, 4-difluoro-2-methoxyaniline (87 mg,0.55mmol,1.20 eq.) in DMF (4 mL) was added Ephos Pd G4 (42 mg,0.046mmol,0.10 eq.) and Cs ₂ CO ₃ (300 mg,0.92mmol,2.00 eq.). The resulting mixture was stirred at 50℃under argon for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (20:1) elution to afford (2R) -2- { [ (4- {3- [ (3, 4-difluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (200 mg, 75.86%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 556.55.

82.2: synthesis of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3, 4-difluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

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To a stirred solution of tert-butyl (2R) -2- { [ (4- {3- [ (3, 4-difluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (90 mg,0.162mmol,1.00 eq.) in DCM (1 mL) at room temperature under nitrogen was added TFA (0.3 mL). The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3, 4-difluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (180 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 456.05.

82.3: synthesis of 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3, 4-difluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- {3- [ (2R) -azetidin-2-ylmethoxy ] with DIEA]Pyridin-4-yl } -3- [ (3, 4-difluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (90 mg, 0.198m)mol,1.00 eq.) in THF (2 mL) to pH 8. 2-butynoic acid (24.8 mg, 0.294 mmol,1.50 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (125 mg,0.396mmol,2.0 eq, 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (60 mg) which was purified by preparative HPLC under the following conditions (column: XBRID Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/LNH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient from 37% b to 65% b, 65% b over 8 min; wavelength is 254/220nm; RT1 (min) 5.78; running number 0) to provide 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ]Methoxy } pyridin-4-yl) -3- [ (3, 4-difluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (30.3 mg, 29.28%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 522.10.

¹ h NMR (400 MHz, chloroform-d) δ11.31 (s, 1H), 8.17 (s, 1H), 7.94 (d, 1H), 7.41 (d, 1H), 7.29 (s, 1H), 6.46-6.33 (m, 1H), 5.93-5.84 (m, 1H), 5.14 (s, 1H), 4.92-4.79 (m, 1H), 4.42 (t, 1H), 4.26-4.13 (m, 3H), 4.06 (s, 3H), 3.53-3.46 (m, 2H), 3.16-2.94 (m, 2H), 2.60-2.50 (m, 1H), 2.11-2.01 (m, 1H), 1.96 (s, 3H).

Example 83:2- (3- {2- [ (1S, 3S, 5S) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 516)

83.1: synthesis of tert-butyl (1S, 3S, 5S) -3- (hydroxymethyl) -2-azabicyclo [3.1.0] hexane-2-carboxylate

Stirring (1S, 3S, 5S) -2- (tert-Butoxycarbonyl) -2-azabicyclo [3.1.0] at 0deg.C under nitrogen]Hexane-3-carboxylic acid (0.5 g,2.20mmol,1 eq.) and BH ₃ A mixture of THF (4.40 mL,4.400mmol,2 eq.) in THF (5 mL) for 1h. The desired product can be detected by TLC. The resulting mixture was treated with CH ₂ Cl ₂ (2X 100 mL) extraction. The combined organic layers were washed with water (50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (10:1) to provide (1 s,3s,5 s) -3- (hydroxymethyl) -2-azabicyclo [ 3.1.0) ]Hexane-2-carboxylic acid tert-butyl ester (0.45 g, 95.9%) as a colorless oil.

83.2: synthesis of tert-butyl (1S, 3S, 5S) -3-formyl-2-azabicyclo [3.1.0] hexane-2-carboxylate

Stirring (1S, 3S, 5S) -3- (hydroxymethyl) -2-azabicyclo [3.1.0] at room temperature under nitrogen]A mixture of tert-butyl hexane-2-carboxylate (0.45 g,2.11mmol,1 eq.) and Dess-Martin reagent (0.94 g,2.21mmol,1.05 eq.) in DCM (10 mL) for 2h. The desired product can be detected by TLC. The resulting mixture was treated with CH ₂ Cl ₂ (2X 100 mL) extraction. The combined organic layers were washed with water (50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (10:1) to provide (1 s,3s,5 s) -3-formyl-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (390 mg, 87.49%) as a colorless oil.

83.3: synthesis of tert-butyl (1S, 3S, 5S) -3-ethynyl-2-azabicyclo [3.1.0] hexane-2-carboxylate

To (1S, 3S, 5S) -3-formyl-2-azabicyclo [3.1.0] at 0deg.C under nitrogen atmosphere]Hexane-2-carboxylic acid tert-butyl ester (390 mg,1.84mmol,1 eq.) and K ₂ CO ₃ A stirred mixture of (510 mg,3.69mmol,2 eq.) in MeOH (4 mL) was added in portions dimethyl (1-diazo-2-oxopropyl) phosphonate Esters (425 mg,2.21mmol,1.2 eq.). The resulting mixture was stirred overnight at room temperature under nitrogen. The desired product can be detected by TLC. The reaction was quenched with saturated sodium potassium tartrate (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (2X 200 mL). The combined organic layers were washed with water (100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (10:1) to provide (1 s,3s,5 s) -3-ethynyl-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (300 mg, 78.4%) as a pale yellow oil.

83.4: synthesis of tert-butyl (1S, 3S, 5S) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylate

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (130 mg,0.26mmol,1 eq), (1S, 3S, 5S) -3-ethynyl-2-azabicyclo [ 3.1.0)]A stirred mixture of tert-butyl hexane-2-carboxylate (163 mg,0.78mmol,3 eq.) and DIEA (169 mg,1.31mmol,5 eq.) in DMF (2 mL) was added in portions CuI (25 mg,0.13mmol,0.5 eq.) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (32 mg,0.039mmol,0.15 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) elution to afford (1S, 3S, 5S) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (110 mg, 72.92%) as a yellow solid.

LC-MS: [ M+H ] + actual: 574.00.

83.5: synthesis of 2- (3- {2- [ (1S, 3S, 5S) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

A mixture of (1S, 3S, 5S) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (110 mg,0.19mmol,1 eq.) in TFA (1 mL) and DCM (1 mL) was stirred at room temperature under an air atmosphere for 1h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. This gave 2- (3- {2- [ (1 s,3s,5 s) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (80 mg, 88.09%) as a yellow oil.

LC-MS:[M+H] ⁺ Actual: 474.00.

83.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1S, 3S, 5S) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Stirring 2- (3- {2- [ (1S, 3S, 5S) -2-azabicyclo [3.1.0] at 0℃under an air atmosphere]Hex-3-yl]Ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (70 mg,0.14mmol,1 eq.) and acryloyl chloride (12 mg,0.13mmol,0.9 eq.) in THF (1 mL) and NaHCO ₃ (aqueous solution) (1 mL) for 1h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC and using the following conditions (column: xselect CSH F-phenyl OBD column, 30X 250mm,5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 19% B to 49% B over 7 min; wavelength: 254nm; RT1 (min): 6.5; running number: 0) to provide 3- [ (3-chloro-2-methoxybenzene)Radical) amino group]-2- (3- {2- [ (1S, 3S, 5S) -2- (prop-2-enoyl) -2-azabicyclo [ 3.1.0)]Hex-3-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (24.4 mg, 31.20%) was a yellow solid.

LC-MS:[M+H] ⁺ Actual: 454.93.

¹ h NMR (300 MHz, chloroform-d) δ11.08 (s, 1H), 8.52 (s, 1H), 8.08 (d, j=5.9 hz, 1H), 7.92 (s, 1H), 7.39 (d, j=5.9 hz, 1H), 6.80-6.70 (m, 2H), 6.62 (t, j=8.1 hz, 1H), 6.43-6.37 (m, 1H), 6.20-6.17 (m, 1H), 5.82-5.78 (m, 1H), 5.29-5.23 (m, 2H), 4.07 (s, 3H), 3.64-3.55 (m, 3H), 3.29 (t, j=6.7 hz, 2H), 2.78-2.68 (m, 1H), 2.39-2.33 (m, 1H), 1.99-1.68 (m, 1H), 1.82-5.78 (m, 1H), 1.29-3.55 (m, 2H).

Example 84:2- (3- { [ (3R) -4- [ (2E) -4- (dimethylamino) but-2-enoyl ] morpholin-3-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one) (compound 196

To 3- [ (3-fluoro-2-methoxyphenyl) amino group at 0℃under argon atmosphere]-2- {3- [ (3R) -morpholin-3-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (100 mg,0.21mmol,1.00 eq.) in NMP (3.00 mL) was added in portions (2E) -4- (dimethylamino) but-2-enoyl chloride (95 mg,0.63mmol,3.00 eq.). The resulting mixture was stirred at 0℃under argon for 1h. The desired product was detectable by LCMS. The reaction was quenched by the addition of MeOH (3 mL) at 0deg.C. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by preparative HPLC using the following conditions (column: xselect CSH F-phenyl OBD column, 19X 250mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 25mL/min; gradient 55% b to 58% b, 58% b in 11 min; wavelength of 254nm; RT1 (min) 9.85; running number 0) to provide 2- (3- { [ (3R) -4- [ (2E) -4- (dimethylamino) but-2-enoyl]Morpholin-3-yl]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one) (7.6 mg, 6.12%) as a white solid.

LC-MS:(M+H) ⁺ Actual: 579.40.

¹ H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.45(s,1H),8.11-7.90(m,1H),7.53(d,1H),7.41-7.25(m,1H),7.14(d,1H),6.80-6.30(m,4H),5.98(d,1H),5.10-4.65(m,1H),4.57-4.16(m,2H),4.17-3.82(m,6H),3.71-3.52(m,2H),3.52-3.37(m,3H),3.01(d,3H),2.93-2.71(m,1H),2.05(d,6H)。

example 85:3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 213)

85.1: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

(2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) was reacted at room temperature under argon atmosphere]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (90 mg,0.16mmol,1 eq.) and 3-chloro-5-fluoro-2-methoxyaniline (29 mg,0.16mmol,1.0 eq.) in DMF (1.5 mL) was added in portions EPhos Pd G4 (15 mg,0.017mmol,0.1 eq.) and Cs ₂ CO ₃ (163 mg,0.50mmol,3 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2S) -2- { [ (4- {3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (90 mg, 91.87%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 586.0

85.2: synthesis of (S) -3- ((3-chloro-5-fluoro-2-methoxyphenyl) amino) -2- (3- (pyrrolidin-2-ylmethoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (90 mg,0.15mmol,1 eq.) in DCM (1.5 mL) at 0deg.C under air was added TFA (0.3 mL). The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 486.2

85.3: synthesis of 3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino group at 0℃under argon atmosphere]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (crude) in THF and NaHCO ₃ An stirred solution of acryloyl chloride (27 mg,0.30mmol,2 eq.) in aqueous solution (3 mL) was added dropwise. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The crude product (100 mg) was purified by preparative HPLC and using the following conditions (column: XB ridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH4HCO 3), mobile phase B: ACN; flow rate: 60mL/min; gradient: 26% B to 54% B,8min, 54% B; wavelength: 254/220nm; RT1 (min): 7.53; running number: 0) to provide 3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino group]-2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (6.5 mg, 7.79%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 540.0

¹ H NMR (400 MHz, chloroform-d) δ11.55 (s, 1H), 8.24 (s, 1H), 8.02 (d, 1H), 7.58-7.40 (m, 2H), 7.25 (s, 1H), 6.63-6.48 (m, 1H), 6.46-6.28 (m, 2H), 6.05-5.96 (m, 1H), 5.82-5.70 (m, 1H), 5.27 (s, 1H), 5.03 (s, 1H), 4.25-4.10 (m, 1H), 4.17-3.81 (m, 4H), 3.90-3.66 (m, 2H), 3.65-3.55 (m, 2H), 3.29-3.15 (m, 2H), 2.30-2.04 (m, 3H), 1.87 (s, 2H).

Example 86:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R, 5R) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 267)

86.1: synthesis of (2R, 5R) -2- (hydroxymethyl) -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

BH3-THF (6.50 mL,67.92mmol,15.57 eq.) was added dropwise to a stirred solution of (2R, 5R) -1- (tert-butoxycarbonyl) -5-methylpyrrolidine-2-carboxylic acid (1.0 g,4.36mmol,1 eq.) in THF (10 mL) at 0deg.C under argon. The resulting mixture was stirred at 60℃under argon for 1h. The desired product can be detected by TLC. The mixture was cooled to room temperature. The reaction was quenched by the addition of MeOH (5 mL) at 0deg.C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (2:1) to give (2 r,5 r) -2- (hydroxymethyl) -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (900 mg, 95.85%) as a yellow oil. The desired product can be detected by TLC.

86.2: synthesis of tert-butyl (2R, 5R) -2- { [ (4-bromopyridin-3-yl) oxy ] methyl } -5-methylpyrrolidine-1-carboxylate

To a stirred solution of (2R, 5R) -2- (hydroxymethyl) -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (890.88 mg,4.138mmol,1.2 eq.) and 4-bromopyridin-3-ol (600 mg,3.44mmol,1.00 eq.) in THF at 0deg.C under argon atmosphere was added dropwise DEAD (900 mg,5.17mmol,1.5 eq.). At room temperature The resulting mixture was stirred under argon for 4h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2R, 5R) -2- { [ (4-bromopyridin-3-yl) oxy]Methyl } -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 93.73%) was a colorless oil.

LC-MS:(M+H) ⁺ Actual: 372.90

86.3: synthesis of tert-butyl (2R, 5R) -2-methyl-5- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

To (2R, 5R) -2- { [ (4-bromopyridin-3-yl) oxy group at room temperature under argon atmosphere]Methyl } -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (1 g,2.69mmol,1 eq.) and 2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]]Pyridin-4-one (0.85 g,3.23mmol,1.2 eq.) in THF/H ₂ Xphos Pd G2 (0.21G, 0.27mmol,0.1 eq.) was added to the stirred mixture in O. The resulting mixture was stirred overnight at 50℃under argon. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (5X 30 mL). The combined organic layers were washed with water (3×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2 r,5 r) -2-methyl-5- { [ (4- { 4-oxo-1 h,5h,6h,7 h-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (730 mg, 63.55%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 427.3.

86.4: synthesis of tert-butyl (2R, 5R) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -5-methylpyrrolidine-1-carboxylate

To a stirred mixture of tert-butyl (2R, 5R) -2-methyl-5- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (300 mg,1 eq) in DMF was added NIS (189 mg,0.84mmol,1.2 eq) in portions under argon atmosphere at 0 ℃. The resulting mixture was stirred at room temperature under argon for 1h. The reaction was monitored by LCMS. The reaction was quenched by the addition of saturated aqueous sodium sulfite solution (50 mL) at 0 ℃. The precipitated solid was collected by filtration and washed with water (3×10 mL). The resulting mixture was concentrated in vacuo. This gave (2 r,5 r) -2- { [ (4- { 3-iodo-4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (700 mg, 74.04%) as a light yellow solid.

LC-MS:(M+H) ⁺ Actual: 552.95.

86.5: synthesis of tert-butyl (2R, 5R) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -5-methylpyrrolidine-1-carboxylate

(2R, 5R) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) under argon at room temperature]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of methyl } -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (300 mg,0.54mmol,1 eq.) and 3-chloro-2-methoxyaniline (85 mg,0.54mmol,1 eq.) in DMF was added EPhos Pd G4 (49 mg,0.054mmol,0.1 eq.) and Cs ₂ CO ₃ (530 mg,1.62mmol,3 eq.). The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2R, 5R) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 94.90%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 582.25.

86.6: synthesis of 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (((2 r,5 r) -5-methylpyrrolidin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2 r,5 r) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -5-methylpyrrolidine-1-carboxylate (150 mg,0.25mmol,1 eq.) in DCM was added TFA (0.5 mL) dropwise under argon. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 482.25.

86.7: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2 r,5 r) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group at 0℃under argon atmosphere]-2- (3- { [ (2R, 5R) -5-methylpyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (125 mg,0.25mmol,1 eq.) in THF and saturated NaHCO ₃ (aqueous solution) (3 mL) was added dropwise to the stirred solution of acryloyl chloride (23 mg,0.25mmol,1 eq.). The resulting mixture was concentrated in vacuo. The crude product (150 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 36% b to 66% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl)Amino group]-2- (3- { [ (2R, 5R) -5-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (29.4 mg, 21.06%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 536.1

¹ H NMR (400 MHz, chloroform-d) δ11.67 (s, 1H), 8.24 (s, 1H), 8.00 (d, 1H), 7.59 (s, 1H), 7.51 (d, 1H), 6.77-6.71 (m, 1H), 6.69-6.54 (m, 2H), 6.47-6.41 (m, 1H), 6.27-6.21 (m, 1H), 5.85-5.80 (m, 1H), 5.26 (s, 1H), 5.07-4.94 (m, 1H), 4.35-4.20 (m, 3H), 4.11 (s, 3H), 3.69-3.57 (m, 2H), 3.23 (m, 2H), 2.38-2.18 (m, 2H), 1.98-1.90 (m, 2H), 1.44 (d, 3H).

Example 87:3- [ (2-methoxy-3-methylphenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 277)

87.1: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (2-methoxy-3-methylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

(2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) was reacted at room temperature under argon atmosphere ]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (100 mg,0.18mmol,1 eq.) and 2-methoxy-3-methylaniline (50 mg,0.37mmol,2 eq.) in DMF (1 mL) was added Cs in portions ₂ CO ₃ (121 mg,0.37mmol,2 eq.) and Ephos Pd G4 (17 mg,0.019mmol,0.1 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The desired product was detectable by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (15:1) elution to afford (2S) -2- { [ (4- {3- [ (2-methoxy-3-methylphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (80 mg, 78.65%) was a yellow solid.

LC-MS: [ M+H ] -actual: 548.00.

87.2: synthesis of 3- [ (2-methoxy-3-methylphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

A mixture of tert-butyl (2S) -2- { [ (4- {3- [ (2-methoxy-3-methylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (80 mg,0.14mmol,1 eq.) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature under an air atmosphere for 1h. The desired product was detectable by LCMS. The resulting mixture was concentrated in vacuo. This gave 3- [ (2-methoxy-3-methylphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (65 mg, 99.43%) as a yellow oil.

LC-MS:[M+H] ⁺ Actual: 448.00.

87.3: synthesis of 3- [ (2-methoxy-3-methylphenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Stirring 3- [ (2-methoxy-3-methylphenyl) amino group at 0deg.C under air atmosphere]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (80 mg,0.17mmol,1 eq.) and acryloyl chloride (17 mg,0.19mmol,1.1 eq.) in THF (1 mL) and saturated NaHCO ₃ (aqueous solution) (1 mL) for 1h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC and using the following conditions (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 24% B to 45% B in45% b within 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 3- [ (2-methoxy-3-methylphenyl) amino group]-2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (9.8 mg, 10.83%) was a pale yellow solid.

LC-MS:[M+H] ⁺ Actual: 502.00.

¹ h NMR (300 MHz, chloroform-d) δ11.44 (s, 1H), 8.20 (s, 1H), 7.94 (d, j=4.8 hz, 1H), 7.65 (s, 1H), 7.48 (d, j=5.4 hz, 1H), 6.63-6.50 (m, 3H), 6.42-6.36 (m, 1H), 6.17-6.14 (m, 1H), 5.79-5.75 (m, 1H), 5.20 (s, 1H), 5.04 (s, 1H), 4.26 (t, j=9.6 hz, 1H), 4.12-4.08 (m, 1H), 3.97 (s, 3H), 3.75 (t, j=6.5 hz, 2H), 3.66-3.53 (m, 2H), 3.21 (t, j=6.5 hz, 2H), 2.32 (s, 3.16 (s, 1H), 1 s, 1H).

Example 88:2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 289)

88.1: synthesis of tert-butyl (2R) -2- { [ (4-bromopyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

PPh was added portionwise to a stirred solution/mixture of 4-bromopyridin-3-ol (5 g,28.73mmol,1 eq.) and tert-butyl (2R) -2- (hydroxymethyl) azetidine-1-carboxylate (6.44 mg,34.47mmol,1.2 eq.) in 8mL THF at 0deg.C under nitrogen ₃ (11.31 g,43.10mmol,1.5 eq.). Stirred at the same temperature for 30min and DEAD (7.51 g,43.10mmol,1.5 eq.) was added and stirred overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, C18 silica gel; a mobile phase, ACN in water, gradient from 10% to 100%, within 30 min; a detector: UV 254nm. Obtaining (2R) -2- { [ (4-bromopyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (7.5 g, 76.04%) as a light grey oil.

LC-MS:(M+H) ⁺ Actual: 344.85

88.2: synthesis of tert-butyl (2R) -2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

(2R) -2- { [ (4-bromopyridin-3-yl) oxy was added to a 15mL lock tube at room temperature]Methyl } azetidine-1-carboxylic acid tert-butyl ester (500 mg,1.45mmol,1 eq.) 2- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c]Pyridin-4-one (216 mg,1.60mmol,1.1 eq.) Na ₂ CO ₃ (463 mg,4.37mmol,3.0 eq.) XPhos palladium (II) biphenyl-2-amine chloride (114 mg,0.14mmol,0.1 eq.), dioxane (5 mL), meOH (1.5 mL) and H ₂ O (1 mL) was stirred at 50deg.C under Ar for 2.5h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, C18 silica gel; a mobile phase, ACN in water, gradient 0% to 100%, within 30 min; a detector: UV 254nm. This gives (2R) -2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (400 mg, 68.91%) as a light brown solid.

LC-MS (M+H) + actual: 399.10

88.3: synthesis of tert-butyl (2R) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

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To a stirred solution of tert-butyl (2R) -2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (5.5 g,13.80mmol,1 eq.) in DMF (15 mL) was added NIS (3.42 g,15.18mmol,1.1 eq.) in portions at room temperature. Stirred for 1h, then purified by reverse phase flash chromatography and using the following conditions: column, C18 silica gel; a mobile phase, ACN in water, gradient 0% to 100%, within 30 min; a detector: UV 254nm to give tert-butyl (2R) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (6.1 g, 84.28%) as a tan solid.

LC-MS:(M+H) ⁺ Actual: 525.15

88.4: synthesis of tert-butyl (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

(2R) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) was added in a 10mL lock at room temperature]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } azetidine-1-carboxylic acid tert-butyl ester (500 mg,0.95mmol,1 eq.) 3-fluoro-2-methoxyaniline (201 mg,1.43mmol,1.5 eq.) Cs ₂ CO ₃ (932 mg,2.86mmol,3.0 eq.) EPhos Pd G4 (87 mg,0.095mmol,0.1 eq.) and DMF (2 mL) and then stirred under Ar for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (9:1) elution to afford (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (505 mg, 98.51%) as a tan solid.

LC-MS:(M+H) ⁺ Actual: 538.15.

88.5: synthesis of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a 50mL round bottom flask was added tert-butyl (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (400 mg,0.74mmol,1 eq.) followed by trifluoroacetaldehyde (10 mL) and DCM (30 mL) at 0deg.C. Stirring for 2h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (320 mg, 98.31%) as a tan solid.

LC-MS:(M+H) ⁺ Actual: 438.05

88.6: synthesis of 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- {3- [ (2R) -azetidin-2-ylmethoxy at room temperature]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (330 mg,0.75mmol,1 eq.) of 2-butynoic acid (190 mg,2.26mmol,3 eq.) in tetrahydrofuran (10 mL) was added to T ₃ P (480 mg,1.50mmol,2.0 eq). Stirring for 2h at room temperature. The resulting mixture was extracted with EtOAc (2X 50 mL) and dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (500 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 28% b to 58% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number 0) to provide 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (150 mg, 39.49%) was a tan solid.

LC-MS:(M+H) ⁺ Actual: 504.10

¹ H NMR (300 MHz, chloroform-d) δ11.37 (s, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.52 (d, J=6.8 Hz, 2H), 6.57 (td, J=8.2, 5.9Hz, 1H), 6.45 #ddd,J＝10.9,8.3,1.5Hz,1H),6.07(d,J＝8.2Hz,1H),5.21(s,1H),4.94(q,J＝8.6Hz,1H),4.49(t,J＝9.8Hz,1H),4.25(ddd,J＝10.9,5.7,2.4Hz,3H),4.10(d,J＝1.2Hz,3H),3.57(td,J＝6.8,2.5Hz,2H),3.25-2.95(m,2H),2.71-2.53(m,1H),2.20-2.06(m,1H),2.03(s,3H)。

Example 89:3- [ (2-ethyl-3-fluorophenyl) amino ] -2- (3- { [ (2R) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 294)

89.1: synthesis of tert-butyl (2R) -2- { [ (4- {3- [ (2-ethyl-3-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

(2R) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) under argon at room temperature]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (200 mg,0.37mmol,1 eq.) and 2-ethyl-3-fluoroaniline (62 mg,0.44mmol,1.2 eq.) in DMF (2 mL) was added Cs in portions ₂ CO ₃ (242 mg,0.74mmol,2 eq.) and Ephos Pd G4 (34 mg,0.037mmol,0.1 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) elution to provide (2R) -2- { [ (4- {3- [ (2-ethyl-3-fluorophenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (182 mg, 89.14%) was a yellow solid.

LC-MS: [ M+H ] -actual: 550.00.

89.2: synthesis of 3- [ (2-ethyl-3-fluorophenyl) amino ] -2- {3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

A mixture of tert-butyl (2R) -2- { [ (4- {3- [ (2-ethyl-3-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (170 mg,0.30mmol,1 eq.) in TFA (3 mL) and DCM (3 mL) was stirred at room temperature under an air atmosphere for 1h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. This gave 3- [ (2-ethyl-3-fluorophenyl) amino ] -2- {3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (130 mg, 93.50%) as a yellow oil.

LC-MS:[M+H] ⁺ Actual: 450.00.

89.3: synthesis of 3- [ (2-ethyl-3-fluorophenyl) amino ] -2- (3- { [ (2R) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Stirring 3- [ (2-ethyl-3-fluorophenyl) amino group at 0℃under air atmosphere ]-2- {3- [ (2R) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (110 mg,0.24mmol,1 eq.) and acryloyl chloride (26 mg,0.29mmol,1.2 eq.) in THF (2 mL) and saturated NaHCO ₃ (aqueous solution) (2 mL) for 1h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 26% b to 50% b, 50% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 3- [ (2-ethyl-3-fluorophenyl) amino group]-2- (3- { [ (2R) -1- (prop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (10.5 mg, 8.50%) was a yellow solid.

LC-MS:[M+H] ⁺ Actual: 504.00.

¹ H NMR(300MHz,DMSO-d6)δ11.50(s,1H),8.39(s,1H),7.91(d,J＝5.1Hz,1H),7.36(s,1H),7.24(d,J＝12.9Hz,1H),7.15(s,1H),6.78-6.62(m,2H),6.48-6.32(m,1H),6.27-6.21(m,1H),6.07(d,J＝8.2Hz,1H),5.77-5.73(m,1H),4.68(s,1H),4.32(t,J＝8.7Hz,1H),4.17-4.13(m,1H),3.65(s,2H),3.45(s,2H),2.99(t,J＝6.8Hz,2H),2.70(d,J＝7.8Hz,2H),2.09-1.87(m,4H),1.25-1.16(m,3H)。

example 90:2- (3- { [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 298)

90.1: synthesis of tert-butyl (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

(2R) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) under argon at room temperature]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (200 mg,0.37mmol,1 eq.) and 3-fluoro-2-methoxyaniline (104 mg,0.74mmol,2 eq.) in DMF (2 mL) was added in portions Ephos Pd G4 (34 mg,0.037mmol,0.1 eq.) and Cs ₂ CO ₃ (242 mg,0.74mmol,2 eq.). The resulting mixture was stirred at 50℃under argon for 1h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) elution to afford (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (160 mg, 78.08%) was a yellow solid.

LC-MS: [ M+H ] -actual: 552.00.

90.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

(2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] at room temperature under an air atmosphere was stirred]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-2-yl } pyridin-3-yl) oxy]A mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (80 mg,0.14mmol,1 eq.) in TFA (1 mL) and DCM (1 mL) for 1h. The desired product was detectable by LCMS. The resulting mixture was concentrated in vacuo. The resulting mixture was treated with CH ₂ Cl ₂ (2X 30 mL) extraction. The combined organic layers were saturated with NaHCO ₃ (aqueous solution) (2X 30 mL) washed, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- {3- [ (2R) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (60 mg, 91.63%) was a yellow solid.

LC-MS:[M+H] ⁺ Actual: 452.00.

90.3: synthesis of 2- (3- { [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0℃under an air atmosphere to 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- {3- [ (2R) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (60 mg,0.13mmol,1 eq.) and (2E) -4- (dimethylamino) but-2-enoic acid (25 mg,0.20mmol,1.5 eq.) in THF (2 mL) was added in portions DIEA (171 mg,1.33mmol,10 eq.) and T ₃ P (126 mg,0.39mmol,3 eq.). The resulting mixture was stirred at room temperature under an air atmosphere for 1h. The desired product was detectable by LCMS. CH for aqueous layer ₂ Cl ₂ (2X 20 mL) extraction. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC and using the following conditions (column: XBIridge Prep C18 OBD column, 30 x 100mm,5 μm; mobile phase A water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 18% b to 43% b, 43% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 2- (3- { [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl]Pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (16.6 mg, 21.54%) was a pale yellow solid.

LC-MS:[M+H] ⁺ Actual: 563.00.

¹ H NMR(300MHz,DMSO-d6)δ11.53(s,1H),8.41(s,1H),7.98(d,J＝5.1Hz,1H),7.46(s,1H),7.36(d,J＝5.1Hz,1H),7.13(s,1H),6.80-6.54(m,2H),6.52-6.38(m,2H),5.98(d,J＝8.1Hz,1H),4.67(s,1H),4.38-4.32(m,1H),4.18-4.13(m,1H),3.91(s,3H),3.63(d,J＝5.9Hz,2H),3.42(d,J＝2.4Hz,3H),3.08-2.92(m,3H),2.13(s,5H),2.08-1.84(m,5H)

example 91:2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- { [3- (trifluoromethyl) phenyl ] amino } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 349)

91.1: synthesis of tert-butyl (2R) -2- ({ [4- (4-oxo-3- { [3- (trifluoromethyl) phenyl ] amino } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl) pyridin-3-yl ] oxy } methyl) azetidine-1-carboxylate

(2R) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) under argon at room temperature]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } azetidine-1-carboxylate (200 mg,0.38mmol,1 eq.) and 3- (trifluoromethyl) aniline (122 mg,0.76mmol,2 eq.) in DMF (2 mL) was added in portions Ephos Pd G4 (35 mg,0.038mmol,0.1 eq.) and Cs ₂ CO ₃ (248 mg,0.76mmol,2 eq.). The resulting mixture was stirred at 50℃under argon for 1h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was passed through a silica gel columnPurification by chromatography using CH ₂ Cl ₂ MeOH (20:1) elution to afford (2R) -2- ({ [4- (4-oxo-3- { [3- (trifluoromethyl) phenyl)]Amino } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl) pyridin-3-yl]Tert-butyl oxy } methyl) azetidine-1-carboxylate (267 mg, 125.55%) as a yellow solid.

LC-MS: [ M+H ] -actual: 558.00.

91.2: synthesis of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- { [3- (trifluoromethyl) phenyl ] amino } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

A mixture of tert-butyl (2R) -2- ({ [4- (4-oxo-3- { [3- (trifluoromethyl) phenyl ] amino } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl) pyridin-3-yl ] oxy } methyl) azetidine-1-carboxylate (90 mg,0.16mmol,1 eq.) in TFA (3 mL) and DCM (3 mL) was stirred at room temperature under an air atmosphere for 1h. The desired product was detectable by LCMS. The resulting mixture was concentrated in vacuo. This gave 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- { [3- (trifluoromethyl) phenyl ] amino } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (70 mg, 94.80%) as a yellow oil.

LC-MS:[M+H] ⁺ Actual: 458.00.

91.3: synthesis of 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- { [3- (trifluoromethyl) phenyl ] amino } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- {3- [ (2R) -azetidin-2-ylmethoxy at 0℃under an air atmosphere]Pyridin-4-yl } -3- { [3- (trifluoromethyl) phenyl]Amino } -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (70 mg,0.15mmol,1 eq.) and 2-butynoic acid (19 mg,0.22mmol,1.5 eq.) in THF (3 mL) was added in portions DIEA (197mg, 1.53mmol,10 eq.)) And T ₃ P (146 mg,0.45mmol,3 eq.). The resulting mixture was stirred at room temperature under an air atmosphere for 1h. The desired product was detectable by LCMS. CH for aqueous layer ₂ Cl ₂ (2X 20 mL) extraction. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/LNH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 24% b to 49% b, 49% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl]Methoxy } pyridin-4-yl) -3- { [3- (trifluoromethyl) phenyl ]Amino } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (28.3 mg, 35.19%) was a pale yellow solid.

LC-MS:[M+H] ⁺ Actual: 524.00.

¹ H NMR(300MHz,DMSO-d6)δ11.48(s,1H),8.37(s,1H),8.00(d,J＝5.0Hz,1H),7.83(s,1H),7.41(d,J＝5.1Hz,1H),7.27-7.04(m,2H),6.86-6.74(m,3H),4.82-4.71(m,1H),4.51-4.29(m,2H),4.16-4.02(m,2H),3.41-3.34(m,2H),2.96-2.80(m,2H),2.15-20.2(m,4H)。

example 92:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- (3-methoxyazetidin-1-yl) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 225)

92.1: (2E) Synthesis of (E) -4-bromobut-2-enoyl chloride

SOCl was added dropwise to a stirred mixture of 4-bromo-trans-crotonic acid (200 mg,1.21mmol,1.00 eq.) and 1 drop DMF in DCM (5 mL) at 0deg.C ₂ (288 mg,2.42mmol,2.00 eq.). The resulting mixture was stirred at 25℃for 2h. TLC (PE: ea=2:1) showed that a new spot was detected. The resulting mixture was concentrated under reduced pressure to give (2E) -4-bromobut-2-enoyl chloride (180 mg, 80.95%) as a brown oil.

92.2: synthesis of (R, E) -2- (3- ((1- (4-bromobut-2-enoyl) azetidin-2-yl) methoxy) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (100 mg,0.22mmol,1.00 eq.) and DIEA (85 mg,0.66mmol,3.00 eq.) in DCM (2 mL) was added dropwise (2E) -4-bromobut-2-enoyl chloride (48 mg,0.26mmol,1.20 eq.) at 0 ℃. The resulting mixture was stirred at 25℃for 2h. The resulting mixture was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 600.

92.3: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- (3-methoxyazetidin-1-yl) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a solution of 3-methoxyazetidine hydrochloride (32 mg,0.26mmol,1.20 eq.) in DMF (0.5 mL) was added K ₂ CO ₃ (90 mg,0.65mmol,3.00 eq.) and stirring the mixture for 30min. The mixture is then added to 2- (3- { [ (2R) -1- [ (2E) -4-bromobut-2-enoyl]Azetidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (130 mg,0.22mmol,1.00 eq.) in 2mL DCM was stirred at room temperature for 24h. The desired product was detectable by LCMS. The reaction mixture was quenched with water and extracted with DCM (3×10 ml). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XSelect CSH fluorophenyl, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; ladderThe degree is 39% B to 55% B, and 55% B within 8 min; wavelength is 254/220nm; RT1 (min) 8; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group ]-2- (3- { [ (2R) -1- [ (2E) -4- (3-methoxyazetidin-1-yl) but-2-enoyl]Azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (28.3 mg, 21.55%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 607.15.

¹ h NMR (300 MHz, chloroform-d) δ11.77 (s, 1H), 8.22 (s, 1H), 7.99 (d, 1H), 7.53 (s, 1H), 7.45 (d, 1H), 6.90-6.76 (m, 1H), 6.74-6.66 (m, 1H), 6.60 (t, 1H), 6.28-6.17 (m, 1H), 6.15-6.04 (m, 1H), 5.17 (t, 1H), 5.07-4.93 (m, 1H), 4.50 (t, 1H), 4.35-4.20 (m, 3H), 4.16-4.02 (m, 4H), 3.79-3.52 (m, 4H), 3.27 (s, 5H), 3.19-2.98 (m, 4H), 2.67-2.55 (m, 1H), 2.13 (m, 1H).

Example 93:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- (pyrrolidin-1-yl) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 224)

93.1: synthesis of tert-butyl (2R) -2- { [ (4-cyanopyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

Cs was added in portions to a stirred solution of tert-butyl (2R) -2- (hydroxymethyl) azetidine-1-carboxylate (6.50 g,34.71mmol,1.00 eq.) and 3-fluoropyridine-4-carbonitrile (4.24 g,34.71mmol,1.00 eq.) in DMF (150 mL) at room temperature under argon ₂ CO ₃ (33.93 g,104.14mmol,3.00 eq.). The resulting mixture was stirred at 80℃under argon for 4h. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with water (3×60 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (1:1) to provide (2R) -2- { [ (4-cyanopyridin-3-yl) oxy]Methyl } azetidine-1-carboxylic acid tert-butyl ester (10.00 g, 99.56%), which wasYellow solid.

LC-MS:(M+H) ⁺ Actual: 290.2

93.2: synthesis of tert-butyl (2R) -2- ([ [4- (aminomethyl) pyridin-3-yl ] oxy ] methyl) azetidine-1-carboxylate

To (2R) -2- [ [ (4-cyanopyridin-3-yl) oxy group at room temperature under hydrogen atmosphere]Methyl group]A stirred solution of tert-butyl azetidine-1-carboxylate (10.50 g,36.29mmol,1.00 eq.) in MeOH (100 mL) was added ammonia (7.0M in MeOH, 100mL,700.00 mmol) and Raney Ni (4.66 g,44 w/w%). The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2R) -2- ([ [4- (aminomethyl) pyridin-3-yl) ]Oxy group]Tert-butyl methyl-azetidine-1-carboxylate (10.00 g, 93.93%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 294.2.

93.3: synthesis of tert-butyl 4- { [ (3- { [ (2R) -1- (tert-butoxycarbonyl) azetidin-2-yl ] methoxy } pyridin-4-yl) methyl ] amino } -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydropyridine-1-carboxylate

To (2R) -2- ({ [4- (aminomethyl) pyridin-3-yl)]Tert-butyl oxy } methyl) azetidine-1-carboxylate (10.00 g,34.09mmol,1.00 eq.) and 3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl]A stirred solution of tert-butyl 4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylate (14.07 g,34.09mmol,1.00 eq.) and DIEA (13.22 g,102.26mmol,3.00 eq.) in DMF (150 mL) was added in portions to PyBOP (26.61 g,51.13mmol,1.50 eq.). The resulting mixture was stirred overnight at room temperature under argon. The resulting mixture was treated with water (100 mL) dilution. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with water (3×100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (1:2) to provide 4- { [ (3- { [ (2R) -1- (tert-butoxycarbonyl) azetidin-2-yl ]Methoxy } pyridin-4-yl) methyl]Amino } -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl]-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (17.00 g, 72.46%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 688.1.

93.4: synthesis of tert-butyl (2R) -2- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl } oxy) methyl ] azetidine-1-carboxylate

At 80 ℃ N ₂ 4- { [ (3- { [ (2R) -1- (tert-butoxycarbonyl) azetidin-2-yl was stirred under an atmosphere]Methoxy } pyridin-4-yl) methyl]Amino } -3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl]-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (8.00 g, 10.463mmol, 1.00 eq., 90%) and H ₂ O ₂ (30 w/w%,1.54g,13.60mmol,1.30 eq.) in MeOH (100 mL) for 1h. The desired product was detectable by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was treated with CH ₂ Cl ₂ (3X 100 mL) extraction. The combined organic layers were washed with water (3×50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. This gives (2R) -2- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino) ]-4-oxo-1H, 6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl } oxy) methyl]Azetidine-1-carboxylic acid tert-butyl ester (6.3 g, 58.00%) was a yellow solid.

93.5: synthesis of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To (2R) -2- [ ({ 4- [5- (tert-butoxycarbonyl) -3- [ (3-chloro-2-methoxyphenyl) amino) at 0℃under argon atmosphere]-4-oxo-1H, 6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl } oxy) methyl]Azetidine-1-carboxylic acid tert-butyl ester (6.30 g,9.63mmol,1.00 eq.) in CH ₂ Cl ₂ A stirred solution in (60 mL) was added TFA (12 mL) in portions. The resulting mixture was stirred at room temperature under argon for 6h. The desired product was detectable by LCMS. With saturated NaHCO ₃ The aqueous solution basifies the mixture to pH 8. The resulting mixture was treated with CH ₂ Cl ₂ (3X 100 mL) extraction. The combined organic layers were washed with brine (3×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford 2- {3- [ (2R) -azetidin-2-ylmethoxy]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group ]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (2.8 g, 64.05%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 454.05.

93.6: synthesis of (R, E) -2- (3- ((1- (4-bromobut-2-enoyl) azetidin-2-yl) methoxy) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (60 mg,0.13mmol,1.00 eq.) and DIEA (51 mg,0.39mmol,3 eq.) in DCM (3 mL) at 0deg.C under nitrogen was added (2E) -4-bromobut-2-enoyl chloride (29 mg,0.15mmol,1.2 eq.). The resulting mixture was stirred at 0℃under nitrogen for 0.5h. The resulting mixture was used directly in the next step without further purification.

93.7: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- (pyrrolidin-1-yl) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Pyrrolidine (24 mg,0.33mmol,3.00 eq.) was added dropwise to the mixture obtained in the previous step at 0 ℃. The resulting mixture was stirred at room temperature overnight. The desired product was detectable by LCMS. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 50 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and dissolved in DMSO. The crude product (100 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 11% B to 22% B, 22% B over 7 min; wavelength: 254/220nm; RT1 (min): 6.5; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (2R) -1- [ (2E) -4- (pyrrolidin-1-yl) but-2-enoyl]Azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (22.6 mg, 34.71%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 591.00.

¹ h NMR (400 MHz, chloroform-d) δ11.77 (s, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 7.97 (d, 1H), 7.55 (s, 1H), 7.46 (d, 1H), 6.96-6.91 (m, 1H), 6.71-6.93 (m, 1H), 6.61 (t, 1H), 6.32-6.12 (m, 2H), 5.51 (t, 1H), 5.01 (q, 1H), 4.50 (t, 1H), 4.38-4.17 (m, 3H), 4.08 (s, 3H), 3.68-3.47 (m, 4H), 3.21-3.01 (m, 2H), 2.89 (q, 4H), 2.63-2.60 (m, 1H), 2.15-2.13 (m, 1H), 1.96-1.95 (m, 4H).

Example 94:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- [ (3R) -3-methoxypyrrolidin-1-yl ] but-2-enyi-nyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 223)

To a solution of (3R) -3-methoxypyrrolidine hydrochloride (36 mg,0.26mmol,1.20 eq.) in DMF (1 mL) was added K ₂ CO ₃ (90 mg,0.65mmol,3.00 eq.) and stirring the mixture for 30min. The mixture is then added to 2- (3- { [ (2R) -1- [ (2E) -4-bromobut-2-enoyl]Azetidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (130 mg,0.22mmol,1.00 eq.) in 2mL DCM was stirred at room temperature for 4h. The desired product was detectable by LCMS. The reaction mixture was quenched with water and extracted with DCM (3×10 ml). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep C18OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 18% b to 40% b, 40% b over 9 min; wavelength is 254/220nm; RT1 (min) 9.67; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (2R) -1- [ (2E) -4- [ (3R) -3-methoxypyrrolidin-1-yl]But-2-enoyl]Azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (19.7 mg, 14.60%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 621.20.

¹ h NMR (400 MHz, chloroform-d) delta 11.69 (s, 1H), 8.16 (s, 1H), 7.92 (d, 1H), 7.52-7.33 (m, 2H), 6.97-6.83 (m, 1H), 6.67-6.48 (m, 2H), 6.22-5.98 (m, 2H), 5.11 (s, 1H), 5.00-4.88 (m, 1H), 4.43 (t, 1H), 4.29-4.10 (m, 3H), 4.02 (s, 3H), 3.87 (d, 1H), 3.52 (m, 2H), 3.27 (s, 2H), 3.22 (s, 3H), 3.15-2.99 (m, 2H), 2.83-2.43 (m, 5H), 2.12-1.97 (m, 2H), 1.88-1.78

Example 95:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- (3, 3-difluoropyrrolidin-1-yl) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 221)

K was added to a solution of 3, 3-difluoropyrrolidine hydrochloride (28 mg,0.20mmol,1.20 eq.) in DMF (0.5 mL) at 0deg.C ₂ CO ₃ (69 mg,0.49mmol,3.00 eq.) and stirring the mixture for 30min. Then, the mixture obtained in the previous step was added dropwise at 0 ℃. The resulting mixture was stirred at room temperature for a further 48h. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 50 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and dissolved in DMSO. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Shield RP OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient from 22% b to 52% b, 52% b over 10 min; wavelength is 220/254nm; RT1 (min) 10.55; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (2R) -1- [ (2E) -4- (3, 3-difluoropyrrolidin-1-yl) but-2-enoyl]Azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (36.8 mg, 26.64%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 627.15.

¹ h NMR (400 MHz, chloroform-d) δ11.78 (s, 1H), 8.25 (s, 1H), 8.01 (d, 1H), 7.57 (s, 1H), 7.47 (d, 1H), 6.92-6.86 (m, 1H), 6.72-6.69 (m, 1H), 6.63 (t, 1H), 6.24-6.21 (m, 1H), 6.15-6.11 (m, 1H), 5.21 (d, 1H), 5.04 (q, 1H), 4.53 (t, 1H), 4.45-4.18 (m, 3H), 4.11 (s, 3H), 3.62-3.57 (m, 2H), 3.32-3.12 (m, 2H), 3.25-3.07 (m, 2H), 2.94-2.88 (m, 2H), 2.81 (t, 2H), 2.65-2.61 (m, 1H), 4.45-4.18 (m, 3H), 4.62-3.57 (m, 2H), 2.34-2.34 (m, 2H).

Example 96:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- (3-fluoroazetidin-1-yl) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 219)

To a solution of 3-fluoroazetidine hydrochloride (28.96 mg, 0.299 mmol,1.2 eq.) in DMF (1 mL) was added K ₂ CO ₃ (90 mg,0.65mmol,3.00 eq.) and stirring the mixture for 30min. The mixture was then added to 2- (3- { [ (2R) -1- [ (2E) -4-bromobut-2-enoyl at room temperature]Azetidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (130 mg,0.22mmol,1.00 eq.) in 2mL DCM was stirred for 24h. The desired product was detectable by LCMS. The reaction mixture was quenched with water and extracted with DCM (3×10 ml). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient from 22% b to 46% b, 46% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (2R) -1- [ (2E) -4- (3-fluoroazetidin-1-yl) but-2-enoyl]Azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (13.6 mg, 10.50%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 595.15.

¹ h NMR (300 MHz, chloroform-d) delta 11.79 (s, 1H), 8.23 (s, 1H), 7.97 (d, 1H), 7.56 (s, 1H), 7.44 (d, 1H), 6.91-6.75 (m, 1H), 6.75-6.65 (m, 1H), 6.60 (t, 1H), 6.27-6.14 (m, 1H), 6.13-5.99 (m, 1H), 5.33-4.92 (m, 3H), 4.50 (t, 1H), 4.38-4.17 (m, 3H), 4.08 (s, 3H), 3.81-3.63 (m, 2H), 3.64-3.51 (m, 2H), 3.38-3.06 (m, 6H), 2.71-2.49 (m, 1H), 2.21-2.05 (m, 1H).

Example 97: rel-3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 244)

97.1: synthesis of tert-butyl 2-formyl-2-methylazetidine-1-carboxylate

at-78deg.C under nitrogen atmosphere, to (COCl) ₂ A stirred solution of (757 mg,5.96mmol,1.20 eq.) in DCM (50 mL) was added dropwise DMSO (0.9 mL,12.42mmol,2.50 eq.). The resulting mixture was stirred at-78℃under nitrogen for 30min. To the above mixture was added dropwise tert-butyl 2- (hydroxymethyl) -2-methylazetidine-1-carboxylate (1 g,4.97mmol,1.00 eq.) at-78 ℃. The resulting mixture was stirred at-78℃for a further 30min. The desired product can be detected by TLC. TEA (3.5 mL,24.85mmol,5.00 eq.) was added to the above mixture at-78deg.C. The resulting mixture was stirred at 0deg.C for a further 30min. The resulting mixture was treated with CH ₂ Cl ₂ (3X 50 mL) extraction. The combined organic layers were washed with water (3×50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product, tert-butyl 2-formyl-2-methylazetidine-1-carboxylate (1 g), was used directly in the next step without further purification.

97.2: synthesis of tert-butyl 2-ethynyl-2-methylazetidine-1-carboxylate

To a stirred solution of tert-butyl 2-formyl-2-methylazetidine-1-carboxylate (1 g,5.02mmol,1.00 eq.) in MeOH (10 mL) at 0deg.C under nitrogen ₂ CO ₃ (1.4 g,10.04mmol,2.00 eq.) and Seyferth-Gilbert homologating reagent (1.15 mg,6.02mmol,1.2 eq.). The resulting mixture was stirred at 0℃under nitrogen for 1h. The desired product can be detected by TLC. The reaction was quenched by the addition of aqueous potassium sodium tartrate (5 mL) at 0deg.C. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (10:1) to provide tert-butyl 2-ethynyl-2-methylazetidine-1-carboxylate (700)mg, 71.43%) as a colorless oil.

97.3: synthesis of tert-butyl 2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylazetidine-1-carboxylate

To 3- [ (3-fluoro-2-methoxyphenyl) amino group under nitrogen atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]A stirred solution of pyridin-4-one (500 mg,1.05mmol,1.00 eq.) and tert-butyl 2-ethynyl-2-methylazetidine-1-carboxylate (408 mg,2.09mmol,2.00 eq.) in DMF (5 mL) was added Pd (dppf) Cl ₂ CH ₂ Cl ₂ (426 mg,0.52mmol,0.50 eq.) and DIEA (676 mg,5.23mmol,5.00 eq.). The resulting mixture was stirred at 50℃under nitrogen for 4h. The residue was purified by reverse phase flash chromatography using column, C18 spherical column; a mobile phase, ACN in water, gradient 0% to 100%, within 20 min; a detector: UV 254nm to provide 2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-methylazetidine-1-carboxylic acid tert-butyl ester (280 mg, 49.09%) as yellow solid.

LC-MS:(M+H) ⁺ Actual: 546.20

97.4: synthesis of 2- {3- [2- (azetidin-2-yl) ethynyl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl 2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylazetidine-1-carboxylate (350 mg,0.64mmol,1.00 eq.) in DCM (3 mL) was added TFA (1 mL) dropwise at room temperature under nitrogen. The resulting mixture was stirred overnight at room temperature under nitrogen. The resulting mixture was concentrated in vacuo to afford the crude 2- {3- [2- (azetidin-2-yl) ethynyl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (500 mg) as a yellow oil.

LC-MS: M+Hactual: 446.10.

97.5: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-fluoro-2-methoxyphenyl) amino group at 0℃under nitrogen atmosphere]-2- {3- [2- (2-methylazetidin-2-yl) ethynyl]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (250 mg,0.56mmol,1.00 eq.) in THF (3 mL) was added dropwise to NaHCO ₃ Aqueous (0.5 mL) and acryloyl chloride (46 mg,0.51mmol,0.90 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 20 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) to afford crude product. The crude product was concentrated in vacuo and dissolved in DMSO. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: YMC-actual Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/LNH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 18% b to 35% b, 35% b in 11 min; wavelength is 254/220nm; RT1 (min) 10.38; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group ]-2- (3- {2- [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (43 mg, 15.34%) was a yellow solid.

LC-MS: M+Hactual: 500.10

97.6: synthesis of rel-3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (43 mg,0.086mmol,1.00 eq) was purified by chiral HPLC and purified using the following conditions (column: CHIRALPAK ID-3,4.6 x 50mm,3 μm; mobile phase A (Hex: DCM=3:1) (0.1% DEA): IPA=90:10; flow rate: 1mL/min; gradient: 0% B to 0% B; injection volume: 5ul mL) to provide rel-3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl) -1H,5H, 7H-pyrrolo [3, 6 g ] pyridin-4-yl ] 1H, 6 g of a yellow solid (1 mg, 35.12%).

LC-MS:(M+H) ⁺ Actual: 500.10.

¹ h NMR (400 MHz, chloroform-d) δ9.52 (brs, 1H), 8.80 (s, 1H), 8.27-8.21 (m, 2H), 7.21 (d, J=5.9 Hz, 1H), 6.77-6.73 (m, 1H), 6.58-6.55 (m, 1H), 6.27 (t, J=6.1 Hz, 1H), 6.15-6.11 (m, 1H), 5.94-5.88 (m, 1H), 5.57-5.55 (m, 1H), 5.42 (s, 1H), 3.99 (d, J=1.3 Hz, 3H), 3.63-3.40 (m, 3H), 3.15-2.82 (m, 3H), 2.25-2.17 (m, 1H), 2.01-1.95 (m, 1H), 1.82 (s, 3H).

Example 98: rel-3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 243)

3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (43 mg,0.09mmol,1.00 eq) was purified by chiral HPLC and purified using the following conditions (column CHIRALPAK ID-3,4.6 x 50mm,3 μm; mobile phase a (Hex: dcm=3:1) (0.1% dea): ipa=90:10; flow rate: 1mL/min; gradient: 0% b to 0% b; injection volume: 5ul mL) to provide rel-3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl) pyridin-4-yl) -1h,5h, 7h, 6 h-pyrrolo [3, 26 mg ] pyridin-4-one as a yellow solid (14 mg, 33.14%).

LC-MS:(M+H) ⁺ Actual: 500.10.

¹ h NMR (400 MHz, chloroform-d) δ9.42 (s, 1H), 8.73 (s, 1H), 8.40-8.19 (m, 2H), 7.15 (d, 1H), 6.78-6.74 (m, 1H), 6.57-6.52 (m, 1H), 6.28 (t, 1H), 6.15-6.10 (m, 1H), 5.95-5.88 (m, 1H), 5.56-5.52 (m, 1H), 5.43 (s, 1H), 3.98 (d, 3H), 3.61-3.38 (m, 3H), 3.12-2.79 (m, 3H), 2.23-2.16 (m, 1H), 2.04-1.95 (m, 1H), 1.81 (s, 3H).

Example 99:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1- (2-fluoroprop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 287)

99.1: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

Under argon atmosphere, to (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (400 mg,0.74mmol,1.00 eq.) and 3-fluoro-2-methoxyaniline (210 mg,1.49mmol,2.00 eq.) in DMF (5 mL) was added EPhos Pd G4 (68 mg,0.07mmol,0.10 eq.) and Cs ₂ CO ₃ (254 mg,1.49mmol,2.00 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The resulting mixture was filtered and the filter cake was washed with DCM (2X 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) elutionTo provide (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (310 mg, 75.64%) was a brown solid.

LC-MS:(M+H) ⁺ Actual: 552.20

99.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

A mixture of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (290 mg,0.53mmol,1.00 eq.) and TFA (1 mL) in DCM (3 mL) was stirred under nitrogen at room temperature for 1h. The resulting mixture was concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (540 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 452.20

99.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1- (2-fluoroprop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Preparation of 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (60 mg,0.13mmol,1.00 eq.) in THF (1.5 mL). The mixture was basified with DIEA to pH 8 at 0 ℃ under nitrogen atmosphere, 2-fluoroprop-2-enoic acid (18 mg,0.20mmol,1.50 eq.) was added followed by dropwise addition of T3P (169 mg,0.26mmol,2.00 eq., 50% in EA) at 0 ℃. The resulting mixture was at room temperature under nitrogen atmosphere Stirred for 1h. The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (1X 10 mL) and the resulting mixture was washed with 1X10mL of NaHCO ₃ (aqueous solution) washing. Anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (60 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 23% b to 53% b over 10 min; wavelength of 254nm; RT1 (min) 9.5; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- { [ (2S) -1- (2-fluoroprop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (27.6 mg, 39.55%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 524.10.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.25(s,1H),8.41(s,1H),8.02(d,1H),7.40(s,1H),7.33(d,1H),7.10(s,1H),6.61–6.49(m,1H),6.47(t,1H),5.99(d,1H),5.45–5.31(m,2H),4.63(s,1H),4.37–4.34(m,1H),4.25–4.21(m,1H),3.89(s,3H),3.69(s,1H),3.59(s,1H),3.41–3.39(m,2H),2.89(t,2H),2.07–1.82(m,4H)。

example 100:2- (3- { [ (2S) -1- (but-2-ynyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 282)

Preparation of 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (60 mg,0.13mmol,1.00 eq.) in THF (1.5 mL). The mixture was basified to pH 8 with DIEA, and 2-butynoic acid (17 mg,0.20mmol,1.50 eq.) was added over 2min at 0deg.C under nitrogen followed by dropwise addition of T3P (169 mg,0.27mmol,2.00 eq., 50% in EA) at 0deg.C. The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was extracted with EtOAc (3X 10 mL) Taking. The combined organic layers were washed with brine (1×10 mL). NaHCO for residue ₃ (aqueous solution) (1X 10 mL) washed, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (60 mg) was purified by preparative HPLC and using the following conditions (column: XSelect CSH fluorophenyl, 30 x 150mm,5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 12% B to 42% B over 7min, 42% B; wavelength: 254nm; RT1 (min): 5.83; running number: 0) to provide 2- (3- { [ (2S) -1- (but-2-ynyl) pyrrolidin-2-yl)]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (29.1 mg, 42.10%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 518.5.

¹ h NMR (300 MHz, chloroform-d) δ11.37 (s, 1H), 8.29 (s, 1H), 7.90 (d, 1H), 7.77 (s, 1H), 7.53 (d, 1H), 6.67-6.45 (m, 2H), 6.02-5.99 (m, 1H), 5.59 (s, 1H), 4.91-4.90 (m, 1H), 4.26-4.20 (m, 1H), 4.16-4.07 (m, 4H), 4.03-4.01 (m, 1H), 3.74-3.70 (m, 1H), 3.64-3.61 (m, 2H), 3.24-3.15 (m, 2H), 2.32-1.99 (m, 2H), 2.04 (s, 3H), 1.95 (s, 1H), 1.92-1.80 (m, 1H).

Example 101:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 297)

101.1: synthesis of 2- {3- [ (2S) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under nitrogen atmosphere]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl methyl } azetidine-1-carboxylate (150 mg,0.28mmol,1.00 eq.) in DCM (2 mL) was added dropwise to TFA (1 mL). The resulting mixture was stirred at room temperature under nitrogen for 1h. Vacuum concentrationThe resulting mixture is condensed. The residue was dissolved in CH ₂ Cl ₂ (5 mL). With saturated NaHCO ₃ The mixture was acidified to pH7 with aqueous solution. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 10 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford 2- {3- [ (2S) -azetidin-2-ylmethoxy]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100 mg, 81.92%) was a pale yellow solid. LC-MS (M+H) ⁺ Actual: 438.10.

101.2: synthesis of (S, E) -2- (3- ((1- (4-bromobut-2-enoyl) azetidin-2-yl) methoxy) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of 2- {3- [ (2S) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (90 mg,0.21mmol,1.00 eq.) and DIEA (80 mg,0.62mmol,3.00 eq.) in DCM (5 mL) at 0 ℃ under nitrogen was added (2E) -4-bromobut-2-enoyl chloride (46 mg,0.25mmol,1.20 eq.). The resulting mixture was stirred at 0℃under nitrogen for 0.5h. The resulting mixture was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 584

101.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0 ℃ and the previous stepMorpholine (54 mg,0.62mmol,3.00 eq.) was added dropwise to the resulting mixture. The resulting mixture was stirred at room temperature for a further 48h. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 10 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and dissolved in DMSO. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 18% b to 38% b, 38% b over 10 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- { [ (2S) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl]Azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (53.2 mg, 43.78%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 591.15.

¹ h NMR (400 MHz, chloroform-d) delta 11.79 (s, 1H), 8.25 (s, 1H), 8.01 (d, 1H), 7.61 (s, 1H), 7.53 (d, 1H), 6.94-6.87 (m, 1H), 6.60-6.55 (m, 1H), 6.48-6.43 (m, 1H), 6.19-6.04 (m, 2H), 5.22 (s, 1H), 5.04 (q, 1H), 4.53 (t, 1H), 4.42-4.19 (m, 3H), 4.13 (d, 3H), 3.76 (t, 4H), 3.62-3.57 (m, 2H), 3.26-3.05 (m, 4H), 2.70-2.61 (m, 1H), 2.51-2.49 (m, 4H), 2.21-2.13 (m, 1H).

Example 102:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl ] pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 300)

102.1: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under nitrogen atmosphere]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidinesA stirred solution of tert-butyl 1-carboxylate (150 mg,0.27mmol,1.00 eq.) in DCM (2 mL) was added dropwise to TFA (1 mL). The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (5 mL). With saturated NaHCO ₃ The mixture was acidified to pH 7 with aqueous solution. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 10 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100 mg, 81.45%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 452.10

102.2: synthesis of (S, E) -2- (3- ((1- (4-bromobut-2-enoyl) pyrrolidin-2-yl) methoxy) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (100 mg,0.22mmol,1.00 eq.) and DIEA (86 mg,0.66mmol,3.00 eq.) in DCM (5 mL) at 0 ℃ under nitrogen was added (2E) -4-bromobut-2-enoyl chloride (49 mg,0.26mmol,1.20 eq.). The resulting mixture was stirred at 0℃under nitrogen for 0.5h. The resulting mixture was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 554.10

102.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl ] pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Morpholine (58 mg,0.66mmol,3.00 eq.) was added dropwise to the mixture obtained in the previous step at 0 ℃. The resulting mixture was stirred at room temperature for a further 36h. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 20 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and dissolved in DMSO. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 24% b to 39% b, 39% b over 10 min; wavelength is 254/220nm; RT1 (min) 7.53; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- { [ (2S) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl]Pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (40.4 mg, 30.17%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 605.15.

¹ h NMR (400 MHz, chloroform-d) δ11.56 (s, 1H), 8.20 (brs, 1H), 7.96 (brs, 1H), 7.65 (s, 1H), 7.56 (brs, 1H), 6.96-6.89 (m, 1H), 6.62-6.56 (m, 1H), 6.50-6.40 (m, 2H), 6.06-6.04 (m, 1H), 5.21 (s, 1H), 5.03 (t, 1H), 4.28 (t, 1H), 4.21-4.06 (m, 4H), 3.77-3.72 (m, 6H), 3.64-3.57 (m, 2H), 3.29-3.14 (m, 4H), 2.49 (t, 4H), 2.24-2.09 (m, 3H), 1.88-1.85 (m, 1H).

Example 103:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl ] pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 299)

103.1: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under nitrogen atmosphere]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl methyl } pyrrolidine-1-carboxylate (150 mg,0.27mmol,1.00 eq.) in DCM (2 mL) was added dropwise TFA (1 mL). The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (5 mL). With saturated NaHCO ₃ The mixture was acidified to pH 7 with aqueous solution. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 10 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- {3- [ (2R) -pyrrolidin-2-ylmethoxy ]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100 mg, 81.45%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 452.10

103.2: synthesis of (R, E) -2- (3- ((1- (4-bromobut-2-enoyl) pyrrolidin-2-yl) methoxy) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (90 mg,0.20mmol,1.00 eq.) and DIEA (78 mg,0.60mmol,3.00 eq.) in DCM (5 mL) at 0 ℃ under nitrogen was added (2E) -4-bromobut-2-enoyl chloride (44 mg,0.24mmol,1.20 eq.). The resulting mixture was stirred at 0℃under nitrogen for 0.5h. The resulting mixture was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 554.10

103.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl ] pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Morpholine (52 mg,0.59mmol,3 eq.) was added dropwise to the mixture obtained in the previous step at 0 ℃. The resulting mixture was stirred at room temperature for a further 48h. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 50 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and dissolved in DMSO. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 20% B to 40% B, 40% B over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- { [ (2R) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl]Pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (51.2 mg, 42.48%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 605.15.

¹ h NMR (400 MHz, chloroform-d) δ11.54 (s, 1H), 8.23 (s, 1H), 8.00 (d, 1H), 7.63-7.49 (m, 2H), 6.94-6.88 (m, 1H), 6.61-6.55 (m, 1H), 6.49-6.39 (m, 2H), 6.12-6.05 (m, 1H), 5.23 (s, 1H), 5.06 (t, 1H), 4.28 (t, 1H), 4.19-4.05 (m, 4H), 3.76-3.71 (m, 6H), 3.67-3.54 (m, 2H), 3.27-3.07 (m, 4H), 2.50 (t, 4H), 2.21-2.16 (m, 3H), 1.92-1.83 (m, 1H).

Example 104:2- (3- { [ (2R) -1- [4- (dimethylamino) but-2-ynyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 326)

104.1: synthesis of (R) -2- (3- (azetidin-2-ylmethoxy) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (200 mg,0.19mmol,1.00 eq.) in DCM (1 mL) was added TFA (0.2 mL). The resulting mixture was stirred at room temperature under nitrogen for 3h. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 438.05

104.2: synthesis of 2- (3- { [ (2R) -1- [4- (dimethylamino) but-2-ynyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- {3- [ (2R) -azetidin-2-ylmethoxy at 0℃under nitrogen atmosphere]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (110 mg,0.251mmol,1 eq.) and 4- (dimethylamino) but-2-enoic acid (95.91 mg,0.753mmol,3 eq.) in THF (3 mL) was added dropwise DIEA (162.49 mg,1.255mmol,5 eq.). T3P (480.03 mg,0.753mmol,3 eq., 50% in EA) was added dropwise to the above mixture at 0deg.C. The resulting mixture was stirred at room temperature for an additional 2h. Saturated NaHCO at 0deg.C ₃ The reaction was quenched (in water). The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (1×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (90 mg) was purified by preparative HPLC using the following conditions (column: XSelect CSH fluorophenyl, 30 x 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 30% B to 60% B, over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number 0) to provide 2- (3- { [ (2R) -1-[4- (dimethylamino) but-2-ynyl]Azetidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (12.2 mg, 8.83%) was a pale yellow solid. LC-MS (M+H) ⁺ Actual: 547.15.

¹ h NMR (400 MHz, chloroform-d) δ11.43 (s, 1H), 8.26 (s, 1H), 7.96 (d, 1H), 7.71 (s, 1H), 7.49 (d, 1H), 6.61-6.55 (m, 1H), 6.51-6.46 (m, 1H), 6.10-5.99 (m, 1H), 5.26 (s, 1H), 4.98 (q, 1H), 4.53 (t, 1H), 4.38-4.23 (m, 3H), 4.10 (d, 3H), 3.61-3.57 (m, 2H), 3.51 (s, 2H), 3.24-3.12 (m, 1H), 3.10-3.03 (m, 1H), 2.71-2.61 (m, 1H), 2.19-2.15 (m, 1H).

Example 105:2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (4-chlorophenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 353)

105.1: synthesis of tert-butyl (2R) -2- { [ (4- {3- [ (4-chlorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

To (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl methyl } azetidine-1-carboxylate (300 mg,0.57mmol,1.00 eq.) and 4-chloroaniline (73 mg,0.57mmol,1.00 eq.) in DMF (5 mL) was added Cs ₂ CO ₃ (559 mg,1.71mmol,3.00 eq.) and Ephos Pd G4 (78.83 mg,0.08mmol,0.15 eq.). The resulting mixture was stirred at 50℃under argon for 3h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2R) -2- { [ (4- {3- [ (4-chlorophenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (180 mg, 60.04%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 524.10

105.2: synthesis of (R) -2- (3- (azetidin-2-ylmethoxy) pyridin-4-yl) -3- ((4-chlorophenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2R) -2- { [ (4- {3- [ (4-chlorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (100 mg,0.19mmol,1.00 eq.) in DCM (2 mL) was added TFA (0.4 mL). The resulting mixture was stirred at room temperature under nitrogen for 3h. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 424.00

105.3: synthesis of 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (4-chlorophenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0℃to 2- {3- [ (2R) -azetidin-2-ylmethoxy]Pyridin-4-yl } -3- [ (4-chlorophenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (90 mg,0.21mmol,1.00 eq.) and 2-butynoic acid (27 mg,0.32mmol,1.50 eq.) in THF (2 mL) was added DIEA (137 mg,1.06mmol,5.00 eq.) to adjust the pH to 8. T3P (270 mg,0.42mmol,2.00 eq., 50% in EA) was added dropwise to the above mixture at 0deg.C. The resulting mixture was stirred at room temperature for an additional 2h. Saturated NaHCO at 0deg.C ₃ The reaction was quenched (in water). The resulting mixture was extracted with EtOAc (3X 10 mL). Combined organic layers were treated with NaHCO ₃ (saturated) (2X 10 mL) washed, over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (90 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Stream, streamACN is the mobile phase B; the flow rate is 60mL/min; gradient 25% b to 48% b, 48% b over 9 min; wavelength is 254/220nm; RT1 (min) 7.53; running number 0) to provide 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ]Methoxy } pyridin-4-yl) -3- [ (4-chlorophenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (24 mg, 23.00%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 490.05.

¹ h NMR (400 MHz, chloroform-d) δ11.42 (s, 1H), 8.23 (s, 1H), 7.92 (d, 1H), 7.48 (s, 1H), 7.38 (d, 1H), 7.07-6.96 (m, 2H), 6.68-6.53 (m, 2H), 5.26 (s, 1H), 4.95 (q, 1H), 4.50 (t, 1H), 4.26-4.25 (m, 3H), 3.59-3.57 (m, 2H), 3.26-3.00 (m, 2H), 2.69-2.58 (m, 1H), 2.17-2.11 (m, 1H), 2.04 (s, 3H).

Example 106:2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-chloro-2-ethylphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 348)

106.1: synthesis of tert-butyl (2R) -2- { [ (4- {3- [ (3-chloro-2-ethylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

(2R) -2- { [ (4- { 7-iodo-1-oxo-2H, 3H,4H, 5H-cyclopenta [ c ] at room temperature under argon atmosphere]Pyridin-6-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl methyl } azetidine-1-carboxylate (300 mg,0.57mmol,1.00 eq.) and 3-chloro-2-ethylaniline (89 mg,0.57mmol,1.00 eq.) in DMF (3 mL) was added in portions EPhos Pd G4 (53 mg,0.06mmol,0.10 eq.) and Cs ₂ CO ₃ (560 mg,1.72mmol,3.00 eq.). The resulting mixture was stirred at 50℃under argon for 6h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (97:3) elution to afford (2R) -2- { [ (4- {3- [ (3-chloro-2-ethylphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } azetidine-1-carboxylic acidTert-butyl acid (210 mg, 66.36%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 552.15

106.2: synthesis of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-ethylphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2R) -2- { [ (4- {3- [ (3-chloro-2-ethylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (100 mg,0.18mmol,1.00 eq.) in DCM (2 mL) under nitrogen at room temperature was added TFA (1 mL). The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was concentrated under reduced pressure. The crude 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-ethylphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (150 mg) was used in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 452.00

106.3: synthesis of 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-chloro-2-ethylphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- {3- [ (2R) -azetidin-2-ylmethoxy]Pyridin-4-yl } -3- [ (3-chloro-2-ethylphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (100 mg,0.22mmol,1.00 eq.) in THF (4 mL) was added DIEA (143 mg,1.11mmol,5.00 eq.) to basify the mixture. To the above mixture was added dropwise 2-butynoic acid (28 mg,0.33mmol,1.50 eq.) and T3P (282 mg,0.44mmol,2.00 eq., 50% in EA). The resulting mixture was stirred at room temperature for 1h. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 20 mL) extraction. MergingNaHCO for organic layer ₃ (saturated) (2X 20 mL) washed, over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and dissolved in DMSO. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/LNH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 37% b to 60% b, 60% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ]Methoxy } pyridin-4-yl) -3- [ (3-chloro-2-ethylphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (23.5 mg, 20.50%) was an orange solid.

LC-MS:(M+H) ⁺ Actual: 518.10.

¹ h NMR (400 MHz, chloroform-d) δ11.41 (s, 1H), 8.22 (s, 1H), 7.91 (d, 1H), 7.61 (s, 1H), 7.24 (d, 1H), 6.80-6.78 (m, 1H), 6.69 (t, 1H), 6.36-6.32 (m, 1H), 5.26 (t, 1H), 4.97 (q, 1H), 4.51 (t, 1H), 4.28-4.23 (m, 3H), 3.60-3.57 (m, 2H), 3.26-2.91 (m, 4H), 2.70-2.58 (m, 1H), 2.14-2.11 (m, 1H), 2.06 (s, 3H), 1.39 (t, 3H).

Example 107:3- [ (2-Ethyl-3-fluorophenyl) amino ] -2- (3- { [ (2R) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 364)

107.1: synthesis of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (2-ethyl-3-fluorophenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

A mixture of tert-butyl (2S) -2- { [ (4- {3- [ (2-ethyl-3-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (100 mg,0.18mmol,1.00 eq.) and TFA (0.2 mL) in DCM (1 mL) was stirred at room temperature under a nitrogen atmosphere for 1h. The resulting mixture was concentrated under reduced pressure to afford 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (2-ethyl-3-fluorophenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (200 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 436.20

107.2: synthesis of 3- [ (2-ethyl-3-fluorophenyl) amino ] -2- (3- { [ (2R) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- {3- [ (2R) -azetidin-2-ylmethoxy was prepared by DIEA at 0℃under nitrogen atmosphere]Pyridin-4-yl } -3- [ (2-ethyl-3-fluorophenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (60 mg,0.14mmol,1.00 eq.) in THF (2 mL) was basified to pH 8 and 2-fluoroprop-2-enoic acid (25 mg,0.28mmol,2.00 eq.) and T3P (175 mg,0.28mmol,2.00 eq., 50% in EA) were added dropwise. The resulting mixture was stirred at room temperature under nitrogen for 3h. The resulting mixture was extracted with EtOAc (3X 10 mL). Combined organic layers were treated with NaHCO ₃ (aqueous solution) (1X 10 mL) washed, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (60 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH C18OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 17% B to 47% B over 7 min; wavelength: 254nm; RT1 (min): 6.5; running number: 0) to provide 3- [ (2-ethyl-3-fluorophenyl) amino group]-2- (3- { [ (2R) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl ]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (25.6 mg, 35.18%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 508.2

¹ H NMR (400 MHz, chloroform-d) δ11.48 (s, 1H), 8.23 (s, 1H), 7.93 (d, 1H), 7.54 (s, 1H), 7.29 (d, 1H), 6.72-6.69 (m, 1H), 6.50 (t, 1H), 6.25 (d, 1H), 5.71-5.59 (m, 1H), 5.34 (s, 1H), 5.22 (d, 1H), 5.11 (q, 1H), 4.62-4.40 (m, 3H), 4.30 (d, 1H), 3.62-3.58 (m, 2H), 3.13 (t, 2H), 2.97-2.77 (m, 2H), 2.70-2.66 (m, 1H), 2.26-2.15 (m, 1H), 1.38 (t, 3H).

Example 108:2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 335)

108.1: synthesis of tert-butyl (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate

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To 3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (150 mg,0.31mmol,1.00 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ A stirred mixture of (63 mg,0.08mmol,0.25 eq.) in DMF (2 mL) was added DIEA (202 mg,1.58mmol,5.00 eq.) and tert-butyl (2R) -2-ethynyl-2-methylpyrrolidine-1-carboxylate (196 mg,0.94mmol,3.00 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The residue was purified by reverse phase flash chromatography using mobile phase, meCN in water, gradient 10% to 70% over 20 min; a detector: UV 254nm. This gives (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 85.46%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 560.1

108.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate (120 mg,0.21mmol,1.00 eq.) in DCM (3 mL) was added TFA (1 mL) dropwise at room temperature under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting oil was dried under nitrogen to provide 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (90 mg, 91.34%) as a yellow solid. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 460.05

108.3: synthesis of 2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Treatment of 3- [ (3-fluoro-2-methoxyphenyl) amino group with DIEA (50 mg,0.39mmol,3.00 eq.) at 0deg.C under nitrogen atmosphere]-2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (60 mg,0.13mmol,1.00 eq.) in THF (2 mL) was added dropwise at 0deg.C followed by (2E) -4- (dimethylamino) but-2-enoate (33 mg,0.26mmol,2.00 eq.) and T3P (165 mg,0.26mmol,2.00 eq., 50% in EA) for 10 min. The resulting mixture was stirred at room temperature under nitrogen for 1h. By addition of saturated NaHCO at room temperature ₃ The reaction was quenched with aqueous solution (2 mL). The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 48% b to 78% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number 0) to provide 2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl]-2-methylpyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (29.9 mg, 39.93%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 571.20

¹ H NMR (400 MHz, chloroform-d) δ11.52 (s, 1H), 8.51 (s, 1H), 8.17 (d, 1H), 7.69 (s, 1H), 7.51-7.45 (m, 1H), 6.99-6.88 (m, 1H), 6.65-6.55 (m, 1H), 6.53-6.44 (m, 1H), 6.44-6.36 (m, 1H), 6.16-6.09 (m, 1H), 5.23 (s, 1H), 4.12 (d, 3H), 3.88-3.71 (m, 2H), 3.69-3.59 (m, 2H), 3.37-3.25 (m, 1H), 3.25-3.15 (m, 3H), 2.35 (s, 6H), 2.25-2.05 (m, 4H), 1.79 (s, 3H).

Example 109: n- {1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] -2-methylpropan-2-yl } but-2-yninamide; trifluoroacetic acid (Compound 340)

109.1: synthesis of 2- [3- (2-amino-2-methylpropyloxy) pyridin-4-yl ] -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl N- {1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] -2-methylpropan-2-yl } carbamate (710 mg,1.32mmol,1.00 eq.) in DCM (6.00 mL) was added TFA (2.00 mL) at 0deg.C. The mixture was stirred at room temperature under nitrogen for 1h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, C18 spherical column; mobile phase, meCN in water, gradient 10% to 60%, within 15 min; a detector: UV 254nm to afford 2- [3- (2-amino-2-methylpropyloxy) pyridin-4-yl ] -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (460 mg, 79.55%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 440.15.

109.2: n- {1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] -2-methylpropan-2-yl } but-2-yninamide; synthesis of trifluoroacetic acid

To 2- [3- (2-amino-2-methylpropyloxy) pyridin-4-yl under nitrogen at 0 ℃C]-3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (60 mg,0.14mmol,1.00 eq.) in THF (2.00 mL) was added dropwise DIEA (53 mg,0.41mmol,3.00 eq.) and but-2-ynyl chloride (14 mg,0.14mmol,1.00 eq.). The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (10:1) (2X 5 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (80 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH C18 OBD column 30X 150mm 5 μm, N; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 11% B to 41% B over 7 min; wavelength: 254nm; RT1 (min): 6.5; running number: 0) to provide N- {1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy ]-2-methylpropan-2-yl } but-2-ynamide; trifluoroacetic acid (36.2 mg, 42.41%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 506.2.

¹ h NMR (300 MHz, chloroform-d): delta 11.72 (s, 1H), 8.48 (brs, 1H), 8.01 (brs, 1H), 7.90 (d, 1H), 7.49 (d, 1H), 6.67-6.55 (m, 2H), 6.43 (brs, 1H), 6.23 (s, 1H), 5.95 (d, 1H), 4.22 (brs, 2H), 4.11 (s, 3H), 3.67 (t, 2H), 3.20 (t, 2H), 1.92 (s, 3H), 1.61 (s, 6H)

Example 110: n- {1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] -2-methylpropan-2-yl } prop-2-enamide (compound 339)

110.1: synthesis of tert-butyl N- {1- [ (4-bromopyridin-3-yl) oxy ] -2-methylpropan-2-yl } carbamate

To a stirred solution of 4-bromopyridin-3-ol (2.1 g,12.14mmol,1.00 eq.) in DMF (20.00 mL) was added 4, 4-dimethyl-2, 2-dioxo-1, 2λ6, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester (3.35 g,13.35mmol,1.10 eq.) and K at room temperature ₂ CO ₃ (5.03 g,36.42mmol,3.00 eq.). The mixture was stirred at 80℃under nitrogen for 2h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (4:1) to provide N- {1- [ (4-bromopyridin-3-yl) oxy ]-tert-butyl 2-methylpropan-2-yl } carbamate (4.0 g, 95.78%) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 344.85.

110.2: synthesis of tert-butyl N- { 2-methyl-1- [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] propan-2-yl } carbamate

To N- {1- [ (4-bromopyridin-3-yl) oxy at room temperature]A stirred solution of tert-butyl-2-methylpropan-2-yl } carbamate (500 mg,1.45mmol,1.00 eq.) in 1, 4-dioxane (10 mL) was added 2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] in 1, 4-dioxane (10 mL)]Pyridin-4-one (418 mg,1.59mmol,1.10 eq.) Pd (dtbpf) Cl ₂ (95 mg,0.15mmol,0.10 eq.) and Na ₂ CO ₃ (463mg, 4.34mmol,3.00 eq.) and H ₂ O (2.50 mL). The mixture was stirred at 50℃under argon for 2h. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was purified using 1, 4-dioxane (3X 8 mL)And (5) washing. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, C18 spherical column; mobile phase, meCN in water, gradient 10% to 50%, within 20 min; a detector: UV 254nm to provide N- { 2-methyl-1- [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) ]Pyridin-2-yl } pyridin-3-yl) oxy]Tert-butyl prop-2-yl } carbamate (490 mg, 84.48%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 401.2.

110.3: n- {1- [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] -2-methylpropan-2-yl } carbamic acid tert-butyl ester

At 0℃to N- { 2-methyl-1- [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl propan-2-yl } carbamate (440 mg,1.10mmol,1.00 eq.) in DMF (5.00 mL) was added dropwise NIS (247 mg,1.10mmol,1.00 eq.). The mixture was stirred at room temperature under nitrogen for 1h. The reaction was monitored by LCMS. At 0deg.C with saturated Na ₂ SO ₃ The reaction was quenched with aqueous solution. The residue was purified by reverse phase flash chromatography using column, C18 spherical column; mobile phase, meCN in water, gradient 10% to 70%, within 20 min; a detector: UV 254nm to provide N- {1- [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]-tert-butyl 2-methylpropan-2-yl } carbamate (380 mg, 65.71%) as a yellowish green solid.

LC-MS:(M+H) ⁺ Actual: 527.15.

110.4: synthesis of tert-butyl N- {1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] -2-methylpropan-2-yl } carbamate

To N- {1- [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] at room temperature]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl-2-methylpropan-2-yl } carbamate (350 mg,0.66mmol,1.00 eq.) in DMF (3.00 mL) was added EPhos Pd G4 (57 mg,0.07mmol,0.10 eq.) Cs ₂ CO ₃ (650 mg,1.99mmol,3.00 eq.) and 3-fluoro-2-methoxyaniline (280 mg,1.99mmol,3.00 eq.). The mixture was stirred at 50℃under argon for 2h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (93:7) to afford N- {1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]-tert-butyl 2-methylpropan-2-yl } carbamate (330 mg, 91.79%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 540.35.

110.5: synthesis of 2- [3- (2-amino-2-methylpropyloxy) pyridin-4-yl ] -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl N- {1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] -2-methylpropan-2-yl } carbamate (290 mg,0.54mmol,1.00 eq.) in DCM (4.00 mL) was added TFA (1.00 mL) at 0deg.C. The mixture was stirred at room temperature under nitrogen for 1h. The reaction was monitored by LCMS. The resulting mixture was concentrated under nitrogen atmosphere. The residue was purified by reverse phase flash chromatography using a C18 spherical column; mobile phase, meCN in water, gradient 10% to 60%, within 15 min; a detector: UV 254nm to provide 2- [3- (2-amino-2-methylpropyloxy) pyridin-4-yl ] -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (140 mg, 59.27%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 440.10.

110.6: synthesis of N- {1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] -2-methylpropan-2-yl } prop-2-enamide

To 2- [3- (2-amino-2-methylpropyloxy) pyridin-4-yl at 0 ℃C]-3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (120 mg,0.27mmol,1.00 eq.) in THF (3.00 mL) was added DIEA (106 mg,0.82mmol,3.00 eq.). Acryloyl chloride (24 mg,0.27mmol,1.00 eq.) was added dropwise at 0deg.C. The mixture was stirred at room temperature under nitrogen for 1h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (93:7) to afford crude product. The crude product (80 mg) was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 18% b to 43% b, 43% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide N- {1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy ]-2-methylpropan-2-yl } prop-2-enamide (14.4 mg, 10.59%) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 494.10.

¹ H NMR(300MHz,DMSO-d ₆ ):δ11.22(s,1H),8.39(s,1H),8.02–7.99(m,2H),7.42(s,1H),7.30(d,J＝4.8Hz,1H),7.12(s,1H),6.66–6.59(m,1H),6.51–6.44(m,1H),6.37–6.28(m,1H),6.11–6.00(m,2H),5.58–5.54(m,1H),4.30(s,2H),3.90(s,3H),3.43–3.40(m,2H),2.87(t,J＝6.6Hz,2H),1.42(s,6H)。

example 111:2- (3- {2- [ (6R) -5- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5-azaspiro [2.4] hept-6-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 343)

111.1: synthesis of tert-butyl (6R) -6- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -5-azaspiro [2.4] heptane-5-carboxylate

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To 3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (130 mg,0.27mmol,1.00 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (55 mg,0.07mmol,0.25 eq.) CuI (25 mg,0.13mmol,0.50 eq.) in DMF (1.5 mL) was added to a stirred solution of (6R) -6-ethynyl-5-azaspiro [2.4]]Tert-butyl heptane-5-carboxylate (300 mg,1.36mmol,5.00 eq.) and DIEA (175 mg,1.36mmol,5.00 eq.). The resulting mixture was stirred in a closed tube at 50℃under Ar atmosphere for 2h. The residue was purified by reverse phase flash chromatography to provide (6R) -6- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-5-azaspiro [2.4]]Heptane-5-carboxylic acid tert-butyl ester (80 mg, 51.49%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 572.20.

111.2: synthesis of (R) -2- (3- ((5-azaspiro [2.4] hept-6-yl) ethynyl) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (6R) -6- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-C ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -5-azaspiro [2.4] heptane-5-carboxylate (80 mg,0.14mmol,1.00 eq.) in DCM (2.00 mL) was added TFA (0.80 mL) at 0C. The resulting mixture was stirred at room temperature for 2h. The mixture was dried using nitrogen. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 472.20.

111.3: synthesis of 2- (3- {2- [ (6R) -5- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5-azaspiro [2.4] hept-6-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0℃to 2- (3- {2- [ (6R) -5-azaspiro [2.4]]Hept-6-yl]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (60 mg,0.12mmol,1.00 eq.) and (2E) -4- (dimethylamino) but-2-ene hydrochloride (42 mg,0.25mmol,2.00 eq.) in THF was added dropwise T3P (202 mg,0.31mmol,2.50 eq., 50% in EA) and DIEA (0.8 mL). The resulting mixture was extracted with EtOAc (3×5 mL). Combined organic layers were treated with NaHCO ₃ Washing with aqueous solution (1X 10 mL), washing with anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC and using the following conditions (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 11% B to 27% B,8min, 27% B; wavelength: 254/220nm; RT1 (min): 8; running number: 0) to provide 2- (3- {2- [ (6R) -5- [ (2E) -4- (dimethylamino) but-2-enoyl)]-5-azaspiro [2.4 ]]Hept-6-yl]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (30 mg) was a yellow solid. The product (30 mg) was then isolated by chiral preparative HPLC and purified using the following conditions (column: CHIRAL ART Cellulose-SC,2 x 25cm,5 μm; mobile phase a: hex: dcm=3:1 (0.5% 2 mnh) ₃ -MeOH) -HPLC, mobile phase B EtOH-HPLC; the flow rate is 20mL/min; gradient from 30% b to 30% b for 11 min; wavelength is 220/254nm; RT1 (min) 8.59; RT2 (min) 9.39; sample solvent ETOH, dcm=1:1; injection volume 0.5mL; running number: 7) to provide 2- (3- {2- [ (6R) -5- [ (2E) -4- (dimethylamino) but-2-enoyl ]-5-azaspiro [2.4 ]]Hept-6-yl]Ethynyl pyridin-4-yl) -3-[ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (23.1 mg, 33.07%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 583.3.

¹ h NMR (400 MHz, chloroform-d) δ11.09 (s, 1H), 8.53 (s, 1H), 8.16 (d, 1H), 7.69 (s, 1H), 7.47 (d, 1H), 6.99-6.95 (m, 1H), 6.58-6.43 (m, 3H), 6.09 (d, 1H), 5.20 (s, 1H), 5.03-5.00 (m, 1H), 4.10 (s, 3H), 3.70-3.61 (m, 4H), 3.39-3.37 (m, 2H), 3.27 (t, 2H), 2.66 (s, 1H), 2.52 (s, 5H), 2.33-2.27 (m, 1H), 2.18-2.14 (m, 1H), 0.90-0.81 (m, 2H), 0.71 (t, 2H).

Example 112.3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1- (2-fluoro-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 363)

2- {3- [ (2S) -azetidin-2-ylmethoxy was added to a 50mL round bottom flask at room temperature]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (60 mg,0.13mmol,1.00 eq.) and THF (2 mL). The above mixture was basified with DIEA (52 mg,0.39mmol,3.00 eq.) at 0 ℃ to pH 8. 2-Fluoroprop-2-enoic acid (18 mg,0.20mmol,1.50 eq.) and T3P (169 mg,0.26mmol,2.00 eq., 50% in EA) were then added to the above mixture at 0deg.C. The resulting mixture was stirred at room temperature for 1h. The reaction was monitored by LCMS. The resulting mixture was extracted with DCM, meoh=10:1 (4×20 mL). Combined organic layers were treated with NaHCO ₃ Aqueous solution (1×20 mL) and washed with anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (178 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 26% b to 51% b, 51% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (2S) -1- (2-fluoroprop-2-ene)Acyl) azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (10.2 mg, 14.67%) was a pale yellow solid.

LC-MS: M+Hactual: 526.05.

¹ h NMR (400 MHz, chloroform-d) δ11.67 (s, 1H), 8.28 (s, 1H), 7.95 (d, 1H), 7.89 (s, 1H), 7.46 (d, 1H), 6.79-6.75 (m, 1H), 6.66 (t, 1H), 6.19-6.15 (m, 1H), 5.68-5.56 (m, 1H), 5.30-5.24 (m, 2H), 5.15-5.05 (m, 1H), 4.65-4.42 (m, 3H), 4.33 (d, 1H), 4.11 (s, 3H), 3.68-3.60 (m, 2H), 3.20-3.12 (m, 2H), 2.80-2.66 (m, 1H), 2.15-2.25 (m, 1H).

Example 113:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 362)

113.1: synthesis of tert-butyl (2R) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate

To 2- (3-bromopyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (300 mg,0.67mmol,1.00 eq.) and CuI (63 mg,0.33mmol,0.50 eq.) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (136 mg,0.17mmol,0.25 eq.) of tert-butyl (2R) -2-ethynyl-2-methylpyrrolidine-1-carboxylate (28 mg,0.14mmol,3.00 eq.) and DIEA (319 mg,2.01mmol,3.00 eq.) are added dropwise in DMF (5 mL). The resulting mixture was stirred overnight at 50℃under argon. The residue was purified by reverse phase flash chromatography using column, C18 sphere column i; mobile phase, meCN in water, gradient 10% to 70%, within 30 min; a detector: UV 254nm to provide (2R) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (290 mg,75.13%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 576.15.

113.2: synthesis of (R) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((2-methylpyrrolidin-2-yl) ethynyl) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2R) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate (80 mg,0.13mmol,1.00 eq.) in DCM (2 mL) was added TFA (0.5 mL) dropwise at room temperature under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting oil was dried under nitrogen. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 476.10

113.3: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group at 0℃under nitrogen atmosphere]-2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (82 mg,0.17mmol,1.00 eq.) and (2E) -4- (dimethylamino) but-2-ene hydrochloride (56 mg,0.34mmol,2.00 eq.) in THF (4 mL) was added dropwise DIEA (44 mg,0.34mmol,2.00 eq.) and T3P (216 mg,0.34mmol,2.00 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 4h. The resulting mixture was treated with 3X10mL of NaHCO ₃ (aqueous solution) washing. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 8% B to 30% B, 30% B over 10 min; wavelength: 254/220nm; RT1 (min): 9; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl]-2-methylpyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (27.1 mg, 26.50%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 587.2

¹ H NMR (300 MHz, chloroform-d) δ11.49 (s, 1H), 8.52 (s, 1H), 8.14 (d, j=5.6 hz, 1H), 7.66 (s, 1H), 7.40 (d, j=5.6 hz, 1H), 7.04-6.83 (m, 1H), 6.78-6.66 (m, 1H), 6.61 (t, j=8.1 hz, 1H), 6.46-6.41 (m, 1H), 6.26-6.18 (m, 1H), 5.34 (s, 1H), 4.07 (s, 3H), 3.88-3.70 (m, 2H), 3.63-3.59 (m, 2H), 3.35-3.10 (m, 4H), 2.41 (s, 6H), 2.24-2.03 (m, 4H), 1.76 (s, 3H).

Example 114:3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 366)

114.1: synthesis of tert-butyl (2R) -2- { [ (4- {3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

At room temperature, to (2R) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl methyl } azetidine-1-carboxylate (320 mg,0.61mmol,1.00 eq.) and 3-chloro-5-fluoro-2-methoxyaniline (118 mg,0.67mmol,1.10 eq.) in DMF (4 mL) was added Ephos Pd G4 (56 mg,0.06mmol,0.10 eq.) and Cs ₂ CO ₃ (597 mg,1.83mmol,3.00 eq.). At 50 ℃ under argonThe resulting mixture was stirred for 2h under an atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with DCM: meOH (10:1, 4X20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM: meOH (10:1) to provide (2R) -2- { [ (4- {3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (222 mg, 63.74%) as a yellow solid.

LC-MS: M+Hactual: 572.15.

114.2: synthesis of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a 25mL round bottom flask was added tert-butyl (2R) -2- { [ (4- {3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (260 mg,0.45mmol,1.00 eq.) and DCM (3 mL) at room temperature. TFA (2 mL) was added dropwise to the above mixture at 0deg.C over 0.5 min. The resulting mixture was stirred at room temperature for 1h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions (column, C18 spherical column; mobile phase, meCN in water, 10% to 50% gradient, 30 min; detector: UV 254 nm) to afford 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-C ] pyridin-4-one (146 mg, 68.20%) as a brown solid.

LC-MS (M+H) + actual: 472.00.

114.3: synthesis of 3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- {3- [ (2R) -azetidin-2-ylmethoxy was added to an 8mL vial at room temperature]Pyridin-4-yl } -3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (75 mg,0.16mmol,1.00 eq.) and THF (1.5 mL). The mixture was basified with DIEA (123 mg,0.95mmol,6.00 eq.) to pH 9 at 0 ℃. 2-Fluoroprop-2-enoic acid (43 mg,0.48mmol,3.00 eq.) and T3P (405 mg,0.64mmol,4.00 eq., 50% in EA) were added to the above mixture at 0deg.C. The resulting mixture was stirred at room temperature for 1h. The reaction was monitored by LCMS. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (10:1, 4X20 mL) extraction. Combined organic layers were treated with NaHCO ₃ Aqueous solution (1×20 mL) and washed with anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (112 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 29% b to 48% b, 48% b over 10 min; wavelength is 254/220nm; RT1 (min) 9.67; running number 0) to provide 3- [ (3-chloro-5-fluoro-2-methoxyphenyl) amino group]-2- (3- { [ (2R) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-one (18.0 mg, 20.54%) was a milky white solid.

LC-MS:(M+H) ⁺ Actual: 544.1

¹ H NMR (400 MHz, chloroform-d) δ11.61 (s, 1H), 8.30 (s, 1H), 8.03 (d, 1H), 7.56-7.46 (m, 2H), 6.46-6.43 (m, 1H), 5.97-5.94 (m, 1H), 5.68-5.56 (m, 1H), 5.26-5.16 (m, 3H), 4.64-4.39 (m, 3H), 4.32-4.29 (m, 1H), 4.05 (s, 3H), 3.63-3.59 (m, 2H), 3.13-3.10 (m, 2H), 2.77-2.63 (m, 1H), 2.22-2.17 (m, 1H).

Example 115: n- [ (2R) -4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl ] prop-2-enamide (compound 377)

115.1: synthesis of tert-butyl N- [ (2R) -4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl ] carbamate

To 2- (3-bromopyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino group at 0℃under Ar atmosphere]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (250 mg,0.56mmol,1.00 eq.) and N- [ (2R) -but-3-yn-2-yl]A stirred solution of tert-butyl carbamate (236 mg,1.40mmol,2.50 eq.) in DMF (3.00 mL) was added dropwise DIEA (180 mg,1.40mmol,2.50 eq.), cuI (53 mg,0.28mmol,0.50 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (114 mg,0.14mmol,0.25 eq.). The resulting mixture was stirred at 50℃under Ar atmosphere for 1h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash chromatography using column, C18 spherical column; a mobile phase, ACN in water, gradient 0% to 100%, within 30 min; a detector: UV 254nm, then the residue was purified by column chromatography on silica gel eluting with MeOH/DCM (3%) to provide N- [ (2R) -4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl]Tert-butyl carbamate (190 mg, 60.31%) as a yellow solid.

LC-MS (M+H) + actual: 536.20.

115.2: synthesis of 2- {3- [ (3R) -3-aminobut-1-yn-1-yl ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

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To DCM (3.00 mL) was added tert-butyl N- [ (2R) -4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl ] carbamate (250 mg,0.47mmol,1.00 eq.) and TFA (1.00 mL) at 0deg.C. The resulting mixture was stirred at 25℃for 1h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, C18 spherical column; a mobile phase, ACN in water, gradient 0% to 100%, within 30 min; a detector: UV 254nm to provide 2- {3- [ (3R) -3-aminobut-1-yn-1-yl ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (150 mg, 70.09%) as a yellow solid.

LC-MS (M+H) + actual: 436.00.

115.3: synthesis of N- [ (2R) -4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl ] prop-2-enamide

To 2- {3- [ (3R) -3-aminobut-1-yn-1-yl at-40 ℃C]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (100 mg,0.23mmol,1.00 eq.) and DIEA (148 mg,1.15mmol,5.00 eq.) in DCM (1.50 mL) was added acrylic anhydride (58 mg,0.46mmol,2.00 eq.). The resulting mixture was stirred at-40℃for 1h. The reaction was monitored by LCMS. By addition of NaHCO at-40 DEG C ₃ The reaction was quenched with aqueous solution (1.00 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with MeOH/DCM (3%) to provide the crude product. The crude product was purified by preparative HPLC and was purified using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient from 22% b to 46% b, 46% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide N- [ (2R) -4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl]Prop-2-enamide (32.7 mg, 28.92%) as a white solid.

LC-MS:(M+H) ⁺ Actual: 490.05.

¹ h NMR (400 MHz, chloroform-d)δ10.90(s,1H),8.53(s,1H),8.13(s,1H),7.77(s,1H),7.39(d,1H),6.72(d,1H),6.61(t,1H),6.36–6.14(m,4H),5.74(d,1H),5.25(s,1H),4.82–4.76(m,1H),4.07(s,3H),3.62–3.61(m,2H),3.30–3.18(m,2H),1.66(d,3H)。

Example 116: n- [ (2S) -4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl ] prop-2-enamide (compound 376)

116.1: synthesis of tert-butyl N- [ (2S) -4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl ] carbamate

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (300 mg,0.61mmol,1.00 eq.) in DMF (5.00 mL) was added CuI (58 mg,0.30mmol,0.50 eq.) Pd (dppf) Cl ₂ CH ₂ Cl ₂ (124 mg,0.15mmol,0.25 eq.) N- [ (2S) -but-3-yn-2-yl]Tert-butyl carbamate (205 mg,1.21mmol,2.00 eq.) and DIEA (236 mg,1.82mmol,3.00 eq.). The mixture was stirred at 50℃under argon for 1h. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was treated with CH ₂ Cl ₂ MeOH (3X 5 mL) wash. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, C18 spherical column; a mobile phase, ACN in water, gradient from 10% to 70%, within 25 min; a detector: UV 254nm to provide a crude product. The crude product was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (97:3) elution to afford N- [ (2S) -4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl]Tert-butyl carbamate (110 mg, 33.84%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 536.10.

116.2: synthesis of 2- {3- [ (3S) -3-aminobut-1-yn-1-yl ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl N- [ (2S) -4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl ] carbamate (110 mg,0.19mmol,1.00 eq.) in DCM (3.00 mL) was added TFA (1.00 mL) at 0deg.C. The mixture was stirred at room temperature under nitrogen for 1h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure nitrogen atmosphere. The residue was purified by reverse phase flash chromatography using column, C18 spherical column; a mobile phase, ACN in water, gradient from 10% to 60% within 25 min; a detector: UV 254nm to provide 2- {3- [ (3S) -3-aminobut-1-yn-1-yl ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (85 mg, 95.12%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 435.95.

116.3: synthesis of N- [ (2S) -4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl ] prop-2-enamide

To 2- {3- [ (3S) -3-aminobut-1-yn-1-yl at room temperature]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (80 mg,0.18mmol,1.00 eq.) in DCM (2.00 mL) was added DIEA (119 mg,0.92mmol,5.00 eq.). Acrylic anhydride (46 mg,0.37mmol,2.00 eq.) was added dropwise at-40 ℃. The mixture was stirred at-40℃under nitrogen for 0.5h. The reaction was monitored by LCMS. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 20 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, concentrating under reduced pressureAnd (3) filtering the filtrate. The crude product (90 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 28% B to 42% B, 42% B over 10 min; wavelength is 254/220nm; RT1 (min) 9; running number 0) to provide N- [ (2S) -4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl]Prop-2-enamide (35.6 mg, 39.27%) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 490.05.

¹ h NMR (400 MHz, chloroform-d): delta 10.94 (s, 1H), 8.52 (s, 1H), 8.12 (d, 1H), 7.81 (s, 1H), 7.38 (d, 1H), 6.72 (d, 1H), 6.61 (t, 1H), 6.37-6.14 (m, 4H), 5.76 (d, 1H), 5.25 (s, 1H), 4.82-4.76 (m, 1H), 4.07 (s, 3H), 3.65-3.59 (m, 2H), 3.30-3.23 (m, 2H), 1.66 (d, 3H).

Example 117: n- [ (2S) -4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl ] prop-2-enamide (compound 375)

117.1: synthesis of tert-butyl N- [ (2S) -4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl ] carbamate

To 3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (250 mg,0.52mmol,1.00 eq.) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (106 mg,0.13mmol,0.25 eq.) and CuI (49 mg,0.26mmol,0.50 eq.) in DMF (3 mL) were added N- [ (2S) -but-3-yn-2-yl]Tert-butyl carbamate (221 mg,1.30mmol,2.50 eq.) and DIEA (337 mg,2.61mmol,5.00 eq.). The resulting mixture was stirred in a closed tube at 50℃under Ar atmosphere for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography and employed to Under the following conditions (column, C18 spherical column; mobile phase, meCN in water, gradient 10% to 60%, 30 min; detector: UV 254 nm) to afford N- [ (2S) -4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl]Tert-butyl carbamate (195 mg, 71.80%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 520.20.

117.2: synthesis of 2- {3- [ (3S) -3-aminobut-1-yn-1-yl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl N- [ (2S) -4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl ] carbamate (170 mg,0.32mmol,1.00 eq.) in DCM (2.00 mL) was added TFA (2.00 mL) at 0deg.C. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was worked up and dried with nitrogen. The residue was purified by reverse phase flash chromatography using the following conditions (column, C18 spherical column; mobile phase, meOH in water, 10% to 50% gradient, 20 min; detector: UV 254 nm) to afford 2- {3- [ (3S) -3-aminobut-1-yn-1-yl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-C ] pyridin-4-one (75 mg, 54.65%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 420.05.

117.3: synthesis of N- [ (2S) -4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl ] prop-2-enamide

To 2- {3- [ (3S) -3-aminobut-1-yn-1-yl at 0 ℃C]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (75 mg,0.17mmol,1.00 eq.) and DIEA (115 mg,0.89mmol,5.00 eq.) in THF was added dropwise acrylic anhydride (33 mg,0.26mmol,1.50 eq.). The resulting mixture was stirred at room temperature for 2h. The resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (1×5 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford N- [ (2S) -4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl]Prop-2-enamide (80 mg) as a yellow oil. The crude product (80 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 19% b to 44% b, 44% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide N- [ (2S) -4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) but-3-yn-2-yl]Prop-2-enamide (22.5 mg, 26.23%) as an orange solid.

LC-MS:(M+H) ⁺ Actual: 474.2

¹ H NMR (300 MHz, chloroform-d) δ10.85 (s, 1H), 8.55 (s, 1H), 8.16 (s, 1H), 7.72 (s, 1H), 7.45 (s, 1H), 6.61-6.43 (m, 2H), 6.37-6.31 (m, 1H), 6.20-6.06 (m, 3H), 5.76-5.72 (m, 1H), 5.21 (s, 1H), 4.81-4.77 (m, 1H), 4.10 (s, 3H), 3.61-3.59 (m, 2H), 3.25-3.20 (m, 2H), 1.66 (d, 3H).

Example 118: n- [4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] prop-2-enamide (compound 492)

118.1: synthesis of tert-butyl N- [4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] carbamate

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under nitrogen atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (150 mg,0.30mmol,1.00 eq.) and tert-butyl N- (2-methylbut-3-yn-2-yl) carbamate (111 mg,0.60mmol,2.00 eq.) in DMF (3.00 mL) was added Pd (dppf) Cl ₂ CH ₂ Cl ₂ (123 mg,0.15mmol,0.50 eq.) and CuI (28 mg,0.15mmol,0.50 eq.) and DIEA (235 mg,1.81mmol,6.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). Concentrating the filtrate under reduced pressure, purifying by reverse phase flash chromatography and employing the following conditions: column, silica gel; mobile phase, meCN in water, gradient 0% to 100%, within 50 min; a detector: UV 254nm to provide N- [4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl]Tert-butyl carbamate (190 mg, 96.0%) as a yellow solid.

LC-MS (M+H) + actual: 550.1.

118.2: synthesis of 2- [3- (3-amino-3-methylbut-1-yn-1-yl) pyridin-4-yl ] -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl N- [4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] carbamate (150 mg,0.27mmol,1.00 eq.) in DCM (3 mL) was added TFA (1 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- [3- (3-amino-3-methylbut-1-yn-1-yl) pyridin-4-yl ] -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (250 mg, crude) as a red oil.

LC-MS (M+H) + actual: 450.

118.3: synthesis of N- [4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] prop-2-enamide

To 2- [3- (3-amino-3-methylbut-1-yn-1-yl) pyridin-4-yl under nitrogen at 0℃]-3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (80 mg,0.17mmol,1.00 eq.) in THF (1.50 mL) and NaHCO ₃ A stirred solution in (saturated) (1.50 mL) was added to acryloyl chloride (18 mg,0.20mmol,1.15 eq.). The resulting mixture was stirred at 0℃under nitrogen for 1h. The reaction was monitored by LCMS. LCMS showed the reaction was complete. The resulting mixture was extracted with EtOAc (3X 15 mL) and dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC and using the following conditions (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 32% b to 46% b, 46% b over 9 min; wavelength is 254/220nm; RT1 (min) 9.78; running number 0) to provide N- [4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl]Prop-2-enamide (13.70 mg, 15.21%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 503.95.

¹ H NMR(300MHz,DMSO-d6)δ11.65(s,1H),8.75(s,1H),8.51(s,1H),8.23(d,1H),7.65(s,1H),7.35(d,,1H),7.21(s,1H),6.70(d,2H),6.34-6.32(m,1H),6.29-6.24(m,1H),6.14(t,1H),5.71-5.67(m,1H),3.89(s,3H),3.45-3.42(m,2.4Hz,2H),3.02(t,2H),1.64(s,6H)。

example 119:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1S, 3R, 5S) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 517)

119.1: synthesis of tert-butyl (1S, 3R, 5S) -3- (hydroxymethyl) -2-azabicyclo [3.1.0] hexane-2-carboxylate

To (1S, 3R, 5S) -2- (tert-Butoxycarbonyl) -2-azabicyclo [3.1.0] at 0deg.C under nitrogen]A stirred solution of hexane-3-carboxylic acid (1 g,4.40mmol,1.00 eq.) in THF (10 mL) was added drop wise to BH ₃ (1M in THF, 8.80mL,8.80mmol,2.00 eq.). The resulting mixture was stirred at room temperature under nitrogen for 2h. The reaction was quenched by the addition of MeOH (5 mL) at 0deg.C. The resulting mixture was concentrated under reduced pressure to afford (1 s,3r,5 s) -3- (hydroxymethyl) -2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (1.1 g crude) as a colorless oil.

LC-MS:(M+H-56) ⁺ Actual: 157.95

119.2: synthesis of (1S, 3R, 5S) -3-formyl-2-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester

To (1S, 3R, 5S) -3- (hydroxymethyl) -2-azabicyclo [3.1.0 under nitrogen at 0deg.C ]A stirred mixture of tert-butyl hexane-2-carboxylate (0.97 g,4.54mmol,1.00 eq.) in DCM (20 mL) was added dropwise Dess-Martin reagent (2.31 g,5.45mmol,1.20 eq.). The resulting mixture was stirred at room temperature under nitrogen for 2h. By addition of saturated Na at room temperature ₂ SO ₃ The reaction was quenched with aqueous solution (5 mL). Na is added to the reaction ₂ CO ₃ (saturation) to adjust the pH to 7-8. The resulting mixture was treated with CH ₂ Cl ₂ (3X 20 mL) extraction over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (5:1) to provide (1 s,3r,5 s) -3-formyl-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl esterColorless oil.

¹ H-NMR (300 MHz, chloroform-d) δ9.50 (s, 1H), 4.01-3.21 (m, 2H), 2.34-2.01 (m, 2H), 1.59-1.52 (m, 1H), 1.46 (s, 9H), 0.80-0.70 (m, 1H), 0.54 (s, 1H).

119.3: synthesis of (1S, 3R, 5S) -3-ethynyl-2-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester

To (1S, 3R, 5S) -3-formyl-2-azabicyclo [3.1.0] at 0deg.C under nitrogen atmosphere]Hexane-2-carboxylic acid tert-butyl ester (520 mg,2.46mmol,1.00 eq.) and K ₂ CO ₃ A stirred solution of (680 mg,4.92mmol,2.00 eq.) in methanol (10.00 mL) was added dropwise Bestmann-Ohira reagent (567 mg,2.95mmol,1.20 eq.). The resulting mixture was stirred at room temperature under nitrogen for 2h. The reaction was quenched by addition of sodium potassium tartrate (saturated) (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (5:1) to provide (1 s,3r,5 s) -3-ethynyl-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (470 mg, 92.12%) as a white oil.

¹ H-NMR (400 MHz, chloroform-d) delta 4.24 (t, 1H), 3.27 (s, 1H), 2.38-2.12 (m, 3H), 1.67-1.49 (m, 1H), 1.42 (s, 9H), 0.84-0.70 (m, 1H), 0.42-0.26 (m, 1H).

119.4: synthesis of tert-butyl (1R, 3S, 5R) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylate

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (150 mg,0.30mmol,1.00 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (61 mg,0.07mmol,0.25 eq.) in DMF (2 mL) was added dropwise (1R, 3S, 5R) -3-ethynyl-2-azabicyclo [ 3.1.0)]Hexane-2-carboxylic acid tert-butyl ester (25 mg,0.12mmol,3.00 eq.) and DIEA (195 mg,1.52mmol,5.00 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The residue was purified by reverse phase flash chromatography using column, silica gel; mobile phase, meCN in water, gradient 10% to 70%, within 20 min; a detector: UV 254nm. This gives (1R, 3S, 5R) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (170 mg, 97.67%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 574.05.

119.5: synthesis of 2- (3- {2- [ (1S, 3R, 5S) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of (1 s,3r,5 s) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (120 mg,0.04mmol,1.00 eq) in DCM (3.00 mL) was added TFA (1.00 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- (3- {2- [ (1 s,3r,5 s) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (160 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 474.05

119.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1S, 3R, 5S) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- (3- {2- [ (1S, 3R, 5S) -2-azabicyclo [3.1.0 ] at room temperature under nitrogen]Hex-3-yl]Ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100 mg,0.21mmol,1.00 eq.) and NaHCO ₃ (saturated) (1.00 mL) an stirred solution of acryloyl chloride (19 mg,0.21mmol,1.00 eq.) in THF (1.00 mL) was added dropwise. The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (10/1) (3X 10 mL) extraction. The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 28% B to 50% B, 50% B over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (1S, 3R, 5S) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0]Hex-3-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (10.8 mg, 9.55%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 527.90

¹ H NMR (400 MHz, chloroform-d) δ11.00 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 7.74 (s, 1H), 7.44 (s, 1H), 6.84-6.65 (m, 2H), 6.60 (t, 1H), 6.48-6.33 (m, 1H), 6.24-6.14 (m, 1H), 5.88-5.69 (m, 1H), 5.22 (s, 1H), 4.89-4.73 (m, 1H), 4.07 (s, 3H), 3.67-3.52 (m, 3H), 3.30-3.20 (m, 2H), 2.66-2.45 (m, 2H), 2.06-1.95 (m, 1H), 1.13-1.01 (m, 1H), 0.70-0.60 (m, 1H).

Example 120.3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1R, 3R, 5R) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 518)

120.1: synthesis of (1R, 3R, 5R) -3- (hydroxymethyl) -2-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester

To (1R, 3R, 5R) -2- (tert-Butoxycarbonyl) -2-azabicyclo [3.1.0] at 0deg.C under nitrogen]A stirred solution of hexane-3-carboxylic acid (1.0 g,4.40mmol,1.00 eq.) in THF (20.00 mL) was added drop wise to BH ₃ (1M in THF, 6.6mL,6.60mmol,1.50 eq.). The mixture was stirred at 70℃under nitrogen for 1h. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The reaction was quenched by the addition of MeOH (3 mL) at 0deg.C. The resulting mixture was concentrated under reduced pressure to obtain (1 r,3r,5 r) -3- (hydroxymethyl) -2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (1.2 g, crude) as a colorless oil.

LC-MS:(M+H) ⁺ Actual: 157.95.

1202: synthesis of (1R, 3R, 5R) -3-formyl-2-azabicyclo [310] hexane-2-carboxylic acid tert-butyl ester

To (1R, 3R, 5R) -3- (hydroxymethyl) -2-azabicyclo [3.1.0 at 0deg.C]A stirred solution of tert-butyl hexane-2-carboxylate (900 mg,4.22mmol,1.00 eq.) in DCM (20.00 mL) was added Dess-Martin reagent (2.15 g,5.06mmol,1.2 eq.). The mixture was stirred at room temperature under nitrogen for 2h. The reaction was monitored by LCMS. By addition of saturated Na at room temperature ₂ SO ₃ The reaction was quenched with aqueous solution (2 mL). With saturated NaHCO ₃ The mixture was neutralized to pH 7 with aqueous solution. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (10:1) to provide (1 r,3r,5 r) -3-formyl-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (620 mg, 69.55%) as a colorless oil.

LC-MS:(M+H) ⁺ Actual: 155.95.

120.3: synthesis of (1R, 3R, 5R) -3-ethynyl-2-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester

To (1R, 3R, 5R) -3-formyl-2-azabicyclo [3.1.0] at 0]]A stirred solution of tert-butyl hexane-2-carboxylate (500 mg,2.37mmol,1.00 eq.) in MeOH (5.00 mL) was added K ₂ CO ₃ (981 mg,7.10mmol,3.00 eq.) and Bestmann-Ohira reagent (682 mg,3.55mmol,1.50 eq.). The mixture was stirred at 0℃under nitrogen for 2h. The reaction was quenched by addition of sodium potassium tartrate (saturated) (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (10:1) to provide (1 r,3r,5 r) -3-ethynyl-2-azabicyclo [3.1.0 ]Hexane-2-carboxylic acid tert-butyl ester (420 mg, 85.62%) as a colorless oil.

LC-MS:(M+H) ⁺ Actual: 152.3.

120.4: synthesis of tert-butyl (1R, 3R, 5R) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [310] hexane-2-carboxylate

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (100 mg,0.20mmol,1.00 eq.) in DMF (2.00 mL) was added (1R, 3R, 5R) -3-ethynyl-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (105 mg,0.51mmol,2.50 eq.), cuI (19 mg,0.10mmol,0.50 eq.), pd (dppf) Cl ₂ .CH ₂ Cl ₂ (82 mg,0.10mmol,0.50 eq.) and DIAD (123 mg,0.61mmol,3.00 eq.). Stirring at 50deg.C under argon atmosphereThe mixture was stirred for 2h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash chromatography using column C18 silica gel; mobile phase, meCN in water, gradient 10% to 50% within 10 min; a detector: UV 254nm. This gives (1R, 3R, 5R) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl ]-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (100 mg, 86.18%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 574.15.

120.5: synthesis of 2- (3- {2- [ (1R, 3R, 5R) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of (1 r,3r,5 r) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (90 mg,0.16mmol,1.00 eq) in DCM (3.00 mL) was added TFA (1.00 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- (3- {2- [ (1 r,3r,5 r) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (150 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 474.15.

120.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1R, 3R, 5R) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0 ℃,2- (3- {2- [ (1R, 3R, 5R) -2-azabicyclo [ 3.1). 0]Hex-3-yl]Ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (90 mg,0.19mmol,1.00 eq.) in THF (1.50 mL) was added to NaHCO ₃ Aqueous solution (1.50 mL) to adjust pH to 9. At 0deg.C, acryloyl chloride (17 mg,0.19mmol,1.00 eq.) was added dropwise. The mixture was stirred at 0℃under nitrogen for 0.5h. The reaction was monitored by LCMS. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (10:1) (3X 10 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (97:3) to afford crude product. The crude product (30 mg) was purified by preparative HPLC using the following conditions (column: xselect CSH F-phenyl OBD column, 30X 250mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 19% b to 49% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (1R, 3R, 5R) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0]Hex-3-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (8.2 mg, 8.16%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 528.10.

¹ h NMR (400 MHz, chloroform-d): δ11.09 (s, 1H), 8.51 (s, 1H), 8.07 (d, 1H), 7.94 (s, 1H), 7.39 (d, 1H), 6.79-6.76 (m, 2H), 6.62 (t, 1H), 6.46-6.38 (m, 1H), 6.18 (d, 1H), 5.79 (d, 1H), 5.28-5.24 (m, 2H), 4.07 (s, 3H), 3.65-3.56 (m, 3H), 3.31-3.28 (m, 2H), 2.75-2.71 (m, 1H), 2.39-2.35 (m, 1H), 1.94-1.86 (m, 1H), 1.12-1.09 (m, 2H).

Example 121:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [2- [ (2R) -4, 4-difluoro-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 519)

121.1: synthesis of (2R) -4, 4-difluoro-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl (2R) -4, 4-difluoro-2- (hydroxymethyl) pyrrolidine-1-carboxylate (100.00 mg,0.42mmol,1.00 eq.) in DCM (10.00 mL) was added dropwise Dess-Martin reagent (214 mg,0.50mmol,1.20 eq.) at 0deg.C under nitrogen. The resulting mixture was stirred at 0℃under nitrogen for 3h. By addition of saturated Na at room temperature ₂ SO ₃ The reaction was quenched with aqueous solution (2 mL). Na is added to the reaction ₂ CO ₃ (saturation) to adjust the pH to 7-8. The resulting mixture was treated with CH ₂ Cl ₂ (3X 10 mL) extraction over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (5:1) to give tert-butyl (2R) -4, 4-difluoro-2-formylpyrrolidine-1-carboxylate (46 mg, 46.39%) as a colorless oil.

LC-MS:(M+H-56) ⁺ Actual: 180.

121.2: synthesis of (2R) -2-ethynyl-4, 4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred mixture of tert-butyl (2R) -4, 4-difluoro-2-formylpyrrolidine-1-carboxylate (100 mg,0.43mmol,1.00 eq.) in MeOH (5 mL) at 0deg.C was added K dropwise ₂ CO ₃ (117 mg,0.85mmol,2.00 eq.) and Best-Ohria reagent (98 mg,0.51mmol,1.20 eq.). The resulting mixture was stirred at room temperature under nitrogen for 3h. The reaction was quenched by addition of sodium potassium tartrate (saturated) (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (5:1) to give tert-butyl (2R) -2-ethynyl-4, 4-difluoropyrrolidine-1-carboxylate (75 mg, 76.29%) as a yellow oil.

121.3: synthesis of (2R) -2- [2- (4- [3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl) ethynyl ] -4, 4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature]-2- (pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (150 mg,0.41mmol,1.00 eq.) and tert-butyl (2R) -2-ethynyl-4, 4-difluoropyrrolidine-1-carboxylate (282 mg,1.22mmol,3.00 eq.) in DMF (3.00 mL) was added Pd (dppf) Cl dropwise ₂ DCM (148 mg,0.20mmol,0.50 eq.), DIEA (157 mg,1.22mmol,3.00 eq.) and CuI (38 mg,0.20mmol,0.50 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (20:1) elution to afford (2R) -2- [2- (4- [3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl) ethynyl]-4, 4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (90 mg, 37.00%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 598.15.

121.4: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [2- [ (2R) -4, 4-difluoropyrrolidin-2-yl ] ethynyl ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2R) -2- [2- (4- [3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl) ethynyl ] -4, 4-difluoropyrrolidine-1-carboxylate (200 mg,0.33mmol,1.00 eq.) in DCM (3 mL) was added TFA (1 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [2- [ (2R) -4, 4-difluoropyrrolidin-2-yl ] ethynyl ] pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (300 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 498.05.

121.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [2- [ (2R) -4, 4-difluoro-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0℃to 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- [2- [ (2R) -4, 4-difluoropyrrolidin-2-yl)]Ethynyl group]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (167 mg,0.34mmol,1.00 eq.) in THF (2.00 mL) and NaHCO ₃ The stirred mixture in (2 mL) was added dropwise with acryloyl chloride (28 mg,0.32mmol,0.95 eq.). The resulting mixture was stirred at room temperature under nitrogen for 2h. The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ Meoh=20:1) to afford 3- [ (3-chloro-2-methoxyphenyl) amino]-2- (3- [2- [ (2R) -4, 4-difluoro-1- (prop-2-enoyl) pyrrolidin-2-yl)]Ethynyl group]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (37.8 mg, 19.99%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 552.00.

¹ H-NMR(400MHz,DMSO-d ₆ )δ11.12(s,1H),8.50(s,1H),8.28(d,1H),7.30(d,2H),6.84(s,1H),6.58(d,3H),6.29–5.97(m,2H),5.70(d,1H),5.27(s,1H),4.03(m,2H),3.85(s,3H),3.53–3.35(m,2H),2.88(s,2H),2.78–2.56(m,2H)。

example 122:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [2- [1- (trifluoromethyl) cyclopropyl ] ethynyl ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 528)

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (100 mg,0.20mmol,1.00 eq.) in DMF (2 mL) was added in portions Pd (dppf) Cl ₂ CH ₂ Cl ₂ (82 mg,0.10mmol,0.50 eq.), cuI (19 mg,0.10mmol,0.50 eq.), DIEA (78 mg,0.60mmol,3.00 eq.) and 1-ethynyl-1- (trifluoromethyl) cyclopropane (108 mg,0.81mmol,4.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (20:1) to obtain the crude product. The crude product (90 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 28% b to 58% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- [2- [1- (trifluoromethyl) cyclopropyl)]Ethynyl group]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-one (47.2 mg, 45.22%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 501.00.

1H NMR (400 MHz, methanol-d 4) delta 8.54 (s, 1H), 8.28 (s, 1H), 7.39 (s, 1H), 6.63-6.54 (m, 2H), 6.19-6.13 (m, 1H), 3.91 (s, 3H), 3.58 (t, 2H), 2.93 (t, 2H), 1.50-1.35 (m, 4H).

Example 123:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [2- [2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 560)

123.1: synthesis of tert-butyl 3- (methoxy (methyl) carbamoyl) -2-azabicyclo [3.1.0] hexane-2-carboxylate

To a stirred solution of 2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid (2.5 g,11.01mmol,1.00 eq.) in dry DMF was added N, O-dimethylhydroxylamine hydrochloride (1.3 g,13.21mmol,1.20 eq.) at 0deg.C. After stirring at 0℃for 15 minutes, NMM (1.33 g,13.21mmol,1.20 eq.) HOBT (1.78 g,13.21mmol,1.20 eq.) and EDCI (2.55 g,13.21mmol,1.20 eq.) were added at the same temperature. The reaction mixture was stirred at room temperature overnight and worked up with dilute aqueous HCl. The resulting mixture was concentrated in vacuo. Flash chromatography on a short pad of silica gel using 1:1PE/EA as eluent provided tert-butyl 3- (methoxy (methyl) carbamoyl) -2-azabicyclo [3.1.0] hexane-2-carboxylate (2.9 g, 97%) as a white solid.

LC-MS:(M+H-56) ⁺ Actual: 215.

123.2: synthesis of tert-butyl 3-ethynyl-2-azabicyclo [3.1.0] hexane-2-carboxylate

To 3- (methoxy (methyl) carbamoyl) -2-azabicyclo [3.1.0] at-78℃under argon atmosphere]A solution of tert-butyl hexane-2-carboxylate (2.6 g,9.63mmol,1.00 eq.) in dry dichloromethane (20 mL) was added DIBAL-H (12 mL,11.56mmol,1.20 eq., 1.0M in dichloromethane) dropwise. The reaction was stirred at this temperature for an additional 2H (TLC monitored reaction was complete) and the residual DIBAL-H was quenched by dropwise addition of anhydrous MeOH. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The reaction was then brought to 0℃and K was added ₂ CO ₃ (2.66 g,19.26mmol,2.00 eq.), bestmann-Ohira reagent (2.22 g,11.56mmol,1.20 eq.) and anhydrous MeOH (30 mL). The reaction mixture was stirred at room temperature overnight, then saturated rochelle (seignette) salt (30 mL) and diethyl ether (50 mL) were added, and the mixture was vigorously stirred for 1h. The organic layer was separated and extracted with diethyl ether (3×40 mL), washed with brine, and dried over Na ₂ SO ₄ And (5) drying. Removal in a rotary evaporatorAnd (3) a solvent. Flash chromatography on a short pad of silica gel using 10:1PE/EA as eluent to purify the residue to give 3-ethynyl-2-azabicyclo [3.1.0]]Hexane-2-carboxylic acid tert-butyl ester (1.5 g, 80%) as a white solid.

¹ H NMR (300 MHz, chloroform-d) δ4.31 (t, 1H), 3.34 (s, 1H), 2.50-2.21 (m, 3H), 1.73-1.57 (m, 1H), 1.49 (s, 9H), 0.89-0.81 (m, 1H), 0.41 (s, 1H).

123.3: synthesis of tert-butyl 3- [2- (4- [3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylate

Stirring 3- [ (3-chloro-2-methoxyphenyl) amino group at 50℃under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (200 mg,0.40mmol,1.00 eq.) and 3-ethynyl-2-azabicyclo [3.1.0]]Hexane-2-carboxylic acid tert-butyl ester (335 mg,1.61mmol,4.00 eq.) and CuI (38 mg,0.20mmol,0.50 eq.) and DIEA (781 mg,6.06mmol,15 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (33 mg,0.04mmol,0.10 eq.) in DMF (5.00 mL) for 72h. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (2X 30 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, C18 silica gel; mobile phase, meCN in water (NH ₄ HCO ₃ ) Gradient from 20% to 80% within 30 min; a detector: UV 254nm. This gives 3- [2- (4- [3- [ (3-chloro-2-methoxyphenyl) amino ] amino group ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl) ethynyl]-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (180 mg, 77.6%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 574.10

123.4: synthesis of 2- [3- (2- [ 2-azabicyclo [3.1.0] hex-3-yl ] ethynyl) pyridin-4-yl ] -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

A solution of 3- [2- (4- [3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (160 mg,0.28mmol,1.00 eq.) and TFA (5.00 mL) in DCM (5.00 mL) was stirred overnight at room temperature under nitrogen. The resulting mixture was concentrated under reduced pressure. This gave 2- [3- (2- [ 2-azabicyclo [3.1.0] hex-3-yl ] ethynyl) pyridin-4-yl ] -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (140 mg, crude) as a brown solid.

LC-MS:(M+H) ⁺ Actual: 474.20

123.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [2- [2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Stirring 2- [3- (2- [ 2-azabicyclo [3.1.0 ] at 0deg.C under nitrogen atmosphere]Hex-3-yl]Ethynyl) pyridin-4-yl]-3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (140 mg,0.29mmol,1.00 eq.) in THF (1.00 mL) and saturated NaHCO ₃ Solution in water (1.00 mL) for 30 min. Acryloyl chloride (27 mg,0.29mmol,1.00 eq.) was added dropwise to the above mixture over 1min at 0deg.C. The resulting mixture was stirred at room temperature for an additional 2h. The reaction was quenched with water/ice at 0 ℃. The resulting mixture was extracted with EtOAc (2X 50 mL). The combined organic layers were washed with brine (1×120 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography and the following conditions were used: XBRIThe edge Prep C18 OBD column, 30 x 100mm,mobile phase A Water (10 mmol/LNH) ₄ HCO ₃ +0.1％NH ₃ .H ₂ O) mobile phase B, ACN; the flow rate is 60mL/min; gradient 23% b to 53% b, 53% b over 10 min; wavelength is 254/220nm; RT1 (min) 7.53; running number 0. This gives 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- [2- [2- (prop-2-enoyl) -2-azabicyclo [ 3.1.0)]Hex-3-yl]Ethynyl group]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (12.3 mg, 7.93%) was a yellow solid. .

LC-MS:(M+H) ⁺ Actual: 528.00.

¹ H NMR(300MHz,DMSO-d ₆ )δ11.36(s,1H),8.55(s,1H),8.28(d,1H),7.55(s,1H),7.35(d,1H),7.19(s,1H),6.95-6.84(m,1H),6.67(d,2H),6.33-6.23(m,1H),6.12(t,1H),5.86-5.75(m,1H),4.89(t,1H),3.86(s,3H),3.73(s,1H),3.49-3.37(m,2H),2.98(t,2H),2.41-2.33(m,2H),1.95-1.85(m,1H),1.01-0.91(m,1H),0.69-0.62(s,1H)。

example 124: n- {1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclopropyl } prop-2-enamide (compound 207)

124.1 Synthesis of N- {1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclopropyl } carbamate

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To 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (100 mg,0.20mmol,1.00 eq.) and tert-butyl N- (1-ethynylcyclopropyl) carbamate (73 mg,0.40mmol,2.00 eq.) in DMF (2.00 mL) and DIEA (78 mg,0.61mmol,3.00 eq.) was added to CuI (19 mg,0.10mmol,0.50 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (8 mg,0.01mmol,0.25 eq.). The resulting suspensionThe mixture was again aerated three times with argon and stirred at 50℃for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with MeOH/DCM (3%) to provide N- {1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ]]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl ]Tert-butyl cyclopropyl } carbamate (60 mg, 51.45%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 548.10.

124.2: synthesis of 2- (3- ((1-aminocyclopropyl) ethynyl) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To tert-butyl N- {1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclopropyl } carbamate (50 mg,0.09mmol,1.00 eq) was added TFA (0.30 mL) and DCM (0.60 mL) at 0deg.C. The resulting mixture was stirred at room temperature for 1h. The reaction was monitored by LCMS. The resulting mixture was stirred for 1H and concentrated under reduced pressure to afford 2- (3- ((1-aminocyclopropyl) ethynyl) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (80 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 448.05.

124.3: synthesis of N- {1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclopropyl } prop-2-enamide

At 0 ℃ under argon atmosphere, to 2- {3- [2- (1-aminocyclopropyl) ethynyl group]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group ]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridine compound-4-one (50 mg,0.11mmol,1.00 eq.) and saturated NaHCO ₃ (aqueous solution) (0.60 mL) an stirred solution of acryloyl chloride (10 mg,0.11mmol,1.00 eq.) in tetrahydrofuran (0.60 mL) was added dropwise. The resulting mixture was stirred at room temperature under argon for 1h. The reaction was monitored by LCMS. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (10/1) (3X 20 mL) extraction. The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (80 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient from 22% b to 47% b, 47% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide N- {1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Cyclopropyl } prop-2-enamide (9.5 mg, 16.9%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 502.30

¹ H NMR(300MHz,DMSO-d ₆ )δ11.37(s,1H),8.94(s,1H),8.50(s,1H),8.26(d,1H),7.51(s,1H),7.31(d,1H),7.16(s,1H),6.66(d,2H),6.17(d,2H),6.10(t,1H),5.66(t,1H),3.86(s,3H),3.47–3.42(m,2H),2.97(t,2H),1.35–1.31(m,2H),1.17–1.13(m,2H)。

EXAMPLE 125N- {1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclopropyl } prop-2-enamide (compound 206)

125.1: synthesis of tert-butyl N- {1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclopropyl } carbamate

To 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (800 mg,1.86mmol,1.00 eq.) and tert-butyl N- (1-ethynylcyclopropyl) carbamate (1.01 g,5.57mmol,3.00 eq.) in DMF (15 mL) was added dropwise DIEA (599 mg,4.64mmol,2.50 eq.), cuI (177 mg,0.93mmol,0.50 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (378 mg,0.46mmol,0.25 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). Concentrating the filtrate under reduced pressure, which is purified by reverse phase flash chromatography and employing the following conditions: column, C18 silica gel; a mobile phase, ACN in water, gradient 0% to 100%, within 10 min; a detector: UV 254nm to provide a crude product. The residue was purified by silica gel column chromatography eluting with MeOH/DCM (3%) to provide N- {1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Tert-butyl cyclopropyl } carbamate (500 mg, 48.17%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 532.10.

125.2: synthesis of 2- {3- [2- (1-aminocyclopropyl) ethynyl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Tert-butyl N- {1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclopropyl } carbamate (200 mg,0.38mmol,1.00 eq) and TFA (1.50 mL) were added to DCM (4.50 mL) at 0deg.C. The resulting mixture was stirred for 1h and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, silica gel; mobile phase, meCN in water, gradient 0% to 100%, within 10 min; a detector: UV 254nm to provide 2- {3- [2- (1-aminocyclopropyl) ethynyl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (120 mg, 70.23%) as a yellow solid.

LC-MS (M+H) + actual: 432.05.

125.3: synthesis of N- {1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclopropyl } prop-2-enamide

To a stirred solution of 2- {3- [2- (1-aminocyclopropyl) ethynyl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (200 mg,0.46mmol,1.00 eq.) and DIEA (180 mg,1.39mmol,3.00 eq.) in tetrahydrofuran (2.00 mL) was added dropwise acryloyl chloride (38 mg,0.04mmol,0.90 eq.) at 0 ℃. The resulting mixture was stirred for 1h and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with MeOH/DCM (3%) to give N- {1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclopropyl } prop-2-enamide (160 mg crude). The crude product (160 mg) was purified by preparative HPLC and using the following conditions (column: XB ridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/LNH4HCO 3), mobile phase B: ACN; flow rate: 60mL/min; gradient: 20% B to 45% B, 45% B over 9 min; wavelength: 254/220nm; RT1 (min): 8.65; running number: 0) to afford N- {1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-C ] pyridin-2-yl } pyridin-3-yl) ethynyl ] cyclopropyl } prop-2-enamide (100 mg, 44.39%) as an off-white solid.

LC-MS:(M+H) ⁺ Actual: 486.10.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.36(s,1H),8.97(s,1H),8.50(s,1H),8.26(d,1H),7.53(s,1H),7.32(d,1H),7.19(s,1H),6.64–6.61(m,1H),6.50–6.45(m,1H),6.18(d,2H),5.95(d,1H),5.67(t,1H),3.90(s,3H),3.45–3.42(m,2H),2.97(t,2H),1.35–1.32(m,2H),1.17–1.14(m,2H)。

example 126:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1S, 5R) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-1-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 205)

126.1: synthesis of tert-butyl 1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylate

To 3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (200 mg,0.42mmol,1.00 eq.), cuI (20 mg,0.10mmol,0.50 eq.) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (170 mg,0.21mmol,0.50 eq.) in DMF (2.00 mL) was added dropwise 1-ethynyl-2-azabicyclo [ 3.1.0)]Hexane-2-carboxylic acid tert-butyl ester (260 mg,1.25mmol,3.00 eq.) and DIEA (270 mg,2.09mmol,5.00 eq.). The final reaction mixture was stirred at 50℃under argon for 2h. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, C18 silica gel (gel); a mobile phase, ACN in water, gradient from 10% to 60% within 25 min; a detector: UV 254nm. This gives 1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (250 mg, 76.12%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 558.15.

126.2: synthesis of 2- (3- ((2-azabicyclo [3.1.0] hex-1-yl) ethynyl) pyridin-4-yl) -3- ((3-fluoro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

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To a stirred solution of tert-butyl 1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylate (220 mg,0.39mmol,1.00 eq.) in DCM (6.00 mL) was added TFA (2.00 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 458.1.

126.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-1-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- [3- (2- { 2-azabicyclo [3.1.0] at 0deg.C under nitrogen atmosphere]Hex-1-yl } ethynyl) pyridin-4-yl ]-3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (180 mg,0.39mmol,1.00 eq.) in THF (6.00 mL) and NaHCO ₃ (saturated) (6.00 mL) was added dropwise to the stirred solution of acryloyl chloride (32 mg,0.35mmol,0.9 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM/MeOH (10:1) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino groups]-2- (3- {2- [2- (prop-2-enoyl) -2-azabicyclo [ 3.1.0)]Hex-1-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (30 mg, 14.86%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 512.1.

126.4: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1S, 5R) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-1-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

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The crude product (30 mg) was purified by chiral preparative HPLC and employed toUnder the conditions (column CHIRALPAK IG, 2X 25cm,5 μm; mobile phase A: hex: DCM=3:1 (0.5% 2M NH) ₃ -MeOH) -HPLC, mobile phase B EtOH-HPLC; the flow rate is 20mL/min; gradient from 20% b to 20% b, within 20 min; wavelength is 220/254nm; RT1 (min) 10.98; RT2 (min) 17.32; sample solvent ETOH, dcm=1:1; injection volume 0.8mL; running number: 5) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group ]-2- (3- {2- [ (1S, 5R) -2- (prop-2-enoyl) -2-azabicyclo [ 3.1.0)]Hex-1-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (8.8 mg, 29.16%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 512.00.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.55(s,1H),8.43(s,1H),8.27(d,1H),7.40(d,1H),6.91(s,1H),6.71–6.59(m,4H),6.47(t,1H),6.16-6.10(m,1H),5.66–5.39(m,1H),4.09-3.93(m,2H),3.46-3.42(m,2H),3.31(s,1H),2.92-2.87(m,3H),2.40-2.28(m,1H),2.20-2.10(m,1H),1.78-1.64(m,1H),0.92(s,1H)。

example 127.3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1S, 5R) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-1-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 204)

The crude product (30 mg) was purified by chiral preparative HPLC using the following conditions (column: CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex: dcm=3:1 (0.5% 2m NH) ₃ -MeOH) -HPLC, mobile phase B EtOH-HPLC; the flow rate is 20mL/min; gradient from 20% b to 20% b, within 20 min; wavelength is 220/254nm; RT1 (min) 10.98; RT2 (min) 17.32; sample solvent ETOH, dcm=1:1; injection volume 0.8mL; running number: 5) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- {2- [ (1S, 5R) -2- (prop-2-enoyl) -2-azabicyclo [ 3.1.0)]Hex-1-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (8.8 mg, 29.16%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 512.00

¹ H NMR(400MHz,DMSO-d ₆ )δ11.55(s,1H),8.43(s,1H),8.28(d,1H),7.40(d,1H),7.05–6.60(m,5H),6.53–6.42(m,1H),6.18–6.03(m,1H),5.56(d,1H),4.09–3.77(m,2H),3.49–3.40(m,2H),3.30(s,3H),2.93–2.84(m,3H),2.36-2.25(m,1H),2.18–2.07(m,1H),1.73–1.62(m,1H),0.94(s,1H)。

Example 128:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1R, 5S) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-1-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 203)

128.1: synthesis of tert-butyl 1- (hydroxymethyl) -2-azabicyclo [3.1.0] hexane-2-carboxylate

To 2- (tert-Butoxycarbonyl) -2-azabicyclo [3.1.0] at 0deg.C under nitrogen]A stirred solution of hexane-1-carboxylic acid (1.5 g,6.60mmol,1.00 eq.) in THF (30 mL) was added drop wise BH ₃ (1M in THF, 7.26mL,7.26mmol,1.10 eq.). The resulting mixture was stirred at 80℃under nitrogen for 1h. The reaction was quenched by the addition of MeOH (10 mL) at 0deg.C. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

LC-MS:(M+H-56) ⁺ Actual: 157.85.

128.2: synthesis of tert-butyl 1-formyl-2-azabicyclo [3.1.0] hexane-2-carboxylate

To a stirred solution of tert-butyl 1- (hydroxymethyl) -2-azabicyclo [3.1.0] hexane-2-carboxylate (1.71 g,8.02mmol,1.00 eq.) in DCM (30 mL) was added dropwise Dess-Martin reagent (4.08 g,9.62mmol,1.20 eq.) at 0deg.C under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (5:1) to provide tert-butyl 1-formyl-2-azabicyclo [3.1.0] hexane-2-carboxylate (1.38 g, 81.47%) as a yellow oil.

LC-MS:(M+H-56) ⁺ Actual: 155.85.

128.3: synthesis of tert-butyl 1-ethynyl-2-azabicyclo [3.1.0] hexane-2-carboxylate

To 1-formyl-2-azabicyclo [3.1.0] at 0deg.C under nitrogen atmosphere]Hexane-2-carboxylic acid tert-butyl ester (1.38 g,6.53mmol,1.00 eq.) and K ₂ CO ₃ (2.71 g,19.59mmol,3.00 eq.) of dimethyl (1-diazo-2-oxopropyl) phosphonate (1.51 g,7.84mmol,1.20 eq.) in MeOH (30 mL) was added dropwise. The resulting mixture was stirred at room temperature under nitrogen for 2h. The reaction was quenched by addition of sodium potassium tartrate (saturated) (10 mL) at room temperature. The mixture was stirred for 30min. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (3×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (5:1) to provide 1-ethynyl-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (1.18 g, 87.15%) as a yellow oil.

LC-MS:(M+H-56) ⁺ Actual: 151.90.

128.4: synthesis of tert-butyl 1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylate

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere ]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (200 mg,0.40mmol,1.00 eq.) and 1-ethynyl-2-azabicyclo [3.1.0]]Hexane-2-carboxylic acid tert-butyl ester (251 mg,1.21mmol,3.00 eq.) inPd (dppf) Cl was added dropwise to a stirred solution in DMF (2.00 mL) ₂ CH ₂ Cl ₂ (82 mg,0.10mmol,0.25 eq.) and DIEA (261 mg,2.02mmol,5.00 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, silica gel; mobile phase, meCN in water, gradient 10% to 70%, within 30 min; a detector: UV 254nm. This gives 1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (210 mg, 90.48%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 574.1.

128.5: synthesis of 2- (3- ((2-azabicyclo [3.1.0] hex-1-yl) ethynyl) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of 1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (260 mg,0.45mmol,1.00 eq.) in DCM (6.00 mL) was added TFA (2.00 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 474.15.

128.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-1-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0 ℃ with nitrogenIn the atmosphere, to 2- [3- (2- { 2-azabicyclo [3.1.0]]Hex-1-yl } ethynyl) pyridin-4-yl]-3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (215 mg,0.45mmol,1.00 eq.) and NaHCO ₃ (5.00 mL) in THF (5.00 mL) was added dropwise acryloyl chloride (36 mg,0.41mmol,0.90 eq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (15:1) elution to afford 3- [ (3-chloro-2-methoxyphenyl) amino)]-2- (3- {2- [2- (prop-2-enoyl) -2-azabicyclo [ 3.1.0)]Hex-1-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (50 mg, 20.88%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 528.20.

128.7: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1R, 5S) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-1-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

The crude product (50 mg) was purified by chiral preparative HPLC and using the following conditions (column: CHIRAL ART Amylose-SA, 2X 25cm,5 μm; mobile phase A: hex (0.5% 2M NH3-MeOH) -HPLC, mobile phase B: etOH- -HPLC; flow rate: 20mL/min; gradient: 30% B to 30% B,17 min; wavelength: 220/254nm; RT1 (min): 8.301; RT2 (min): 12.494; sample solvent: etOH- -HPLC; injection volume: 0.3mL; running number: 10) to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1R, 5S) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0] Hex-1-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (12 mg, 23.71%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 528.30.

1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),8.43(s,1H),8.27(d,1H),7.39(d,1H),6.73–6.59(m,5H),6.15-6.09(m,1H),5.66–5.49(m,1H),4.10-3.85(m,2H),3.46-3.42(m,2H),3.25(s,3H),2.90-2.87(m,3H),2.40-2.28(m,1H),2.15-2.04(m,1H),1.78-1.62(m,1H),0.93(t,1H)。

example 129:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1S, 5R) -2- (prop-2-enoyl) -2-azabicyclo [3.1.0] hex-1-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 202)

The crude product (50 mg) was purified by chiral preparative HPLC using the following conditions (column: CHIRAL ART Amylose-SA, 2X 25cm,5 μm; mobile phase A: hex (0.5% 2M NH) ₃ -MeOH) -HPLC, mobile phase B EtOH-HPLC; the flow rate is 20mL/min; gradient from 30% B to 30% B for 17 min; wavelength is 220/254nm; RT1 (min): 8.301; RT2 (min): 12.494; sample solvent EtOH- -HPLC; injection volume 0.3mL; running 10) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (1S, 5R) -2- (prop-2-enoyl) -2-azabicyclo [ 3.1.0)]Hex-1-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (11.5 mg, 22.42%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 528.30.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.54(s,1H),8.43(s,1H),8.25(d,1H),7.35(d,1H),6.73–6.59(m,5H),6.16-6.10(m,1H),5.66–5.39(m,1H),4.09-3.84(m,2H),3.46-3.42(m,2H),3.25(s,3H),2.90-2.87(m,3H),2.40-2.28(m,1H),2.15-2.04(m,1H),1.68-1.66(m,1H),0.93(t,1H)。

example 130:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 210)

130.1: synthesis of (R) -2- (hydroxymethyl) -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To (2R) -1- (tert-butoxycarbonyl) -2-methylpyrrolidine-2-carboxylic acid at 0℃under nitrogen atmosphereA stirred solution of acid (1 g,4.36mmol,1.00 eq.) in THF (10.00 mL) was added drop wise to BH ₃ (1M in THF) (8.72 mL,8.724mmol,2 eq.). The resulting mixture was stirred at 75℃under nitrogen for 1h. The reaction was quenched by the addition of MeOH (5.00 mL) at 0deg.C. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

LC-MS:(M+H-56) ⁺ Actual: 160.3

130.2: synthesis of (2R) -2-formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred mixture of tert-butyl (2R) -2- (hydroxymethyl) -2-methylpyrrolidine-1-carboxylate (1.1 g,5.1mmol,1.00 eq.) in DCM (20.00 mL) at 0deg.C under nitrogen was added dropwise Dess-Martin reagent (2.60 g,6.13mmol,1.20 eq.). The resulting mixture was stirred at room temperature under nitrogen for 2h. By addition of Na at room temperature ₂ SO ₄ (saturated) (5.00 mL) quench the reaction. The resulting mixture was treated with CH ₂ Cl ₂ (3X 20 mL) extraction over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (5:1) to give tert-butyl (2R) -2-formyl-2-methylpyrrolidine-1-carboxylate (750 mg, 68.83%) as a colorless oil.

¹ H NMR (400 MHz, chloroform-d) δ9.38 (d, 1H), 3.70-3.40 (m, 2H), 2.05-1.87 (m, 3H), 1.78-1.57 (m, 1H), 1.46 (s, 3H), 1.40 (d, J=12.8 Hz, 9H).

130.3: synthesis of (2R) -2-ethynyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To (2R) -2-formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (700 mg,3.28mmol,1.00 eq.) and K at 0deg.C under nitrogen ₂ CO ₃ (907 mg,6.56mmol,2.00 eq) A stirred solution of Bestmann-Ohira reagent (756 mg,3.94mmol,1.20 eq.) in methanol (10.00 mL) was added dropwise. The resulting mixture was stirred at room temperature under nitrogen for 2h. The reaction was quenched by addition of sodium potassium tartrate (saturated) (2 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (5:1) to give tert-butyl (2R) -2-ethynyl-2-methylpyrrolidine-1-carboxylate (600 mg, 87.35%) as a white oil.

¹ H-NMR (300 MHz, chloroform-d) delta 3.63-3.28 (m, 2H), 2.34-2.24 (m, 2H), 2.08-1.72 (m, 3H), 1.70 (s, 3H), 1.49 (s, 9H).

130.4: synthesis of tert-butyl (2R) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (150 mg,0.30mmol,1.00 eq.), cuI (28 mg,0.15mmol,0.50 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (61 mg,0.076mmol,0.25 eq.) in DMF (2.00 mL) was added dropwise (2R) -tert-butyl 2-ethynyl-2-methylpyrrolidine-1-carboxylate (25 mg,0.12mmol,3.00 eq.) and DIEA (195 mg,1.51mmol,5.00 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 70%, within 20 min; a detector: UV 254nm. This gives (2R) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (160 mg, 91.6%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 576.05.

130.5: synthesis of (R) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((2-methylpyrrolidin-2-yl) ethynyl) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2R) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate (140 mg,0.035mmol,1.00 eq.) in DCM (1.00 mL) was added TFA (3.00 mL) dropwise at room temperature under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 1h. The mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 476.1

130.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group at 0℃under nitrogen atmosphere]-2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100 mg,0.21mmol,1.00 eq.) and NaHCO ₃ (saturated) (3.00 mL) an stirred solution of acryloyl chloride (19 mg,0.21mmol,1.00 eq.) in THF (3.00 mL) was added dropwise. The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (10/1) (3X 20 mL) extraction. The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by preparative HPLC using the following conditions (column: XBRID Prep C18 OBD column, 30X 100mm, 5. Mu.)m; mobile phase A water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient from 35% b to 55% b, 55% b over 10 min; wavelength is 254/220nm; RT1 (min) 9.67; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (17 mg, 15.00%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 530.30

¹ HTEM-NMR(400MHz,DMSO-d ₆ )δ11.35(s,1H),8.50(s,1H),8.20(d,2H),7.46–7.29(m,2H),6.82–6.54(m,4H),6.22–6.10(m,2H),5.65(d,1H),3.89(s,3H),3.68(d,2H),3.47–3.40(m,2H),3.10-3.02(m,2H),2.44–2.35(m,1H),2.19–2.09(m,1H),2.05–1.93(m,2H),1.69(s,3H)。

Example 131:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one) (compound 209

131.1: synthesis of (S) -2- (hydroxymethyl) -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of (2S) -1- (tert-butoxycarbonyl) -2-methylpyrrolidine-2-carboxylic acid (1 g,4.36mmol,1.00 eq.) in THF (8.00 mL) at room temperature was added BH ₃ (1M in THF, 8.7mL,8.7mmol,2.0 eq.). The resulting mixture was stirred at 75℃under an N2 atmosphere for 1h. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (2.00 mL) at 0deg.C. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

LC-MS:(M+H-56) ⁺ Actual: 160.15.

131.2: synthesis of (2S) -2-formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl (2S) -2- (hydroxymethyl) -2-methylpyrrolidine-1-carboxylate (938 mg,4.36mmol,1.00 eq.) in DCM (10.00 mL) was added Dess-Martin reagent (2.22 g,5.23mmol,1.20 eq.) at 0deg.C. The resulting mixture was stirred at room temperature under nitrogen for 2h. The reaction was monitored by TLC. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EA/PE (20%) to give (2S) -2-formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (640 mg, 68.88%) as a colorless oil.

131.3: synthesis of (2S) -2-ethynyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

K was added dropwise to a stirred solution of tert-butyl (2S) -2-formyl-2-methylpyrrolidine-1-carboxylate (600 mg,2.81mmol,1.00 eq.) in MeOH (6.00 mL) at 0deg.C under nitrogen ₂ CO ₃ (778 mg,5.63mmol,2 eq.) dimethyl (1-diazo-2-oxopropyl) phosphonate (640 mg,3.38mmol,1.20 eq.). The resulting mixture was stirred at room temperature under nitrogen for 2h. The reaction was quenched by addition of sodium potassium tartrate (saturated) (5.00 mL) at 0deg.C. The resulting mixture was stirred at room temperature for 0.5h. The reaction was monitored by TLC and H-NMR. The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA/PE (5%) to give (2S) -2-ethynyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (640 mg, 68.88%) as a colorless oil.

¹ H NMR (400 MHz, chloroform-d) delta 3.55 (s, 1H), 3.41-3.35 (m, 1H), 2.30-2.27 (m, 2H), 1.99-1.90 (m, 2H), 1.83-1.77 (m, 1H), 1.63 (s, 3H), 1.49 (s, 9H).

131.4: synthesis of (2S) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (150 mg,0.30mmol,1.00 eq.) and tert-butyl (2S) -2-ethynyl-2-methylpyrrolidine-1-carboxylate (127 mg,0.61mmol,2.00 eq.) in DMF (2.00 mL) was added DIEA (98 mg,0.76mmol,2.50 eq.), cuI (29 mg,0.15mmol,0.50 eq.) Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (62 mg,0.08mmol,0.25 eq.). The mixture was stirred at 50℃under nitrogen for 2h. The resulting mixture was concentrated under reduced pressure. The desired product was detectable by LCMS. The residue was purified by reverse phase flash chromatography using column, C18 silica gel; a mobile phase, ACN in water, gradient 0% to 100%, within 30 min; a detector: UV 254nm to provide (2S) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (155 mg, 84.30%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 576.10.

131.5: synthesis of (S) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((2-methylpyrrolidin-2-yl) ethynyl) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a solution of tert-butyl (2S) -2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate (60 mg,0.10mmol,1.00 eq.) in DCM (1.00 mL) was added TFA (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5h. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 476.10.

131.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group at 0℃under nitrogen atmosphere]-2- (3- {2- [ (2S) -2-methylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (60 mg,0.17mmol,1.00 eq.) in THF (2.00 mL) and NaHCO ₃ (saturated) (2.00 mL) was added dropwise to the stirred solution of acryloyl chloride (10 mg,0.11mmol,0.9 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 35% b to 58% b, 58% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2S) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-one) (8.1 mg, 11.81%) as an off-white solid.

LC-MS:(M+H) ⁺ Actual: 530.00

¹ HTEM NMR(400MHz,DMSO-d ₆ )δ11.36(s,1H),8.49(s,1H),8.22–8.20(m,1H),7.35–7.34(m,2H),6.77(s,1H),6.67–6.61(m,3H),6.27–6.00(m,2H),5.67(d,J＝9.6Hz,1H),3.90(s,3H),3.75–3.60(m,2H),3.46–3.43(m,2H),3.08–2.98(m,2H),2.49–2.47(m,1H),2.18–2.07(m,1H),2.03–1.94(m,2H),1.71(s,3H)。

Example 132:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (6R) -5- (prop-2-enoyl) -5-azaspiro [2.4] hept-6-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 234)

132.1: synthesis of tert-butyl (R) -6- (hydroxymethyl) -5-azaspiro [2.4] heptane-5-carboxylate

At 0℃to (6S) -5- (tert-butoxycarbonyl) -5-azaspiro [2.4]]A solution of heptane-6-carboxylic acid (2.40 g,9.95mmol,1.00 eq.) in THF was added drop wise BH ₃ (15.00 mL,15.00mmoL,1.5 eq, 1M in THF). The resulting mixture was stirred at room temperature for 2h. The reaction was quenched by the addition of MeOH (15.00 mL) at 0deg.C. Concentrating the resulting mixture under reduced pressure to obtain (R) -6- (hydroxymethyl) -5-azaspiro [2.4]]Heptane-5-carboxylic acid tert-butyl ester (2.6 g, crude) was a colorless oil.

132.2: synthesis of (6R) -6-formyl-5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester

At 0 ℃, to (6R) -6- (hydroxymethyl) -5-azaspiro [2.4]]A solution of tert-butyl heptane-5-carboxylate (2.30 g,10.11mmol,1.00 eq.) in DCM (25.00 mL) was added the Dess-Martin reagent (5.15 g,12.14mmol,1.20 eq.). The resulting mixture was stirred at room temperature for 2.5h. By addition of saturated Na at 0 DEG C ₂ S ₂ O ₃ The reaction was quenched with aqueous solution (15 mL). The resulting mixture was treated with CH ₂ Cl ₂ (3X 10 mL) extraction. The combined organic layers were washed with brine (1×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (5:1) to provide (6R) -6-formyl-5-azaspiro [ 2.4)]Heptane-5-carboxylic acid tert-butyl ester (1.99 g, 87.30%) was a pale yellow oil.

LC-MS:(M+H-56) ⁺ Actual: 169.95.

¹ h NMR (300 MHz, chloroform-d) delta 9.66-9.58 (m, 1H), 4.36-4.17 (m, 1H), 3.48–3.41(m,1H),3.37–3.22(m,1H),2.15 -2.08(m,1H),1.88–1.82(m,1H),1.48 -1.45(m,9H),0.66–0.49(m,4H)。

132.3: synthesis of tert-butyl (6R) -6-ethynyl-5-azaspiro [2.4] heptane-5-carboxylate

At 0 ℃, to (6R) -6-formyl-5-azaspiro [2.4]]Heptane-5-carboxylic acid tert-butyl ester (1.2 g,5.327mmol,1 eq.) and K ₂ CO ₃ A stirred mixture of (1.47 g,10.65mmol,2.0 eq.) in MeOH (8.00 mL) was added dropwise dimethyl (1-diazo-2-oxopropyl) phosphonate (1.23 g, 6.390 mmol,1.2 eq.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by addition of a solution of potassium sodium tartrate tetrahydrate (aqueous solution, 20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 15 mL). The combined organic layers were washed with brine (1×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel and PE/EA (5:1) was used. This gives (6R) -6-ethynyl-5-azaspiro [2.4] ]Heptane-5-carboxylic acid tert-butyl ester (900 mg, 76.35%) was a yellow oil.

LC-MS:(M+H-56) ⁺ Actual: 166.3.

¹ H-NMR (400 MHz, chloroform-d) delta 4.61-4.52 (m, 1H), 3.40 (d, 1H), 3.19 (s, 1H), 2.32-2.24 (m, 2H), 1.74-1.71 (m, 1H), 1.48 (s, 9H), 0.71-0.67 (m, 2H), 0.58-0.54 (m, 2H).

132.4: synthesis of tert-butyl (6R) -6- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -5-azaspiro [2.4] heptane-5-carboxylate

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (150 mg,0.30mmol,1.00 eq.) andPd(dppf)Cl ₂ CH ₂ Cl ₂ (61 mg,0.076mmol,0.25 eq.) and CuI (28 mg,0.15mmol,0.50 eq.) in DMF was added (6R) -6-ethynyl-5-azaspiro [ 2.4)]Heptane-5-carboxylic acid tert-butyl ester (335 mg,1.51mmol,5.00 eq.) and DIEA (195 mg,1.51mmol,5.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to afford (6R) -6- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-5-azaspiro [2.4]]Heptane-5-carboxylic acid tert-butyl ester (150 mg, 84.12%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 588.15.

132.5: synthesis of 2- (3- {2- [ (6R) -5-azaspiro [2.4] hept-6-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- { [ (4- {3- [ (2-chloro-3-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (140 mg,0.252mmol,1 eq.) in DCM (3 mL) was added TFA (1 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- (3- {2- [ (6R) -5-azaspiro [2.4] hept-6-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (200 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 488.1

132.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (6R) -5- (prop-2-enoyl) -5-azaspiro [2.4] hept-6-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0℃to 2- (3- {2- [ (6R) -5-azaspiro [2.4] ]Hept-6-yl]Ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (110 mg,0.22mmol,1 eq.) and saturated NaHCO ₃ (aqueous solution) (1.50 mL) an stirred solution of acryloyl chloride (22 mg,0.22mmol,1.00 eq.) in THF (1.50 mL) was added dropwise. The resulting mixture was stirred at room temperature for 1.5h. The resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (1×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (130 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH C18 OBD column 30 x 150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 28% B to 49% B,8min, 49% B; wavelength: 254/220nm; RT1 (min): 8; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (6R) -5- (prop-2-enoyl) -5-azaspiro [2.4 ]]Hept-6-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (33.6 mg, 26.66%) was a yellow solid.

LC-MS (M+H) + actual: 542.10.

¹ h NMR (400 MHz, chloroform-d) δ11.15 (s, 1H), 8.53 (s, 1H), 8.13 (d, 1H), 7.77 (s, 1H), 7.42 (d, 1H), 6.73-6.71 (m, 1H), 6.60 (t, 1H), 6.41 (d, 2H), 6.24-6.21 (m, 1H), 5.77 (t, 1H), 5.27 (s, 1H), 5.04-5.01 (m, 1H), 4.07 (s, 3H), 3.67-3.50 (m, 4H), 3.31-3.27 (m, 2H), 2.34-2.29 (m, 1H), 2.19-2.14 (m, 1H), 0.89-0.81 (m, 2H), 0.74-0.70 (m, 2H).

Example 133:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 233)

133.1: synthesis of tert-butyl 2-ethynyl-3, 3-dimethyl azetidine-1-carboxylate

K was added dropwise to a stirred solution of tert-butyl 2-formyl-3, 3-dimethyl azetidine-1-carboxylate (200 mg,0.94mmol,1.00 eq.) in methanol (10 mL) at 0deg.C under nitrogen ₂ CO ₃ (319 mg,1.88mmol,2.00 eq.) and dimethyl (1-diazo-2-oxopropyl) phosphonate (216 mg,1.13mmol,1.20 eq.). The resulting mixture was stirred at room temperature under nitrogen for 2h. The reaction was quenched by addition of saturated sodium potassium tartrate (5.00 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (5:1) to give tert-butyl 2-ethynyl-3, 3-dimethyl azetidine-1-carboxylate (160 mg, 81.52%) as a white oil.

¹ H NMR (300 MHz, chloroform-d) δ4.37 (d, 1H), 3.54 (s, 2H), 2.53 (d, 1H), 1.48 (s, 9H), 1.31 (s, 3H), 1.27 (s, 3H).

133.2: synthesis of tert-butyl 2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -3, 3-dimethyl azetidine-1-carboxylate

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (400 mg,0.81mmol,1.00 eq.), cuI (76 mg,0.40mmol,0.50 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (164 mg,0.20mmol,0.25 eq.) in DMF (3.00 mL) was added dropwise tert-butyl 2-ethynyl-3, 3-dimethyl azetidine-1-carboxylate (507 mg,2.42mmol,3.00 eq.) and DIEA (522 mg,4.04mmol,5.00 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The residue was purified by reverse phase flash chromatography using column, silica gel; mobile phase, meCN in water, gradient 10% to 70%, within 20 min; a detector: UV 254nm. This gives 2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) ammoniaBase group]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-3, 3-Dimethylazetidine-1-carboxylic acid tert-butyl ester (270 mg, 57.97%) as yellow solid.

LC-MS:(M+H) ⁺ Actual: 576.20.

133.3: synthesis of 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((3, 3-dimethylbenzidin-2-yl) ethynyl) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl 2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -3, 3-dimethyl azetidine-1-carboxylate (270 mg,0.47mmol,1.00 eq.) in DCM (6.00 mL) was added TFA (2.00 mL) dropwise at room temperature under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 476.2.

133.4: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group at 0℃under nitrogen atmosphere]-2- {3- [2- (3, 3-dimethyl azetidin-2-yl) ethynyl]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (200 mg,0.42mmol,1.00 eq.) in THF (6 mL) and NaHCO ₃ The stirred mixture in (6 mL) was added dropwise with acryloyl chloride (38 mg,0.42mmol,1.00 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) to afford the crude product, the crude product (100 mg) was purified by preparative HPLC and using the following conditions (column: XBridge Prep C18 OBD column, 30 x 100mm,5 μm; mobile phase a: water (10 mmol/L NH ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 28% b to 52% b, 52% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (60 mg, 26.94%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 530.35

133.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

The crude product (60 mg) was purified by chiral preparative HPLC and using the following conditions (column: CHIRAL ART Amylose-SA, 2X 25cm,5 μm; mobile phase A: hex (0.5% 2M NH3-MeOH) -HPLC, mobile phase B: etOH- -HPLC; flow rate: 20mL/min; gradient: 25% B to 25% B,27 min; wavelength: 220/254nm; RT1 (min): 15.594; RT2 (min): 22.091; sample solvent: etOH- -HPLC; injection volume: 1.25mL; running number: 2) to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (22.8 mg, 45.42%) as a solid).

LC-MS:(M+H) ⁺ Actual: 530.10

¹ H NMR (300 MHz, chloroform-d) δ10.97 (s, 1H), 8.56 (s, 1H), 8.12 (d, 1H), 7.86 (s, 1H), 7.41 (d, 1H), 6.78-6.69 (m, 1H), 6.61 (t, 1H), 6.43-6.31 (m, 1H), 6.28-6.13 (m, 2H), 5.82-5.72 (m, 1H), 5.26 (s, 1H), 4.86 (s, 1H), 4.07 (s, 3H), 3.98 (d, 2H), 3.64-3.52 (m, 2H), 3.30-3.19 (m, 2H), 1.54 (s, 3H), 1.45 (s, 3H).

Example 134:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 232)

The crude product (60 mg) was purified by chiral preparative HPLC and using the following conditions (column: CHIRAL ART Amylose-SA, 2X 25cm,5 μm; mobile phase A: hex (0.5% 2M NH3-MeOH) -HPLC, mobile phase B: etOH- -HPLC; flow rate: 20mL/min; gradient: 25% B to 25% B,27 min; wavelength: 220/254nm; RT1 (min): 15.594; RT2 (min): 22.091; sample solvent: etOH- -HPLC; injection volume: 1.25mL; running number: 2) to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (22.7 mg, 45.31%) as a solid).

LC-MS:(M+H) ⁺ Actual: 530.10

¹ H NMR (300 MHz, chloroform-d) δ10.96 (s, 1H), 8.56 (s, 1H), 8.13 (d, 1H), 7.84 (s, 1H), 7.41 (d, 1H), 6.78-6.69 (m, 1H), 6.61 (t, 1H), 6.43-6.31 (m, 1H), 6.28-6.13 (m, 2H), 5.81-5.71 (m, 1H), 5.26 (s, 1H), 4.86 (s, 1H), 4.07 (s, 3H), 3.98 (d, 2H), 3.67-3.54 (m, 2H), 3.29-3.19 (m, 2H), 1.54 (s, 3H), 1.45 (s, 3H).

Example 135:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- (prop-2-enoyl) piperidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 231)

135.1: synthesis of tert-butyl 2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] piperidine-1-carboxylate

To 3- [ (3-chloro-2-methoxybenzene) at room temperatureRadical) amino group]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (300 mg,0.61mmol,1.00 eq.) and tert-butyl 2-ethynyl piperidine-1-carboxylate (317 mg,1.51mmol,2.50 eq.) in DMF (5 mL) was added Pd (dppf) Cl ₂ CH ₂ Cl ₂ (124 mg,0.15mmol,0.25 eq.) and CuI (57 mg,0.30mmol,0.50 eq.). DIEA (235 mg,1.82mmol,3.00 eq.) was added dropwise to the above mixture at room temperature. The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). Concentrating the filtrate under reduced pressure, purifying by reverse phase flash chromatography and employing the following conditions: column, silica gel; mobile phase, meCN in water, gradient 10% to 50% within 10 min; a detector: UV 254nm. The resulting mixture was concentrated under reduced pressure. The residue was further purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford 2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Piperidine-1-carboxylic acid tert-butyl ester (227 mg, 64.98%) was a pale yellow solid.

LC-MS: M+Hactual: 576.2.

135.2: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [2- (piperidin-2-yl) ethynyl ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl 2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] piperidine-1-carboxylate (185 mg,0.32mmol,1.00 eq) in DCM (3 mL) was added TFA (1 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [2- (piperidin-2-yl) ethynyl ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (230 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 476.2.

135.3: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [1- (prop-2-enoyl) piperidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (3-chloro-2-methoxyphenyl) amino group was added to a 50mL round bottom flask at room temperature ]-2- {3- [2- (piperidin-2-yl) ethynyl ]]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (153 mg,0.32mmol,1.00 eq.) and THF (6 mL). With saturated NaHCO ₃ The aqueous solution basifies the mixture to pH 8. To the above mixture was added dropwise acryloyl chloride (38 mg,0.41mmol,1.30 eq.) at 0deg.C. The resulting mixture was stirred at room temperature for an additional 2h. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (10:1) (3X 40 mL) extraction over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford 3- [ (3-chloro-2-methoxyphenyl) amino)]-2- (3- {2- [1- (prop-2-enoyl) piperidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (60 mg, 37.01%) was a red solid.

LC-MS:(M+H) ⁺ Actual: 530.15.

135.4: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- (prop-2-enoyl) piperidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

The crude product (60 mg) was purified by chiral preparative HPLC and was purified using the following conditions (column: CHIRALPAK IH-3,4.6 x 50mm,3 μm; mobile phase A: hex (0.1% DEA): etOH=60:40; flow rate: 1mL/min; gradient: 0% B to 0% B; injection volume: 5ul mL) to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- (prop-2-enoyl) piperidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (4.5 mg, 6.52%) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 530.4.

¹ H-NMR (400 MHz, chloroform-d) delta 10.54 (s, 1H), 8.60 (s, 1H), 8.11 (d, 1H), 7.94 (s, 1H), 7.36 (d, 1H), 6.78 (d, 1H), 6.69-6.53 (m, 2H), 6.36-6.29 (m, 1H), 6.22-6.13 (m, 1H), 5.82-5.76 (m, 1H), 5.63 (s, 1H), 5.30 (s, 1H), 4.09 (s, 3H), 3.95-3.87 (s, 1H), 3.71-3.56 (m, 2H), 3.42-3.30 (m, 1H), 3.29-3.12 (m, 2H), 2.11-2.05 (m, 1H), 1.90 (d, 5H).

Example 136:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S) -1- (prop-2-enoyl) piperidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 230)

The crude product (69 mg) was purified by chiral preparative HPLC and was purified using the following conditions (column: CHIRALPAK IH-3,4.6 x 50mm,3 μm; mobile phase A: hex (0.1% DEA): etOH=60:40; flow rate: 1mL/min; gradient: 0% B to 0% B; injection volume: 5ul mL) to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S) -1- (prop-2-enoyl) piperidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (6.8 mg, 10.37%) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 530.40.

¹ h NMR (400 MHz, chloroform-d) δ10.49 (s, 1H), 8.60 (s, 1H), 8.13 (d, 1H), 7.87 (s, 1H), 7.37 (d, 1H), 6.78 (d, 1H), 6.68-6.58 (m, 2H), 6.34-6.28 (m, 1H), 6.21-6.17 (m, 1H), 5.80-5.73 (m, 1H), 5.66 (s, 1H), 5.29 (s, 1H), 4.09 (s, 3H), 3.99-3.89 (m, 1H), 3.69-3.55 (m, 2H), 3.42-3.09 (m, 3H), 2.12-2.02 (m, 1H), 1.92 (d, 5H).

Example 137:2- (3- {2- [ (2R) -4, 4-dimethyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 253)

137.1: synthesis of (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

To 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (200 mg,0.46mmol,1.00 eq.) and CuI (44 mg,0.23mmol,0.50 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (94 mg,0.11mmol,0.25 eq.) in DMF (4 mL) was added dropwise (2R) -2-ethynyl-4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (207 mg,0.92mmol,2.00 eq.) and DIEA (299 mg,2.32mmol,5.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC and using the following conditions (0.1% nh ₄ HCO ₃ In water and ACN (33% ACN up to 90%, within 20 min) to provide (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-4, 4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (180 mg, 66.9%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 574.15.

137.2: synthesis of 2- (3- {2- [ (2R) -4, 4-dimethylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -4, 4-dimethylpyrrolidine-1-carboxylate (80 mg,0.13mmol,1.00 eq.) in DCM (3 mL) was added TFA (1 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- (3- {2- [ (2R) -4, 4-dimethylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (110 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 474.25.

137.3: synthesis of 2- (3- {2- [ (2R) -4, 4-dimethyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- (3- {2- [ (2R) -4, 4-dimethylpyrrolidin-2-yl) at 0℃under nitrogen]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (80 mg,0.17mmol,1.00 eq.) and saturated NaHCO ₃ (aqueous solution) (3.00 mL) A stirred solution of acryloyl chloride (15 mg,0.17mmol,1.00 eq. The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (10/1) (3X 30 mL) extraction. The combined organic layers were washed with brine (3×30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC and using the following conditions (column: xselect CSH C18 OBD column 30X 150mm5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 32% B to 50% B,8min, 50% B; wavelength: 254/220nm; RT1 (min): 8; running number: 0) to provide 2- (3- {2- [ (2R) -4, 4-dimethyl-1- (prop-2-enoyl) pyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (38.5 mg, 42.3%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 528.50.

¹ H-NMR (400 MHz, chloroform-d) δ11.14 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 7.43 (s, 1H), 6.56-6.27 (m, 4H), 6.02 (d, 1H), 5.71-5.67 (m, 1H), 5.24 (s, 1H), 4.87 (t, 1H), 4.03 (d, 3H), 3.60-3.43 (m, 3H), 3.39-3.32 (m, 1H), 3.25-3.14 (m, 2H), 2.19-2.11 (m, 1H), 2.06-1.98 (m, 1H), 1.27 (s, 3H), 1.08 (s, 3H).

EXAMPLE 138 (2E) -4- (dimethylamino) -N- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] but-2-enamide (compound 334)

To 2- [3- (3-amino-3-methylbut-1-yn-1-yl) pyridin-4-yl under argon atmosphere at 0 ℃C]-3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (80 mg,0.18mmol,1.00 eq.) and DIEA (119 mg,0.93mmol,5.00 eq.) in THF (2.00 mL) was added dropwise to (2E) -4- (dimethylamino) but-2-enoyl chloride (29 mg,0.20mmol,1.10 eq.). The resulting mixture was stirred at 0℃under argon for 1h. The reaction was quenched with water at 0 ℃. The resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (1×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XSelect CSH fluorophenyl, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 43% b to 73% b, 73% b over 7 min; wavelength of 254nm; RT1 (min) 6.55; running number 0) to provide (2E) -4- (dimethylamino) -N- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl]But-2-enamide (30.4 mg, 30.09%) as an off-white solid.

LC-MS:(M+H) ⁺ Actual: 545.20

¹ H NMR(400MHz,CDCl3)δ11.40(s,1H),8.53(s,1H),8.15(d,1H),7.45(d,1H),6.90-6.80(m,1H),6.63-6.55(m,1H),6.50-6.42(m,1H),6.14-5.98(m,2H),5.23(s,1H),4.09(d,3H),3.65-3.58(m,2H),3.25-3.12(m,4H),2.35(s,6H),1.73(s,6H)。

Example 139:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (6R) -5- (prop-2-enoyl) -5-azaspiro [2.4] hept-6-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 251)

139.1: synthesis of tert-butyl (6R) -6- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -5-azaspiro [2.4] heptane-5-carboxylate

To 3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (80 mg,0.16mmol,1.00 eq.) and (6R) -6-ethynyl-5-azaspiro [2.4]]A stirred mixture of tert-butyl heptane-5-carboxylate (46 mg,0.21mmol,5.00 eq.) in dimethylformamide (1.00 mL) was added copper (I) iodide (15 mg,0.08mmol,0.50 eq.) Pd (dppf) Cl ₂ DCM (34 mg,0.04mmol,0.25 eq.) and DIEA (108 mg,0.83mmol,5.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was purified by reverse phase flash chromatography using column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 50% within 10 min; a detector: UV 254nm. This gives (6R) -6- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-5-azaspiro [2.4]]Heptane-5-carboxylic acid tert-butyl ester (80 mg, 83.66%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 572.30.

139.2: synthesis of 2- (3- {2- [ (6R) -5-azaspiro [2.4] hept-6-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of (6R) -6- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester (70 mg,0.12mmol,1.00 eq.) in DCM (6.00 mL) was added TFA (2.00 mL) at 0 ℃. The resulting mixture was stirred at room temperature for 2h and dried using nitrogen to afford 2- (3- {2- [ (6R) -5-azaspiro [2.4] hept-6-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (57 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 472.10.

139.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (6R) -5- (prop-2-enoyl) -5-azaspiro [2.4] hept-6-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With NaHCO ₃ Aqueous solution (0.40 mL) 2- (3- {2- [ (6R) -5-azaspiro [ 2.4)]Hept-6-yl]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (57 mg,0.12mmol,1.00 eq.) in THF (0.40 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (12 mg,0.13mmol,1.10 eq.) at 0℃under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen for 1h. Will be NaHCO at 0 DEG C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product which was purified by Preparative HPLC and was purified using the following conditions (column: xselect CSH F-phenyl OBD column, 19X 250mm,5 μm; mobile phase A: water (0.1% FA), mobile phase B: meOH-Preparative; flow rate: 25mL/min, gradient: 47% B to 77% B, over 7min, 77% B; wavelength: 254nm; RT1 (min): 6.67; running number: 0)) To provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- {2- [ (6R) -5- (prop-2-enoyl) -5-azaspiro [2.4 ]]Hept-6-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (7.0 mg, 11.01%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 526.45.

¹ H NMR (400 MHz, chloroform-d) δ11.25 (s, 1H), 8.51 (s, 1H), 8.06-7.99 (m, 2H), 7.46 (d, 1H), 6.59-6.51 (m, 2H), 6.41-6.39 (m, 2H), 6.07-6.05 (m, 1H), 5.79-5.76 (m, 1H), 5.26 (s, 1H), 5.03-5.00 (m, 1H), 4.10 (d, 3H), 3.67-3.56 (m, 4H), 3.33-3.29 (m, 2H), 2.34-2.29 (m, 1H), 2.18-2.14 (m, 1H), 0.90-0.80 (m, 2H), 0.74-0.68 (m, 2H).

Example 140: rel-2- (3- {2- [ (2R) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 250)

140.1: synthesis of tert-butyl 2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -3, 3-dimethyl azetidine-1-carboxylate

To 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (350 mg,0.81mmol,1.00 eq.) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ A stirred solution of (165 mg,0.20mmol,0.25 eq.) and CuI (77 mg,0.40mmol,0.50 eq.) in DMF (3.00 mL) was added tert-butyl 2-ethynyl-3, 3-dimethyl azetidine-1-carboxylate (509 mg,2.43mmol,3.00 eq.) and DIEA (254 mg,4.06mmol,5.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was purified by reverse phase flash chromatography and subjected to the following conditions (column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 80%, 30 min; detector: UV 254 nm) to afford 2- [2- (4- {3- [ (3-fluoro-2-methoxy) Phenyl) amino group]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-3, 3-Dimethylazetidine-1-carboxylic acid tert-butyl ester (310 mg) as a yellow solid. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford 2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-3, 3-Dimethylazetidine-1-carboxylic acid tert-butyl ester (300 mg, 66.05%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 560.2.

140.2: synthesis of 2- {3- [2- (3, 3-dimethyl azetidin-2-yl) ethynyl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl 2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -3, 3-dimethyl azetidine-1-carboxylate (180 mg,0.32mmol,1.00 eq.) in DCM (4.00 mL) was added TFA (2.00 mL) at 0 ℃. The resulting mixture was stirred at room temperature for 2h and dried with nitrogen to afford 2- {3- [2- (3, 3-dimethylbenzimidazol-2-yl) ethynyl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (160 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 460.2.

140.3: synthesis of 2- (3- {2- [3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With NaHCO ₃ Aqueous solution (1.5 mL) 2- {3- [2- (3, 3-dimethyl)Azazetidin-2-yl) ethynyl]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (160 mg,0.34mmol,1.00 eq.) in THF (1.50 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (37 mg,0.41mmol,1.20 eq.) at 0deg.C under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 1h. At 0 ℃, naHCO is added ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30 x 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 26% b to 56% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number 0) to provide 2- (3- {2- [3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl) ]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (90 mg, 50.33%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 514.20.

140.4: synthesis of rel-2- (3- {2- [ (2R) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- (3- {2- [3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl)]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (90 mg) was isolated by chiral HPLC and the following conditions were employed (column: CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex: dcm=3:1 (0.5% 2m NH) ₃ -MeOH) -HPLC, mobile phase B EtOH-HPLC; the flow rate is 20mL/min; gradient 10% B to 10% B, over 22 min; wavelength is 220/254nm; RT1 (min) 17.99; RT2 (min): 21.96; sample solvent ETOH, dcm=1:1; injection volume 1mL; running 3) to provide rel-2-3- {2- [ (2R) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (31.0 mg, 34.44%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 514.10.

¹ h NMR (300 MHz, chloroform-d) δ10.94 (s, 1H), 8.56 (s, 1H), 8.13 (d, 1H), 7.83 (s, 1H), 7.46 (d, 1H), 6.61-6.45 (m, 2H), 6.40-6.34 (m, 1H), 6.25-6.16 (m, 1H), 6.08 (d, 1H), 5.78-5.74 (m, 1H), 5.21 (s, 1H), 4.86 (s, 1H), 4.10 (s, 3H), 3.97 (s, 2H), 3.59 (d, 2H), 3.24 (t, 2H), 1.54 (s, 3H), 1.45 (s, 3H).

EXAMPLE 141 rel-2- (3- {2- [ (2R) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 249)

2- (3- {2- [3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (90 mg) was isolated by chiral HPLC and using the following conditions (column: CHIRALPAK IG-3,4.6 x 50mm,3um; mobile phase a (Hex: dcm=3:1) (0.1% dea): etoh=90:10; flow rate: 1mL/min; gradient: 0% b to 0% b; injection volume: 5ul mL) to provide rel-2- (3- {2- [ (2R) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6 h-pyrrolo [ 2-yl ] pyridin-4-yl ] as a yellow solid (35 mg).

LC-MS:(M+H) ⁺ Actual: 514.15.

¹ h NMR (300 MHz, chloroform-d) δ10.94 (s, 1H), 8.56 (s, 1H), 8.13 (d, 1H), 7.83 (s, 1H), 7.46 (d, 1H), 6.61-6.45 (m, 2H), 6.40-6.34 (m, 1H), 6.25-6.16 (m, 1H), 6.08 (d, 1H), 5.78-5.74 (m, 1H), 5.23 (s, 1H), 4.86 (s, 1H), 4.10 (s, 3H), 3.97 (s, 2H), 3.59 (d, 2H), 3.24 (t, 2H), 1.54 (s, 3H), 1.45 (s, 3H).

Example 142.3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- (prop-2-enoyl) piperidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 248)

142.1: synthesis of tert-butyl 2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] piperidine-1-carboxylate

To 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (300 mg,0.70mmol,1.00 eq.) in DMF (3.00 mL) was added tert-butyl 2-acetylenyl piperidine-1-carboxylate (436 mg,2.08mmol,3.00 eq.) Pd (dppf) Cl ₂ CH ₂ Cl ₂ (141 mg,0.17mmol,0.25 eq.), cuI (66 mg,0.34mmol,0.50 eq.) and DIEA (449 mg,3.48mmol,5.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was purified by reverse phase flash chromatography and subjected to the following conditions (column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 60%, within 10 min; detector: UV 254 nm) to afford 2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Tert-butyl piperidine-1-carboxylate (220 mg, 56.51%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 560.20.

142.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [2- (piperidin-2-yl) ethynyl ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl 2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] piperidine-1-carboxylate (200 mg,0.36 mmol) in DCM (6.00 mL) was added TFA (2.00 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and dried using nitrogen to provide 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [2- (piperidin-2-yl) ethynyl ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (120 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 460.10.

142.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [1- (prop-2-enoyl) piperidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With NaHCO ₃ Aqueous solution (3.00 mL) of 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- {3- [2- (piperidin-2-yl) ethynyl ] ]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (120 mg,0.26mmol,1.00 eq.) in THF (3.00 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (23 mg,0.26mmol,1.00 eq.) at 0℃under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (20:1) elution to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- {2- [1- (prop-2-enoyl) piperidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (50 mg, 27.96%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 514.40.

142.4: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- (prop-2-enoyl) piperidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

The racemic product (50 mg) was purified by chiral preparative HPLC using the following conditions (column: CHIRAL ART Cellulose-SB, 2X 25cm,5 μm; mobile phase A: mtBE (0.5% 2M NH) ₃ -MeOH) -HPLC, mobile phase B MeOH: dcm=1:1 (0.1% 2m NH3-MeOH); the flow rate is 20mL/min; gradient 10% B to 10% B in 21min; wavelength is 220/254nm; RT1 (min): 15.613; RT2 (min): 17.482; sample solvent EtOH- -HPLC; injection volume 0.3mL; running number 12) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group ]-2- (3- {2- [ (2R) -1- (prop-2-enoyl) piperidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (10.2 mg, 20.32%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 514.10.

¹ h NMR (400 MHz, chloroform-d) δ10.47 (s, 1H), 8.60 (s, 1H), 8.15 (d, 1H), 7.83 (s, 1H), 7.42 (d, 1H), 6.67-6.46 (m, 3H), 6.36-6.27 (m, 1H), 6.09-6.02 (m, 1H), 5.81-5.73 (m, 1H), 5.64 (s, 1H), 5.30 (s, 1H), 4.10 (d, 3H), 3.92 (s, 1H), 3.68-3.56 (m, 2H), 3.36 (s, 1H), 3.19 (s, 2H), 2.08 (s, 1H), 1.91-1.82 (m, 4H), 1.61 (s, 1H).

Example 143:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- (prop-2-enoyl) piperidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 247)

The racemic product (50 mg) was purified by chiral preparative HPLC using the following conditions (column: CHIRAL ART Cellulose-SB, 2X 25cm,5 μm; mobile phase A: mtBE (0.5% 2M NH) ₃ MeOH) -HPLC, mobile phase B MeOH: dcm=1:1 (0.1% 2m NH ₃ MEOH); the flow rate is 20mL/min; gradient 10% b to 10% b over 21 min; wavelength is 220/254nm; RT1 (min): 15.613; RT2 (min): 17.482; sample solvent EtOH- -HPLC; injection volume 0.3mL; running number 12) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group ]-2- (3- {2- [ (2R) -1- (prop-2-enoyl) piper-ridinPyridin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (10.2 mg, 20.32%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 514.15.

¹ h NMR (400 MHz, chloroform-d) delta 10.48 (s, 1H), 8.60 (s, 1H), 8.14 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 6.67-6.55 (m, 2H), 6.55-6.46 (m, 1H), 6.36-6.27 (m, 1H), 6.09-6.02 (m, 1H), 5.81-5.73 (m, 1H), 5.64 (s, 1H), 5.30 (s, 1H), 4.10 (d, 3H), 3.99-3.93 (m, 1H), 3.68-3.54 (m, 2H), 3.42-3.33 (m, 1H), 3.20 (s, 2H), 2.10-2.08 (m, 1H), 1.91-1.83 (m, 4H), 1.62 (s, 1H).

Example 144:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 246)

144.1: synthesis of tert-butyl (2S) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate

To 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (130 mg,0.27mmol,1.00 eq.) and tert-butyl (2S) -2-ethynyl-2-methylpyrrolidine-1-carboxylate (114 mg,0.54mmol,2.00 eq.) in DMF (2.00 mL) was added to CuI (26 mg,0.14mmol,0.50 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (55 mg,0.07mmol,0.25 eq.) and DIEA (88 mg,0.68mmol,2.50 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was purified by reverse phase flash chromatography and subjected to the following conditions (column, C18 silica gel; mobile phase, ACN in water, gradient from 10% to 100%, within 10 min; detector: UV 254 nm) to afford (2S) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester100mg, 62.45%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 560.20.

144.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate (80 mg,0.14 mmol) in DCM (1.00 mL) was added TFA (1.00 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to give 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (80 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 460.45.

144.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one

With NaHCO ₃ (aqueous solution) (1.00 mL) of 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2S) -2-methylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (80 mg,0.17mmol,1.00 eq.) in THF (1.00 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (14 mg,0.18mmol,0.90 eq.) at 0deg.C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (60 mg) which was purified by preparative HPLC (column: xselect CSH F-phenyl OBD column, 30X 250mm,5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 32% B to 62% B, over 7 min; wavelength: 254nm; RT1 (min): 6.5; running number: 0) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2S) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (9.9 mg, 10.63%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 460.45.

¹ h NMR (400 MHz, chloroform-d) δ11.49 (s, 1H), 8.52 (s, 1H), 8.14 (d, 1H), 7.68 (s, 1H), 7.46 (d, 1H), 6.59-6.56 (m, 1H), 6.52-6.44 (m, 2H), 6.39-6.35 (m, 1H), 6.12-6.10 (m, 1H), 5.75-5.72 (m, 1H), 5.24 (s, 1H), 4.10 (s, 3H), 3.80-3.74 (m, 2H), 3.63-3.60 (m, 2H), 3.29-3.22 (m, 2H), 2.19-2.14 (m, 4H), 1.78 (s, 3H).

Example 145:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 245)

145.1: synthesis of tert-butyl (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate

To 3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (150 mg,0.31mmol,1.00 eq.) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ A stirred mixture of (63 mg,0.08mmol,0.25 eq.) in DMF (2.00 mL) was added DIEA (202 mg,1.58mmol,5.00 eq.) and tert-butyl (2R) -2-ethynyl-2-methylpyrrolidine-1-carboxylate (196 mg,0.94mmol,3.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction The desired product was completed and observed. The residue was purified by reverse phase flash chromatography using column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 70%, within 20 min; a detector: UV 254nm. This gives (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 85.46%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 560.1

145.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate (120 mg,0.21 mmol) in DCM (3.00 mL) was added TFA (1.00 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (98 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 460.1

145.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With NaHCO ₃ Aqueous solution (3.00 mL) of 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-piraPyrrolo [3,2-c]A solution of pyridin-4-one (98 mg,0.21mmol,1.00 eq.) in THF (3.00 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (19 mg,0.21mmol,1.00 eq.) at 0℃under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (120 mg) which was purified by preparative HPLC under the following conditions (column: xcel CSH F-phenyl OBD column, 19X 250mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 25mL/min; gradient from 40% b to 60% b, 60% b over 10 min; wavelength is 254/220nm; RT1 (min) 8.32; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group ]-2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (16.5 mg, 13.91%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 514.10

¹ H NMR (300 MHz, chloroform-d) δ11.49 (s, 1H), 8.52 (s, 1H), 8.14 (s, 1H), 7.71 (s, 1H), 7.47 (s, 1H), 6.64-6.52 (m, 1H), 6.51-6.32 (m, 3H), 6.10 (d, J=8.1 Hz, 1H), 5.78-5.70 (m, 1H), 5.19 (s, 1H), 4.10 (s 3H), 3.85-3.68 (m, 2H), 3.64-3.60 (m, 2H), 3.37-3.13 (m, 2H), 2.58-2.43 (m, 1H), 2.23-2.03 (m, 3H), 1.78 (s, 3H).

Example 146: rel-3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (3R) -4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 242)

146.1: synthesis of tert-butyl 3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] morpholine-4-carboxylate

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To 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature]-1H,5H,6H, 7H-pyrroleAnd [3,2-c ]]A stirred solution/mixture of pyridin-4-one (320 mg,0.74mmol,1.00 eq.) and tert-butyl 3-ethynylmorpholine-4-carboxylate (470 mg,2.22mmol,3.00 eq.) in DMF (7.00 mL) was added CuI (71 mg,0.371mmol,0.50 eq.) Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (302 mg,0.37mmol,0.50 eq.) and DIEA (288 mg,2.22mmol,3.00 eq.) at RT. The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 1.5h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was purified by reverse phase flash chromatography using the following conditions (column, silica gel; mobile phase, meCN in water, gradient 10% to 50%, within 10 min; detector: UV 254 nm) to afford 3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Morpholine-4-carboxylic acid tert-butyl ester (230 mg, 55.19%) as a yellow solid.

LC-MS: M+Hactual: 562.3.

146.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [2- (morpholin-3-yl) ethynyl ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl 3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] morpholine-4-carboxylate (200 mg,0.356 mmol) in DCM (4.00 mL) was added TFA (2.00 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [2- (morpholin-3-yl) ethynyl ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (164 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 462.1.

146.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With NaHCO ₃ Aqueous solution (2.00 mL) of 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- {3- [2- (morpholin-3-yl) ethynyl ]]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (164 mg,0.35mmol,1.00 eq.) in THF (3.00 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (51 mg,0.57mmol,1.60 eq.) at 0deg.C under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (60 mg) which was purified by preparative HPLC (column XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 24% b to 54% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- {2- [4- (prop-2-enoyl) morpholin-3-yl) ]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (50 mg, 27.66%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 530.15.

146.4: synthesis of rel-3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (3R) -4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

The crude product (50 mg) was isolated by chiral HPLC and purified using the following conditions (column: CHIRALPAK IG-3,4.6 x 50mm,3 μm; mobile phase A (Hex: DCM=3:1) (0.1% DEA): etOH=80:20; flow rate: 1mL/min; gradient: 0% B to 0% B; injection volume: 5ul mL) to afford rel-3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (3R) -4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (11.4 mg, 21.88%) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 516.10.

¹ h NMR (400 MHz, chloroform-d) δ10.54 (s, 1H), 8.64 (s, 1H), 8.17 (d, 1H), 7.96 (s, 1H), 7.45 (d, 1H), 6.63-6.40 (m, 4H), 6.08 (d, 1H), 5.88 (d, 1H), 5.53 (s, 1H), 5.28 (s, 1H), 4.24 (m, 1H), 4.13 (m, 4H), 3.75-3.60 (m, 6H), 3.15 (s, 2H).

Example 147: rel-3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (3R) -4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 241)

The crude product (50 mg) was isolated by chiral HPLC and purified using the following conditions (column: CHIRALPAK IG-3,4.6 x 50mm,3 μm; mobile phase A (Hex: DCM=3:1) (0.1% DEA): etOH=80:20; flow rate: 1mL/min; gradient: 0% B to 0% B; injection volume: 5ul mL) to afford rel-3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (3R) -4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (13.1 mg, 25.48%) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 516.10.

¹ h NMR (400 MHz, chloroform-d) δ10.78 (s, 1H), 8.59 (s, 1H), 8.51 (s, 1H), 7.98 (d, 1H), 7.40 (d, 1H), 6.67-6.55 (m, 3H), 6.45 (m, 1H), 6.07-6.00 (m, 1H), 5.91 (d, 1H), 5.38 (s, 2H), 4.24 (d, 1H), 4.15 (d, 3H), 4.10-4.07 (m, 1H), 3.87-3.83 (m, 1H), 3.77-3.66 (m 5H), 3.24 (s, 2H).

Example 148: n- [4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] -N-methylpropan-2-enamide (Compound 260)

148.1: synthesis of tert-butyl N-methyl-N- (2-methylbut-3-yn-2-yl) carbamate

To a stirred mixture of tert-butyl N- (2-methylbut-3-yn-2-yl) carbamate (310 mg,1.69mmol,1.00 eq.) in DMF (5.00 mL) was added NaH (81 mg,3.38mmol,2.00 eq.) at 0deg.C. The resulting mixture was stirred at 0℃for 0.5h. Methyl iodide (480 mg,3.38mmol,2.00 eq.) was added dropwise to the above mixture at 0deg.C. The resulting mixture was stirred at 0℃for a further 2h. By adding H at 0 ℃ ₂ O (2 mL) quenched the reaction. The resulting mixture was extracted with EA (3 x10 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (5/1) to provide tert-butyl N-methyl-N- (2-methylbut-3-yn-2-yl) carbamate (187 mg, 53.23%) as a colorless oil.

LC-MS:(M+H-56) ⁺ Actual: 142.1.

148.2: synthesis of tert-butyl N- [4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] -N-methylcarbamate

To 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (100 mg,0.20mmol,1.00 eq.) and tert-butyl N-methyl-N- (2-methylbut-3-yn-2-yl) carbamate (80 mg,0.40mmol,2.00 eq.) in DMF (2.00 mL) was added DIEA (65 mg,0.50mmol,2.50 eq.), cuI (19 mg,0.10mmol,0.50 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (41 mg,0.05mmol,0.25 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, ACN in water, gradient from 10% to 100%, within 10 min; detector: UV 254 n) m) to provide N- [4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl]Tert-butyl N-methylcarbamate (70 mg, 58.32%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 564.10.

148.3: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ 3-methyl-3- (methylamino) but-1-yn-1-yl ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

N- [4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] -N-methylcarbamic acid tert-butyl ester (80 mg,0.14 mmol) and TFA (2.00 mL) were added to an 8mL container at room temperature. The resulting mixture was stirred for 15h and dried using nitrogen to provide 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ 3-methyl-3- (methylamino) but-1-yn-1-yl ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (80 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 464.45

148.4: synthesis of N- [4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] -N-methylpropan-2-enamide

At 0℃to 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- {3- [ 3-methyl-3- (methylamino) but-1-yn-1-yl]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (80 mg,0.17mmol,1.00 eq.) in THF (1.00 mL) was added dropwise to NaHCO ₃ Aqueous (1.00 mL) and acryloyl chloride (14 mg,0.15mmol,0.90 eq.). The resulting mixture was stirred at room temperature for 1h. The crude product was purified by preparative HPLCAnd using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 37% b to 58% b, 58% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide N- [4- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl]-N-methylprop-2-enamide (4.3 mg, 4.66%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 517.19.

¹ H NMR(400MHz,DMSO-d6)δ11.75(s,1H),8.53(s,1H),8.25(d,1H),7.63(s,1H),7.36(d,1H),7.21(s,1H),6.84-6.77(m,1H),6.72(d,2H),6.20-6.13(m,2H),5.74-5.71(m,1H),3.89(s,3H),3.51-3.42(m,2H),3.09(s,3H),3.01-2.91(m,2H),1.72(s,6H)。

example 149: n- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] -N-methylpropan-2-enamide (compound 259)

149.1: synthesis of tert-butyl N- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] -N-methylcarbamate

To 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino group under argon atmosphere]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (250 mg,0.58mmol,1.00 eq.) and tert-butyl N-methyl-N- (2-methylbut-3-yn-2-yl) carbamate (229 mg,1.16mmol,2.00 eq.) in DMF (2.00 mL) was added DIEA (87 mg,1.45mmol,2.50 eq.), cuI (55 mg,0.29mmol,0.50 eq.) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (118 mg,0.15mmol,0.25 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The mixture was purified by reverse phase flash chromatographyAnd the following conditions (column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 10 min; detector: UV 254 nm) were employed to provide N- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl]Tert-butyl N-methylcarbamate (170 mg, 48.20%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 548.25.

149.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ 3-methyl-3- (methylamino) but-1-yn-1-yl ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

TMSOTF (0.50 mL,1.30mmol,5.00 eq.) was added dropwise to a stirred solution of 2, 6-lutidine (685 mg,6.40mmol,25.00 eq.) and N- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbutan-3-yn-2-yl ] -N-methylcarbamic acid tert-butyl ester (140 mg,0.26mmol,1.00 eq.) in DCM (5.00 mL) at 0deg.C. The resulting mixture was stirred at 0℃for 10min and then at 25℃for 60 min. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, ACN in water, gradient 10% to 50%, within 10 min; detector: UV 254 nm) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ 3-methyl-3- (methylamino) but-1-yn-1-yl ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-C ] pyridin-4-one (80 mg, 62.93%) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 448.10.

149.3: synthesis of N- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] -N-methylpropan-2-enamide

At 0℃to 3- [ (3-fluoro-2-methoxyphenyl) amino group ]-2- {3- [ 3-methyl-3- (methylamino) but-1-yn-1-yl]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (70 mg,0.16mmol,1.00 eq.) and DIEA (61 mg,0.47mmol,3.00 eq.) in tetrahydrofuran (1.00 mL) was added dropwise acryloyl chloride (13 mg,0.14mmol,0.90 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product which was purified by preparative HPLC under the following conditions (column: XBridge Prep C18 OBD column, 30 x 100mm,5 μm; mobile phase a: water (10 mmol/L NH ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 32% b to 57% b, 57% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide N- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl]-N-methylprop-2-enamide (14.9 mg, 17.43%) as an off-white solid.

LC-MS:(M+H) ⁺ Actual: 502.10.

¹ H NMR(300MHz,DMSO-d6)δ11.74(s,1H),8.52(s,1H),8.24(d,1H),7.64(s,1H),7.36(d,1H),7.22(s,1H),6.85-6.76(m,1H),6.70-6.65(m,1H)，6.63-6.42(m,1H),6.20-6.15(m,1H),6.14-5.98(m,1H),5.74-5.70(m,1H),3.92(s,3H),3.45-3.41(m,2H),3.09(s,3H),3.09-2.87(m,2H),1.72(s,6H)。

example 150: n- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] prop-2-enamide (compound 258)

150.1: synthesis of tert-butyl N- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] carbamate

To 3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (130 mg,0.27mmol,1.00 eq.) and tert-butyl N- (2-methylbut-3-yn-2-yl) carbamate (99 mg,0.54mmol,2.00 eq.) in DMF (3.00 mL) was added Pd (dppf) Cl ₂ CH ₂ Cl ₂ (110 mg,0.13mmol,0.50 eq.) and CuI (25 mg,0.13mmol,0.50 eq.) and DIEA (210 mg,1.63mmol,6.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100%, 50 min; detector: UV 254 nm) to afford N- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl]Tert-butyl carbamate (120 mg, 82.73%) as an off-white solid.

LC-MS:(M+H) ⁺ Actual: 534.1.

150.2: synthesis of 2- [3- (3-amino-3-methylbut-1-yn-1-yl) pyridin-4-yl ] -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl N- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] carbamate (90 mg,0.16mmol,1.00 eq.) in DCM (1.00 mL) at 0deg.C under nitrogen. The resulting mixture was stirred for 1h and dried using nitrogen to provide 2- [3- (3-amino-3-methylbut-1-yn-1-yl) pyridin-4-yl ] -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (90 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 434.1.

150.3: synthesis of N- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] prop-2-enamide

With NaHCO ₃ (saturation) (1.00 mL) of 2- [3- (3-amino-3-methylbut-1-yn-1-yl) pyridin-4-yl)]-3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (90 mg,0.20mmol,1.00 eq.) in THF (1.00 mL) was basified to pH 8. To the above mixture was added acryloyl chloride (21 mg,0.23mmol,1.15 eq.) at 0deg.C under nitrogen atmosphere, followed by dropwise addition of T ₃ P (169 mg,0.27mmol,2.00 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product which was purified by preparative HPLC under the following conditions (column: XBridge Prep C18 OBD column, 30 x 100mm,5 μm; mobile phase a: water (10 mmol/L NH ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 26% b to 50% b, 50% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide N- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl]Prop-2-enamide (5.0 mg, 4.88%) as an off-white solid.

LC-MS:(M+H) ⁺ Actual: 488.00.

¹ H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.75(s,1H),8.51(s,1H),8.23-8.21(m,1H),7.65(s,1H),7.36(d,1H),7.21(s,1H),6.67-6.66(m,1H),6.55-6.52(m,1H),6.32-6.19(m,2H),5.99(d,1H),5.70-5.67(m,1H),3.92(s,3H),3.44(t,2H),3.02(t,2H),1.64(s,6H)。

example 151: n- {3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] oxetan-3-yl } prop-2-enamide (compound 263)

151.1: synthesis of tert-butyl N- {3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] oxetan-3-yl } carbamate

To 3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (100 mg,0.21mmol,1.00 eq.) and tert-butyl N- (3-ethynyloxetan-3-yl) carbamate (206 mg,1.05mmol,5.00 eq.) in dimethylformamide (2.00 mL) was added to copper (I) iodide (19 mg,0.10mmol,0.50 eq.), DIEA (13 mg,0.10mmol,0.50 eq.) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (42 mg,0.05mmol,0.25 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The residue was purified by reverse phase flash chromatography using column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 70%, within 20 min; a detector: UV 254nm. This gives N- {3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Tert-butyl oxetan-3-yl } carbamate (110 mg, 95.9%) was a yellow solid.

LC-MS:[M+H] ⁺ Actual: 548.25.

151.2: synthesis of 2- {3- [2- (3-amino-oxetan-3-yl) ethynyl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl N- {3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] oxetan-3-yl } carbamate (90 mg,0.16mmol,1.00 eq.) in DCM (2.00 mL) was added TFA (1.00 mL) under argon at room temperature. The resulting mixture was stirred at room temperature for 2h and dried using nitrogen to provide 2- {3- [2- (3-aminooxetan-3-yl) ethynyl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (73 mg, crude) as a red oil.

LC-MS:[M+H] ⁺ Actual: 448.15.

151.3: synthesis of N- {3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] oxetan-3-yl } prop-2-enamide

With NaHCO ₃ (aqueous solution) (2.00 mL) of 2- {3- [2- (3-aminooxetan-3-yl) ethynyl ]]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (73 mg,0.16mmol,1.00 eq.) in THF (2.00 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (16 mg,0.18mmol,1.10 eq.) at 0deg.C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product which was purified by preparative HPLC under the following conditions (column: XBridge Prep C18 OBD column, 30 x 100mm,5 μm; mobile phase a: water (10 mmol/L NH ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 18% b to 38% b, 38% b over 9 min; wavelength is 254/220nm; RT1 (min) 9.28; running number 0) to provide N- {3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Oxetan-3-yl } prop-2-enamide (9.8 mg, 11.8%) as a yellow solidA body.

LC-MS:[M+H] ⁺ Actual: 502.35.

¹ H NMR(400MHz,DMSO-d6)δ11.27(s,1H),9.45(s,1H),8.58(s,1H),8.30(d,1H),7.51(s,1H),7.35(d,1H),7.17(s,1H),6.65-6.60(m,1H),6.48-6.45(m,1H),6.32-6.18(m,2H),5.99-5.97(m,1H),5.76-5.73(m,1H),4.90(d,2H),4.73(d,2H),3.89(s,3H),3.43-3.39(m,2H),3.02-2.92(m,2H)。

example 152:3- { [2- (difluoromethoxy) -3-fluorophenyl ] amino } -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 280)

152.1: synthesis of tert-butyl (2S) -2- ({ [4- (3- { [2- (difluoromethoxy) -3-fluorophenyl ] amino } -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl) pyridin-3-yl ] oxy } methyl) pyrrolidine-1-carboxylate

Under argon atmosphere, to (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) ]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (100 mg,0.19mmol,1.00 eq.) and 2- (difluoromethoxy) -3-fluoroaniline (49 mg,0.28mmol,1.50 eq.) in DMF (5.00 mL) was added EPhos Pd G4 (17 mg,0.02mmol,0.10 eq.) and Cs ₂ CO ₃ (121 mg,0.37mmol,2.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (20:1) to afford (2S) -2- ({ [4- (3- { [2- (difluoromethoxy) -3-fluorophenyl)]Amino } -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl) pyridin-3-yl]Tert-butyl oxy } methyl) pyrrolidine-1-carboxylate (80 mg, 73.30%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 588.1.

152.2: synthesis of 3- { [2- (difluoromethoxy) -3-fluorophenyl ] amino } -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- ({ [4- (3- { [2- (difluoromethoxy) -3-fluorophenyl ] amino } -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl) pyridin-3-yl ] oxy } methyl) pyrrolidine-1-carboxylate (60 mg,0.04mmol in DCM (3.00 mL) was added TFA (1.00 mL) under a nitrogen atmosphere, the resulting mixture was stirred for 1h and concentrated under reduced pressure to provide 3- { [2- (difluoromethoxy) -3-fluorophenyl ] amino } -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (48 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 488.2

152.3: synthesis of 3- { [2- (difluoromethoxy) -3-fluorophenyl ] amino } -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With NaHCO ₃ (2.00 mL) 3- { [2- (difluoromethoxy) -3-fluorophenyl]Amino } -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (48 mg,0.10mmol,1.00 eq.) in THF (1.5 mL) was basified to pH 8. To the above mixture was added dropwise acryloyl chloride (9 mg,0.09mmol,1.00 eq.) at 0℃under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) to afford crude product (40 mg). The crude product (40 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient from 24% b to 48% b, 48% b over 8 min; wavelength is 254/220nm; RT1 (min) 8; running number 0) to provide 3- { [2- (difluoromethoxy) -3-fluorophenyl]Amino } -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (19.7 mg, 36.69%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 542.1.

¹ h NMR (400 MHz, chloroform-d) δ11.58 (s, 1H), 8.24 (s, 1H), 8.00 (d, 1H), 7.59 (d, 1H), 7.31 (s, 1H), 7.01-6.73 (m, 2H), 6.64-6.37 (m, 3H), 6.26-6.19 (m, 1H), 5.85-5.78 (m, 1H), 5.28 (s, 1H), 5.12-5.00 (m, 1H), 4.28 (t, 1H), 4.15-4.08 (m, 1H), 3.78 (t, 2H), 3.71-3.56 (m, 2H), 3.28-3.18 (m, 2H), 2.26-2.10 (m, 3H), 1.93-1.90 (m, 1H).

Example 153:3- [ (3-chloro-2-fluorophenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 279)

153.1: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

Under argon atmosphere, to (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (100 mg,0.19mmol,1.00 eq.) and 3-chloro-2-fluoroaniline (27 mg,0.19mmol,1.00 eq.) in DMF (2.00 mL) was added EPhos Pd G4 (17 mg,0.02mmol,0.10 eq.) and Cs ₂ CO ₃ (182 mg,0.56mmol,3.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (20:1) elution to provide (2S) -2- { [ (4- {3- [ (3-chloro-2-fluorophenyl) amino group]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (73 mg, 70.68%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 556.2.

153.2: synthesis of 3- [ (3-chloro-2-fluorophenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (73 mg,0.13 mmol) in DCM (3.00 mL) at 0℃under nitrogen was added TFA (1.50 mL). The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-chloro-2-fluorophenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (59 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 456.10.

153.3: synthesis of 3- [ (3-chloro-2-fluorophenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

With NaHCO ₃ (aqueous solution) (1.5 mL) 3- [ (3-chloro-2-fluorophenyl) amino group]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (59 mg,0.13mmol,1.00 eq.) in THF (1.50 mL) was basified to pH 8. Acryloyl chloride (12 mg,0.13mmol,1.00 eq.) was added dropwise at 0deg.C. The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL), passed throughAnhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (70 mg) which was purified by preparative HPLC under the following conditions (column: XBRID Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/LNH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 25% b to 43% b, 43% b over 9 min; wavelength is 254/220nm; RT1 (min) 9.67; running number 0) to provide 3- [ (3-chloro-2-fluorophenyl) amino group]-2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-one (14.2 mg, 20.98%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 510.10.

¹ h NMR (400 MHz, chloroform-d): δ11.63 (s, 1H), 8.21 (s, 1H), 7.93 (d, 1H), 7.52-7.47 (m, 2H), 6.78 (t, 1H), 6.65-6.54 (m, 2H), 6.42-6.37 (m, 1H), 6.28-6.24 (m, 1H), 5.81-5.78 (m, 1H), 5.32 (s, 1H), 5.09-5.04 (m, 1H), 4.27 (t, 1H), 4.12-4.09 (m, 1H), 3.78-3.74 (m, 2H), 3.64-3.61 (m, 2H), 3.25-3.21 (m, 2H), 2.17-2.13 (m, 3H), 1.95-1.83 (m, 1H).

Example 154:3- [ (2-chloro-3-fluorophenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 278)

154.1: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (2-chloro-3-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

To (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl methyl } pyrrolidine-1-carboxylate (150 mg,0.27mmol,1.00 eq.) and 2-chloro-3-fluoroaniline (40 mg,0.27mmol,1.00 eq.) in DMF (1.50 mL) was added EPhos Pd G4 (51 mg,0.056mmol,0.20 eq.) and Cs ₂ CO ₃ (181 mg,0.55mmol,2.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed completion of the reaction and was observed The desired product. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2S) -2- { [ (4- {3- [ (2-chloro-3-fluorophenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (75 mg, 48.41%) was a yellow oil.

LC-MS:(M+H) ⁺ Actual: 556.10.

154.2: synthesis of 3- [ (2-chloro-3-fluorophenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2S) -2- { [ (4- {3- [ (2-chloro-3-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (55 mg,0.10 mmol) in DCM (3.00 mL) was added TFA (1.50 mL) at 0deg.C. The resulting mixture was stirred for 2h and concentrated under reduced pressure to afford 3- [ (2-chloro-3-fluorophenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (45 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 456.00.

154.3:3- [ (2-chloro-3-fluorophenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one

At 0℃to 3- [ (2-chloro-3-fluorophenyl) amino group]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (45 mg,0.10mmol,1.00 eq.) and NaHCO ₃ (saturated) (1.00 mL) A stirred solution of propylene in THF (1.00 mL) was added dropwiseAcid chloride (10 mg,0.11mmol,1.20 eq.). The resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (1×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 20% B to 45% B, 45% B over 9 min; wavelength is 254/220nm; RT1 (min) 9.67; running number 0) to provide 3- [ (2-chloro-3-fluorophenyl) amino group]-2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (9.1 mg, 17.90%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 510.10.

¹ h NMR (300 MHz, chloroform-d) δ11.60 (s, 1H), 8.22 (s, 1H), 7.94 (d, 1H), 7.71 (s, 1H), 7.42 (d, 1H), 6.82-6.75 (m, 1H), 6.60-6.51 (m, 2H), 6.43-6.36 (m, 1H), 6.21-6.17 (m, 1H), 5.81-5.77 (m, 1H), 5.26 (s, 1H), 5.04 (t, 1H), 4.26 (t, 1H), 4.13-4.09 (m, 1H), 3.76-3.74 (m, 2H), 3.63-3.60 (m, 2H), 3.25-3.20 (m, 2H), 2.19-2.12 (m, 3H), 2.09-1.87 (m, 1H).

Example 155:3- [ (3-chloro-2-methylphenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 276)

155.1: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-methylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

Under argon atmosphere, to (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (100 mg,0.18mmol,1.00 eq.) and 2-methyl-3-chloroaniline (26 mg,0.18mmol,1.00 eq.) in DMF (2.00 mL) was added Cs ₂ CO ₃ (182mg,0.55mmol,3.00 eq.) and Ephos Pd G4 (17 mg,0.02mmol,0.10 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (10:1) elution to provide (2S) -2- { [ (4- {3- [ (3-chloro-2-methylphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (75 mg, 73.14%) was a yellow solid.

LC-MS:[M+H] ⁺ Actual: 552.07.

155.2: synthesis of 3- [ (3-chloro-2-methylphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-methylphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (20 mg,0.04 mmol) in DCM (2.00 mL) was added TFA (1.00 mL) at room temperature under nitrogen. The resulting mixture was stirred for 3h and concentrated under reduced pressure to afford 3- [ (3-chloro-2-methylphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (49 mg, crude) as a red oil.

LC-MS:[M+H] ⁺ Actual: 452.2.

155.3: synthesis of 3- [ (3-chloro-2-methylphenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methylphenyl) at 0deg.C under air atmosphere) Amino group]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-one (49 mg,0.11mmol,1.00 eq.) in tetrahydrofuran (2.00 mL) and NaHCO ₃ An stirred solution of acryloyl chloride (10 mg,0.12mmol,1.10 eq.) in aqueous solution (2.00 mL) was added dropwise. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was extracted with DCM (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 33% b to 55% b, 55% b over 8 min; wavelength is 254/220nm; RT1 (min) 6.32; running number 0) to provide 3- [ (3-chloro-2-methylphenyl) amino group]-2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (12.8 mg, 22.31%) was a yellow solid.

LC-MS:[M+H] ⁺ Actual: 506.10.

¹ h NMR (400 MHz, chloroform-d) δ11.46 (s, 1H), 8.18 (s, 1H), 7.93 (d, 1H), 7.39 (s, 1H), 7.31 (d, 1H), 6.81-6.79 (m, 1H), 6.70 (t, 1H), 6.58-6.51 (m, 1H), 6.42-6.37 (m, 1H), 6.31-6.29 (d, 1H), 5.79-5.76 (m, 1H), 5.22 (s, 1H), 5.04 (t, 1H), 4.25 (t, 1H), 4.11-4.08 (m, 1H), 3.75 (t, 2H), 3.62-3.58 (m, 2H), 3.23-3.19 (m, 2H), 2.51 (s, 3H), 2.17-2.12 (m, 3H), 1.17-1.12 (m, 1H).

Example 156:2- (3- {2- [ (2R) -1- (but-2-ynyl) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 291)

156.1: synthesis of tert-butyl (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate

To 2- (3-bromopyridin-4-yl) -3- [ (3-fluoro) at room temperature under argon atmosphere-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (300 mg,0.69mmol,1.00 eq.) and tert-butyl (2R) -2-ethynyl-2-methylpyrrolidine-1-carboxylate (509 mg,2.43mmol,3.50 eq.) in DMF (5.00 mL) was added Pd (dppf) Cl ₂ DCM (142 mg,0.17mmol,0.25 eq.) and CuI (66 mg,0.35mmol,0.50 eq.). The resulting mixture was stirred overnight at 50℃under argon. The residue was purified by reverse phase flash chromatography using the following conditions (column, silica gel; mobile phase, meCN in water, gradient from 10% to 80%, within 10 min; detector: UV 254 nm) to afford (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (270 mg, crude). The residue was purified by silica gel column chromatography eluting with DCM/MeOH (10:1) to provide (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 64.22%) as a yellow solid.

LC-MS:[M+H] ⁺ Actual: 560.20.

156.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2R) -2- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylpyrrolidine-1-carboxylate (80 mg,0.14mmol,1.00 eq) in DCM (1.50 mL) was added TFA (0.50 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (80 mg, crude) as a red oil.

LC-MS:[M+H] ⁺ Actual: 460.10.

156.3: synthesis of 2- (3- {2- [ (2R) -1- (but-2-ynyl) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (3-fluoro-2-methoxyphenyl) amino group was cleaved with DIEA]-2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (65 mg,0.14mmol,1.00 eq.) in THF (1.00 mL) was basified to pH 8. 2-butynoic acid (18 mg,0.21mmol,1.50 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (90 mg,0.28mmol,2.00 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (80 mg) which was purified by preparative HPLC (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 21% B to 47% B,8min, 47% B; wavelength: 254/220nm; RT1 (min): 8; running number: 0) to provide 2- (3- {2- [ (2R) -1- (but-2-ynyl) -2-methylpyrrolidin-2-yl) ]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (27.8 mg, 37.06%) was a yellow solid.

LC-MS:[M+H] ⁺ Actual: 526.10.

¹ h NMR (400 MHz, chloroform-d) δ11.48 (s, 1H), 8.70 (s, 1H), 8.15 (s, 1H), 7.97 (d, j=6.4 hz, 1H), 7.49 (d, j=6.4 hz, 1H), 6.66-6.57 (m, 2H), 6.24 (s, 1H), 6.02 (d, j=7.2 hz, 1H), 4.10 (d, j=1.6 hz, 3H), 3.94-3.79 (m, 2H), 3.66 (t, j=6.4 hz, 2H), 3.43-3.35 (m, 1H), 3.22-3.15 (m, 1H), 2.58-2.52 (m, 1H), 2.24-2.07 (m, 3H), 2.04 (s, 3H), 1.74 (s, 3H).

Example 157:2- (3- { [ (2S) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 290)

157.1: synthesis of tert-butyl (2S) -2- { [ (4-bromopyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

To a stirred solution of 4-bromopyridin-3-ol (1.5 g, 8.6271 mmol,1 eq.) in THF (50 mL) at 0deg.C were added PPh3 (3.39 g,12.93mmol,1.50 eq.) and tert-butyl (2S) -2- (hydroxymethyl) azetidine-1-carboxylate (1.78 g,9.48mmol,1.10 eq.) and the mixture was stirred at 0deg.C under nitrogen for 10min. DEAD (2.25 g,12.93mmol,1.50 eq.) was added dropwise at 0deg.C. The mixture was stirred at 0℃under nitrogen for 1.5h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, meCN in water, 10% to 60% gradient, 20 min; detector: UV 254 nm) to afford tert-butyl (2S) -2- { [ (4-bromopyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (2.57 g, 86.86%) as a yellow oil.

LC-MS:(M+H) ⁺ Actual: 344.95.

157.2: synthesis of tert-butyl (2S) -2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

To (2S) -2- { [ (4-bromopyridin-3-yl) oxy at room temperature]A stirred solution of tert-butyl methyl } azetidine-1-carboxylate (500 mg,1.46mmol,1.00 eq.) in 1, 4-dioxane (10.00 mL) was added XPhos Pd G2 (115 mg,0.15mmol,0.10 eq.), 2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]]Pyridin-4-one (458 mg,1.74mmol,1.20 eq.) and Na ₂ CO ₃ (460 mg,4.37mmol,3.00 eq.) in H ₂ In O (2.00 mL)The solution was stirred. The mixture was stirred at 50℃under argon for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, meCN in water, 10% to 60% gradient, 15 min; detector: UV 254 nm) to afford (2S) -2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-C)]Pyridin-2-yl } pyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (0.56 g, 96.22%) as a tan solid.

LC-MS:(M+H) ⁺ Actual: 399.05.

157.3: synthesis of tert-butyl (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

At 0deg.C, to (2S) -2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl methyl } azetidine-1-carboxylate (560 mg,1.41mmol,1.00 eq.) in DMF (7.00 mL) was added dropwise to NIS (316 mg,1.41mmol,1.00 eq.). The mixture was stirred at room temperature under nitrogen for 1h. At 0deg.C with 1mL saturated Na ₂ SO ₃ The reaction was quenched with aqueous solution. The residue was purified by reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, meCN in water, 10% to 60% gradient, 15 min; detector: UV 254 nm) to afford (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-C)]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } azetidine-1-carboxylic acid tert-butyl ester (550 mg, 74.52%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 524.95.

157.4: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

At room temperature, to (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl methyl } azetidine-1-carboxylate (500 mg,0.954mmol,1.00 eq.) in DMF (5.00 mL) was added EPhos Pd G4 (87.59 mg,0.095mmol,0.10 eq.) Cs ₂ CO ₃ (932 mg,2.86mmol,3.00 eq.) and 3-fluoro-2-methoxyaniline (403 mg,2.86mmol,3.00 eq.). The mixture was stirred at 50℃under argon for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (96:4) elution to afford (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (500 mg, 97.66%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 538.30.

157.5: synthesis of 2- {3- [ (2S) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (180 mg,0.33 mmol) in DCM (4.00 mL) at 0deg.C under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- {3- [ (2S) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (260 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 438.05.

157.6: synthesis of 2- (3- { [ (2S) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- {3- [ (2S) -azetidin-2-ylmethoxy ] with DIEA]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (260 mg,0.59mmol,1.00 eq.) in THF (5.00 mL) was basified to pH 8. 2-butynoic acid (75 mg,0.89mmol,1.50 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (756 mg,1.19mmol,2.00 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (280 mg) which was purified by preparative HPLC under the following conditions (column: XBRID Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 20% B to 45% B, 45% B over 10 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 2- (3- { [ (2S) -1- (but-2-ynyl) azetidin-2-yl ]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (28.0 mg, 9.34%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 504.10.

¹ H NMR(400MHz,CDCl ₃ ):δ11.46(s,1H),8.24(s,1H),7.96(d,1H),7.70(s,1H),7.49(d,1H),6.59-6.51(m,1H),6.49-6.46(m,1H),6.04(d,1H),5.20(s,1H),4.98-4.88(m,1H),4.50(t,1H),4.28-4.24(m,3H),4.10(s,3H),3.60-3.56(m,2H),3.21-3.17(m,1H),3.09-3.05(m,1H),2.69-2.57(m,1H),2.14-2.12(m,1H),2.04(s,3H)。

example 158:2- (3- { [ (2S) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 288)

158.1: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

Under argon atmosphere, to (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } azetidine-1-carboxylate (300 mg,0.57mmol,1.00 eq.) and 3-chloro-2-methoxyaniline (90 mg,0.57mmol,1.00 eq.) in DMF (5.00 mL) was added EPhos Pd G4 (52 mg,0.05mmol,0.10 eq.) and Cs ₂ CO ₃ (372 mg,1.14mmol,2.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (300 mg, 75.71%) as an off-white solid.

LC-MS:(M+H) ⁺ Actual: 554.1.

158.2: synthesis of 2- {3- [ (2S) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under nitrogen atmosphere]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } azetidine-1-carboxylate (260 mg,0.46 mmol) in DCM (2.00 mL) was added TFA (2.00 mL). The resulting mixture was stirred for 1h and concentrated under reduced pressure. Residual product pass throughPurification by reverse phase flash chromatography and purification using the following conditions (mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient from 30% b to 100% b for 45 min; ) To provide 2- {3- [ (2S) -azetidin-2-ylmethoxy]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (110 mg, 51.64%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 454.15.

158.3: synthesis of 2- (3- { [ (2S) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- {3- [ (2S) -azetidin-2-ylmethoxy at 0℃under nitrogen atmosphere]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (50 mg,0.11mmol,1.00 eq.) in THF (0.50 mL) was added DIEA (0.50 mL). The resulting mixture was stirred at room temperature under nitrogen for 10min. 2-butynoic acid (13 mg,0.16mmol,1.50 eq.) and T were added to the above mixture at 0deg.C ₃ P (140 mg,0.22mmol,2.00 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (70 mg) which was purified by preparative HPLC and was purified using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 32% b to 62% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number 0) to provide 2- (3- { [ (2S) -1- (but-2-ynyl) azetidin-2-yl ]Methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (28.9 mg, 50.36%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 520.05.

¹ h NMR (300 MHz, chloroform-d) δ11.44 (s, 1H), 8.28 (s, 1H), 7.96 (d, j=3.00 hz, 1H), 7.64 (s, 1H), 7.43 (d, j=3.00 hz, 1H), 6.73-6.70 (m, 1H), 6.60 (t, j=6.00 hz, 1H), 6.19-6.16 (m, 1H), 5.33 (s, 1H), 4.94 (d, j=6.00 hz, 1H), 4.50 (t, j=9 hz, 1H), 4.29-4.22 (m, 3H), 4.07 (s, 3H), 3.60-3.55 (m, 2H), 3.21-3.03 (m, 2H), 2.65-2.54 (m, 1H), 2.16-2.11 (m, 1H), 2.03 (s, 3H).

Example 159:2- (3- { [ (2R) -1- (but-2-ynyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one 2, 2-trifluoroacetate (compound 286)

159.1: synthesis of tert-butyl (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

Under argon atmosphere, to (2R) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (200 mg,0.37mmol,1.00 eq.) and 3-fluoro-2-methoxyaniline (105 mg,0.74mmol,2.00 eq.) in DMF (5.00 mL) was added Ephos Pd G4 (34 mg,0.04mmol,0.10 eq.) and Cs ₂ CO ₃ (242 mg,0.74mmol,2.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (20:1) elution to afford (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 97.60%) was a yellow solid.

LC-MS:[M+H] ⁺ Actual: 552.30.

159.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (200 mg,0.036 mmol) in DCM (1.00 mL) was added TFA (0.50 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (120 mg, crude) as a red oil.

LC-MS:[M+H] ⁺ Actual: 452.05.

159.3: synthesis of 2- (3- { [ (2R) -1- (but-2-ynyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one 2, 2-trifluoroacetate

3- [ (3-fluoro-2-methoxyphenyl) amino group was cleaved with DIEA]-2- {3- [ (2R) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (77 mg,0.17mmol,1.00 eq.) in THF (2.00 mL) was basified to pH 8. 2-butynoic acid (22 mg,0.26mmol,1.50 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (108 mg,0.34mmol,2.00 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (100 mg) which was purified by preparative HPLC under the following conditions (column:xselect CSH C18 OBD column 30 x 150mm 5 μm, n; mobile phase A water (0.05% TFA), mobile phase B ACN; the flow rate is 60mL/min; gradient from 16% b to 36% b, 36% b over 8 min; wavelength is 254/220nm; RT1 (min) 8; running number 0) to provide 2- (3- { [ (2R) -1- (but-2-ynyl) pyrrolidin-2-yl ]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one 2, 2-trifluoroacetate salt (45.6 mg, 51.61%) as a yellow solid.

LC-MS:[M+H] ⁺ Actual: 518.45.

¹ h NMR (400 MHz, chloroform-d) δ11.71 (s, 1H), 8.56 (s, 1H), 7.96 (s, 1H), 7.85 (d, 1H), 7.58 (d, j=6.4 hz, 1H), 6.64-6.56 (m, 2H), 6.36 (s, 1H), 5.97-5.95 (m, 1H), 4.92 (t, 1H), 4.27 (t, j=10 hz, 1H), 4.16-4.14 (m, 1H), 4.11 (d, 3H), 4.05-3.99 (m, 1H), 3.72-3.63 (m, 3H), 3.33-3.17 (m, 2H), 2.25-2.22 (m, 2H), 2.12-2.08 (m, 1H), 2.05 (s, 3H), 1.91-1.88 (m, 1H).

Example 160:2- (3- { [ (2S) -1- (but-2-ynyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 285)

160.1: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

(2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) was reacted at room temperature under argon atmosphere]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl methyl } pyrrolidine-1-carboxylate (150 mg,0.28mmol,1.00 eq.) and 3-chloro-2-methoxyaniline (40 mg,0.25mmol,0.90 eq.) in DMF (2.00 mL) was added dropwise to Cs ₂ CO ₃ (182 mg,0.56mmol,2.00 eq.) and Ephos Pd G4 (26 mg,0.03mmol,0.10 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel,elution with MeOH/DCM (97:3) provided (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (107 mg, 64.23%) was as a yellow-green solid.

LC-MS:(M+H) ⁺ Actual: 567.90.

160.2: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (100 mg,0.18mmol,1.00 eq.) in DCM (1.00 mL) was added TFA (0.50 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (100 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 468.10.

160.3: synthesis of 2- (3- { [ (2S) -1- (but-2-ynyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (3-chloro-2-methoxyphenyl) amino group was cleaved with DIEA]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (100 mg,0.21mmol,1.00 eq.) in THF (1.5 mL) was basified to pH 8. 2-butynoic acid (27 mg,0.32mmol,1.50 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (136 mg,0.43mmol,2.00 eq., 50%)In EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (3.00 mL) was added to the reaction mixture and extracted with EtOAc (3X 5.00 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (100 mg) which was purified by preparative HPLC and was subjected to the following conditions (column: XSelect CSH fluorophenyl, 30X 150mm,5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 14% B to 44% B over 7 min; wavelength: 254nm; RT1 (min): 6.5; running number: 0) to provide 2- (3- { [ (2S) -1- (but-2-ynyl) pyrrolidin-2-yl) ]Methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (44 mg, 38.48%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 534.10.

¹ h NMR (400 MHz, chloroform-d) δ11.66 (s, 1H), 8.55 (s, 1H), 8.06 (s, 1H), 7.84 (d, 1H), 7.52 (d, 1H), 6.85-6.82 (m, 1H), 6.67 (t, 1H), 6.12-6.10 (m, 1H), 5.78 (s, 1H), 4.93 (t, 1H), 4.29-4.24 (m, 1H), 4.17-4.15 (m, 1H), 4.08-3.99 (m, 4H), 3.72-3.63 (m, 3H), 3.34-3.26 (m, 1H), 3.23-3.15 (m, 1H), 2.28-2.23 (m, 1H), 2.14-2.01 (m, 5H), 1.88 (s, 1H).

Example 161:2- (3- { [ (2S) -1- (but-2-ynyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (2-ethyl-3-fluorophenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 284)

161.1: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (2-ethyl-3-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

Under argon atmosphere, to (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (150 mg,0.28mmol,1.00 eq.) and 2-ethyl-3-fluoroaniline (116 mg,0.84mmol,3.00 eq.) in DMF (1.00 mL) was added EPhos Pd G4 (26 mg,0.03mmol, 0.10 equivalent) and Cs ₂ CO ₃ (182 mg,0.56mmol,2.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (15:1) elution to afford (2S) -2- { [ (4- {3- [ (2-ethyl-3-fluorophenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 97.95%) was a yellow solid.

LC-MS:[M+H] ⁺ Actual: 550.00.

161.2: synthesis of 3- [ (2-ethyl-3-fluorophenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (100 mg,0.18mmol,1.00 eq.) in DCM (1.00 mL) was added TFA (0.50 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (2-ethyl-3-fluorophenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (100 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 450.20.

161.3: synthesis of 2- (3- { [ (2S) -1- (but-2-ynyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (2-ethyl-3-fluorophenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

DIEA 3- [(2-ethyl-3-fluorophenyl) amino group]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (100 mg,0.22mmol,1.00 eq.) in THF (3.00 mL) was basified to pH 8. 2-butynoic acid (28 mg,0.33mmol,1.50 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (142 mg,0.44mmol,2.00 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (60 mg) which was purified by preparative HPLC (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 19% B to 43% B,8min, 43% B; wavelength: 254/220nm; RT1 (min): 8; running number: 0) to provide 2- (3- { [ (2S) -1- (but-2-ynyl) pyrrolidin-2-yl) ]Methoxy } pyridin-4-yl) -3- [ (2-ethyl-3-fluorophenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (51.2 mg, 44.51%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 516.50.

¹ h NMR (400 MHz, chloroform-d) δ11.64 (s, 1H), 8.48 (s, 1H), 7.90 (s, 1H), 7.74 (d, 1H), 7.28 (d, 1H), 6.72-6.62 (m, 1H), 6.60 (t, 1H), 6.19 (d, 1H), 6.07 (s, 1H), 4.92 (t, 1H), 4.25 (t, 1H), 4.13 (d, 1H), 4.12-4.01 (m, 1H), 3.70-3.65 (m, 3H), 3.33-3.19 (m, 2H), 2.88-2.80 (m, 2H), 2.35-2.18 (m, 1H), 2.18-2.08 (m, 5H), 1.94-1.82 (m, 1H), 1.35 (t, 3H).

Example 162:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 281)

162.1: synthesis of tert-butyl (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

Under argon atmosphere, to (2R) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (560 mg,1.04mmol,1.00 eq.) and 3-fluoro-2-methoxyaniline (293 mg,2.08mmol,2.00 eq.) in DMF (10.00 mL) was added Ephos Pd G4 (95 mg,0.10mmol,0.10 eq.) and Cs ₂ CO ₃ (677 mg,2.08mmol,2.00 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (550 mg, 95.86%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 552.30.

162.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (155 mg,0.28mmol,1.00 eq.) in DCM (4.00 mL) was added TFA (2.00 mL) at room temperature under nitrogen. The resulting mixture was stirred for 2h and dried using nitrogen to provide 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2R) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (100 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 452.20.

162.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0℃to 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- {3- [ (2R) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100 mg,0.22mmol,1.00 eq.) and NaHCO ₃ An stirred solution of aqueous solution (2.00 mL) in THF was added dropwise acryloyl chloride (24 mg,0.26mmol,1.20 eq.). The resulting mixture was stirred at room temperature for 1.5h. The resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (1×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (130 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 20% b to 43% b, 43% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- { [ (2R) -1- (prop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-one (22.8 mg, 20.36%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 506.10.

¹ h NMR (300 MHz, chloroform-d) δ11.62 (s, 1H), 8.20 (s, 1H), 7.93 (d, 1H), 7.76 (s, 1H), 7.53 (d, 1H), 6.61-6.47 (m, 3H), 6.42-6.36 (m, 1H), 6.04 (d, 1H), 5.81-5.77 (m, 1H), 5.21 (s, 1H), 5.08-5.05 (m, 1H), 4.26 (t, 1H), 4.13-4.09 (m, 4H), 3.76 (t, 2H), 3.64-3.60 (m, 2H), 3.23 (t, 2H), 2.17-2.11 (m, 3H), 1.89-1.86 (m, 1H).

Example 163:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 296)

163.1: synthesis of 2- {3- [ (2S) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (120 mg,0.18 mmol) in DCM (4.00 mL) at 0deg.C under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- {3- [ (2S) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (97 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 438.05.

163.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- {3- [ (2S) -azetidin-2-ylmethoxy ] with DIEA]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (97 mg,0.223mmol,1 eq.) in THF (2.00 mL) was basified to pH 8. 2-Fluoroprop-2-enoic acid (30 mg,0.335mmol,1.5 eq.) was added to the above mixture at 0deg.C under nitrogen atmosphere followed by dropwise addition of T ₃ P (284 mg,0.89mmol,4.00 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30 x 150mm,5 μm;mobile phase A water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 32% b to 62% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group ]-2- (3- { [ (2S) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (37.6 mg, 32.85%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 510.10.

¹ h NMR (300 MHz, chloroform-d) δ11.53 (s, 1H), 8.26 (s, 1H), 7.98 (d, 1H), 7.67 (s, 1H), 7.51 (d, 1H), 6.75-6.35 (m, 2H), 6.11-6.02 (m, 1H), 5.71-5.55 (m, 1H), 5.23-5.08 (m, 3H), 4.61-4.42 (m, 3H), 4.31-4.28 (m, 1H), 4.11 (s, 3H), 3.60 (t, 2H), 3.11 (t, 2H), 2.78-2.60 (m, 1H), 2.30-2.10 (m, 1H).

Example 164:2- (3- { [ (2S) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one 2, 2-trifluoroacetate (compound 295)

164.1: synthesis of 2- {3- [ (2S) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (80 mg,0.15mmol,1.00 eq.) in DCM (2.00 mL) was added TFA (1.00 mL) at 0deg.C. The mixture was stirred at room temperature under nitrogen for 1h. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was concentrated under nitrogen to afford 2- {3- [ (2S) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (80 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 438.05.

164.2: synthesis of 2- (3- { [ (2S) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one 2, 2-trifluoroacetate

2- {3- [ (2S) -azetidin-2-ylmethoxy ] with DIEA]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (80 mg,0.18mmol,1.00 eq.) in THF (2.00 mL) was basified to pH 8. (2E) -4- (dimethylamino) but-2-enoic acid (47 mg,0.37mmol,2.00 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (233 mg,0.37mmol,2.00 eq., 50% in EA). The resulting mixture was stirred overnight at room temperature under nitrogen. At 0 ℃, naHCO is added ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (80 mg) which was purified by preparative HPLC (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.1% TFA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 8% B to 28% B,8min, 28% B; wavelength: 254/220nm; RT1 (min): 8; running number: 0) to afford 2- (3- { [ (2S) -1- [ (2E) -4- (dimethylamino) but-2-enoyl) ]Azetidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one 2, 2-trifluoroacetate salt (42.1 mg, 34.71%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 549.5.

¹ H NMR(300MHz,DMSO-d6):δ12.08(s,1H),9.97(s,1H),8.50(s,1H),8.19(d,1H),7.96(s,1H),7.52(d,1H),7.39(s,1H),6.75-6.70(m,3H),6.46(d,1H),6.02(d,1H),4.94 -4.92(m,1H),4.61(t,1H),4.47(d,1H),4.20(t,2H),4.04(s,3H),3.90(d,2H),3.45(t,2H),3.05(t,2H),2.64(s,6H),2.51-2.49(m,1H),2.14-2.07(m,1H)。

example 165:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- (2-fluoroprop-2-enoyl) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 306)

165.1: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (80 mg,0.17mmol,1.00 eq.) in DCM (1.00 mL) at 0 ℃ was added TFA (0.30 mL). The resulting mixture was stirred for 1h and dried using nitrogen to provide 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (80 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 460.20

165.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- (2-fluoroprop-2-enoyl) -2-methylpyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (3-fluoro-2-methoxyphenyl) amino group was cleaved with DIEA]-2- (3- {2- [ (2R) -2-methylpyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (80 mg,0.17mmol,1.00 eq.) in THF (1.00 mL) was basified to pH 8. 2-Fluoroprop-2-enoic acid (23 mg,0.26mmol,1.50 eq.) was added to the above mixture at 0deg.C under nitrogen atmosphere followed by dropwise addition of T ₃ P (111 mg,0.35mmol,2.00 eq., 50% in EA). Stirring the resulting mixture 1 at room temperature under nitrogen atmosphereh. NaHCO at 0deg.C ₃ Saturated aqueous solution (5 mL) was added to the reaction mixture and extracted with EtOAc (3X 5 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC and using the following conditions (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 26% B to 44% B,8min, 44% B; wavelength: 254/220nm; RT1 (min): 8; running number: 0) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino group ]-2- (3- {2- [ (2R) -1- (2-fluoroprop-2-enoyl) -2-methylpyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (24.5 mg, 26.45%) was an orange solid.

LC-MS:(M+H) ⁺ Actual: 534.10

¹ H NMR (300 MHz, chloroform-d) δ11.53 (s, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 7.99 (d, 1H), 7.48 (d, 1H), 6.70-6.59 (m, 2H), 6.07 (d, 1H), 5.60-5.57 (m, 1H), 5.43-5.22 (m, 2H), 4.14 (s, 3H), 3.92-3.83 (m, 2H), 3.82-3.66 (m, 2H), 3.39-3.20 (m, 2H), 2.56-2.52 (m, 1H), 2.18-2.14 (m, 3H), 1.83 (s, 3H).

Example 166: n- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl ] but-2-ynamide (compound 302)

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2- [3- (3-amino-3-methylbut-1-yn-1-yl) pyridin-4-yl ] was added in an 8mL vial at room temperature]-3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (75 mg,0.17mmol,1.00 eq.) and THF (2.50 mL). DIEA (90 mg,0.69mmol,4.00 eq.) and but-2-ynyl chloride (18 mg,0.17mmol,1.00 eq.) were added to the mixture at 0deg.C. The resulting mixture was stirred at room temperature for 1h. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (10:1, 4X20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After the filtration, the water is filtered,the filtrate was concentrated under reduced pressure. The crude product (102 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 28% B to 48% B, 48% B over 10 min; wavelength is 254/220nm; RT1 (min) 9.67; running number 0) to provide N- [4- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) -2-methylbut-3-yn-2-yl]But-2-ynamide (20.8 mg, 24.02%) as a reddish brown solid.

LC-MS:(M+H) ⁺ Actual: 500.10

¹ H NMR (400 MHz, chloroform-d) δ11.08 (s, 1H), 8.54 (s, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.43 (s, 1H), 6.62-6.47 (m, 2H), 6.14-6.06 (m, 2H), 5.23 (s, 1H), 4.10 (s, 3H), 3.63-3.59 (m, 2H), 3.20 (t, 2H), 1.98 (s, 3H), 1.73 (s, 6H).

Example 167:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (1R) -1- [ (2R) -1- (prop-2-enoyl) azetidin-2-yl ] ethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 311)

To 2- {3- [ (1R) -1- [ (2R) -azetidin-2-yl at-40℃under nitrogen ]Ethoxy group]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (40 mg,0.08mmol,1.00 eq.) in DCM (1.00 mL) was added DIEA (57 mg,0.44mmol,5.00 eq.) and acrylic anhydride (16 mg,0.13mmol,1.50 eq.). The resulting mixture was stirred at-40℃under nitrogen for 1h. NaHCO is added at-40 DEG C ₃ The reaction was quenched with aqueous solution (1 mL). The resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase BACN; the flow rate is 60mL/min; gradient 27% b to 43% b, 43% b over 9 min; wavelength is 254/220nm; RT1 (min) 9; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- {3- [ (1R) -1- [ (2R) -1- (prop-2-enoyl) azetidin-2-yl]Ethoxy group]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (11 mg, 24.44%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 506.1.

¹ h NMR (400 MHz, chloroform-d) δ11.85 (s, 1H), 8.25 (s, 1H), 7.91 (s, 1H), 7.63 (s, 1H), 7.46 (s, 1H), 6.59-6.53 (m, 1H), 6.46 (t, 1H), 6.39-6.35 (m, 1H), 6.27-6.20 (m, 1H), 6.04 (d, 1H), 5.76 (d, 1H), 5.18 (s, 1H), 4.96-4.94 (m, 1H), 4.75-4.69 (m, 1H), 4.36-4.32 (m, 1H), 4.22-4.16 (m, 1H), 4.09 (s, 3H), 3.62-3.60 (m, 2H), 3.18-3.06 (m, 2H), 2.71-2.67 (m, 1H), 2.96 (m, 1H), 1.35 (s, 1H).

Example 168:2- {3- [ (1R) -1- [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] ethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 312)

168.1: synthesis of tert-butyl 2- [ (1R) -1- [ (4-bromopyridin-3-yl) oxy ] ethyl ] azetidine-1-carboxylate

To (2S) -2- [ (1S) -1-hydroxyethyl at 0℃under nitrogen atmosphere]A stirred mixture of tert-butyl azetidine-1-carboxylate (730 mg,3.62mmol,1.00 eq.) and 4-bromopyridin-3-ol (631 mg,3.62mmol,1.00 eq.) in THF (7.00 mL) was added to PPh ₃ (1.43 g,5.44mmol,1.50 eq.). The resulting mixture was stirred at 0℃under nitrogen for 5min. DEAD (947 mg,5.44mmol,1.50 eq.) was added dropwise to the above mixture at 0deg.C. The resulting mixture was stirred at 0℃for a further 3h. The reaction was monitored by LCMS. LCMS showed the reaction was complete. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography using the following conditions (mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; gradient 0% B to 100% B within 50 min) to provide 2- [ (1R) -1- [ (4-bromopyridine)-3-yl) oxy]Ethyl group]Azetidine-1-carboxylic acid tert-butyl ester (250 mg, 19.29%) was a colorless oil.

LC-MS:(M+H) ⁺ Actual: 359.1.

168.2: synthesis of tert-butyl (2R) -2- [ (1R) -1- [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] ethyl ] azetidine-1-carboxylate

To 2- [ (1R) -1- [ (4-bromopyridin-3-yl) oxy at room temperature under nitrogen atmosphere]Ethyl group]Azetidine-1-carboxylic acid tert-butyl ester (250 mg,0.70mmol,1.00 eq.) and 2- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]]Pyridin-4-one (220 mg,0.84mmol,1.20 eq.) in 1, 4-dioxane (3.00 mL) and H ₂ Pd (DtBPF) Cl was added to the stirred mixture in O (0.60 mL) ₂ (45 mg,0.07mmol,0.10 eq.) and Na ₂ CO ₃ (222 mg,2.10mmol,3.00 eq.). The resulting mixture was stirred at 50℃for a further 2h. The reaction was monitored by LCMS. LCMS showed the reaction was complete. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2R) -2- [ (1R) -1- [ (4- { 4-oxo-1 h,5h,6h,7 h-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]Ethyl group]Azetidine-1-carboxylic acid tert-butyl ester (270 mg, 93.54%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 413.05.

168.3: synthesis of tert-butyl (2R) -2- [ (1R) -1- [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] ethyl ] azetidine-1-carboxylate

To (2R) -2- [ (1R) -1- [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] at 0℃under nitrogen atmosphere]Pyridin-2-yl } pyridin-3-yl) oxy]Ethyl group]A stirred solution of tert-butyl azetidine-1-carboxylate (270 mg,0.65mmol,1.00 eq.) in DMF (5.00 mL) was added in portions N-iodosuccinimide (161 mg,0.72mmol,1.10 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1.5h. The reaction was monitored by LCMS. LCMS showed the reaction was complete. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2R) -2- [ (1R) -1- [ (4- { 3-iodo-4-oxo-1 h,5h,6h,7 h-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]Ethyl group]Azetidine-1-carboxylic acid tert-butyl ester (310 mg, 87.97%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 539.00.

168.4: synthesis of tert-butyl (2R) -2- [ (1R) -1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] ethyl ] azetidine-1-carboxylate

To (2R) -2- [ (1R) -1- [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] under argon at room temperature]Pyridin-2-yl } pyridin-3-yl) oxy]Ethyl group]A stirred mixture of tert-butyl azetidine-1-carboxylate (310 mg,0.57mmol,1.00 eq.) and 3-fluoro-2-methoxyaniline (243 mg,1.72mmol,3.00 eq.) in DMF (6.00 mL) was added EPhos Pd G4 (52 mg,0.05mmol,0.10 eq.) and Cs ₂ CO ₃ (375 mg,1.15mmol,2.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DMF (2x0.50 ml). The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2R) -2- [ (1R) -1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Ethyl group]Azetidine-1-carboxylic acid tert-butyl ester (250 mg, 78.71%) was a brown solid.

LC-MS:(M+H) ⁺ Actual: 552.15.

168.5: synthesis of 2- {3- [ (1R) -1- [ (2R) -azetidin-2-yl ] ethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To (2R) -2- [ (1R) -1- [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group at 0℃under nitrogen atmosphere]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Ethyl group]A stirred solution of tert-butyl azetidine-1-carboxylate (250 mg,0.45mmol,1.00 eq.) in DCM (3.00 mL) was added TFA (1.00 mL). The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography using the following conditions (mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; gradient 0% B to 100% B within 50 min) to provide 2- {3- [ (1R) -1- [ (2R) -azetidin-2-yl]Ethoxy group]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (120 mg, 58.64%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 452.05.

168.6: synthesis of 2- {3- [ (1R) -1- [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] ethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- {3- [ (1R) -1- [ (2R) -azetidin-2-yl at 0℃under nitrogen]Ethoxy group]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (80 mg,0.17mmol,1.00 eq.) in THF (0.50 mL) was added DIEA (0.50 mL). The resulting mixture was stirred at 0℃under nitrogen for 10min. Dripping 2-butynoic acid into the mixture at 0deg.C(22 mg,0.26mmol,1.50 eq.) and T ₃ P (563 mg,0.88mmol,5.00 eq., 50% in EA). The resulting mixture was stirred at room temperature for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: YMC-actual Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 25% b to 49% b, 49% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 2- {3- [ (1R) -1- [ (2R) -1- (but-2-ynyl) azetidin-2-yl]Ethoxy group]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (27 mg, 29.18%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 518.15.

¹ h NMR (400 MHz, chloroform-d) δ11.47 (s, 1H), 8.28 (s, 1H), 7.93 (s, 1H), 7.51-7.46 (m, 2H), 6.56-6.43 (m, 2H), 6.02 (d, 1H), 5.21 (s, 1H), 4.96-4.92 (m, 1H), 4.63-4.61 (m, 1H), 4.23 (t, 2H), 4.09 (d, 3H), 3.60-3.56 (m, 2H), 3.18-3.14 (m, 1H), 3.04-2.98 (m, 1H), 2.70-2.66 (m, 1H), 2.12-2.07 (m, 1H), 2.02 (s, 3H), 1.32 (d, 3H).

Example 169: rel-N- [ (3R) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuran-3-yl ] prop-2-enamide (compound 323)

169.1: synthesis of tert-butyl N- {3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuranyl } carbamate

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere ]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (350 mg,0.70mmol,1.00 eq.) and Pd (d)ppf)Cl ₂ .CH ₂ Cl ₂ A stirred solution of (144 mg,0.17mmol,0.25 eq.) and CuI (67 mg,0.35mmol,0.50 eq.) in DMF (3.00 mL) was added tert-butyl N- (3-ethynyl tetrahydrofuran-3-yl) carbamate (373 mg,1.76mmol,2.50 eq.) and DIEA (457 mg,3.53mmol,5.00 eq.). The resulting mixture was stirred in a closed tube at 50℃under Ar atmosphere for 2h. The residue was purified by reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 80%, 30 min; detector: UV 254 nm) to afford N- {3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Tetrahydrofuran-3-yl } carbamic acid tert-butyl ester (270 mg, 66.02%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 578.15.

169.2: synthesis of 2- {3- [2- (3-aminotetrahydrofuran-3-yl) ethynyl ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl N- {3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuran-3-yl } carbamate (240 mg,0.41mmol,1 eq.) in DCM (2.00 mL) was added TFA (2.00 mL) at 0deg.C. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was worked up and dried using nitrogen. The residue was purified by reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, meOH in water, gradient 10% to 60%, within 10 min; detector: UV 254 nm) to afford 2- {3- [2- (3-aminotetrahydrofuran-3-yl) ethynyl ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-C ] pyridin-4-one (130 mg, 65.51%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 478.05.

169.3: synthesis of N- {3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuran-3-yl } prop-2-enamide

At 0℃to 2- {3- [2- (3-aminotetrahydrofuran-3-yl) ethynyl ]]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (125 mg,0.26mmol,1.00 eq.) and DIEA (169 mg,1.31mmol,5.00 eq.) in THF (2.50 mL) was added dropwise acryloyl chloride (35 mg,0.39mmol,1.50 eq.) to THF (0.50 mL). The aqueous layer was extracted with EtOAc (3X 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was then purified by preparative HPLC and using the following conditions (column: xselect CSH C18 OBD column 30X 150mm 5 μm, N; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 16% B to 36% B over 10min, 36% B; wavelength: 254/220nm; RT1 (min): 9; running number: 0) to afford N- {3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino group)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Tetrahydrofuran-3-yl } prop-2-enamide (40 mg, 28.75%) as an orange solid.

LC-MS:(M+H) ⁺ Actual: 532.1.

169.4: synthesis of rel-N- [ (3R) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofu-N-3-yl ] prop-2-enamide

The racemic product (40 mg) was purified by preparative HPLC and using the following conditions (column: CHIRALPAK IF, 2X 25cm,5 μm; flow: 20mL/min; gradient: 15% B to 15% B,27 min; wavelength: 220/254nm; RT1 (min): 23.53; RT2 (min): 29.97; injection volume: 0.875mL; running number: 4) to afford rel-N- [ (3R) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuran-3-yl ] prop-2-enamide (6.8 mg, 16.91%) as an orange solid.

LC-MS:(M+H) ⁺ Actual: 532.05.

¹ h NMR (400 MHz, chloroform-d) δ11.37 (s, 1H), 8.59 (s, 1H), 8.10-7.99 (m, 2H), 7.40 (d, 1H), 6.82-6.79 (m, 1H), 6.67-6.60 (m, 2H), 6.37-6.32 (m, 1H), 6.25-6.18 (m, 2H), 5.78-5.76 (m, 1H), 5.38 (s, 1H), 4.20 (d, 1H), 4.21-4.07 (m, 6H), 3.68-3.64 (m, 2H), 3.28 (t, 2H), 2.64-2.57 (m, 2H).

Example 170: rel-N- [ (3R) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuran-3-yl ] prop-2-enamide (compound 322)

The racemic product (40 mg) was purified by preparative HPLC and using the following conditions (column: CHIRALPAK IF, 2X 25cm,5 μm; flow: 20mL/min; gradient: 15% B to 15% B,27 min; wavelength: 220/254nm; RT1 (min): 23.53; RT2 (min): 29.97; injection volume: 0.875mL; running number: 4) to afford rel-N- [ (3R) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuran-3-yl ] prop-2-enamide (9.3 mg, 23.13%) as an orange solid.

LC-MS:(M+H) ⁺ Actual: 532.05.

¹ h NMR (400 MHz, chloroform-d) δ11.46 (s, 1H), 8.50 (s, 1H), 8.29 (s, 1H), 7.96 (d, 1H), 7.37 (d, 1H), 6.85-6.83 (m, 2H), 6.67 (t, 1H), 6.33-6.19 (m, 3H), 5.77 (d, 1H), 5.33 (s, 1H), 4.20 (d, 1H), 4.11-4.08 (m, 6H), 3.68-3.65 (m, 2H), 3.31 (t, 2H), 2.62 (t, 2H).

Example 171: rel-N- [ (3R) -3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuran-3-yl ] prop-2-enamide (compound 321)

171.1: synthesis of tert-butyl N- {3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuranyl } carbamate

To 3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under Ar atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (330 mg,0.69mmol,1.00 eq.) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ To a stirred solution of (140 mg,0.17mmol,0.25 eq.) and CuI (65 mg,0.34mmol,0.50 eq.) in DMF (3.00 mL) were added tert-butyl N- (3-ethynyl tetrahydrofuran-3-yl) carbamate (349 mg,1.65mmol,2.40 eq.) and DIEA (445 mg,3.45mmol,5.00 eq.). The resulting mixture was stirred in a closed tube at 50℃under Ar atmosphere for 2h. The residue was purified by reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 80%, 30 min; detector: UV 254 nm) to afford N- {3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Tetrahydrofuran-3-yl } carbamic acid tert-butyl ester (320 mg, 82.58%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 562.20.

171.2: synthesis of 2- {3- [2- (3-aminotetrahydrofuran-3-yl) ethynyl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl N- {3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuran-3-yl } carbamate (310 mg,0.55mmol,1.00 eq.) in DCM (3.00 mL) was added TFA (3.00 mL) at 0deg.C. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was worked up and dried using nitrogen. The residue was purified by reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, meOH in water, gradient 10% to 60%, within 10 min; detector: UV 254 nm) to afford 2- {3- [2- (3-aminotetrahydrofuran-3-yl) ethynyl ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-C ] pyridin-4-one (190 mg, 74.59%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 462.10.

171.3: synthesis of N- {3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuran-3-yl } prop-2-enamide

At 0℃to 2- {3- [2- (3-aminotetrahydrofuran-3-yl) ethynyl ]]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (170 mg,0.36mmol,1.00 eq.) and DIEA (238 mg,1.84mmol,5.00 eq.) in THF (2.50 mL) was added dropwise acryloyl chloride (66 mg,0.73mmol,2.00 eq.) to THF (0.50 mL). The aqueous layer was extracted with EtOAc (3X 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to provide N- {3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Tetrahydrofuran-3-yl } prop-2-enamide (120 mg) as a yellow solid. The product (120 mg) was then purified by preparative HPLC and using the following conditions (column: XSelect CSH fluorophenyl, 30 x 150mm,5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 12% B to 32% B,13min, 32% B; wavelength: 254nm; RT1 (min): 12.4; running number: 0) to provide N- {3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethanAlkynyl group]Tetrahydrofuran-3-yl } prop-2-enamide (80 mg, 42.13%) as an orange solid.

LC-MS:(M+H) ⁺ Actual: 516.2.

171.4: synthesis of rel-N- [ (3R) -3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofu-N-3-yl ] prop-2-enamide

The racemic product (80 mg) was purified by chiral preparative HPLC and applied to the following conditions (column: CHIRALPAK IF,2 x 25cm,5 μm; flow: 20mL/min; gradient: 15% B to 15% B,27 min; wavelength: 220/254nm; RT1 (min): 23.53; RT2 (min): 29.97; injection volume: 0.875mL; running number: 4) to afford rel-N- [ (3R) -3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuran-3-yl ] prop-2-enamide (20.8 mg, 26.00%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 516.10.

¹ h NMR (300 MHz, chloroform-d) δ11.22 (s, 1H), 8.57 (s, 1H), 8.13 (d, 1H), 7.81 (s, 1H), 7.46 (d, 1H), 6.60-6.56 (m, 1H), 6.53-6.46 (m, 1H), 6.42-6.32 (m, 2H), 6.22-6.08 (m, 2H), 5.78-5.74 (m, 1H), 5.31 (s, 1H), 4.20 (d, 1H), 4.10-4.04 (m, 6H), 3.65-3.61 (m, 2H), 3.24 (t, 2H), 2.63-2.55 (m, 2H).

Example 172: rel-N- [ (3R) -3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuran-3-yl ] prop-2-enamide (compound 320)

The racemic product (80 mg) was purified by preparative HPLC and using the following conditions (column: CHIRALPAK IF, 2X 25cm,5 μm; flow: 20mL/min; gradient: 15% B to 15% B,27 min; wavelength: 220/254nm; RT1 (min): 23.53; RT2 (min): 29.97; injection volume: 0.875mL; running number: 4) to afford rel-N- [ (3R) -3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] tetrahydrofuran-3-yl ] prop-2-enamide (23.3 mg, 29.13%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 516.10.

¹ h NMR (300 MHz, chloroform-d) δ11.39 (s, 1H), 8.56 (s, 1H), 8.15 (s, 1H), 8.02 (d, 1H), 7.44 (d, 1H), 6.70-6.53 (m, 3H), 6.37-6.19 (m, 2H), 6.07 (d, 1H), 5.77 (d, 1H), 5.35 (s, 1H), 4.20 (d, 1H), 4.12-4.06 (m, 6H), 3.66 (t, 2H), 3.29 (t, 2H), 2.61 (t, 2H).

Example 173:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [2- (prop-2-enoyl) -2-azabicyclo [2.1.1] hex-1-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 319)

173.1: synthesis of tert-butyl 1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [2.1.1] hexane-2-carboxylate

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (240 mg,0.49mmol,1.00 eq.) and 1-ethynyl-2-azabicyclo [2.1.1]]A stirred mixture of tert-butyl hexane-2-carboxylate (201 mg,0.97mmol,2.00 eq.) in DMF (4.00 mL) was added Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (99 mg,0.12mmol,0.25 eq.) DIEA (188 mg,1.46mmol,3.00 eq.) and CuI (46 mg,0.24mmol,0.50 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was purified by reverse phase flash chromatography using column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 60% within 10 min; a detector: UV 254nm. Concentrating the resulting mixture under reduced pressureAnd (3) an object. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) elution to afford 1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-azabicyclo [2.1.1]Hexane-2-carboxylic acid tert-butyl ester (190 mg, 68.22%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 574.15.

173.2: synthesis of 2- [3- (2- { 2-azabicyclo [2.1.1] hex-1-yl } ethynyl) pyridin-4-yl ] -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

TMSOTF (2.90 mL,1.48mmol,5.00 eq.) was added dropwise to a stirred solution of 1- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [2.1.1] hexane-2-carboxylic acid tert-butyl ester (170 mg,0.29mmol,1.00 eq.) and 2, 6-dimethylpyridine (793 mg,7.40mmol,25.00 eq.) in DCM (5.00 mL) at 0deg.C under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 3h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 50% within 10 min; a detector: UV 254nm. This gave 2- [3- (2- { 2-azabicyclo [2.1.1] hex-1-yl } ethynyl) pyridin-4-yl ] -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (130 mg, 92.62%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 474.00

173.3: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [2- (prop-2-enoyl) -2-azabicyclo [2.1.1] hex-1-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- [3- (2- { 2-azabicyclo [2.1.1] at 0deg.C under nitrogen atmosphere]Hex-1-yl } ethynyl) pyridin-4-yl]-3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (110 mg,0.23mmol,1.00 eq.) and DIEA (150 mg,1.16mmol,5.00 eq.) in DCM (5.00 mL) was added dropwise acrylic anhydride (59 mg,0.46mmol,2.00 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) elution to afford 3- [ (3-chloro-2-methoxyphenyl) amino)]-2- (3- {2- [2- (prop-2-enoyl) -2-azabicyclo [2.1.1]]Hex-1-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (30 mg, crude) as a yellow solid. The residue was purified by trituration with acetonitrile (5 mL) to give 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [2- (prop-2-enoyl) -2-azabicyclo [2.1.1]]Hex-1-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-one (25.1 mg, 19.99%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 528.05

¹ H NMR (300 MHz, chloroform-d) δ11.53 (s, 1H), 8.61 (s, 1H), 8.14 (d, 1H), 7.74 (s, 1H), 7.42 (d, 1H), 6.76-6.67 (m, 1H), 6.65-6.53 (m, 1H), 6.53-6.37 (m, 2H), 6.29-6.18 (m, 1H), 5.86-5.75 (m, 1H), 5.24 (s, 1H), 4.07 (s, 3H), 3.68 (s, 2H), 3.62-3.51 (m, 2H), 3.07 (t, 2H), 2.96 (t, 1H), 2.46-2.32 (m, 2H), 2.00-1.92 (m, 2H).

Example 174:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [2- (prop-2-enoyl) -2-azabicyclo [2.1.1] hex-1-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 318)

174.1: synthesis of tert-butyl 1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [2.1.1] hexane-2-carboxylate

At room temperatureTo 3- [ (3-fluoro-2-methoxyphenyl) amino group under nitrogen atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (200 mg,0.42mmol,1.00 eq.) and CuI (39 mg,0.21mmol,0.50 eq.) Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (85 mg,0.10mmol,0.25 eq.) in DMF (2.00 mL) was added 1-ethynyl-2-azabicyclo [2.1.1]]Hexane-2-carboxylic acid tert-butyl ester (173 mg,0.84mmol,2.00 eq.) and DIEA (162 mg,1.25mmol,3.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was purified by reverse phase flash chromatography and subjected to the following conditions (column, C18 silica gel; mobile phase, meCN in water, gradient 10% to 50%, within 10 min; detector: UV 254 nm) to afford 1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-azabicyclo [2.1.1]Hexane-2-carboxylic acid tert-butyl ester (150 mg, 64.33%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 558.15.

174.2: synthesis of 2- [3- (2- { 2-azabicyclo [2.1.1] hex-1-yl } ethynyl) pyridin-4-yl ] -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2, 6-lutidine (480 mg,4.47mmol,25.00 eq.) and 1- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group under nitrogen at 0 ]]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-azabicyclo [2.1.1]A stirred solution of tert-butyl hexane-2-carboxylate (100 mg,0.18mmol,1.00 eq.) in DCM (4.00 mL) was added dropwise TMSOTF (0.20 mL,0.90mmol,5.00 eq.). The resulting mixture was stirred at room temperature under nitrogen for 4h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to provide 2- [3- (2- { 2-azabicyclo [2.1.1]]Hex-1-yl } ethynyl) pyridin-4-yl]-3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (80 mg, 97.51%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 458.05

174.3: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- {2- [2- (prop-2-enoyl) -2-azabicyclo [2.1.1] hex-1-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- [3- (2- { 2-azabicyclo [2.1.1] at 0deg.C under nitrogen atmosphere]Hex-1-yl } ethynyl) pyridin-4-yl]-3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (70 mg,0.15mmol,1.00 eq.) in THF (0.50 mL) and DIEA (39 mg,0.30mmol,2.00 eq.) was added dropwise acryloyl chloride (13 mg,0.15mmol,1.00 eq.). The resulting mixture was stirred at room temperature under nitrogen for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) to afford crude product. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/LNH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 34% b to 58% b, 58% b over 10 min; wavelength is 254/220nm; RT1 (min) 7.53; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- {2- [2- (prop-2-enoyl) -2-azabicyclo [2.1.1] ]Hex-1-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (6.1 mg, 7.72%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 512.05

¹ H NMR (400 MHz, chloroform-d) δ11.55 (s, 1H), 8.61 (s, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 7.48 (s, 1H), 6.61-6.57 (m, 1H), 6.55-6.40 (m, 3H), 6.10 (d, 1H), 5.86-5.76 (m, 1H), 5.20 (s, 1H), 4.10 (s, 3H), 3.68 (s, 2H), 3.61-3.42 (m, 2H), 3.08 (t, 2H), 2.96 (d, 1H), 2.39 (d, 2H), 2.00-1.91 (m, 2H).

Example 175:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- (3-fluoro-3-methylbut-1-yn-1-yl) pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 489)

175.1: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (100.00 mg,0.20mmol,1.00 eq.) and 2-methyl-3-butyn-2-ol (85.02 mg,1.01mmol,5.00 eq.) in DMF (2 mL) was added dropwise Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (82.33 mg,0.10mmol,0.50 eq.) and DIEA (0.50 mL,2.87mmol,14.35 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The residue was purified by reverse phase flash chromatography using the following conditions (column: C18 silica gel; mobile phase, ACN in water, gradient 10% to 50%, within 10 min; detector: UV 254 nm) to afford 3- [ (3-chloro-2-methoxyphenyl) amino group ]-2- [3- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (85.00 mg, 94.44%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 451.0.

175.2: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- (3-fluoro-3-methylbut-1-yn-1-yl) pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0℃under N ₂ To 3- [ (3-chloro-2-methoxyphenyl) amino group under an atmosphere]-2- [3- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (66.00 mg,0.15mmol,1.00 eq.) in DCM (5.00 mL) was added dropwise BAST (64.76 mg,0.29mmol,2.00 eq.). At 0 DEG C、N ₂ The resulting mixture was stirred under an atmosphere for 1h. The resulting mixture was concentrated in vacuo and dissolved in DMF. The crude product (60.00 mg) was purified by preparative HPLC and purified using the following conditions (column: xselect CSH F-phenyl OBD column, 19 x 250mm,mobile phase A water (0.05% FA), mobile phase B ACN; the flow rate is 25mL/min; gradient from 35% b to 43% b, 43% b over 8 min; wavelength of 254nm; RT1 (min) 7.83; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- [3- (3-fluoro-3-methylbut-1-yn-1-yl) pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-one (12.10 mg, 17.85%) was an orange solid.

LC-MS:(M+H) ⁺ Actual: 453.0.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.60(s,1H),8.69(s,1H),8.46(d,J＝5.5Hz,1H),7.58-7.30(m,2H),7.17(s,1H),6.64(d,J＝4.9Hz,2H),6.08(h,J＝4.2Hz,1H),4.2(s,3H),3.44(t,J＝6.8Hz,2H),2.85(t,J＝6.7Hz,2H),1.70(d,J＝20.6Hz,6H)。

example 176:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [2- [ (3R) -4-methylmorpholin-3-yl ] ethynyl ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 493)

176.1: synthesis of tert-butyl 3- [2- (4- [3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl) ethynyl ] morpholine-4-carboxylate

3- [ (3-chloro-2-methoxyphenyl) amino group was placed in a 40-mL tube sealer]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (200.00 mg,0.40mmol,1.00 eq.), DMF (5 mL), cuI (39.00 mg,0.20mmol,0.50 eq.), pd (dppf) Cl ₂ (148.00 mg,0.20mmol,0.50 eq.) DIEA (1 mL), tert-butyl 3-ethynylmorpholine-4-carboxylate (427.00 mg,2.02mmol,5.00 eq.). The resulting solution was stirred at 50℃for 3h. The reaction was monitored by LCMS. Filtering the obtainedThe mixture, filter cake was washed with DMF (2X 1 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions (column: C18 silica gel, mobile phase, meOH in water, gradient from 10% to 50%, within 10 min; detector: UV 254 nm) to afford (200.00 mg, 70.18%) 3- [2- (4- [3- [ (3-chloro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl) ethynyl]Morpholine-4-carboxylic acid tert-butyl ester as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 578.0.

176.2: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- [2- (morpholin-3-yl) ethynyl ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl 3- [2- (4- [3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl) ethynyl ] morpholine-4-carboxylate (300.00 mg,0.52mmol,1.00 eq.) in DCM (5 mL) was added TFA (5 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- [2- (morpholin-3-yl) ethynyl ] pyridin-4-yl ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (220.00 mg, 70.96%) as an orange solid. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 478.0.

176.3: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- [2- (4-methylmorpholin-3-yl) ethynyl ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

In a 20-mL vial is placed 3- [ (3-chloro-2-methoxyphenyl) amino ]-2- [3- [2- (morpholin-3-yl) ethynyl group]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridine compound4-Ketone (125.00 mg,0.26mmol,1.00 eq.), meOH (4 mL), HCHO (16.00 mg,0.52mmol,2.00 eq.). The resulting solution was stirred for 30min. NaBH (AcO) was then added ₃ (111.00 mg,0.52mmol,2.00 eq.). The resulting solution was allowed to react at room temperature for an additional 2h under stirring. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (100.00 mg) was purified by preparative HPLC and purified using the following conditions (column: XBridge Prep Amide OBD column, 19 x 150mm,13nm; mobile phase A water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 25mL/min; gradient from 32% b to 33% b, over 12 min; wavelength of 254nm; RT1 (min) 11.48; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- [3- [2- (4-methylmorpholin-3-yl) ethynyl group]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (45.00 mg, 34.90%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 492.0.

176.4: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [2- [ (3R) -4-methylmorpholin-3-yl ] ethynyl ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

The crude product (45.00 mg) was purified by chiral preparative HPLC using the following conditions (column: CHIRALPAK IG,2 x 25cm,5 μm; mobile phase A: hex (0.5% 2M NH) ₃ -MeOH) -HPLC, mobile phase B EtOH-HPLC; the flow rate is 20mL/min; gradient from 50% b to 50% b for 27 min; wavelength is 254/220nm; RT1 (min) 18.4; RT2 (min) 22.98; sample solvent EtOH- -HPLC; injection volume 0.4mL; running 20) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- [2- [ (3R) -4-methylmorpholin-3-yl)]Ethynyl group]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (13.70 mg, 30.38%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 492.0.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.45(s,1H),8.61(s,1H),8.38(d,J＝5.3Hz,1H),7.36(d,J＝5.3Hz,1H),7.27(s,1H),7.10(t,J＝2.6Hz,1H),6.68-6.57(m,2H),6.16(dd,J＝7.4,2.3Hz,1H),3.84(s,3H),3.74(d,J＝3.6Hz,2H),3.69-3.53(m,3H),3.50(s,1H),3.40(td,J＝6.9,2.6Hz,2H),2.82(t,J＝6.8Hz,2H),2.31-2.23(m,1H),2.24(s,3H)。

example 177:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [2- [ (3S) -4-methylmorpholin-3-yl ] ethynyl ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 494)

The crude product (45.00 mg) was purified by chiral preparative HPLC using the following conditions (column: CHIRALPAK IG,2 x 25cm,5 μm; mobile phase A: hex (0.5% 2M NH) ₃ -MeOH) -HPLC, mobile phase B EtOH-HPLC; the flow rate is 20mL/min; gradient from 50% b to 50% b for 27 min; wavelength is 254/220nm; RT1 (min) 18.4; RT2 (min) 22.98; sample solvent EtOH- -HPLC; injection volume 0.4mL; running 20) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- [2- [ (3S) -4-methylmorpholin-3-yl)]Ethynyl group]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-one (15.00 mg, 33.17%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 492.0.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.44(s,1H),8.61(s,1H),8.38(d,J＝5.3Hz,1H),7.36(d,J＝5.3Hz,1H),7.27(s,1H),7.10(d,J＝2.7Hz,1H),6.68-6.57(m,2H),6.16(dd,J＝7.4,2.3Hz,1H),3.84(s,3H),3.74(d,J＝3.6Hz,2H),3.69-3.52(m,3H),3.50(s,1H),3.40(td,J＝7.0,2.6Hz,2H),2.82(t,J＝6.8Hz,2H),2.31-2.19(m,1H),2.24(s,3H)。

example 178:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (3R) -4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 514)

178.1: synthesis of 3-ethynyl morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 3-formylmorpholine-4-carboxylate (1.10 g,5.11mmol,1.00 eq.) in MeOH (12 mL) at 0deg.C under nitrogen was added K in portions ₂ CO ₃ (1.42 g,10.22mmol,2.00 eq.). Dimethyl (1-diazo-2-oxopropyl) phosphonate (1.18 g,6.13mmol,1.20 eq.) was added dropwise to the above mixture at 0deg.C. The resulting mixture was stirred at room temperature for 1h. The desired product can be detected by TLC. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE/EA (10:1) to give tert-butyl 3-ethynyl morpholine-4-carboxylate (900.00 mg, 83.36%) as a colorless oil.

178.2: synthesis of tert-butyl 3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] morpholine-4-carboxylate

To 3-Acetylmorpholine-4-carboxylic acid tert-butyl ester (281mg, 1.33mmol,3.00 eq.) and 3- [ (3-chloro-2-methoxyphenyl) amino group ]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (220.00 mg,0.44mmol,1.00 eq.) in DMF (3 mL) was added Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (181.00 mg,0.22mmol,0.50 eq.) and CuI (42.00 mg,0.22mmol,0.50 eq.). The resulting mixture was stirred at 50℃under nitrogen for 1.5h. The residue was purified by reverse phase flash chromatography using the following conditions (column: C18 silica gel; mobile phase, ACN in water, gradient 10% to 50%, 30 min; detector: UV 254 nm) to afford 3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]Morpholine-4-carboxylic acid tert-butyl ester (130.00 s mg, 50.57%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 578.1.

178.3: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [2- (morpholin-3-yl) ethynyl ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl 3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] morpholine-4-carboxylate (130.00 mg,0.23mmol,1.00 eq.) in DCM (2 mL) at 0 ℃ under nitrogen was added TFA (1 mL). The resulting mixture was stirred at room temperature under nitrogen for 1h. The resulting mixture was concentrated under reduced pressure. The crude product 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [2- (morpholin-3-yl) ethynyl ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (119.00 mg, 99.64%) was obtained, which was used in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 478.0.

178.4: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group at 0℃under nitrogen atmosphere]-2- {3- [2- (morpholin-3-yl) ethynyl ]]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (120.00 mg,0.19mmol,1.00 eq.) in THF (2 mL) was added in portions with NaHCO ₃ Aqueous solution (2 mL) to basify the mixture. To the above mixture was added dropwise acryloyl chloride (15.00 mg,0.17mmol,0.90 eq.) at 0deg.C. The resulting mixture was stirred at 0℃for a further 1h. The resulting mixture was treated with CH ₂ Cl ₂ Meoh=10:1 (3×20 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. The resulting mixture was concentrated in vacuo and dissolved in DMSO. The crude product (100.00 mg) was purified by preparative HPLC and the following strips were usedPiece (column: XBridge Prep C18 OBD column, 19X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 20% B to 42% B, 42% B over 10 min; wavelength is 254/220nm; RT1 (min) 9.67; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [4- (prop-2-enoyl) morpholin-3-yl) ]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (50.00 mg, 37.43%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 531.9.

178.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (3R) -4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (50.00 mg) was purified by chiral HPLC and using the following conditions (column CHIRALPAK IG-3,4.6 x 50mm,3um; mobile phase a: hex (0.1% dea): etoh=50:50; flow rate: 1mL/min; gradient: 0% b to 0% b; injection volume: 5ul mL) to provide 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (3R) -4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (19.20 mg,38 mg) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 532.0.

¹ h NMR (400 MHz, chloroform-d) δ10.53 (s, 1H), 8.82-7.99 (m, 2H), 6.79 (d, j=7.9 hz, 1H), 6.61 (m, 2H), 6.45-6.40 (m, 1H), 6.18 (d, j=8.0 hz, 1H), 5.86 (d, j=10.4 hz, 1H), 5.50 (s, 1H), 5.29 (s, 1H), 4.22 (d, j=11.6 hz, 1H), 4.07 (s, 4H), 3.99-3.19 (m, 8H), 3.13 (brs, 2H).

Example 179:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (3S) -4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 515)

3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (50.00 mg,0.09mmol,1.00 eq) was purified by chiral HPLC and using the following conditions (column: CHIRALPAK IG-3,4.6 x 50mm,3um; mobile phase A: hex (0.1% DEA): etOH=50:50; flow rate: 1mL/min; gradient: 0% B to 0% B; injection volume: 5ul mL) to provide 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (3S) -4- (prop-2-enoyl) morpholin-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (16.90 mg, 33.80%) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 532.0.

¹ h NMR (400 MHz, chloroform-d) delta 10.50 (s, 1H), 8.62-7.90 (m, 2H), 6.77 (d, j=7.9 hz, 1H), 6.70-6.50 (m, 2H), 6.44-6.39 (m, 1H), 6.19 (d, j=8.0 hz, 1H), 5.86 (d, j=10.3 hz, 1H), 5.52 (s, 1H), 5.28 (s, 1H), 4.22 (d, j=11.6 hz, 1H), 4.07 (s, 4H), 3.87-3.14 (m, 8H), 3.11 (brs, 2H).

Example 180:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [2- (1-fluorocyclopropyl) ethynyl ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 545)

180.1: synthesis of 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((1-hydroxycyclopropyl) ethynyl) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

At room temperature, 3- [ (3-chloro-2-methoxyphenyl) amino group was added to the tube at room temperature]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100.00 mg,0.20mmol,1.00 eq.), cuI (19.00 mg,0.10mmol,0.50 eq.), csF (61.00 mg,0.40mmol,2.00 eq.), pd (dppf) Cl ₂ .CH ₂ Cl ₂ (82.00 mg,0.10mmol,0.50 eq.), DMF (5 mL),1- ((trimethylsilyl) ethynyl) cyclopropyl-1-ol (154.00 mg,1.00mmol,5.00 eq.) and DIEA (0.5 mL). After stirring at 50℃under Ar atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was filtered. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to provide 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((1-hydroxycyclopropyl) ethynyl) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3, 2-c)]Pyridin-4-one (67.00 mg, 74.8%) was a brown solid.

LC-MS:(M+H) ⁺ Actual: 449.0.

180.2: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [2- (1-fluorocyclopropyl) ethynyl ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group at 0℃under nitrogen atmosphere]-2- {3- [2- (1-hydroxycyclopropyl) ethynyl ]]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one) (60.00 mg,0.13mmol,1.00 eq.) in CH ₂ Cl ₂ BAST (59.00 mg,0.26mmol,2.00 eq.) was added dropwise to the stirred solution of (10 mL). The resulting mixture was stirred at 0℃under nitrogen for 0.5h. The reaction was monitored by LCMS. The reaction was quenched with saturated aqueous sodium thiosulfate at 0 ℃. The resulting mixture was treated with CH ₂ Cl ₂ (3X 30 mL) extraction. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford 3- [ (3-chloro-2-methoxyphenyl) amino)]-2- {3- [2- (1-fluorocyclopropyl) ethynyl ]]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (6.20 mg, 10.29%) was a red solid.

LC-MS:(M+H) ⁺ Actual: 451.0.

¹ h NMR (400 MHz, methanol-d) ₄ )δ8.72(s,1H),8.35(s,1H),7.60(d,J＝5.9Hz,1H),6.75(dd,J＝8.0,1.5Hz,1H),6.66(t,J＝8.1Hz,1H),6.22(dd,J＝8.2,1.5Hz,1H),3.97(s,3H),3.64(t,J＝6.9Hz,2H),3.01(t,J＝6.9Hz,2H),1.57-1.44(m,2H),1.28(dt,J＝9.1,6.2Hz,2H)。

Example 181:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- (prop-1-yn-1-yl) pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 547)

At room temperature, 3- [ (3-chloro-2-methoxyphenyl) amino group was added to the tube at room temperature]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]Pyridin-4-one (100.00 mg,0.20mmol,1.00 eq.), cuI (19.00 mg,0.101mmol,0.50 eq.), csF (61.00 mg,0.40mmol,2.00 eq.), pd (dppf) Cl ₂ .CH ₂ Cl ₂ (83.00 mg,0.10mmol,0.50 eq.) DMF (2 mL), trimethyl (prop-1-yn-1-yl) silane (113.00 mg,1.00mmol,5.00 eq.) and DIEA (0.50 mL). After stirring at 50 ℃ for 2h under argon atmosphere, the reaction was monitored by LCMS. The resulting mixture was filtered. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford 3- [ (3-chloro-2-methoxyphenyl) amino)]-2- [3- (prop-1-yn-1-yl) pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (2.30 mg, 2.71%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 407.0.

¹ h NMR (300 MHz, methanol-d) ₄ )δ8.52(s,1H),8.22(s,1H),7.40(s,1H),6.69-6.53(m,2H),6.23(dd,J＝7.4,2.4Hz,1H),3.95(s,3H),3.62(t,J＝6.9Hz,2H),2.98(t,J＝7.0Hz,2H),2.15(s,3H).

Example 182:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- [2- (1-methylcyclopropyl) ethynyl ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 527)

At room temperature, add into the tube seal3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100.00 mg,0.20mmol,1.00 eq.), cuI (19.00 mg,0.10mmol,0.50 eq.), csF (61.00 mg,0.40mmol,2.00 eq.), pd (dppf) Cl ₂ .CH ₂ Cl ₂ (82.00 mg,0.10mmol,0.50 eq.) DMF (5 mL), trimethyl [2- (1-methylcyclopropyl) ethynyl ] ]Silane (154.00 mg,1.00mmol,5.00 eq.) and DIEA (0.50 ml,2.87mmol,14.20 eq.). After stirring at 50 ℃ for 2h under argon atmosphere, the reaction was monitored by LCMS. The resulting mixture was concentrated, and the residue was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (10:1) to afford crude product. The crude product was purified by preparative HPLC to afford 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- [3- [2- (1-methylcyclopropyl) ethynyl ]]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (10.20 mg, 11.72%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 447.0.

¹ H NMR(400MHz,DMSO-d ₆ ):δ11.45(s,1H),8.51(s,1H),8.32(d,J＝5.2Hz,1H),7.28-7.27(m,2H),7.09(s,1H),6.65-6.59(m,2H),6.09(dd,J＝7.6,2.4Hz,1H),3.83(s,3H),3.43(td,J＝6.8,2.4Hz,2H),2.84(t,J＝6.8Hz,2H),1.31(s,3H),0.99-0.97(m,2H),0.77-0.75(m,2H)。

example 183:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 551)

183.1: synthesis of tert-butyl 2-formyl-2-methylazetidine-1-carboxylate

at-78deg.C under nitrogen atmosphere, to (COCl) ₂ (560.00 mg,4.41mmol,1.20 eq.) in DCM (40 mL) was added dropwise DMSO (0.65 mL,9.19mmol,2.50 eq.). The resulting mixture was stirred at-78℃under nitrogen for 30min. 2- (hydroxymethyl) -2-methylazetidine was added dropwise to the above mixture at-78deg.CTert-butyl alkyl-1-carboxylate (740.00 mg,3.68mmol,1.00 eq.). The resulting mixture was stirred at-78℃for a further 30min. The desired product can be detected by TLC. TEA (2.56 mL,18.39mmol,5.00 eq.) was added to the above mixture at-78deg.C. The resulting mixture was stirred at 0deg.C for a further 30min. The resulting mixture was treated with CH ₂ Cl ₂ (3X 40 mL) extraction. The combined organic layers were washed with water (3×50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude 2-formyl-2-methylazetidine-1-carboxylic acid tert-butyl ester (750.00 mg, 102.38%) was used directly in the next step without further purification.

183.2: synthesis of tert-butyl 2-ethynyl-2-methylazetidine-1-carboxylate

K was added dropwise to a stirred solution of tert-butyl 2-formyl-2-methylazetidine-1-carboxylate (750.00 mg,3.76mmol,1.00 eq.) in MeOH (10 mL) at 0deg.C under nitrogen ₂ CO ₃ (1.04 g,7.53mmol,2.00 eq.) and Seyferth-Gilbert homologating reagent (868.00 mg,4.52mmol,1.20 eq.). The resulting mixture was stirred at 0℃under nitrogen for 1h. The desired product can be detected by TLC. The reaction was quenched by the addition of aqueous potassium sodium tartrate (5 mL) at 0deg.C. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (10:1) to give tert-butyl 2-ethynyl-2-methylazetidine-1-carboxylate (440.00 mg, 59.86%) as a colorless oil.

183.3: synthesis of tert-butyl 2- [2- (4- [3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl ] pyridin-3-yl) ethynyl ] -2-methylazetidine-1-carboxylate

3- [ (3-chloro-2-methoxyphenyl) amino group was added to a 20 mL-sealed tube at room temperature]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (540.00 mg,1.09mmol,1.00 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (178.00 mg,0.22mmol,0.20 eq.) and CuI (83.00 mg,0.44mmol,0.40 eq.) and DIEA (846.00 mg,6.55mmol,6.00 eq.) and DMF (5 0 mL). To the above mixture was added dropwise tert-butyl 2-ethynyl-2-methylazetidine-1-carboxylate (640.00 mg,3.28mmol,3.00 eq.) at room temperature. The resulting mixture was stirred at 50℃under argon for 4h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash chromatography using the following conditions (column: C18 silica gel; mobile phase, ACN in water, gradient 40% to 60%, within 10 min; detector: UV 254 nm) to afford 2- [2- (4- [3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl]Pyridin-3-yl) ethynyl]Tert-butyl 2-methylazetidine-1-carboxylate (640.00 mg, 99.10%) as yellow solid.

LC-MS:(M+H) ⁺ Actual: 562.1.

183.4: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [2- (2-methylazetidin-2-yl) ethynyl ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl 2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-methylazetidine-1-carboxylate (400.00 mg,0.71mmol,1.00 eq.) in DCM (12 mL) was added TFA (4 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [2- (2-methylazetidin-2-yl) ethynyl ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (296.00 mg, 90.04%) as a red oil. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 462.0.

183.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- [2- [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl ] pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-chloro-2-methoxyphenyl) amino group at 0℃under nitrogen atmosphere]-2- [3- [2- (2-methylazetidin-2-yl) ethynyl group]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (300.00 mg,0.65mmol,1.00 eq.) in NaHCO ₃ Stirred solutions of (saturated) (6 mL) and THF (6 mL) were added dropwise to acryloyl chloride (59.00 mg,0.65mmol,1.00 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. The desired product was detectable by LCMS. The reaction was quenched by the addition of MeOH (0.50 mL) at room temperature. The resulting mixture was diluted with water (10 mL). CH for aqueous layer ₂ Cl ₂ (3X 10 mL) extraction. The combined organic layers were concentrated under reduced pressure. The crude product was purified by preparative HPLC and using the following conditions (column: YMC-Actus Triart C18 ExRS, 30X 250mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 21% b to 37% b, 37% b over 10 min; wavelength is 254/220nm; RT1 (min) 9.67; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- [2- [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl)]Ethynyl group]Pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (37.00 mg, 11.04%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 516.2.

183.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (37.00 mg) was purified by chiral preparative HPLC using the following conditions (column: CHIRAL ART Amylose-SA, 2X 25cm,5 μm; mobile phase A: hex (0.5% 2M NH) ₃ -MeOH) -HPLC, mobile phase B EtOH-HPLC; the flow rate is 20mL/min; gradient from 20% b to 20% b, within 20 min; wavelength is 220/254nm; RT1 (min): 12.176; RT2 (min): 16.377; sample solvent EtOH- -HPLC; injection volume 1mL; running number 2) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group ]-2- (3- {2- [ (2R) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (18.80 mg, 49.69%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 516.2.

¹ H NMR(300MHz,DMSO-d ₆ )δ11.14(s,1H),8.76(s,1H),8.40(d,J＝5.2Hz,1H),8.34(s,1H),8.01(s,1H),7.16(d,J＝6.3Hz,2H),6.88(d,J＝8.3Hz,1H),6.77(d,J＝8.3Hz,1H),6.20-5.94(m,2H),5.53(d,J＝3.1Hz,1H),3.73(s,3H),3.36(s,2H),3.11(s,2H),2.83-2.66(m,2H),2.08(s,3H),1.69(s,3H)。

example 184:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2S) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 550)

3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (37.00 mg) was purified by chiral preparative HPLC using the following conditions (column: CHIRAL ART Amylose-SA, 2X 25cm,5 μm; mobile phase A: hex (0.5% 2M NH) ₃ -MeOH) -HPLC, mobile phase B EtOH-HPLC; the flow rate is 20mL/min; gradient from 20% b to 20% b, within 20 min; wavelength is 220/254nm; RT1 (min): 12.176; RT2 (min): 16.377; sample solvent EtOH-)HPLC; injection volume 1mL; running number 2) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2S) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (18.10 mg, 47.89%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 516.1.

¹ H NMR(300MHz,DMSO-d ₆ )δ11.14(s,1H),8.76(s,1H),8.40(d,J＝5.2Hz,1H),8.34(s,1H),8.01(s,1H),7.16(d,J＝6.3Hz,2H),6.88(d,J＝8.3Hz,1H),6.77(d,J＝8.3Hz,1H),6.20-5.94(m,2H),5.53(d,J＝3.1Hz,1H),3.73(s,3H),3.36(s,2H),3.11(s,2H),2.83-2.66(m,2H),2.08(s,2H),1.69(s,3H)。

example 185:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [2- (oxetan-3-yl) ethynyl ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 555)

Stirring 3- [ (3-chloro-2-methoxyphenyl) amino group at 50℃under nitrogen atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100.00 mg,0.20mmol,1.00 eq.) and 3-ethynyloxetane (83.00 mg,1.01mmol,5.00 eq.) and Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (16.00 mg,0.02mmol,0.10 eq.) and CuI (8.00 mg,0.04mmol,0.20 eq.) and TEA (61.00 mg,0.61mmol,3.00 eq.) in DMF (1 mL) for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) to afford crude product. The crude product was purified by preparative HPLC and using the following conditions (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 18% B to 38% B,8min, 38% B; wavelength: 254/220nm; RT1 (min): 7.6; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- {3- [2- (oxetan-3-yl) ethynyl ]]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (16.10 mg, 17.62%) was a dark yellow solid.

LC-MS:(M+H) ⁺ Actual: 449.0.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.58(s,1H),8.59(s,1H),8.38(d,J＝5.3Hz,1H),7.40(s,1H),7.33(d,J＝5.3Hz,1H),7.13(t,J＝2.5Hz,1H),6.68-6.58(m,2H),6.15-6.06(m,1H),4.81-4.77(m,2H),4.64-4.61(m,2H),4.18-4.11(m,1H),3.83(s,3H),3.46-3.41(m,2H),2.85(t,J＝6.8Hz,2H)。

example 186:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- [2- (3-methyloxetan-3-yl) ethynyl ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 554)

3- [ (3-fluoro-2-methoxyphenyl) amino group was added to a 25mL Schlenk (Schlenk) tube at room temperature]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100.00 mg,0.21mmol,1.00 eq.) and Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (85.00 mg,0.11mmol,0.50 eq.) and CuI (20.00 mg,0.11mmol,0.50 eq.) and DIEA (81.00 mg,0.63mmol,3.00 eq.) and DMF (2 mL). 3-ethynyl-3-methyl oxetane (100.50 mg,1.05mmol,5.00 eq.) was added dropwise to the above mixture at room temperature. The resulting mixture was stirred at 50℃under argon for 2h. The reaction was monitored by LCMS. The mixture was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (9:1) to afford crude product. The crude product (150.00 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH OBD column 30 x 150mm 5um, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 17% B to 37% B,8min, 37% B; wavelength: 254/220nm; RT1 (min): 8; running number: 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group ]-2- [3- [2- (3-methyl oxetan-3-yl) ethynyl group]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (26.50 mg, 28.33%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 447.0.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.50(s,1H),8.57(s,1H),8.38(d,J＝5.3Hz,1H),7.42(s,1H),7.33(d,J＝5.3Hz,1H),7.13(t,J＝2.6Hz,1H),6.57(td,J＝8.3,6.0Hz,1H),6.43(ddd,J＝11.0,8.4,1.5Hz,1H),5.93(dt,J＝8.2,1.3Hz,1H),4.75(d,J＝5.4Hz,2H),4.42(d,J＝5.4Hz,2H),3.91-3.82(m,3H),3.43(td,J＝6.9,2.5Hz,2H),2.84(t,J＝6.8Hz,2H),1.63(s,3H)。

example 187:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- [2- (3-methoxyoxetan-3-yl) ethynyl ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 553)

3- [ (3-fluoro-2-methoxyphenyl) amino group was added to a 25mL Schlenk tube at room temperature]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100.00 mg,0.21mmol,1.00 eq.) and Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (85.00 mg,0.11mmol,0.50 eq.) and CuI (20.00 mg,0.11mmol,0.50 eq.) and DIEA (81.00 mg,0.63mmol,3.00 eq.) and DMF (2 mL). 3-ethynyl-3-methoxyoxetane (117.22 mg,1.05mmol,5.00 eq.) was added dropwise to the above mixture at room temperature. The resulting mixture was stirred at 50℃under argon for 2h. The reaction was monitored by LCMS. The mixture was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (9:1) to afford crude product. The crude product (150.00 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH OBD column 30 x 150mm 5um, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 20% B to 41% B,8min, 41% B; wavelength: 254/220nm; RT1 (min): 7.0; running number: 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino ]-2- [3- [2- (3-methoxyoxetan-3-yl) ethynyl group]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (46.30 mg, 47.59%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 463.0.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.59(s,1H),8.68(s,1H),8.44(d,J＝5.2Hz,1H),7.40(s,1H),7.37(d,J＝5.3Hz,1H),7.14(d,J＝2.6Hz,1H),6.57(td,J＝8.3,6.1Hz,1H),6.42(ddd,J＝11.0,8.4,1.5Hz,1H),5.94(dt,J＝8.3,1.2Hz,1H),4.76(d,J＝6.9Hz,2H),4.64(d,J＝6.8Hz,2H),3.86(s,3H),3.42(td,J＝6.9,2.5Hz,2H),3.27(s,3H),2.82(t,J＝6.8Hz,2H)。

example 188:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- [3- [2- (oxetan-3-yl) ethynyl ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 552)

3- [ (3-fluoro-2-methoxyphenyl) amino group was added to a 25mL Schlenk tube at room temperature]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100.00 mg,0.21mmol,1.00 eq.) and Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (85.00 mg,0.11mmol,0.50 eq.) and CuI (20.00 mg,0.11mmol,0.50 eq.) and DIEA (81.00 mg,0.63mmol,3.00 eq.) and DMF (2 mL). 3-Acetyleneoxetane (86.00 mg,1.05mmol,5.00 eq.) was added dropwise to the above mixture at room temperature. The resulting mixture was stirred at 50℃under argon for 2h. The reaction was monitored by LCMS. The mixture was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (9:1) to afford crude product. The crude product (150.00 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH OBD column 30 x 150mm 5um, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 17% B to 37% B,8min, 37% B; wavelength: 254/220nm; RT1 (min): 8; running number: 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group ]-2- [3- [2- (oxetan-3-yl) ethynyl group]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (49.60 mg, 54.58%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 432.0.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.53(s,1H),8.52(d,J＝84.7Hz,2H),7.45(s,1H),7.36(d,J＝4.3Hz,1H),7.15(d,J＝2.5Hz,1H),6.57(td,J＝8.3,6.1Hz,1H),6.44(ddd,J＝10.9,8.3,1.5Hz,1H),5.95(dt,J＝8.3,1.3Hz,1H),4.79(dd,J＝8.5,5.4Hz,2H),4.63(dd,J＝7.1,5.4Hz,2H),4.16(tt,J＝8.6,7.1Hz,1H),3.87(s,3H),3.43(td,J＝6.9,2.5Hz,2H),2.85(t,J＝6.8Hz,2H)。

example 189:3- [ (3-chloro-2-methylphenyl) amino ] -2- (3- {2- [1- (difluoromethyl) cyclopropyl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 556)

189.1: synthesis of 1-chloro-3-isothiocyanato-2-methylbenzene

At 0deg.C under nitrogen, in 2-methyl-3-chloroaniline (20.00 g,141.24mmol,1.00 eq.) in DCM (100 mL) and NaHCO ₃ To the solution in (aq.100 mL) was added thiophosgene (16.24 g,141.24mmol,1.00 eq.) dropwise. The mixture was stirred at room temperature under nitrogen for 2h. The reaction was monitored by TLC. The resulting mixture was extracted with DCM (3X 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE to give 1-chloro-3-isothiocyanato-2-methylbenzene (21.00 g, 80.96%) as a yellow oil.

189.2: synthesis of 3- [ (3-chloro-2-methylphenyl) thiocarbamoyl ] -4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 2, 4-dioxopiperidine-1-carboxylate (21.40 g,100.36mmol,1.00 eq.) and 1-chloro-3-isothiocyanato-2-methylbenzene (20.27 g,110.40mmol,1.10 eq.) in ACN (200 mL) was added DBU (22.92 g,150.54mmol,1.50 eq.) and then stirred at room temperature for 2h. The mixture was acidified to pH 6 with aqueous HCl. The precipitated solid was collected by filtration and washed with water (3×10 mL) to afford 3- [ (3-chloro-2-methylphenyl) thiocarbamoyl ] -4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (32.20 g, 80.84%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 397.0.

189.3: synthesis of tert-butyl 4- [ [ (3-bromopyridin-4-yl) methyl ] amino ] -3- [ (3-chloro-2-methylphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydropyridine-1-carboxylate

To 3- [ (3-chloro-2-methylphenyl) thiocarbamoyl group at 0℃under nitrogen atmosphere]A stirred mixture of tert-butyl 4-hydroxy-2-oxo-5, 6-dihydropyridine-1-carboxylate (21.00 g,52.91mmol,1.00 eq.) and 1- (3-bromopyridin-4-yl) methylamine (9.90 g,52.91mmol,1.00 eq.) in DMF (400 mL) was added PyBop (41.30 g,79.37mmol,1.50 eq.) and DIEA (13.68 g,105.82mmol,2.00 eq.). The resulting mixture was stirred at room temperature under nitrogen for 2h. The reaction was quenched with water. The resulting mixture was extracted with EA (3X 300 mL). The combined organic layers were washed with brine (3×200 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA (0% to 100% gradient in 40 min) in PE to provide 4- [ [ (3-bromopyridin-4-yl) methyl group]Amino group]-3- [ (3-chloro-2-methylphenyl) thiocarbamoyl]-2-oxo-5, 6-dihydropyridine-1-carboxylic acid tert-butyl ester (26.20 g, 87.50%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 565.0.

189.4: synthesis of 2- (3-bromopyridin-4-yl) -3- [ (3-chloro-2-methylphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At room temperature, 4- [ [ (3-bromopyridin-4-yl) methyl]Amino group]-3- [ (3-chloro-2-methylphenyl) thiocarbamoyl]A stirred mixture of tert-butyl-2-oxo-5, 6-dihydropyridine-1-carboxylate (26.00 g,45.94mmol,1.00 eq.) in MeOH (300 mL) was added to H ₂ O ₂ (6.77 g,59.73mmol,1.30 g.)Amount, 30 w/w%). The resulting mixture was stirred at 80 ℃ overnight. The reaction was carried out by adding saturated Na ₂ SO ₃ Quenching with water solution. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions (column: C18 silica gel; mobile phase, ACN in water, gradient 0% to 60%, 30 min; detector: UV 254 nm) to afford 2- (3-bromopyridin-4-yl) -3- [ (3-chloro-2-methylphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (8.50 g, 42.85%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 431.0.

189.5: synthesis of 3- [ (3-chloro-2-methylphenyl) amino ] -2- (3- {2- [1- (difluoromethyl) cyclopropyl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- (3-bromopyridin-4-yl) -3- [ (3-chloro-2-methylphenyl) amino group at 50℃under argon atmosphere]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (100.00 mg,0.23mmol,1.00 eq.) and 1- (difluoromethyl) -1-ethynylcyclopropane (54.00 mg,0.46mmol,2.00 eq.) in DMF (2.5 mL) was added Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (94.00 mg,0.12mmol,0.50 eq.) and CuI (22.00 mg,0.12mmol,0.50 eq.) and DIEA (90.00 mg,0.69mmol,3.00 eq.) were then stirred overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) to afford crude product. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18OBD column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 40% b to 52% b, 52% b over 10 min; wavelength is 220/254nm; RT1 (min) 9.25; running number 0) to provide 3- [ (3-chloro-2-methylphenyl) amino group]-2- (3- {2- [1- (difluoromethyl) cyclopropyl)]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (27.70 mg, 25.36%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 417.0.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.34(s,1H),8.54(s,1H),8.32(s,1H),7.31-7.10(m,3H),6.74-6.66(m,2H),6.17(d,J＝7.8Hz,1H),5.81(t,J＝55.7Hz,1H),3.46-3.41(m,2H),2.83(t,J＝6.8Hz,2H),2.30(s,3H),1.28-1.19(m,4H)。

example 190:3- ((3-fluoro-2-methoxyphenyl) amino) -2- (3- ((1- (trifluoromethyl) cyclopropyl) ethynyl) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (compound 559)

3- [ (3-fluoro-2-methoxyphenyl) amino group was added to a 25mL Schlenk tube at room temperature]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100.00 mg,0.21mmol,1.00 eq.) and Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (85.00 mg,0.11mmol,0.50 eq.) and CuI (20.00 mg,0.11mmol,0.50 eq.) and DIEA (81.00 mg,0.63mmol,3.00 eq.) and DMF (2 mL). 1-ethynyl-1- (trifluoromethyl) cyclopropane (56.00 mg,0.42mmol,2.00 eq.) was added dropwise to the above mixture at room temperature. The resulting mixture was stirred at 50℃under argon for 2h. The reaction was monitored by LCMS. The mixture was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (9:1) to afford crude product. The crude product (80.00 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30 x 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 34% b to 64% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number 0) to provide 3- ((3-fluoro-2-methoxyphenyl) amino) -2- (3- ((1- (trifluoromethyl) cyclopropyl) ethynyl) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3, 2-c)]Pyridin-4-one (49.60 mg, 54.58%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 485.0.

¹ H NMR(300MHz,DMSO-d ₆ )δ11.45(s,1H),8.58(s,1H),8.40(d,J＝5.3Hz,1H),7.36(s,1H),7.33(d,J＝5.3Hz,1H),7.12(d,J＝2.6Hz,1H),6.56(td,J＝8.3,6.0Hz,1H),6.42(ddd,J＝10.1,8.4,1.5Hz,1H),5.91(d,J＝8.3Hz,1H),3.87(s,3H),3.43(td,J＝6.9,2.5Hz,2H),2.82(t,J＝6.8Hz,2H),1.47(td,J＝6.4,2.5Hz,2H),1.43-1.28(m,2H)。

example 191:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [1- (fluoromethyl) cyclopropyl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 561)

3- [ (3-chloro-2-methoxyphenyl) amino group was added to a 20 mL-sealed tube at room temperature ]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100.00 mg,0.20mmol,1.00 eq.), cuI (19 mg,0.10mmol,0.5 eq.), pd (dppf) Cl ₂ .CH ₂ Cl ₂ (82 mg,0.10mmol,0.50 eq.), DMF (2 mL), 1-ethynyl-1- (fluoromethyl) cyclopropane (99.00 mg,1.01mmol,5.00 eq.) and DIEA (0.50 mL,2.86mmol,14.3 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was treated with CH ₂ Cl ₂ (3X 10 mL) washing. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford 3- [ (3-chloro-2-methoxyphenyl) amino)]-2- (3- {2- [1- (fluoromethyl) cyclopropyl ]]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (8.10 mg, 8.62%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 465.0.

¹ h NMR (300 MHz, methanol-d) ₄ )δ8.50(s,1H),8.21(s,1H),7.66-7.47(m,1H),7.39(d,J＝5.3Hz,1H),6.69-6.56(m,1H),6.21(dd,J＝7.6,2.0Hz,1H),4.49(s,1H),4.33(s,1H),3.95(s,3H),3.61(t,J＝6.9Hz,2H),2.97(t,J＝6.9Hz,2H),1.27-1.18(m,2H),1.09(t,J＝3.5Hz,2H)。

Example 192:2- [3- (2-Cyclopropylethynyl) pyridin-4-yl ] -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 563)

Stirring 3- [ (3-fluoro-2-methoxyphenyl) amino group at 50℃under nitrogen atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100.00 mg,0.21mmol,1.00 eq.) and ethynylcyclopropane (69.00 mg,1.05mmol,5.00 eq.) and Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (17.00 mg,0.02mmol,0.10 eq.) and CuI (8.00 mg,0.04mmol,0.20 eq.) and TEA (63.00 mg,0.63mmol,3.00 eq.) in DMF (1 mL) for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) to afford crude product. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 26% b to 50% b, 50% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 2- [3- (2-cyclopropylethynyl) pyridin-4-yl]-3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (19.10 mg, 21.85%) was a dark yellow solid.

LC-MS:(M+H) ⁺ Actual: 417.0.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.43(s,1H),8.53(s,1H),8.33(d,J＝5.1Hz,1H),7.42-7.22(m,2H),7.12(s,1H),6.58(q,J＝7.4Hz,1H),6.42(t,J＝9.7Hz,1H),5.95(d,J＝8.3Hz,1H),3.88(s,3H),3.44(t,J＝6.8Hz,2H),2.85(t,J＝6.8Hz,2H),1.61-1.54(m,1H),0.92-0.79(m,4H)。

example 193:3- [ (3-chloro-2-methylphenyl) amino ] -2- [3- (2-cyclopropylethynyl) pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 562)

At room temperature, add to 25mL Schlenk tubeInto 2- (3-bromopyridin-4-yl) -3- [ (3-chloro-2-methylphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (100.00 mg,0.23mmol,1.00 eq.) and Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (94.00 mg,0.12mmol,0.50 eq.) and CuI (44.00 mg,0.23mmol,1.00 eq.) and DIEA (180.00 mg,1.39mmol,6.00 eq.) and DMF (2 mL). Ethynyl cyclopropane (46.00 mg,0.70mmol,3.00 eq.) was added dropwise to the above mixture at room temperature. The resulting mixture was stirred at 65℃under argon for 2h. The reaction was monitored by LCMS. The mixture was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (9:1) to afford crude product. The crude product (80.00 mg) was purified by preparative HPLC and using the following conditions (column: XBridge Prep OBD C column, 30 x 150mm,5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 22% B to 52% B over 7 min; wavelength: 254nm; RT1 (min): 6.5; running number: 0) to provide 3- [ (3-chloro-2-methylphenyl) amino group]-2- [3- (2-cyclopropylethynyl) pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (5.20 mg, 5.12%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 417.0.

¹ H NMR(300MHz,DMSO-d ₆ )δ11.37(s,1H),8.49(s,1H),8.28(d,J＝5.3Hz,1H),7.23(t,J＝4.5Hz,2H),7.14(s,1H),6.69(d,J＝7.6Hz,2H),6.17(d,J＝7.2Hz,1H),3.44(s,2H),2.85(s,2H),2.32(s,3H),1.57(s,1H),0.91(dt,J＝6.0,3.0Hz,2H),0.77(dd,J＝5.1,2.7Hz,2H)。

example 194:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- [2- (1-hydroxycyclopropyl) ethynyl ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 564)

194.1: synthesis of 1-ethoxycyclopropyl-1-ols

To a 50mL round bottom flask was added (1-ethoxycyclopropoxy) trimethylsilane (2.00 g,11.47mmol,1.00 eq.) in methanol (10.00 mL). The resulting mixture was stirred at room temperature under nitrogen for 8h. The resulting mixture was concentrated under reduced pressure to give 1-ethoxycyclopropyl-1-ol (1.00 g, 85.34%) as a pale yellow oil.

¹ H NMR (400 MHz, chloroform-d) δ3.77 (q, j=7.1 hz, 2H), 3.52 (brs, 1H), 1.22 (t, j=7.1 hz, 3H), 0.94 (dt, j=8.0, 2.1hz, 4H).

194.2: synthesis of 1- [2- (trimethylsilyl) ethynyl ] cyclopropyl-1-ol

To a stirred solution of 1-ethoxycyclopropyl-1-ol (1.00 g,9.79mmol,1.00 eq.) in THF (7.50 mL) was added dropwise MeMgBr (4.24 mL,12.73mmol,1.30 eq.) under nitrogen at 0 ℃. The reaction was stirred for 1h. To a stirred solution of trimethylsilylacetylene (1.06 g,10.79mmol,1.10 eq.) in THF (7.50 mL) at-78deg.C under nitrogen was added dropwise n-BuLi (4.50 mL,11.26mmol,1.15 eq.). At 0℃the [ (trimethylsilyl) ethynyl group obtained]Lithium was added to a solution of 1-ethoxycyclopropanemagnesium bromide. The mixture was allowed to warm to room temperature and held for 16h. Saturated NH at 0deg.C ₄ The reaction was quenched with aqueous Cl. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 1- [2- (trimethylsilyl) ethynyl group]Cyclopropyl-1-ol (600.00 mg, 39.72%) as a yellow oil.

GC-MS:(M+H) ⁺ Actual: 154.0.

194.3: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- [3- [2- (1-hydroxycyclopropyl) ethynyl ] pyridin-4-yl ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (3-chloro-2-methoxyphenyl) amino group was added to a 25mL Schlenk tube at room temperature ]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (200.00 mg,0.40mmol, 1)00 eq.) and Pd (dppf) Cl ₂ (147.90 mg,0.20mmol,0.50 eq.) and CuI (38.50 mg,0.20mmol,0.50 eq.) and DIEA (156.75 mg,1.21mmol,3.00 eq.) and DMF (4.00 mL). 1- [2- (trimethylsilyl) ethynyl was added dropwise to the above mixture at room temperature]Cyclopropyl-1-ol (149.69 mg,0.97mmol,2.40 eq). The resulting mixture was stirred at 50℃under argon for 2h. The reaction was monitored by LCMS. The mixture was purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (9:1) to afford crude product. The crude product (350.00 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH OBD column 30 x 150mm 5um, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 19% B to 37% B, over 7min, 37% B; wavelength: 254/220nm; RT1 (min): 7; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- [3- [2- (1-hydroxycyclopropyl) ethynyl group]Pyridin-4-yl]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (14.20 mg, 7.79%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 449.0.

¹ h NMR (400 MHz, methanol-d) ₄ )δ8.54(s,1H),8.23(d,J＝5.5Hz,1H),7.42(d,J＝5.4Hz,1H),6.65(d,J＝8.0Hz,1H),6.60(t,J＝8.0Hz,1H),6.20(dd,J＝7.9,1.7Hz,1H),3.96(s,3H),3.61(t,J＝6.9Hz,2H),2.98(t,J＝6.9Hz,2H),1.15(s,4H)。

Example 195:2- (3- {2- [ (2R) -1- (but-2-ynyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 208)

195.1: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [2- (pyrrolidin-2-yl) ethynyl ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl 2- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] pyrrolidine-1-carboxylate (100.00 mg,0.18mmol,1.00 eq.) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [2- (pyrrolidin-2-yl) ethynyl ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (220.00 mg, 91.01%) as a red oil. The crude product was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 462.1.

195.2: synthesis of 2- (3- {2- [1- (but-2-ynyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (3-chloro-2-methoxyphenyl) amino group was cleaved with DIEA]-2- {3- [2- (pyrrolidin-2-yl) ethynyl]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (200.00 mg,0.15mmol,1.00 eq.) in THF (5 mL) was basified to pH 8. 2-butynoic acid (25.00 mg,0.29mmol,2.00 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (140.00 mg,0.22mmol,1.50 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 110 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (60 mg) which was purified by preparative HPLC (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 13% B to 43% B, 43% B over 7 min; wavelength: 254nm; RT1 (min): 6.07; running number: 0) to provide 2- (3- {2- [1- (but-2-ynyl) pyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (56.00 mg, 72.05%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 528.2.

195.3: synthesis of 2- (3- {2- [ (2R) -1- (but-2-ynyl) pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- (3- {2- [1- (but-2-ynyl) pyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (56.00 mg,0.11mmol,1.00 eq.) was purified by preparative HPLC and using the following conditions (column: CHIRAL ART Amylose-SA, 2X 25cm,5 μm; mobile phase A: MTBE (0.5% 2 MNH) ₃ -MeOH) -HPLC, mobile phase B IPA-HPLC; the flow rate is 20mL/min; gradient from 30% b to 30% b,15 min; wavelength is 220/254nm; RT1 (min): 9.646; RT2 (min): 13.616; sample solvent EtOH- -HPLC; injection volume 0.67mL; running number: 6) to provide 2- (3- {2- [ (2R) -1- (but-2-ynyl) pyrrolidin-2-yl)]Ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (18.20 mg, 32.34%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 528.0.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.96(s,1H),8.49(d,J＝11.2Hz,1H),8.25(s,1H),7.28(q,J＝5.6Hz,2H),6.61(d,J＝22.5Hz,3H),6.14(m,1H),4.85(s,1H),3.85(d,J＝12.3Hz,3H),3.64(s,1H),3.44(q,J＝7.1Hz,3H),2.78(s,2H),2.26(d,J＝26.0Hz,1H),2.13-2.00(m,2H),1.95(s,4H)。

example 196:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 212)

196.1: synthesis of tert-butyl (2S) -2- { [ (4-bromopyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

At 0℃under N ₂ Under the atmosphereTo a stirred mixture of tert-butyl (2S) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (1.39 g,6.90mmol,1.20 eq.) and 4-bromopyridin-3-ol (1.00 g,5.75mmol,1.00 eq.) in THF was added PPh ₃ (2.26 g,8.62mmol,1.50 eq.) and stirred for 30min, then DEAD (1.50 g,8.62mmol,1.50 eq.) was added in portions under nitrogen at 0℃and stirred overnight. Concentrating under reduced pressure. The crude product was purified by preparative HPLC and using the following conditions (column: C18; mobile phase, ACN in water, gradient 10% to 70%, 30 min; detector: UV 254 nm) to afford (2S) -2- { [ (4-bromopyridin-3-yl) oxy ]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (1.70 g, 82.80%) was a tan oil.

LC-MS:(M+H) ⁺ Actual: 357.0.

196.2: synthesis of tert-butyl (2S) -2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

(2S) -2- { [ (4-bromopyridin-3-yl) oxy was added to a 100mL round bottom flask at 50 ℃]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (500.00 mg,1.40mmol,1.00 eq.) 2- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (477.00 mg,1.82mmol,1.30 eq.) Cs ₂ CO ₃ (1.37 g,4.20mmol,3.00 eq.) XPhos palladium (II) biphenyl-2-amine chloride (110.00 mg,0.14mmol,0.10 eq.), dioxane (5 mL) and H ₂ O (1 mL). Then concentrated and the residue was purified by reverse phase flash chromatography and the following conditions were used: (column: C18; mobile phase, ACN in water, gradient 10% to 80%, within 30 min; detector: UV 254 nm) to provide (2S) -2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-C)]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (400.00 mg, 69.29%) was a brown solid.

LC-MS:(M+H) ⁺ Actual: 413.2.

196.3: synthesis of tert-butyl (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

A solution of (2S) -2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (510.00 mg,1.24mmol,1.00 eq) and NIS (278.17 mg,1.24mmol,1.00 eq) in DMF (5 mL) was stirred at room temperature under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The residue was purified by reverse phase flash chromatography using the following conditions (column: C18 silica gel; mobile phase, ACN in water, gradient 10% to 50%, within 10 min; detector: UV 254 nm) to afford tert-butyl (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-C ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (500.00 mg, 75.11%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 539.0.

196.4: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

Under argon atmosphere, to (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (100.00 mg,0.19mmol,1.00 eq.) and 3-fluoro-2-methoxyaniline (39.00 mg,0.28mmol,1.50 eq.) in DMF (1 mL) was added Ephos Pd G4 (17.00 mg,0.02mmol,0.10 eq.) and Cs ₂ CO ₃ (121.00 mg,0.37mmol,2.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (20:1) elution to afford (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (100.00 mg, 97.60%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 552.1.

196.5: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (100.00 mg,0.18mmol,1.00 eq.) in DCM (3 mL) was added TFA (1 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (210.00 mg, crude) as a brown oil.

LC-MS:(M+H) ⁺ Actual: 452.1.

196.6: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-fluoro-2-methoxyphenyl) amino group at 0℃under nitrogen atmosphere]-2- {3- [ (2S) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (180.00 mg,0.15mmol,1.00 eq.) in NaHCO ₃ (saturated) (1.50 mL) and THF (1.50 mL) was added dropwise to the stirred solution of acryloyl chloride (12.34 mg,0.14mmol,0.90 eq.). Stirring the resulting mixture at room temperature under nitrogen atmosphereCompound 1h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) to afford crude product (70.00 mg). The crude product (70.00 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 19% b to 42% b, 42% b over 9 min; wavelength is 254/220nm; RT1 (min) 9.67; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- { [ (2S) -1- (prop-2-enoyl) pyrrolidin-2-yl ]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (12.30 mg, 15.63%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 506.0.

¹ h NMR (400 MHz, chloroform-d) δ11.49 (s, 1H), 8.21 (s, 1H), 7.97 (d, j=5.3 hz, 1H), 7.58 (s, 1H), 7.55 (d, j=5.3 hz, 1H), 6.62-6.37 (m, 4H), 6.07 (d, j=8.1 hz, 1H), 5.78 (d, j=10.3 hz, 1H), 5.20 (s, 1H), 5.11-4.97 (m, 1H), 4.26 (t, j=9.6 hz, 1H), 4.14-4.08 (m, 4H), 3.76 (t, j=6.7 hz, 2H), 3.66-3.54 (m, 2H), 3.21 (t, j=6.8 hz, 2H), 2.25-1.95 (m, 4H).

Example 197:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- [ (2E) -4- (pyrrolidin-1-yl) but-2-enoyl ] pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 229)

197.1: synthesis of (R, E) -2- (3- ((1- (4-bromobut-2-enoyl) pyrrolidin-2-yl) ethynyl) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (40.00 mg,0.08mmol,1.00 eq.) and DIEA (34.00 mg,0.26mmol,3.00 eq.) in DCM (2.50 mL) was added dropwise (2E) -4-bromobut-2-enoyl chloride (19.00 mg,0.10mmol,1.2 eq.) at 0 ℃ under nitrogen. The resulting mixture was stirred at 0℃under nitrogen for 0.5h. The resulting mixture was used directly in the next step without further purification.

LCMS:(M+H) ⁺ Actual: 608.0 and 564.0.

197.2: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- [ (2E) -4- (pyrrolidin-1-yl) but-2-enoyl ] pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Pyrrolidine (19.00 mg,0.26mmol,3.00 eq.) was added dropwise to the mixture obtained in the previous step at 0 ℃. The resulting mixture was stirred at room temperature for a further 48h. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 50 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and dissolved in DMSO. The crude product (100.00 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 10% B to 28% B,8min, 28% B; wavelength: 254/220nm; RT1 (min): 8; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2R) -1- [ (2E) -4- (pyrrolidin-1-yl) but-2-enoyl]Pyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (12.60 mg, 24.29%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 599.6.

¹ h NMR (400 MHz, chloroform-d) δ11.12 (s, 1H), 8.56 (s, 1H), 8.17 (d, j=5.6 hz, 1H), 7.72 (s, 1H), 7.44 (d, j=5.6 hz, 1H), 6.97 (m, j=15.2, 6.4hz, 1H), 6.73 (m, j=8.0, 1.5hz, 1H), 6.62 (t, j=8.1 hz, 1H), 6.52 (m, j=15.0, 1.5hz, 1H), 6.24 (m, j=8.2, 1.5hz, 1H), 5.52 (s, 1H), 4.91 (m, j=7.3, 4.6hz, 1H), 4.09 (s, 3H), 3.82 (m, j=10.0, 6.4hz, 1H), 3.73-3.54 (m, j=15.0, 1.5hz, 1H), 6.24 (m, j=2.5 hz, 1H), 6.20 (2 j=2.5, 1H), 6.52 (m, 1H), 4.52 (m, j=2.5 hz, 1H), 4.7.5 (2, 1H) H)。

Example 198:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl ] pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 228)

198.1: synthesis of (R, E) -2- (3- ((1- (4-bromobut-2-enoyl) pyrrolidin-2-yl) ethynyl) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (40.00 mg,0.08mmol,1.00 eq.) and DIEA (34.00 mg,0.26mmol,3.00 eq.) in DCM (2.5 0 ml) was added dropwise (2E) -4-bromobut-2-enoyl chloride (19.00 mg,0.10mmol,1.20 eq.) at 0 ℃ under nitrogen. The resulting mixture was stirred at 0℃under nitrogen for 0.5h. The resulting mixture was used directly in the next step without further purification.

LCMS:(M+H) ⁺ Actual: 608.0 and 564.0.

198.2: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (2R) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl ] pyrrolidin-2-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Morpholine (23.00 mg,0.26mmol,3.00 eq.) was added dropwise to the mixture obtained in the previous step at 0 ℃. The resulting mixture was stirred at room temperature for a further 48h. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 50 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and dissolved in DMSO. The crude product (100.00 mg) was purified by preparative HPLC and using the following conditions (column: xselect)CSH C18 OBD column 30 x 150mm 5 μm, n; mobile phase A water (0.1% FA), mobile phase B ACN; the flow rate is 60mL/min; gradient from 10% b to 27% b, 27% b over 8 min; wavelength is 254/220nm; RT1 (min) 8; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- {2- [ (2R) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl]Pyrrolidin-2-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (16.40 mg, 30.79%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 615.2.

¹ h NMR (400 MHz, chloroform-d) δ11.14 (s, 1H), 8.56 (s, 1H), 8.22-8.13 (m, 1H), 7.72 (s, 1H), 7.44 (d, j=5.6 hz, 1H), 6.95 (m, j=15.1, 6.3hz, 1H), 6.73 (m, j=8.1, 1.5hz, 1H), 6.62 (t, j=8.1 hz, 1H), 6.40 (d, j=15.1 hz, 1H), 6.23 (m, j=8.1, 1.5hz, 1H), 5.64 (t, j=2.5 hz, 1H), 4.92 (m, j=7.2, 4.6hz, 1H), 3.89-3.52 (m, 9H), 3.34-3.17 (m, 4H), 2.9 hz, 2.55 (d, 1.1 hz, 1H), 6.23 (m, 1H), 4.34-3.2 (2H), 2.44 (m, 2.4H).

Example 199:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- [ (3S) -3-methoxypyrrolidin-1-yl ] but-2-enyi-nyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 222)

199.1: synthesis of (R, E) -2- (3- ((1- (4-bromobut-2-enoyl) azetidin-2-yl) methoxy) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (100.00 mg,0.22mmol,1.00 eq.) and DIEA (85.00 mg,0.66mmol,3.00 eq.) in DCM (2 mL) was added dropwise (2E) -4-bromobut-2-enoyl chloride (48.00 mg,0.26mmol,1.20 eq.) at 0 ℃. The resulting mixture was stirred at 25℃for 2h. The desired product was detectable by LCMS. The resulting mixture was used directly in the next step without further purification.

LC-MS:(M+H) ⁺ Actual: 600.0.

199.2: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- [ (3S) -3-methoxypyrrolidin-1-yl ] but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a solution of (3S) -3-methoxypyrrolidine hydrochloride (36.00 mg,0.26mmol,1.20 eq.) in DMF (1 mL) was added K ₂ CO ₃ (90.00 mg,0.65mmol,3.00 eq.) and the mixture stirred for 30min. The mixture is then added to 2- (3- { [ (2R) -1- [ (2E) -4-bromobut-2-enoyl]Azetidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (130.00 mg,0.22mmol,1.00 eq.) in 2mL DCM was stirred at room temperature for 4h. The desired product was detectable by LCMS. The reaction mixture was quenched with water and extracted with DCM (3×10 ml). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 23% B to 53% B, 53% B over 8 min; wavelength is 220/254nm; RT1 (min) 7.25; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (2R) -1- [ (2E) -4- [ (3S) -3-methoxypyrrolidin-1-yl]But-2-enoyl]Azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (29.50 mg, 21.78%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 621.2.

¹ h NMR (300 MHz, chloroform-d) δ11.77 (s, 1H), 8.15 (s, 1H), 7.92 (d, J=5.2 Hz, 1H), 7.46 (s, 1H), 7.38 (d, J=5.2 Hz, 1H), 7.01-6.81 (m, 1H), 6.68-6.47 (m, 2H), 6.22-5.98 (m, 2H), 5.22 (s, 1H), 5.02-4.86 (m, 1H), 4.42 (t, J=9.8 Hz, 1H), 4.29-4.10 (m, 3H), 4.01 (s, 3H), 3.93-3.81 (m, 1H), 3.58-3.46 (m, 2H), 3.34-3.16 (m, 5H), 3.14-2.95 (m, 2H), 2.79-2.39(m,5H),2.10-1.96(m,2H),1.88-1.72(m,1H)。

Example 200:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 220)

200.1: synthesis of (R, E) -2- (3- ((1- (4-bromobut-2-enoyl) azetidin-2-yl) methoxy) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (60.00 mg,0.13mmol,1.00 eq.) and DIEA (51.00 mg,0.39mmol,3.00 eq.) in DCM (3 mL) was added dropwise (2E) -4-bromobut-2-enoyl chloride (29.00 mg,0.15mmol,1.20 eq.) at 0deg.C under nitrogen. The resulting mixture was stirred at 0℃under nitrogen for 0.5h. The resulting mixture was used directly in the next step without further purification.

LCMS:(M+H) ⁺ Actual: 600.0 and 556.0.

200.2: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl ] azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Morpholine (35.00 mg,0.39mmol,3.00 eq.) was added dropwise to the mixture obtained in the previous step at 0 ℃. The resulting mixture was stirred at room temperature overnight. The desired product was detectable by LCMS. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 50 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and dissolved in DMSO. The crude product (100.00 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30 x 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 24% b to 54% b over 7 min; wavelength of 254nm; RT1 (min) 6.5; running number 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ (2R) -1- [ (2E) -4- (morpholin-4-yl) but-2-enoyl]Azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (27.10 mg, 33.77%) was an off-white solid.

LC-MS:(M+H) ⁺ Actual: 607.2.

¹ h NMR (400 MHz, chloroform-d) δ11.82 (s, 1H), 8.26 (s, 1H), 7.99 (d, j=5.3 hz, 1H), 7.64 (s, 1H), 7.47 (d, j=5.3 hz, 1H), 6.94 (m, j=15.3, 6.3hz, 1H), 6.74 (m, j=8.1, 1.5hz, 1H), 6.63 (t, j=8.1 hz, 1H), 6.28-6.07 (m, 2H), 5.26 (d, j=2.6 hz, 1H), 5.04 (q, j=8.5 hz, 1H), 4.53 (t, j=9.8 hz, 1H), 4.41-4.18 (m, 3H), 4.11 (s, 3H), 3.76 (t, j=4.6 hz, 4H), 3.63 (m, j=8.1 hz, 1H), 6.28-6.07 (m, 2H), 5.26 (d, j=2.6 hz, 1H), 4.53 (t, 3.4H), 4.41-4.18 (m, 3H), 3.3.3 hz, 2.3.4H), 2.7-2H (m, 2H), 2.3.7.7 (2H, 2H), 2.7.7.2H, 1H).

Example 201: rel-2- (3- { [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 283)

201.1: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate

Under argon atmosphere, to (2S) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } pyrrolidine-1-carboxylate (400.00 mg,0.74mmol,1.00 eq.) and 3-fluoro-2-methoxyaniline (210.00 mg,1.49mmol,2.00 eq.) in DMF (5 mL) was added EPhos Pd G4 (68.00 mg,0.07mmol,0.10 eq.) and Cs ₂ CO ₃ (484.00 mg,1.49mmol,2.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (20:1) elution to afford (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester (310.00 mg, 75.64%) was a brown solid.

LC-MS:(M+H) ⁺ Actual: 552.0.

201.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } pyrrolidine-1-carboxylate (290.00 mg,0.53mmol,1.00 eq.) in DCM (3 mL) was added TFA (1 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (2S) -pyrrolidin-2-ylmethoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (540.00 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 452.0.

201.3: synthesis of rel-2- (3- { [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl ] pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

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Rel-3- [ (3-fluoro-2-methoxyphenyl) amino group was cleaved with DIEA ]-2- {3- [ (2R) -pyrrolidin-2-ylmethoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (60.00 mg,0.13mmol,1.00 eq.) in THF (2 mL) was basified to pH 8. (2E) -4- (dimethylamino) but-2-enoic acid (26.00 mg,0.20mmol,1.50 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (85.00 mg,0.27mmol,2.00 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (50.00 mg) which was purified by preparative HPLC (column: YMC-ActusTriArt C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH4HCO 3), mobile phase B: ACN; flow rate: 60mL/min; gradient: 20% B to 42% B, 42% B over 10 min; wavelength: 254/220nm; RT1 (min): 8.85; running number: 0) to provide rel-2- (3- { [ (2R) -1- [ (2E) -4- (dimethylamino) but-2-enoyl]Pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (7.50 mg, 9.96%) was a white solid.

LC-MS:(M+H) ⁺ Actual: 563.2.

¹ H NMR (300 MHz, chloroform-d) δ11.51 (s, 1H), 8.23 (s, 1H), 8.01 (d, j=5.3 hz, 1H), 7.56 (d, j=3.9 hz, 2H), 6.97 (d, j=6.2 hz, 1H), 6.68-6.42 (m, 3H), 6.09 (d, j=8.1 hz, 1H), 5.20 (s, 1H), 5.05 (s, 1H), 4.29 (t, j=9.5 hz, 1H), 4.13 (d, j=1.2 hz, 4H), 3.80 (t, j=6.6 hz, 2H), 3.63 (t, j=6.8 hz, 2H), 3.30 (d, j=6.2 hz, 2H), 3.22 (t, j=6.8 hz, 2H), 2.43 (s, 6H), 2.29 (t, j=9.5 hz, 1H), 4.13 (d, j=1.8.2 hz, 1H).

Example 202:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 329)

202.1: synthesis of (2S) -2- (hydroxymethyl) -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

BH was added dropwise to a stirred solution of (2S) -1- (tert-butoxycarbonyl) -2-methylpyrrolidine-2-carboxylic acid (2.00 g,8.72mmol,1.00 eq.) in THF (20 mL) at 0deg.C under nitrogen ₃ THF (13.10 mL,13.09mmol,1.50 eq.). The resulting mixture was stirred at 75℃under nitrogen for 1h. The desired product can be detected by TLC. The reaction was quenched with MeOH at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (20:1) to provide (2S) -2- (hydroxymethyl) -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (1.60 g, 85.20%) as a pale yellow oil.

202.2: synthesis of tert-butyl (2S) -2- { [ (4-cyanopyridin-3-yl) oxy ] methyl } -2-methylpyrrolidine-1-carboxylate

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Cs was added in portions to a stirred mixture of tert-butyl (2S) -2- (hydroxymethyl) -2-methylpyrrolidine-1-carboxylate (1.20 g,5.57mmol,1.00 eq.) and 3-fluoropyridine-4-carbonitrile (681.00 mg,5.57mmol,1.00 eq.) in DMF (12 mL) at room temperature under nitrogen ₂ CO ₃ (5.45 g,16.72mmol,3.00 eq.). The resulting mixture was stirred at 80℃under nitrogen for 2h. The desired product was detectable by LCMS. The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with aqueous NaCl (3X 100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (5:1) to provide (2S) -2- { [ (4-cyanopyridin-3-yl) oxy]Methyl } -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (1.60 g, 90.44%) was a colorless oil.

LC-MS:(M+H) ⁺ Actual: 318.0.

202.3: synthesis of (2S) -2- ({ [4- (aminomethyl) pyridin-3-yl ] oxy } methyl) -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To (2S) -2- { [ (4-cyanopyridin-3-yl) oxy at room temperature under argon atmosphere]Methyl } -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g,3.15mmol,1.00 eq.) and NH in MeOH (10 mL) ₃ (g) A stirred solution in MeOH (20 mL) was added in portions with Raney Ni (200.00 mg,1.86mmol,0.59 eq., 80%). The resulting mixture was stirred at room temperature under hydrogen atmosphere for 2h. The desired product was detectable by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) elution to afford (2S) -2- ({ [4- (aminomethyl) pyridin-3-yl)]Oxy } methyl) -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, 98.75%) as a yellow oil.

LC-MS:(M+H) ⁺ Actual: 322.0.

202.4: synthesis of tert-butyl (2S) -2- [ ({ 4- [ ({ 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl ] -2-oxo-5, 6-dihydro-1H-pyridin-4-yl } amino) methyl ] pyridin-3-yl } oxy) methyl ] -2-methylpyrrolidine-1-carboxylate

To (2S) -2- ({ [4- (aminomethyl) pyridin-3-yl) at room temperature under nitrogen atmosphere]A stirred solution of tert-butyl oxy } methyl) -2-methylpyrrolidine-1-carboxylate (960.00 mg,2.99mmol,1.00 eq.) and N- (3-fluoro-2-methoxyphenyl) -4-hydroxy-2-oxo-5, 6-dihydro-1H-pyridine-3-thiocarboxamide (885.00 mg,2.99mmol,1.00 eq.) in DMF (10 mL) was added DIEA (1.16 g,8.96mmol,3.00 eq.) and PyBOP (2.33 g,4.48mmol,1.50 eq.) in one portion. The resulting mixture was stirred overnight at room temperature under nitrogen. The desired product was detectable by LCMS. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with aqueous NaCl (3X 50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (1:1) to provide (2S) -2- [({ 4- [ ({ 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl)]-2-oxo-5, 6-dihydro-1H-pyridin-4-yl } amino) methyl]Pyridin-3-yl } oxy) methyl]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, 55.83%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 600.0.

202.5: synthesis of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -2-methylpyrrolidine-1-carboxylate

To (2S) -2- [ ({ 4- [ ({ 3- [ (3-fluoro-2-methoxyphenyl) thiocarbamoyl) under a nitrogen atmosphere at room temperature]-2-oxo-5, 6-dihydro-1H-pyridin-4-yl } amino) methyl]Pyridin-3-yl } oxy) methyl]A stirred solution of tert-butyl-2-methylpyrrolidine-1-carboxylate (950.00 mg,1.58mmol,1.00 eq.) in MeOH (10 mL) was added dropwise H ₂ O ₂ (234.00 mg,2.06mmol,1.30 eq., 30%). The resulting mixture was stirred overnight at 80 ℃ under nitrogen. The desired product was detectable by LCMS. The residue was purified by reverse phase flash chromatography using the following conditions (column: C18 column; mobile phase, ACN in water, gradient 0% to 60%, within 10 min; detector: UV 254 nm) to afford (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (240.00 mg, 26.78%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 566.0.

202.6: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -2-methylpyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2S) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -2-methylpyrrolidine-1-carboxylate (100.00 mg,0.18mmol,1.00 eq.) in DCM (1 mL) was added TFA (0.5 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -2-methylpyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (70.00 mg, 85.05%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 466.1.

202.7: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl ] methoxy } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one

To 3- [ (3-fluoro-2-methoxyphenyl) amino group at 0℃under nitrogen atmosphere ]-2- (3- { [ (2S) -2-methylpyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (60.00 mg,0.13mmol,1.00 eq.) in DCM (3 mL) was added dropwise DIEA (50.00 mg,0.39mmol,3.00 eq.) and acryloyl chloride (12.00 mg,0.13mmol,1.00 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. The desired product was detectable by LCMS. The resulting mixture was treated with CH ₂ Cl ₂ MeOH (3X 10 mL) extraction. The combined organic layers were dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo and dissolved in DMSO. The crude product (100.00 mg) was purified by preparative HPLC and using the following conditions (column: XBRID Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH4HCO 3), mobile phase B: ACN; flow rate: 60mL/min; gradient: 20% B to 45% B, 45% B over 9 min; wavelength: 254/220nm; RT1 (min): 8.85; running number: 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- { [ (2S) -2-methyl-1- (prop-2-enoyl) pyrrolidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-ones(9.70 mg, 14.48%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 520.1.

¹ h NMR (400 MHz, chloroform-d) δ11.71 (s, 1H), 8.24 (s, 1H), 7.95 (d, j=5.5 hz, 1H), 7.71 (s, 1H), 7.47 (d, j=5.5 hz, 1H), 6.68-6.41 (m, 3H), 6.35 (m, j=16.6, 2.1hz, 1H), 6.07 (m, j=8.2, 1.4hz, 1H), 5.73 (m, j=10.2, 2.1hz, 1H), 5.22 (s, 1H), 4.41-4.20 (m, 2H), 4.11 (d, j=1.3 hz, 3H), 3.91-3.68 (m, 2H), 3.68-3.50 (m, 2H), 3.12 (m, j=7.6, 2.0 hz, 2.16-2.02 (m, 2.0 hz, 1H), 5.22 (s, 1H), 4.41-4.20 (m, 2H).

Example 203:2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (2-ethoxy-3-fluorophenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 352)

203.1: synthesis of tert-butyl (2R) -2- { [ (4- {3- [ (2-ethoxy-3-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

Under argon atmosphere, to (2R) -2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } azetidine-1-carboxylate (20.00 mg,0.04mmol,1.00 eq.) and 2-ethoxy-3-fluoroaniline (9.00 mg,0.06mmol,1.50 eq.) in DMF (0.3 mL) was added Ephos Pd G4 (4.00 mg,0.01mmol,0.10 eq.) and Cs ₂ CO ₃ (25.00 mg,0.08mmol,2.00 eq.). The resulting suspension was re-aerated three times with argon and stirred at 50 ℃ for 2h. LCMS confirmed the reaction was complete and the desired product was observed. The resulting mixture was filtered through a pad of silica and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography using CH ₂ Cl ₂ MeOH (20:1) elution to provide (2R) -2- { [ (4- {3- [ (2-ethoxy-3-fluorophenyl) amino) ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } azetidine-1-carboxylic acid tert-butyl ester (200.00 mg, 950.58%) as yellowColor solids.

LC-MS:(M+H) ⁺ Actual: 552.2.

203.2: synthesis of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (2-ethoxy-3-fluorophenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of tert-butyl (2R) -2- { [ (4- {3- [ (2-ethoxy-3-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (80.00 mg,0.15mmol,1.00 eq.) in DCM (2 mL) was added TFA (1 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (2-ethoxy-3-fluorophenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (160.00 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 452.1.

203.3: synthesis of 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (2-ethoxy-3-fluorophenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- {3- [ (2R) -azetidin-2-ylmethoxy ] with DIEA ]Pyridin-4-yl } -3- [ (2-ethoxy-3-fluorophenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (65.00 mg,0.14mmol,1.00 eq.) in THF (4 mL) was basified to pH 8. 2-butynoic acid (24.00 mg,0.29mmol,2.00 eq.) was added to the above mixture at 0deg.C under nitrogen, followed by dropwise addition of T ₃ P (69.00 mg,0.22mmol,1.50 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. At 0 ℃, naHCO is added ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (60 mg) which was purified by preparative HPLC under the following conditions (column: XBRID Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 31% b to 61% b, 61% b over 9 min; wavelength is 254/220nm; RT1 (min) 8.85; running number 0) to provide 2- (3- { [ (2R) -1- (but-2-ynyl) azetidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (2-ethoxy-3-fluorophenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (24.70 mg, 33.02%) was a white solid.

LC-MS:(M+H) ⁺ Actual: 518.1.

¹ h NMR (300 MHz, chloroform-d) δ11.42 (s, 1H), 8.25 (s, 1H), 7.94 (d, j=5.4 hz, 1H), 7.73 (s, 1H), 7.43 (d, j=5.4 hz, 1H), 6.62-6.40 (m, 2H), 6.05 (d, j=8.1 hz, 1H), 5.27 (s, 1H), 5.05-4.87 (m, 1H), 4.50 (t, j=9.8 hz, 1H), 4.40-4.18 (m, 5H), 3.64-3.53 (m, 2H), 3.25-3.00 (m, 2H), 2.62 (d, j=2.3 hz, 1H), 2.12 (d, j=7.0 hz, 1H), 2.04 (t, j=7.0 hz, 3H), 1.63-1.47 (m, 3H).

Example 204:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 361)

204.1: synthesis of 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

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To a stirred mixture of tert-butyl (2R) -2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (100.00 mg,0.19mmol,1.00 eq.) in DCM (2 mL) was added TFA (1 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- {3- [ (2R) -azetidin-2-ylmethoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (247.00 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 438.2.

204.2: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- {3- [ (2R) -azetidin-2-ylmethoxy ] with DIEA ]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (81.00 mg,0.19mmol,1.00 eq.) in THF (4 mL) was basified to pH 8. 2-Fluoroprop-2-enoic acid (33.00 mg,0.37mmol,2.00 eq.) was added to the above mixture at 0deg.C under nitrogen atmosphere followed by dropwise addition of T ₃ P (88.00 mg,0.28mmol,1.50 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. At 0 ℃, naHCO is added ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give the crude product (60.00 mg) which was purified by preparative HPLC under the following conditions (column: XBridge Prep C18 OBD column, 30X 100mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 60mL/min; gradient 26% B to 52% B, 52% B within 8 min; wavelength is 254/220nm; RT1 (min) 6.32; running number 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino group]-2- (3- { [ (2R) -1- (2-fluoroprop-2-enoyl) azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (19.20 mg, 20.23%) was a white solid.

LC-MS:(M+H) ⁺ Actual: 510.2.

¹ h NMR (400 MHz, chloroform-d) delta 11.59 (s, 1H), 8.26 (s, 1H), 7.95 (d, j=5.6 hz, 1H), 7.79 (s, 1H), 7.49 (d, j=5.6 hz, 1H), 6.69-6.54 (m, 1H), 6.52 (d, j=9.4 hz, 1H), 6.04 (d, j=8.1 hz, 1H), 5.62 (dd, j=45.7, 3.2hz, 1H), 5.28-5.15 (m, 2H), 5.10 (q, j=8.7 hz, 1H), 4.66-4.38 (m, 3H), 4.32 (d, j=l) 9.6Hz,1H),4.11(s,3H),3.70-3.52(m,2H),3.17-3.08(m,2H),2.77-2.63(m,1H),2.23-2.14(m,1H)。

Example 205:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (1S, 3R, 4R) -2- (prop-2-enoyl) -2-azabicyclo [2.2.1] hept-3-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 274)

205.1: synthesis of tert-butyl (1S, 3R, 4R) -3- (hydroxymethyl) -2-azabicyclo [2.2.1] heptane-2-carboxylate

At 0 ℃, N ₂ To (1S, 3R, 4R) -2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1 under an atmosphere]A stirred solution of heptane-3-carboxylic acid (5 g,20.72mmol,1 eq.) in THF (50 mL) was added drop wise BH3-THF (2.15 g,24.865mmol,1.2 eq.). The resulting mixture was stirred at room temperature under an N2 atmosphere for 2h. The reaction was monitored by TLC. The reaction was carried out by adding saturated NaHCO at 0deg.C ₃ Quenching with water solution. The aqueous layer was extracted with 500ml of EA. The resulting mixture was washed with 500ml of saturated aqueous NaCl solution. The resulting mixture was dried over Na2SO 4. The resulting mixture was concentrated under reduced pressure. This gives (1S, 3R, 4R) -3- (hydroxymethyl) -2-azabicyclo [2.2.1]Tert-butyl heptane-2-carboxylate (3.5 g, 99.78%) as a colorless oil.

LC-MS: M+Hactual: 228.

205.2: synthesis of tert-butyl (1S, 3R, 4R) -3- { [ (4-chloropyridin-3-yl) oxy ] methyl } -2-azabicyclo [2.2.1] heptane-2-carboxylate

A mixture of 4-chloro-3-fluoropyridine (1300 mg,10.559mmol,1 eq.) and NaH (760.14 mg,31.677mmol,3 eq.) in DMF (20 mL) was stirred at 0deg.C under nitrogen for 20min. 4-chloro-3-fluoropyridine (1388.77 mg,10.559mmol,1 eq.) was added portionwise to the above mixture. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water at 0 ℃. The obtainedThe mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (1×200 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (2:1) to provide (1S, 3R, 4R) -3- { [ (4-chloropyridin-3-yl) oxy]Methyl } -2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (1000 mg, 40.25%) was a colorless solid.

LC-MS: M+Hactual: 339.

205.3: synthesis of tert-butyl (1S, 3R, 4R) -3- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -2-azabicyclo [2.2.1] heptane-2-carboxylate

To (1S, 3R, 4R) -3- { [ (4-chloropyridin-3-yl) oxy at 50℃under nitrogen atmosphere]Methyl } -2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (1000 mg,0.0295mmol,1 eq.) 2- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] ]Pyridin-4-one (696.245 mg, 2.650 mmol,1 eq.) and Na2CO3 (563.055 mg,5.312mmol,2 eq.) in THF (10 mL) and H ₂ XPhos Pd G3 (250.00 mg,0.003mmol,0.1 eq.) was added dropwise to a stirred solution of O (5 mL). The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) to afford (1S, 3R, 4R) -3- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (1000 mg, 85.85%) was a colorless solid.

LC-MS: M+Hactual: 439.

205.4: synthesis of tert-butyl (1S, 3R, 4R) -3- ((4- (3-iodo-4-oxo-4, 5,6, 7-tetrahydro-1H-pyrrolo [3,2-c ] pyridin-2-yl) pyridin-3-yloxy) methyl) -2-aza-bicyclo [2.2.1] heptane-2-carboxylate

(1S, 3R, 4R) -3- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) was stirred at 50℃under nitrogen atmosphere]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -2-azabicyclo [2.2.1]A solution h of tert-butyl heptane-2-carboxylate (900 mg,0.38mmol,1 eq.) and NIS (102.6 mg,0.457mmol,1.2 eq.) in DMF (10 mL, 8.616 mmol,226.66 eq.). The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) to afford (1 s,3r,4 r) -3- ((4- (3-iodo-4-oxo-4, 5,6, 7-tetrahydro-1H-pyrrolo [3, 2-c)]Pyridin-2-yl) pyridin-3-yloxy) methyl) -2-aza-bicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (800 mg, 80.85%) was a colorless solid.

LC-MS: M+Hactual: 565.

205.5: synthesis of tert-butyl (1S, 3R, 4R) -3- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -2-azabicyclo [2.2.1] heptane-2-carboxylate

(1S, 3R, 4R) -3- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) was stirred at 50℃under nitrogen atmosphere]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (200 mg,0.354mmol,1 eq.) 3-fluoro-2-methoxyaniline (75.02 mg,0.531mmol,1.5 eq.), EPhos Pd G4 (32.55 mg,0.035mmol,0.1 eq.), EPhos (37.90 mg,0.071mmol,0.2 eq.) and Cs ₂ CO ₃ (346.36 mg,1.062mmol,3 eq.) in DMF (4 mL) for 2h. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue passes throughPurification by silica gel column chromatography using CH ₂ Cl ₂ MeOH (20:1) to afford (1S, 3R, 4R) -3- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (100 mg, 48.85%) as a yellow solid.

LC-MS: M+Hactual: 594.

205.6: synthesis of 2- {3- [ (1S, 3R, 4R) -2-azabicyclo [2.2.1] hept-3-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

(1S, 3R, 4R) -3- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] amino were stirred at room temperature under nitrogen atmosphere]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -2-azabicyclo [2.2.1]A solution of tert-butyl heptane-2-carboxylate (100 mg,0.16.8mmol,1 eq.) and TFA (191.923 mg,1.6830mmol,10 eq.) in DCM (5 mL) for 2h. The reaction was quenched with IPA at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (10:1) to provide 2- {3- [ (1 s,3r,4 r) -2-azabicyclo [ 2.2.1)]Hept-3-ylmethoxy ]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (70 mg, 84.19%) was a brown solid.

LC-MS: M+Hactual: 494.

205.7: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (1S, 3R, 4R) -2- (prop-2-enoyl) -2-azabicyclo [2.2.1] hept-3-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0℃to 2- {3- [ (1S, 3R, 4R) -2-azabicyclo [2.2.1]]Hept-3-ylmethoxy]Pyridin-4-yl } -3- [ (3-chloro)-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (60 mg,0.121mmol,1.0 eq.) and TEA (24.58 mg,0.243mmol,2.0 eq.) in CH ₂ Cl ₂ The stirred solution in (5 mL) was added dropwise with acryloyl chloride (10.98 mg,0.121mmol,1.0 eq.). The resulting mixture was stirred at room temperature for 1h. After completion of the reaction, the mixture was diluted with water, extracted with EA, washed with brine, and dried over Na ₂ SO ₄ Drying to obtain crude product. The residue was purified by preparative TLC (column: sunfire prep C18 column, 30X 150mm,5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 15% B to 45% B, 45% B over 7 min; wavelength: 254/220nm; RT1 (min): 6.9; running number: 0) to afford 3- [ (3-chloro-2-methoxyphenyl) amino group ]-2- (3- { [ (1S, 3R, 4R) -2- (prop-2-enoyl) -2-azabicyclo [2.2.1]Hept-3-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (48.4 mg, 70.634%) was a yellow solid.

LC-MS: M+Hactual: 494.

¹ H NMR(300MHz,DMSO-d6)δ11.73(s,1H),8.46(s,1H),8.00(d,J＝5.0Hz,1H),7.54(s,1H),7.34(d,J＝5.1Hz,1H),7.13(s,1H),6.84–6.57(m,3H),6.26(dd,J＝16.6,2.3Hz,1H),6.14(q,J＝4.4Hz,1H),5.75(dd,J＝10.3,2.3Hz,1H),4.61(s,1H),4.34(dd,J＝10.2,6.6Hz,1H),4.18(dd,J＝10.2,4.6Hz,1H),4.05(d,J＝5.6Hz,1H),3.89(s,3H),3.34(s,2H),2.96(t,J＝6.8Hz,2H),2.57(s,1H),2.00(d,J＝10.4Hz,1H),1.72(d,J＝8.1Hz,2H),1.44(t,J＝9.4Hz,3H)。

example 206:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 512)

206.1: synthesis of tert-butyl 2- { [ (4-chloropyridin-3-yl) oxy ] methyl } -3, 3-dimethyl-azetidine-1-carboxylate

To a solution of tert-butyl (2S) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (2 g,9.937mmol,1 eq.) in THF was added sodium hydride (60% in oil, naH (0.60 g, 14.015 mmol,1.5 eq., 60%)). The mixture was stirred for 15min. 4-chloro-3-fluoropyridine (1.31 g,9.937mmol,1 eq.) was added and the mixture was allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was extracted with DCM (3×25 ml) with water and quenched. Thus, tert-butyl 2- { [ (4-chloropyridin-3-yl) oxy ] methyl } -3, 3-dimethyl azetidine-1-carboxylate (1268 mg, 41.76%) was provided as a yellow oil.

LC-MS: M+Hactual: 327.35.

206.2: synthesis of tert-butyl 3, 3-dimethyl-2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

To 2- { [ (4-chloropyridin-3-yl) oxy]Methyl } -3, 3-Dimethylazetidine-1-carboxylic acid tert-butyl ester (1168 mg, 3.514 mmol,1 eq.) and 2- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]]Pyridin-4-one (1405.16 mg,5.361mmol,1.5 eq.) in THF (12 mL) and H ₂ Na was added to the solution in O (3 mL) ₂ CO ₃ (757.57 mg,7.148mmol,2 eq.) and XPhos Pd G3 (302.51 mg, 0.356 mmol,0.1 eq.). After stirring at 50℃under nitrogen for 2 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM and MeOH (92:8) to give 3, 3-dimethyl-2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (1200 mg, 78.72%) as a yellow solid.

LC-MS: M+Hactual: 427.15.

206.3: synthesis of tert-butyl 2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -3, 3-dimethyl azetidine-1-carboxylate

To a stirred solution of tert-butyl 3, 3-dimethyl-2- { [ (4- { 4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (1200 mg,2.813mmol,1 eq.) in DMF (12 mL) was added NIS (949.49 mg,4.220mmol,1.5 eq.) in portions at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (DCM and MeOH 15:1) to give tert-butyl 2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -3, 3-dimethyl azetidine-1-carboxylate (1450 mg, 93.30%) as a yellow solid.

LC-MS: M+Hactual: 553.1.

206.4: synthesis of tert-butyl 2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -3, 3-dimethyl azetidine-1-carboxylate

To 2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] at room temperature under an N2 atmosphere]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } -3, 3-dimethyl-azetidine-1-carboxylate (1400 mg, 2.284 mmol,1 eq.) and 3-chloro-2-methoxyaniline (1198.23 mg,7.602mmol,3 eq.) in DMF (15 mL) was added Cs in portions ₂ CO ₃ (2477.21 mg,7.602mmol,3 eq.) and Ephos Pd G4 (232.79 mg, 0.255 mmol,0.1 eq.). The resulting mixture was stirred at 50℃under an N2 atmosphere for 2 hours. The resulting mixture was filtered, followed by washing the filter cake with EA (1 x1 100 ml). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM and MeOH 20:1) to give 2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -3, 3-dimethyl-azetidine-1-carboxylic acid tert-butyl ester (1.4 g, 94.90%) was a pale yellow solid.

206.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ (3, 3-dimethylbenzimidazol-2-yl) methoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] at room temperature]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl methyl } -3, 3-dimethyl-azetidine-1-carboxylate (1.5 g,2.577mmol,1 eq.) in DCM (15 mL) was added dropwise TFA (7 mL,94.241mmol,36.57 eq.). The resulting mixture was stirred at room temperature for 1.5 hours. DCM and H for aqueous layer ₂ O (3X 1 150 mL) extraction. Thereby providing 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- {3- [ (3, 3-dimethyl azetidin-2-yl) methoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (1.1 g, 88.57%) was a pale yellow solid.

LC-MS: M+Hactual: 482.45.

206.6: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a mixture of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ (3, 3-dimethylbenzimidazol-2-yl) methoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (700 mg,1.452mmol,1 eq.) in THF (10 mL) and aqueous NaHCO3 (366.02 mg,4.356mmol,3 eq.) was added dropwise acryloyl chloride (131.45 mg,1.452mmol,1 eq.) at 0deg.C. The mixture was stirred at 0℃for 1h. The desired product was detectable by LCMS. The resulting mixture was extracted with EA (3×300 ml). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE: ea=10:1) to afford the crude product. The crude product was purified by preparative HPLC to provide 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (404 mg, 51.89%) as a yellow solid.

LC-MS: M+Hactual: 536.15.

206.7: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

The crude product 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (170 mg,0.317mmol,1 eq) was purified by chiral preparative HPLC and using the following conditions (column CHIRAL ART Amylose-SA, 2X 25cm,5 μm; mobile phase A: hex (0.5% 2M NH3-MeOH) - - -HPLC, mobile phase B: etOH- -HPLC; flow rate: 20mL/min; gradient: 50% B to 50% B,18 min; wavelength: 220/254nm; 1 (min): 6.51; 2 (min): 14.92; sample solvent: etOH- -HPLC; injection volume: 3mL; running number: 2) to provide 3- [ (3-chloro-2) amino ] -2- (3-methoxy-2- (2M) N-methyl-pyridin-4-yl) -1H, 5mg, mobile phase B: etOH- -HPLC; flow rate: 20mL/min; gradient: 50% B,18 min; sample solvent: etOH/220/254 nm; 1 (min; 2) was 1 g).

LC-MS (M+H) + actual: 536.15.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.72(s,1H),8.39(s,1H),7.96(d,J＝5.1Hz,1H),7.43(s,1H),7.32(d,J＝5.0Hz,1H),6.81(s,1H),6.68–6.57(m,2H),6.35(dd,J＝17.0,10.2Hz,1H),6.22–6.11(m,2H),5.69(s,1H),4.56(t,J＝9.0Hz,1H),4.45–4.35(m,2H),3.89(s,4H),3.84(s,1H),3.41(td,J＝6.9,2.4Hz,2H),2.92(s,3H),1.24(d,J＝21.7Hz,6H)。

example 207:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 513)

The crude product 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (170 mg,0.317mmol,1 eq) was purified by chiral preparative HPLC and using the following conditions (column CHIRAL ART Amylose-SA, 2X 25cm,5 μm; mobile phase A: hex (0.5% 2M NH3-MeOH) - - -HPLC, mobile phase B: etOH- -HPLC; flow rate: 20mL/min; gradient: 50% B to 50% B,18 min; wavelength: 220/254nm; 1 (min): 6.51; 2 (min): 14.92; sample solvent: etOH- -HPLC; injection volume: 3mL; running number: 2) to provide 3- [ (3-chloro-2) amino ] -2- (3-methoxy-2- (R3-2-methyl) amino ] -pyridin-4-1, 5 g of 3- { [ 2-yl ] methoxy } pyridin-4-1H, 5-yl.

LC-MS (M+H) + actual: 536.15.

¹ H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.39(s,1H),7.96(d,J＝5.1Hz,1H),7.43(s,1H),7.32(d,J＝5.0Hz,1H),6.81(s,1H),6.68–6.57(m,2H),6.35(dd,J＝17.0,10.2Hz,1H),6.22–6.11(m,2H),5.69(s,1H),4.56(t,J＝9.0Hz,1H),4.45–4.35(m,2H),3.89(s,4H),3.84(s,1H),3.41(td,J＝6.9,2.4Hz,2H),2.92(s,3H),1.24(d,J＝21.7Hz,6H)。

example 208: rel-2- (3- { [ (2R) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 356)

208.1: synthesis of tert-butyl 2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -3, 3-dimethyl azetidine-1-carboxylate

To 2- { [ (4- { 3-iodo-4-oxo-1H, 5) at room temperature under N2 atmosphereH,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of tert-butyl methyl } -3, 3-dimethyl-azetidine-1-carboxylate (650 mg,1.177mmol,1 eq.) and 3-fluoro-2-methoxyaniline (498.24 mg,3.531mmol,3 eq.) in DMF (6 mL) was added Cs in portions ₂ CO ₃ (1150.13 mg,3.531mmol,3 eq.) and Ephos Pd G4 (108.08 mg,0.118mmol,0.1 eq.). The resulting mixture was stirred at 50℃under an N2 atmosphere for 2 hours. The resulting mixture was filtered, followed by washing the filter cake with EA (1 x1 30 ml). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM and MeOH 20:1) to give 2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -3, 3-dimethyl-azetidine-1-carboxylic acid tert-butyl ester (650 mg, 97.66%) was a pale yellow solid.

LC-MS (M+H) + actual: 566.2.

208.2: synthesis of 2- {3- [ (3, 3-dimethyl azetidin-2-yl) methoxy ] pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl methyl } -3, 3-dimethyl-azetidine-1-carboxylate (1000 mg,1.768mmol,1 eq.) in DCM (10 mL) was added dropwise TFA (5 mL,67.315mmol,38.08 eq.). The resulting mixture was stirred at room temperature for 1.5 hours. DCM and H for aqueous layer ₂ O (3X 1 150 mL) extraction. To provide 2- {3- [ (3, 3-dimethyl azetidin-2-yl) methoxy]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (540 mg, 65.61%) was a pale yellow solid.

LC-MS (M+H) + actual: 466.1.

208.3: synthesis of 2- (3- { [ (2S) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To 2- {3- [ (3, 3-dimethylazetidin-2-yl) methoxy at-30℃under N2 atmosphere]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (100 mg,0.215mmol,1 eq.) and TEA (108.68 mg,1.075mmol,5 eq.) in DCM (2 mL) was added dropwise acryloyl chloride (19.44 mg,0.215mmol,1 eq.). The resulting mixture was stirred at-30℃for 0.5 hours. The crude product was purified by preparative HPLC and using the following conditions (column: YMC-Actus Triart C18, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH4HCO3+0.1% NH) ₃ .H ₂ O) mobile phase B, ACN; the flow rate is 60mL/min; gradient 45% b to 55% b, 55% b over 8 min; wavelength 254;220nm; RT1 (min) 7.55; running number 0) to provide 2- (3- { [ (2S) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (24 mg, 21.50%) was a yellow solid.

LC-MS (M+H) + actual: 520.25.

208.4: synthesis of rel-2- (3- { [ (2R) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

Crude 2- (3- { [3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl)]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (40 mg,0.077mmol,1 eq.) was purified by chiral preparative HPLC and prepared using the following conditions (column CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex: dcm=3:1 (0.5% 2m NH) ₃ -MeOH) -HPLC, mobile phase B EtOH-HPLC; the flow rate is 20mL/min; gradient from 20% b to 20% b, within 20 min; wavelength 220-254nm; RT1 (min) 13.70; RT2 (min) 19.36; sample solvent ETOH, dcm=1:1; injection volume 2mL; running number 2) to provide rel-2- (3- { [ (2R) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (12.7 mg, 31.59%) was an off-white solid.

LC-MS (M+H) + actual: 520.1.

¹ H NMR(400MHz,DMSO-d6)δ8.38(s,1H),7.95(d,J＝5.0Hz,1H),7.39(s,1H),7.32(d,J＝5.1Hz,1H),6.79(s,1H),6.57(q,J＝7.7Hz,1H),6.43(ddd,J＝10.0,8.4,1.5Hz,1H),6.34(dd,J＝17.0,10.2Hz,1H),6.22–6.13(m,1H),6.00(dt,J＝8.2,1.4Hz,1H),4.59–4.50(m,1H),4.45–4.35(m,2H),3.91(d,J＝1.0Hz,5H),3.40(td,J＝6.9,2.6Hz,2H),2.92(q,J＝4.7,3.1Hz,2H),1.27(s,3H),1.22(d,J＝4.1Hz,3H).

example 209: rel-2- (3- { [ (2R) -1- (but-2-ynyl) -3, 3-dimethylazetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 355)

The crude product 2- (3- { [1- (but-2-ynyl) -3, 3-dimethylazetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (20 mg,0.038mmol,1 eq) was purified by chiral preparative HPLC and was purified using the following conditions (column: CHIRALPAK IA-3,4.6 x 50mm 3um; mobile phase A: hex (0.1% DEA): etOH=50:50; flow rate: 1mL/min; gradient: 0% B to 0% B; injection volume: 5ul mL) to provide rel-2- (3- { [ (2R) -1- (but-2-ynyl) -3, 3-dimethylazetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H, 7H, 6-pyrrolo [3, 4-c ] pyridin-4-yl ] as a pale yellow solid (24.88 g).

LC-MS (M+H) + actual: 532.15.

¹ H NMR(400MHz,DMSO-d6)δ8.38(s,1H),7.95(s,1H),7.36(s,1H),7.31(d,J＝5.1Hz,1H),6.80(s,1H),6.56(d,J＝7.9Hz,1H),6.43(t,J＝9.7Hz,1H),5.99(dt,J＝8.3,1.4Hz,1H),4.56(dd,J＝10.2,7.4Hz,1H),4.40(dd,J＝10.2,4.5Hz,1H),4.33(dd,J＝7.4,4.4Hz,1H),3.91(s,5H),3.39(td,J＝6.9,2.6Hz,2H),2.86(s,2H),1.98(s,3H),1.26(s,3H),1.19(s,3H)。

example 210: rel-2- (3- { [ (2R) -1- (but-2-ynyl) -3, 3-dimethylazetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 325)

210.1: synthesis of 2- (3- { [1- (but-2-ynyl) -3, 3-dimethylazetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0℃to 2- {3- [ (3, 3-dimethylazetidin-2-yl) methoxy ]]Pyridin-4-yl } -3- [ (3-fluoro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred mixture of pyridin-4-one (100 mg,0.215mmol,1 eq.) and T3P (0.5 mL,1.571mmol,7.32 eq.) in pyridine (0.5 mL) and THF (1 mL) was added dropwise 2-butynoic acid (21.67 mg,0.258mmol,1.2 eq.). The resulting mixture was stirred at room temperature for 3 hours. The mixture was neutralized to pH 7 with NaHCO 3. The resulting mixture was extracted with EA (3X 15 mL). The combined organic layers were washed with brine (1×1 30 ml), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM: meOH 20) to give 2- (3- { [1- (but-2-ynyl) -3, 3-dimethyl azetidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (40 mg, 35.03%) was a pale yellow solid.

LC-MS (M+H) + actual: 532.25.

210.2: synthesis of rel-2- (3- { [ (2R) -1- (but-2-ynyl) -3, 3-dimethyl azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

The crude product 2- (3- { [1- (but-2-ynyl) -3, 3-dimethylazetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (20 mg,0.038mmol,1 eq) was purified by chiral preparative HPLC and was purified using the following conditions (column: CHIRALPAK IA-3,4.6 x 50mm 3um; mobile phase A: hex (0.1% DEA): etOH=50:50; flow rate: 1mL/min; gradient: 0% B to 0% B; injection volume: 5ul mL) to provide rel-2- (3- { [ (2R) -1- (but-2-ynyl) -3, 3-dimethylazetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H, 7H, 6-pyrrolo [3, 6-c ] pyridin-4-yl ] as a pale yellow solid (78.5 mg).

LC-MS (M+H) + actual: 532.15.

example 211:2- (3- { [ (2R) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 324)

Crude 2- (3- { [3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl)]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (40 mg,0.077mmol,1 eq.) was purified by chiral preparative HPLC and prepared using the following conditions (column CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex: dcm=3:1 (0.5% 2m NH) ₃ -MeOH) -HPLC, mobile phase B: etOH- -HPLC; the flow rate is 20mL/min; gradient from 20% b to 20% b, within 20 min; wavelength is 220/254nm; RT1 (min) 13.70; RT2 (min) 19.36; sample solvent ETOH, dcm=1:1; injection volume 2mL; running number 2) to provide 2- (3- { [ (2R) -3, 3-dimethyl-1- (prop-2-enoyl) azetidin-2-yl]Methoxy } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (11.5 mg, 28.61%) was an off-white solid.

LC-MS (M+H) + actual: 520.1.

¹ H NMR(400MHz,DMSO-d6)δ8.38(s,1H),7.95(d,J＝5.0Hz,1H),7.39(s,1H),7.32(d,J＝5.1Hz,1H),6.79(s,1H),6.57(q,J＝7.7Hz,1H),6.43(ddd,J＝10.0,8.4,1.5Hz,1H),6.34(dd,J＝17.0,10.2Hz,1H),6.22–6.13(m,1H),6.00(dt,J＝8.2,1.4Hz,1H),4.59–4.50(m,1H),4.45–4.35(m,2H),3.91(d,J＝1.0Hz,5H),3.40(td,J＝6.9,2.6Hz,2H),2.92(q,J＝4.7,3.1Hz,2H),1.27(s,3H),1.22(d,J＝4.1Hz,3H)。

example 212:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -2-methylazetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 510)

212.1: synthesis of tert-butyl 2- { [ (4-bromopyridin-3-yl) oxy ] methyl } -2-methylazetidine-1-carboxylate

To a solution of tert-butyl 2- (hydroxymethyl) -2-methylazetidine-1-carboxylate (600 mg,2.981mmol,1 eq.) in THF (3.0 mL) was added sodium hydride (60% in oil, 107.31mg,4.471mmol,1.5 eq.) at 0 ℃. The mixture was stirred for 15min. 4-bromo-3-fluoropyridine (629.57 mg,3.577mmol,1.20 eq) was added and the mixture was allowed to warm to room temperature and stirred for 2h. The reaction mixture was quenched with water and extracted with DCM (3×25 ml). The residue was purified by silica gel column chromatography eluting with DCM: meOH (15:1) to give tert-butyl 2- { [ (4-bromopyridin-3-yl) oxy ] methyl } -2-methylazetidine-1-carboxylate (500 mg, 51.23%) as a white solid.

212.2: synthesis of tert-butyl 2-methyl-2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

To 2- { [ (4-bromopyridin-3-yl) oxy]Methyl } -2-methylazetidine-1-carboxylic acid tert-butyl ester (50 mg,0.140mmol,1 eq.) and 2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]]A stirred solution of pyridin-4-one (55.03 mg,0.210mmol,1.5 eq.) in dioxane (1.5 mL) was added K ₂ CO ₃ (48.36 mg,0.350mmol,2.5 eq.) and Pd (dppf) Cl ₂ (15.36 mg,0.021mmol,0.15 eq.). After stirring at 80℃under nitrogen for 3h, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC/silica gel column chromatography eluting with DCM: meOH (25:1) to provide 2-methyl-2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]Tert-butyl methyl } azetidine-1-carboxylate (29 mg, 41.23%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 426.05.

212.3: synthesis of tert-butyl 2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -2-methylazetidine-1-carboxylate

To 2-methyl-2- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) under an atmosphere of N2 at room temperature ]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl methyl } azetidine-1-carboxylate (1000 mg,2.424mmol,1 eq.) in DMF (15 mL) was added NIS (654.52 mg,2.909mmol,1.2 eq.) in portions. By addition of Na at 0 DEG C ₂ SO ₃ (50 ml 1 mol/L) quench the reaction. The precipitated solid was collected by filtration and washed with THF (2×2 10 ml). The residue was purified by trituration with EA (15 ml) to give 2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2)-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -2-methylazetidine-1-carboxylic acid tert-butyl ester (1300 mg, 99.60%) as a pale yellow solid.

LC-MS:(M-H) ^- Actual: 450.05.

212.4: synthesis of tert-butyl 2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -2-methylazetidine-1-carboxylate

To 2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]A solution of methyl } -2-methylazetidine-1-carboxylic acid tert-butyl ester (150 mg,0.279mmol,1 eq.) and 3-chloro-2-methoxyaniline (87.82 mg, 0.5538 mmol,2 eq.) in DMF (3.5 mL) was added Cs ₂ CO ₃ (226.94 mg,0.698mmol,2.5 eq.) and Ephos Pd G4 (51.18 mg,0.056mmol,0.2 eq.) and EPhos (29.80 mg,0.056mmol,0.2 eq.). After stirring at 50℃under nitrogen for 2h, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC/silica gel column chromatography eluting with DCM: meOH (20:1) to provide the 2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino group ]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -2-methylazetidine-1-carboxylic acid tert-butyl ester (75 mg, 37.91%) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 541.10.

212.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- {3- [ (2-methylazetidin-2-yl) methoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0 ℃, N ₂ To 2- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino group under an atmosphere]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -2-methylA stirred solution of tert-butyl (75 mg,0.132mmol,1 eq.) of azetidine-1-carboxylate in DCM (2.5 mL) was added dropwise to TFA (1.5 mL). With NaHCO ₃ The mixture was basified to pH 8.5. The resulting mixture was extracted with EA (2×30 ml). The combined organic layers were washed with brine (2×2 10 ml), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- {3- [ (2-methylazetidin-2-yl) methoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (500 mg, 51.23%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 441.10.

212.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0 ℃, N ₂ To 3- [ (3-chloro-2-methoxyphenyl) amino group under an atmosphere]-2- {3- [ (2-methylazetidin-2-yl) methoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (45 mg,0.096mmol,1 eq.) and NaHCO ₃ (20.20 mg,0.240mmol,2.5 eq.) in THF (2 mL) and H ₂ A solution of acryloyl chloride (7.83 mg,0.086mmol,0.9 eq.) in O (2 mL) was added dropwise. The resulting mixture was extracted with EA (2×20 ml). The combined organic layers were washed with brine (2×2 20 ml), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and purified by preparative TLC (DCM/meoh=15:1) to afford 3- [ (3-chloro-2-methoxyphenyl) amino group]-2- (3- { [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (30 mg, 60%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 501.10.

212.5: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -2-methylazetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

The crude product (50 mg) was purified by preparative HPLC and using the following conditions (column: CHIRALPAK IG-3,4.6 x 50mm,3um; mobile phase A (Hex: DCM=3:1) (0.1% DEA): etOH=80:20; flow rate: 1mL/min; gradient: 0% B to 0% B; injection volume: 5ul mL) to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2S) -2-methylazetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (4.6 mg, 10.22%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 501.10.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.93(s,1H),8.39(s,1H),8.00(d,J＝5.0Hz,1H),7.47(s,1H),7.34(d,J＝5.1Hz,1H),7.12(s,1H),6.76–6.63(m,2H),6.34–6.07(m,3H),5.69(dd,J＝9.9,2.5Hz,1H),4.55(d,J＝10.2Hz,1H),4.31(d,J＝10.2Hz,1H),4.23–4.03(m,2H),3.89(s,3H),3.42(s,3H),3.05–2.76(m,2H),2.41–2.29(m,1H),2.12(q,J＝10.0Hz,1H),1.67(s,3H),1.57(s,1H)。

example 213:3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -2-methylazetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (Compound 511)

The crude product (50 mg) was purified by preparative HPLC and using the following conditions (column: CHIRALPAK IG-3,4.6 x 50mm,3um; mobile phase A (Hex: DCM=3:1) (0.1% DEA): etOH=80:20; flow rate: 1mL/min; gradient: 0% B to 0% B; injection volume: 5ul mL) to afford 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (2R) -2-methylazetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (5.6 mg, 11.86%) as a yellow solid.

LC-MS (M+H) + actual: 522.50.

¹ H NMR(400MHz,DMSO-d6)δ11.93(s,1H),8.39(s,1H),8.00(d,J＝5.0Hz,1H),7.47(s,1H),7.34(d,J＝5.1Hz,1H),7.12(s,1H),6.76–6.63(m,2H),6.34–6.07(m,3H),5.69(dd,J＝9.9,2.5Hz,1H),4.55(d,J＝10.2Hz,1H),4.31(d,J＝10.2Hz,1H),4.23–4.03(m,2H),3.89(s,3H),3.42(s,3H),3.05–2.76(m,2H),2.41–2.29(m,1H),2.12(q,J＝10.0Hz,1H),1.67(s,3H),1.57(s,1H)。

example 214: rel-3- [ (2-ethyl-3-fluorophenyl) amino ] -2- (3- { [ (2R) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 359)

3- [ (2-ethyl-3-fluorophenyl) amino ] -2- (3- { [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (15 mg,0.030mmol,1 eq) was purified by: column: CHIRALPAK IG-3,4.6 x 50mm;3um; mobile phase a (Hex: dcm=3:1) (0.1% dea): etoh=70:30; the flow rate is 1mL/min; gradient 0% B to 0% B; injection volume 5ul mL to provide rel-3- [ (2-ethyl-3-fluorophenyl) amino ] -2- (3- { [ (2R) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (1.2 mg, 7.90%) as a yellow solid.

LC-MS: mactual: 504.35.

¹ H NMR(300MHz,DMSO-d6)δ12.01(s,1H),8.38(s,1H),7.99(d,J＝5.3Hz,1H),7.50(s,1H),7.29(d,J＝5.3Hz,1H),7.19(t,J＝2.6Hz,1H),6.78(td,J＝8.2,6.7Hz,1H),6.49(t,J＝8.9Hz,1H),6.30(dd,J＝16.9,9.8Hz,1H),6.23–6.01(m,2H),5.71(dd,J＝9.7,2.7Hz,1H),4.58(d,J＝10.2Hz,1H),4.31(d,J＝10.3Hz,1H),4.16(dtd,J＝24.4,8.9,6.1Hz,2H),3.44(d,J＝2.5Hz,2H),3.04–2.87(m,2H),2.72(q,J＝7.4,6.8Hz,2H),2.38–2.25(m,1H),2.21–2.04(m,1H),1.69(s,3H),1.29–1.12(m,3H)。

example 215: rel-3- [ (2-ethyl-3-fluorophenyl) amino ] -2- (3- { [ (2R) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 309)

215.1: synthesis of 2-vinyl-1-fluoro-3-nitrobenzene

At room temperature, N ₂ Pd (dppf) Cl was added to a stirred solution of 2-bromo-1-fluoro-3-nitrobenzene (2 g,9.091mmol,1 eq.) and 2-vinyl-4, 5-tetramethyl-1, 3, 2-dioxaborolan (2.10 g,13.636mmol,1.5 eq.) in dioxane (20 mL) under an atmosphere ₂ (0.67 g,0.909mmol,0.1 eq.) and K ₂ CO ₃ (2.51 g,18.182mmol,2 eq.). Then, the solution was stirred at 80℃for 3h. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE/EA (100/1) to provide 2-vinyl-1-fluoro-3-nitrobenzene (400 mg, 26.33%) as a colorless oil.

GC-MS: M+1 actual: 167.9.

215.2: synthesis of 2-ethyl-3-fluoroaniline

Pd/C (80 mg) was added to a stirred solution of 2-vinyl-1-fluoro-3-nitrobenzene (400 mg,2.393mmol,1 eq.) in MeOH (20 mL) at room temperature. Then, using H ₂ The solution was re-aerated and the solution was stirred at room temperature for 1h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-ethyl-3-fluoroaniline (90 mg, 27.02%) as a colorless oil.

GC-MS: mactual: 139.0.

215.3: synthesis of tert-butyl 2- { [ (4- {3- [ (2-ethyl-3-fluorophenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -2-methylazetidine-1-carboxylate

To a stirred solution of tert-butyl 2- { [ (4- { 3-iodo-4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -2-methylazetidine-1-carboxylate (250 mg, 0.460 mmol,1 eq.) and 2-ethyl-3-fluoroaniline (129.25 mg,0.928mmol,2 eq.) in DMF (3.5 mL) was added EPhos Pd G4 (63.98 mg,0.070mmol,0.15 eq.) and EPhos (37.25 mg,0.070mmol,0.15 eq.) at room temperature under an N2 atmosphere. Then, the solution was stirred at 50℃for 3h. The aqueous layer was extracted with EA (3×20 mL) and the extract concentrated under reduced pressure to afford tert-butyl 2- { [ (4- {3- [ (2-ethyl-3-fluorophenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -2-methylazetidine-1-carboxylate) (113 mg, 44.3%) as a yellow oil.

LC-MS: M+Hactual: 550.0.

215.4: synthesis of 3- [ (2-ethyl-3-fluorophenyl) amino ] -2- {3- [ (2-methylazetidin-2-yl) methoxy ] pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0 ℃, N ₂ To 2- { [ (4- {3- [ (2-ethyl-3-fluorophenyl) amino group under an atmosphere]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred solution of tert-butyl methyl } -2-methylazetidine-1-carboxylate (113 mg,0.206mmol,1 eq.) in DCM (3 mL) was added TFA (1.5 mL). Subsequently, the solution was stirred at 0℃for 2h. The resulting mixture was concentrated under reduced pressure to provide crude 3- [ (2-ethyl-3-fluorophenyl) amino group]-2- {3- [ (2-methylazetidin-2-yl) methoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (92 mg, 99.55%) was a yellow oil.

LC-MS: M+Hactual: 450.2.

215.5: synthesis of 3- [ (2-ethyl-3-fluorophenyl) amino ] -2- (3- { [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0 ℃, N ₂ To 3- [ (2-ethyl-3-fluorophenyl) amino group under atmosphere]-2- {3- [ (2-methylazetidin-2-yl) methoxy]Pyridin-4-yl } -1H,5H,6H, 7H-pyrrolo [3,2-c]A stirred solution of pyridin-4-one (113 mg,0.251mmol,1 eq.) in THF (3 mL) was added NaHCO3 (2 mL) and acryloyl chloride (22.75 mg,0.251mmol,1 eq.). Next, the solution was stirred at 0deg.C for 30min. The aqueous layer was extracted with EA (3×10 mL) and the extracts concentrated under reduced pressure. The residue was purified by preparative TLC (DCM: meoh=15:1) to afford 3- [ (2-ethyl-3-fluorophenyl) amino group ]-2- (3- { [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (41 mg, 32.39%) was a yellow solid.

LC-MS: M+Hactual: 504.25.

215.6: synthesis of rel-3- [ (2-ethyl-3-fluorophenyl) amino ] -2- (3- { [ (2R) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

3- [ (2-ethyl-3-fluorophenyl) amino ] -2- (3- { [ 2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (15 mg,0.030mmol,1 eq) was purified by: column: CHIRALPAK IG-3,4.6 x 50mm;3um; mobile phase a (Hex: dcm=3:1) (0.1% dea): etoh=70:30; the flow rate is 1mL/min; gradient 0% B to 0% B; injection volume 5ul mL to provide rel-3- [ (2-ethyl-3-fluorophenyl) amino ] -2- (3- { [ (2R) -2-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (2.7 mg, 17.84%) as a yellow solid.

LC-MS: M+Hactual: 504.35.

¹ H NMR(300MHz,DMSO-d6)δ12.03(s,1H),8.39(s,1H),7.99(d,J＝5.4Hz,1H),7.52(s,1H),7.30(d,J＝5.4Hz,1H),7.20(q,J＝2.4Hz,1H),6.78(td,J＝8.2,6.7Hz,1H),6.50(t,J＝8.9Hz,1H),6.44–6.01(m,3H),5.71(dd,J＝9.7,2.7Hz,1H),4.58(d,J＝10.2Hz,1H),4.31(d,J＝10.2Hz,1H),4.16(dtd,J＝24.4,8.9,6.0Hz,2H),3.44(d,J＝2.6Hz,2H),2.97(dt,J＝8.7,6.8Hz,2H),2.72(q,J＝7.2Hz,2H),2.38–2.26(m,1H),2.14(ddd,J＝11.3,9.4,6.2Hz,1H),1.69(s,3H),1.30–1.12(m,3H)。

example 216:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2R, 4R) -4-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (compound 333)

216.1: synthesis of tert-butyl 2- (hydroxymethyl) -4-methylazetidine-1-carboxylate

BH was added dropwise to a stirred solution of 1- (tert-butoxycarbonyl) -4-methylazetidine-2-carboxylic acid (1.9 g,8.827mmol,1 eq.) in THF (19 mL) at 0deg.C under nitrogen ₃ THF (17.8 mL,185.993mmol,21.07 eq.). The resulting mixture was stirred overnight at room temperature under nitrogen. The residue was purified by reverse phase flash chromatography using column, silica gel; mobile phase, meCN in water, gradient 10% to 50% within 10 min; a detector: UV 254nm to afford tert-butyl 2- (hydroxymethyl) -4-methylazetidine-1-carboxylate (1.27 g, 71.49%) as an off-white liquid.

LCMS:[M+H] ⁺ Actual: 202.

216.2: synthesis of tert-butyl 2- { [ (4-bromopyridin-3-yl) oxy ] methyl } -4-methylazetidine-1-carboxylate

To a stirred mixture of tert-butyl 2- (hydroxymethyl) -4-methylazetidine-1-carboxylate (1.27 g,6.310mmol,1 eq.) and 4-bromopyridin-3-ol (1.10 g,6.310mmol,1 eq.) in THF (13 mL) at 0deg.C under nitrogen was added PPh3 (3.31 g,12.620mmol,2 eq.) and DEAD (2.20 g,12.620mmol,2 eq.) dropwise. The resulting mixture was stirred at room temperature under nitrogen for 1h. The residue was purified by reverse phase flash chromatography using column, silica gel; mobile phase, meCN in water, gradient 10% to 50% within 10 min; a detector: UV 254nm to provide tert-butyl 2- { [ (4-bromopyridin-3-yl) oxy ] methyl } -4-methylazetidine-1-carboxylate (910 mg, 40.59%) as a brown liquid.

LCMS:[M+H] ⁺ Actual: 357.

216.3: synthesis of tert-butyl 2-methyl-4- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate

To 2- { [ (4-bromopyridin-3-yl) oxy at room temperature under nitrogen atmosphere]Methyl } -4-methylazetidine-1-carboxylic acid tert-butyl ester (910 mg, 2.560 mmol,1 eq.) and 2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ]]Pyridin-4-one (1.01 g,3.841mmol,1.5 eq.) in dioxane (10 mL) and H ₂ A stirred mixture in O (2 mL) was added in portions Na2CO3 (814.39 mg,7.683mmol,3 eq.) and RuPhos cyclopalladium Gen.3 (428.43 mg,0.512mmol,0.2 eq.). The resulting mixture was stirred overnight at 80℃under nitrogen. The residue was purified by reverse phase flash chromatography using column, silica gel; mobile phase, meCN in water, gradient 10% to 50% within 10 min; a detector: UV 254nm. Thus providing 2-methyl-4- { [ (4- { 4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c)]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } azetidine-1-carboxylic acid tert-butyl ester (800 mg, 75.72%) was a yellow oil.

LCMS:[M+H] ⁺ Actual: 414.

216.4: synthesis of tert-butyl 2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -4-methylazetidine-1-carboxylate

To a stirred solution of tert-butyl 2-methyl-4- { [ (4- { 4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } azetidine-1-carboxylate (800 mg,1.939mmol,1 eq.) in DMF (8 mL) at 0 ℃ under nitrogen was added NIS (523.61 mg,2.327mmol,1.2 eq.) in portions. The resulting mixture was stirred at room temperature under nitrogen for 4h. The reaction was quenched with water at room temperature. The precipitated solid was collected by filtration and washed with water (3×50 mL). Thus provided was tert-butyl 2- { [ (4- { 3-iodo-4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -4-methylazetidine-1-carboxylate (900 mg, 86.19%) as a yellow solid.

LCMS:[M+H] ⁺ Actual: 539.

216.5: synthesis of tert-butyl 2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -4-methylazetidine-1-carboxylate

To 2- { [ (4- { 3-iodo-4-oxo-1H, 5H,6H, 7H-pyrrolo [3, 2-c) under nitrogen at room temperature]Pyridin-2-yl } pyridin-3-yl) oxy]A stirred mixture of methyl } -4-methylazetidine-1-carboxylic acid tert-butyl ester (900 mg,1.672mmol,1 eq.) and 3-fluoro-2-methoxyaniline (353.92 mg,2.508mmol,1.5 eq.) in dioxane (9 mL) was added in portions Cs2CO3 (1089.32 mg,3.34 mmol,2 eq.) and Ephos Pd G4 (307.11 mg,0.334mmol,0.2 eq.). The resulting mixture was stirred overnight at 50 ℃ under nitrogen. The aqueous layer was extracted with EtOAc (3X 50 mL). The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ MeOH (20:1) elution to afford 2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -4-methylazetidine-1-carboxylic acid tert-butyl ester (530 mg, 57.48%) as brownColor solids.

LCMS:[M+H] ⁺ Actual: 552.

216.6: synthesis of 3- ((3-fluoro-2-methoxyphenyl) amino) -2- (3- ((4-methylazetidin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred solution of tert-butyl 2- { [ (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -4-methylazetidine-1-carboxylate (530 mg,0.961mmol,1 eq.) in DCM (20 mL,0.135mmol,0.14 eq.) under nitrogen at room temperature was added TFA (4 mL). The resulting mixture was stirred overnight at room temperature under nitrogen. Basified to pH 9 with saturated aqueous NaHCO3 mixture. The aqueous layer was extracted with DCM (3X 50 mL). The crude mixture obtained was used directly in the next step without further purification.

LCMS:[M+H] ⁺ Actual: 452.

216.7: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ 4-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- {3- [ (4-methylazetidin-2-yl) methoxy ] pyridin-4-yl } -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (400 mg,0.886mmol,1 eq.) and Et3N (268.95 mg, 2.578 mmol,3 eq.) in DCM (4 mL) was added dropwise acryloyl chloride (80.19 mg,0.886mmol,1 eq.) at 0 ℃ under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 10min. The aqueous layer was extracted with EtOAc (3X 50 mL). The crude product (500 mg) was purified by preparative HPLC and using the following conditions (column: xselect CSH C18 OBD column 30X 150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL/min; gradient: 14% B to 30% B over 10min, 30% B; wavelength: 254/220nm; RT1 (min): 10; running number: 0) to provide 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ 4-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-C ] pyridin-4-one (160 mg, 35.72%) as a yellow oil.

LCMS:[M+H] ⁺ Actual: 506.

216.8: synthesis of 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2R, 4R) -4-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one

The crude product (160 mg) was purified by preparative HPLC and using the following conditions (column: CHIRAL ART Amylose-SA, 2X 25cm,5 μm; mobile phase A: mtBE (0.5% 2M NH3-MeOH) - - -HPLC; mobile phase B: etOH- -HPLC; flow rate: 20mL/min; gradient: 30% B to 30% B,17 min; wavelength: 220/254nm; RT1 (min): 8.569; RT2 (min): 14.522; sample solvent: etOH- -HPLC; injection volume: 2mL; running number: 3) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2R, 4R) -4-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (6.7 mg, peak 1) as a white solid.

LCMS:[M+H] ⁺ Actual: 506.

¹ h NMR (300 MHz, chloroform-d) delta 11.98 (s, 1H), 8.23 (s, 1H), 7.99-7.82 (m, 2H), 7.50 (d, j=5.8 hz, 1H), 6.69-6.37 (m, 3H), 6.34-6.20 (m, 1H), 6.03 (d, j=8.0 hz, 1H), 5.91-5.77 (m, 1H), 5.28 (s, 1H), 4.88 (d, j=7.4 hz, 1H), 4.57 (d, j=7.9 hz, 1H), 4.43 (d, j=9.7 hz, 1H), 4.30 (d, j=9.4 hz, 1H), 4.12 (d, j=1.4 hz, 3H), 3.68-3.53 (m, 2H), 3.34-3.12 (m, 2H), 2.91-2.77 (m, 1H), 4.7.7 hz, 1H), 4.30 (d, 1.7 hz, 1H).

Example 217:3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2R, 4R) -4-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (compound 332)

The crude product (160 mg) was purified by preparative HPLC and using the following conditions (column: CHIRAL ART Amylose-SA, 2X 25cm,5 μm; mobile phase A: mtBE (0.5% 2M NH3-MeOH) - - -HPLC; mobile phase B: etOH- -HPLC; flow rate: 20mL/min; gradient: 30% B to 30% B,17 min; wavelength: 220/254nm; RT1 (min): 8.569; RT2 (min): 14.522; sample solvent: etOH- -HPLC; injection volume: 2mL; running number: 3) to afford 3- [ (3-fluoro-2-methoxyphenyl) amino ] -2- (3- { [ (2R, 4R) -4-methyl-1- (prop-2-enoyl) azetidin-2-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (22.3 mg, peak 2) as a white solid.

LCMS:[M+H] ⁺ Actual: 506.

¹ h NMR (300 MHz, chloroform-d) δ11.88 (s, 1H), 8.21 (s, 1H), 7.99 (d, j=5.2 hz, 1H), 7.58-7.41 (m, 2H), 6.65-6.52 (m, 1H), 6.49-6.33 (m, 2H), 6.29-6.17 (m, 1H), 6.14-6.02 (m, 1H), 5.81-5.69 (m, 1H), 5.24 (s, 1H), 5.11-4.93 (m, 1H), 4.75-4.57 (m, 1H), 4.44 (t, j=9.7 hz, 1H), 4.34-4.22 (m, 1H), 4.10 (d, j=1.2 hz, 3.68-3.46 (m, 2H), 3.23-3.00 (m, 2H), 2.39-4.93 (m, 1H), 4.34-4.57 (m, 1H), 4.34 (t, 1H), 3.9-2.2 (m, 1H).

Example 218: rel-3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (1R) -2- (prop-2-enoyl) -2-azaspiro [3.3] hept-1-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 269)

218.1: synthesis of tert-butyl 1- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) oxy ] methyl } -2-azaspiro [3.3] heptane-2-carboxylate

To 1- { [ (4- { 3-iodo under nitrogen at room temperature-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -2-azaspiro [3.3]]A stirred solution of tert-butyl heptane-2-carboxylate (380 mg,0.673mmol,1 eq.) and 3-chloro-2-methoxyaniline (212.21 mg,1.346mmol,2 eq.) in DMF (10 mL) was added Cs in portions ₂ CO ₃ (658.08 mg,2.019mmol,3 eq.) and Ephos Pd G4 (123.68 mg,0.135mmol,0.2 eq.). The resulting mixture was stirred overnight at 50 ℃ under nitrogen. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give 1- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino group]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -2-azaspiro [3.3]]Heptane-2-carboxylic acid tert-butyl ester (120 mg, 30.00%) was a pale yellow solid.

LC-MS (M+H) + actual: 594.60.

218.2: synthesis of rac-2- {3- [ (1R) -2-azaspiro [3.3] hept-1-ylmethoxy ] pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To rac- (1R) -1- { [ (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] at room temperature under a nitrogen atmosphere]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl } pyridin-3-yl) oxy]Methyl } -2-azaspiro [3.3]]A stirred solution of tert-butyl heptane-2-carboxylate (120 mg,0.202mmol,1 eq.) in DCM (1 mL) was added dropwise TFA (3 mL,40.389mmol,199.96 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. The reaction was monitored by LCMS. With saturated NaHCO ₃ The aqueous solution basifies the mixture to pH 10. The resulting mixture was treated with CH ₂ Cl ₂ (3X 20 mL) extraction over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives rac-2- {3- [ (1R) -2-azaspiro [3.3]]Hept-1-ylmethoxy]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H,7H-pyrrolo [3,2-c]Pyridin-4-one (120 mg, 120.27%) was a brown oil. The crude product was used directly in the next step without further purification.

LC-MS (M+H) + actual: 494.50.

218.3: synthesis of rac-3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (1R) -2- (prop-2-enoyl) -2-azaspiro [3.3] hept-1-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

At 0℃under nitrogen, to rac-2- {3- [ (1R) -2-azaspiro [3.3]]Hept-1-ylmethoxy]Pyridin-4-yl } -3- [ (3-chloro-2-methoxyphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (120 mg,0.243mmol,1 eq.) and Et ₃ A stirred solution of N (73.74 mg,0.729mmol,3 eq.) in DCM (1 mL) was added dropwise acryloyl chloride (17.59 mg,0.194mmol,0.8 eq.). The resulting mixture was stirred at room temperature under nitrogen for 1h. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (2×5 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C column, 19 x 250mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) ACN as mobile phase B; the flow rate is 25mL/min; gradient 40% b to 70% b, 70% b in 7 min; wavelength of 254nm; RT1 (min) 6.93; running number 0) to provide rac-3- [ (3-chloro-2-methoxyphenyl) amino]-2- (3- { [ (1R) -2- (prop-2-enoyl) -2-azaspiro [ 3.3)]Hept-1-yl]Methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (120 mg, 90.14%) was a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 548.50.

218.4: synthesis of rel-3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (1R) -2- (prop-2-enoyl) -2-azaspiro [3.3] hept-1-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

The product (50 mg) was purified by chiral HPLC and purified using the following conditions (column: CHIRALPAK IA-3,4.6 x 50mm 3um; mobile phase a: hex (0.1% dea): etoh=50:50; flow rate: 1mL/min; gradient: 0% b to 0% b; injection volume: 5ul mL) to afford rel-3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (1R) -2- (prop-2-enoyl) -2-azaspiro [3.3] hept-1-yl ] methoxy } pyridin-4-yl) -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (2 mg,4.00%, peak 1) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 548.50.

¹ h NMR (300 MHz, chloroform-d) δ11.85 (s, 1H), 8.30 (s, 1H), 7.97 (s, 1H), 7.63 (s, 1H), 7.46 (s, 1H), 6.72 (dd, j=8.0, 1.6hz, 1H), 6.62 (t, 1H), 6.39 (dd, j=16.8, 2.2hz, 1H), 6.32-6.17 (m, 2H), 5.78 (dd, j=10.0, 2.2hz, 1H), 5.33 (s, 1H), 4.82-4.71 (m, 1H), 4.43 (d, j=7.5 hz, 2H), 4.36 (d, j=8.5 hz, 1H), 4.25 (d, j=8.5 hz, 1H), 4.08 (s, 3H), 3.65-3.55 (m, 2.26-2H), 5.32-6.17 (m, 2H), 4.82-4.71 (m, 1H), 4.43 (d, j=7.5 hz, 2H), 4.36 (2.8.2H), 2.44-2.2H (m, 2H).

Example 219: rel-3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (1R) -2- (prop-2-enoyl) -2-azaspiro [3.3] hept-1-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 268)

The product (50 mg) was purified by chiral HPLC and purified using the following conditions (column: CHIRALPAK IA-3,4.6 x 50mm 3um; mobile phase A: hex (0.1% DEA): etOH=50:50; flow rate: 1mL/min; gradient: 0% B to 0% B; injection volume: 5ul mL) to afford rel-3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- { [ (1R) -2- (prop-2-enoyl) -2-azaspiro [3.3] hept-1-yl ] methoxy } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (2.1 mg,4.20%, peak 2) as a pale yellow solid.

LC-MS:(M+H) ⁺ Actual: 548.20.

¹ h NMR (300 MHz, chloroform-d) δ11.86 (s, 1H), 8.28 (s, 1H), 7.96 (s, 1H), 7.64 (s, 1H), 7.45 (s, 1H), 6.73 (dd, j=8.1, 1.6hz, 1H), 6.62 (t, 1H), 6.39 (dd, j=16.8, 2.2hz, 1H), 6.31-6.19 (m, 2H), 5.78 (dd, j=9.9, 2.2hz, 1H), 5.31 (s, 1H), 4.82-4.69 (m, 1H), 4.43 (d, j=7.6 hz, 2H), 4.36 (d, j=8.7 hz, 1H), 4.25 (d, j=8.6 hz, 1H), 4.08 (s, 3H), 3.65-3.55 (m, 2.22-2H), 3.31-6.19 (m, 2H), 4.82-4.69 (m, 1H), 4.43 (d, j=7.6 hz, 2H), 4.36 (2H), 2.45-2.2 (2H).

Example 220:3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (2- (pyridin-2-yl) ethoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (compound 473)

220-step 1

To 2- (pyridin-2-yl) ethan-1-ol (1 g,8.1 mmol), 3-hydroxyisonicotinic acid nitrile (972 mg,8.1 mmol) and PPh at 0deg.C ₃ (2.55 g,9.72 mmol) in THF (20 mL) was added DIAD (1.96 g,9.72 mmol). At N ₂ The mixture was stirred at 0℃for 2h. After completion, the reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (40 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (eluent: PE/EtOAc from 0 to 40%) to give 3- (2- (pyridin-2-yl) ethoxy) isonicotinic acid nitrile (200 mg, yield: 11%) as a yellow solid.

MS(ESI):C ₁₃ H ₁₁ N ₃ The calculated mass of O: 225.09, m/z actual: 226.1[ M+H ]]+。

220-step 2

A mixture of 3- (2- (pyridin-2-yl) ethoxy) isonicotinic nitrile (200 mg,0.89 mmol) and Raney Ni (50 mg) in MeOH (20 mL)/AcOH (5 mL) was stirred at room temperature under a hydrogen atmosphere for 1h. After completion, the mixture was filtered and washed with MeOH (40 mL). The filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (eluent: DCM/MeOH/nh4oh=10/1/0.1) to afford (3- (2- (pyridin-2-yl) ethoxy) pyridin-4-yl) methylamine (150 mg, 74%) as a yellow solid.

MS(ESI):C ₁₃ H ₁₅ N ₃ The calculated mass of O: 229.12, m/z actual: 230.2[ M+H ]] ⁺ 。

220-step 3

A mixture of (3- (2- (pyridin-2-yl) ethoxy) pyridin-4-yl) methylamine (140 mg,0.61 mmol), 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4-hydroxy-6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (252 mg,0.61 mmol), pyBOP (380 mg,0.73 mmol) and DIPEA (236 mg,1.83 mmol) in DMF (10 mL) was stirred at room temperature for 3H. After completion, the resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/meoh=15:1) to give tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -6-oxo-4- (((3- (2- (pyridin-2-yl) ethoxy) pyridin-4-yl) methyl) amino) -3, 6-dihydropyridine-1 (2H) -carboxylate (140 mg, 37%) as a yellow solid.

MS(ESI):C ₃₁ H ₃₄ ClN ₅ O ₅ The calculated mass of S: 623.20, m/z actual: 624.2[ M+H ]] ⁺ 。

220-step 4

To a solution of tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -6-oxo-4- (((3- (2- (pyridin-2-yl) ethoxy) pyridin-4-yl) methyl) amino) -3, 6-dihydropyridine-1 (2H) -carboxylate (140 mg,0.22 mmol) in 1, 4-dioxane (5 mL) was added TFA (75 mg,0.66 mmol) and H ₂ O ₂ (74.8 mg,0.66mmol,30% H) ₂ O solution). The resulting mixture was stirred at 80℃for 3h. The reaction mixture was concentrated to give the crude product, which was purified by preparative TLC (DCM/meoh=15/1) to give 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (2- (pyridin-2-yl) ethoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3, 2-c)]Pyridin-4-one (20 mg, yield: 18.5%) was a yellow solid.

MS(ESI):C ₂₆ H ₂₄ ClN ₅ O ₃ Calculated mass of (2): 489.16, m/z actual: 490.0[ M+H ]]+。

¹ H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.57(d,J＝4.9Hz,1H),8.35(s,1H),7.98(d,J＝5.1Hz,1H),7.81-7.77(m,1H),7.53(s,1H),7.44(d,J＝7.8Hz,1H),7.32–7.29(m,2H),7.15(s,1H),6.68–6.64(m,2H),6.09(dd,J＝5.9,3.8Hz,1H),4.52-4.49(m,2H),3.89(s,3H),3.46-3.42(m,2H),3.31-3.28(m,2H),2.93(t,J＝6.8Hz,2H)。

Example 221:3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((6-fluoropyridin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (compound 529)

221-step 1

To 3-hydroxyisonicotinic acid nitrile (354 mg,2.95 mmol), (6-fluoropyridin-2-yl) methanol (340 mg,2.68 mmol) and PPh at 0deg.C ₃ (844 mg,3.22 mmol) in THF (35 mL) was added DIAD (651 mg,3.22 mmol). At 0 ℃, N ₂ The reaction mixture was stirred for 2h. After completion, use H ₂ The reaction was quenched with O (50 mL) and extracted with EtOAc (50 mL. Times.3). The combined organic layers were washed with brine (40 mL), and dried over Na ₂ SO ₄ Dried, concentrated in vacuo to give crude, which was purified by preparative TLC (PE/ea=2/1) to give 3- ((6-fluoropyridin-2-yl) methoxy) isonicotinic nitrile (300 mg, yield: 49%) as a yellow solid.

MS(ESI):C ₁₂ H ₈ FN ₃ The calculated mass of O: 229.07, m/z actual: 230.0[ M+H ]] ⁺ 。

221-step 2

A mixture of 3- ((6-fluoropyridin-2-yl) methoxy) isonicotinic nitrile (300 mg,1.31 mmol) and Raney Ni (500 mg) in MeOH (20 mL) and AcOH (5 mL) was stirred at room temperature under a hydrogen atmosphere for 1h. The reaction mixture was filtered and washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (eluent: DCM/MeOH/NH) ₄ Oh=10/1/0.5) to afford (3- ((6-fluoropyridin-2-yl) methoxy) pyridin-4-yl) methylamine (150 mg, 49%) as a yellow solid.

MS(ESI):C ₁₂ H ₁₂ FN ₃ The calculated mass of O: 233.10, m/z actual: 234.1[ M+H ]] ⁺ 。

221-step 3

A mixture of 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4-hydroxy-6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (264 mg,0.64 mmol), (3- ((6-fluoropyridin-2-yl) methoxy) pyridin-4-yl) methylamine (150 mg,0.64 mmol), pyBOP (400 mg,0.77 mmol) and DIEA (248 mg,1.92 mmol) in DMF (10 mL) was stirred at room temperature for 3H. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (30 mL. Times.3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/meoh=15:1) to give tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4- (((3- ((6-fluoropyridin-2-yl) methoxy) pyridin-4-yl) methyl) amino) -6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylate (100 mg, 25%) as a yellow solid.

MS(ESI):C ₃₀ H ₃₁ ClFN ₅ O ₅ The calculated mass of S: 627.17, m/z actual: 628.1[ M+H ]] ⁺ 。

221-step 4

To a solution of tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4- (((3- ((6-fluoropyridin-2-yl) methoxy) pyridin-4-yl) methyl) amino) -6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylate (100 mg 0.16 mmol) in dioxane (5 mL) was added H ₂ O ₂ (30% at H) ₂ O, 0.2 mL). The reaction was stirred at 80℃for 1h. The reaction was concentrated in vacuo to give crude which was purified by preparative TLC (DCM/meoh=15/1) to give 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((6-fluoropyridin-2-yl) methoxy) pyridin-4-yl) -4-oxo-1, 4,6, 7-tetrahydro-5H-pyrrolo [3, 2-c)]Pyridine-5-carboxylic acid tert-butyl ester (50 mg, yield: 52.6%) as a yellow solid.

MS(ESI):C ₃₀ H ₂₉ ClFN ₅ O ₅ Calculated mass of (2): 593.18, m/z actual: 594.2[ M+H ]] ⁺ 。

221-step 5

To a solution of 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((6-fluoropyridin-2-yl) methoxy) pyridin-4-yl) -4-oxo-1, 4,6, 7-tetrahydro-5H-pyrrolo [3,2-c ] pyridine-5-carboxylic acid tert-butyl ester (50 mg,0.084 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 0.5 mL). The resulting mixture was stirred at room temperature for 1h. The reaction mixture was concentrated to give the crude product, which was purified by preparative TLC (DCM/meoh=15/1) to give 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((6-fluoropyridin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (25 mg, yield: 61%) as a yellow solid.

MS(ESI):C ₂₅ H ₂₁ ClFN ₅ O ₃ Calculated mass of (2): 493.13, m/z actual: 494.2[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO)δ11.54(s,1H),8.39(s,1H),8.13–8.00(m,2H),7.53(s,1H),7.41(dd,J＝7.4,2.0Hz,1H),7.34(d,J＝5.0Hz,1H),7.23–7.11(m,2H),6.71–6.62(m,2H),6.16(dd,J＝6.8,2.8Hz,1H),5.45(s,2H),3.85(s,3H),3.53–3.37(m,2H),2.92(t,J＝6.8Hz,2H)。

Example 222:3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((3-fluoropyridin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (compound 530)

222-step 1

To 3-hydroxyisonicotinic acid nitrile (600 mg,5.0 mmol), (3-fluoropyridin-2-yl) methanol (635 mg,5.0 mmol) and PPh at 0deg.C ₃ (2.63 g,10.0 mmol) in THF (25 mL) was added DIAD (2.02 g,10.0 mmol). At 0 ℃, N ₂ The resulting reaction mixture was stirred for 2h. After completion, reaction H ₂ O (40 mL) was quenched and extracted with EtOAc (40 mL. Times.3). The combined organic layers were washed with brine (30 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM/meoh=1/20) to give 3- ((3-fluoropyridin-2-yl) methoxy) isonicotinic acid (420 mg, yield: 36.7%) as a yellow solid.

MS(ESI):C ₁₂ H ₈ FN ₃ The calculated mass of O: 229.07, m/z actual: 230.1[ M+H ]] ⁺ 。

222-step 2

A mixture of 3- ((3-fluoropyridin-2-yl) methoxy) isonicotinic nitrile (420 mg,1.83 mmol) and Raney-Ni (100 mg) in MeOH (20 mL) and AcOH (5 mL) was stirred at room temperature under a hydrogen atmosphere for 1h. After completion, the reaction mixture was filtered through celite and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM/MeOH/NH) ₄ Oh=10/1/0.1) to afford (3- ((3-fluoropyridin-2-yl) methoxy) pyridin-4-yl) methylamine (310 mg, yield: 72.7%) as a yellow solid.

MS(ESI):C ₁₂ H ₁₂ FN ₃ The calculated mass of O: 233.10, m/z actual: 234.2[ M+H ]] ⁺ 。

222-step 3

At room temperature, N ₂ A mixture of 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4-hydroxy-6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (354 mg,0.86 mmol), (3- ((3-fluoropyridin-2-yl) methoxy) pyridin-4-yl) methylamine (240 mg,1.03 mmol), pyBOP (534 mg,1.03 mmol) and DIPEA (333 mg,2.58 mmol) in DMF (15 mL) was stirred for 3H. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give crude which was purified by preparative TLC (DCM/meoh=30/1) to give tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4- (((3- ((3-fluoropyridin-2-yl) methoxy) pyridin-4-yl) methyl) amino) -6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylate (120 mg, yield: 22%) as a yellow solid.

MS(ESI):C ₃₀ H ₃₁ ClFN ₅ O ₅ The calculated mass of S: 627.17, m/z actual: 628.2[ M+H ]] ⁺ 。

222-step 4

To 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4- (((3- ((3-fluoropyridin-2-yl) methoxy) pyridin-4-yl) methyl) amino) -6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (120 mg,0.19 mmo) l) solution in 1, 4-Dioxacyclohexane (5 mL) H was added ₂ O ₂ (30% H) ₂ O solution, 64.5mg,0.57 mmol). The resulting mixture was stirred at 80℃for 1h. The reaction was concentrated in vacuo to give crude which was purified by preparative TLC (DCM/meoh=20/1) to give 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((3-fluoropyridin-2-yl) methoxy) pyridin-4-yl) -4-oxo-1, 4,6, 7-tetrahydro-5H-pyrrolo [3, 2-c)]Pyridine-5-carboxylic acid tert-butyl ester (60 mg, yield: 53%) as a yellow solid.

222-step 5

To a solution of tert-butyl 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((3-fluoropyridin-2-yl) methoxy) pyridin-4-yl) -4-oxo-1, 4,6, 7-tetrahydro-5H-pyrrolo [3,2-c ] pyridine-5-carboxylate (60 mg,0.10 mmol) in MeOH (5 mL) was added HCl (4M in 1, 4-dioxane, 0.5 mL). The resulting mixture was stirred at room temperature for 1h. The reaction mixture was concentrated to give the crude product, which was purified by preparative TLC (DCM/meoh=15/1) to give 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((3-fluoropyridin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (35 mg, yield: 71%) as a yellow solid.

MS(ESI):C ₂₅ H ₂₁ ClFN ₅ O ₃ Calculated mass of (2): 493.13, m/z actual: 494.1[ M+H ] ]+。

¹ H NMR(400MHz,DMSO)δ12.28(s,1H),8.60(d,J＝4.7Hz,1H),8.56(s,1H),8.04(d,J＝5.1Hz,1H),7.89(t,J＝9.3Hz,1H),7.61-7.57(m,1H),7.56(s,1H),7.36(d,J＝5.1Hz,1H),7.18(s,1H),6.71–6.67(m,2H),6.16(dd,J＝6.8,2.8Hz,1H),5.69(s,2H),3.90(s,3H),3.47-3.43(m,2H),2.98(t,J＝6.8Hz,2H)。

Example 223:3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((5-fluoropyridin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (compound 531)

223-step 1

(5-fluoropyridin-2-yl) methanol (700 mg,5.5 mmol), 3-hydroxyisonicotinic acid nitrile (660 mg,5.5 mmol) and PPh at 0deg.C ₃ (1.74 g,6.6 mmol) in THF (30 mL) was added DIAD (1.33 g,6.6 mmol). At 0 ℃, N ₂ The reaction mixture was stirred for 2 hours. After completion, reaction H ₂ O (30 mL) was quenched and extracted with EtOAc (50 mL. Times.3). The combined organic layers were washed with brine (40 mL), and dried over Na ₂ SO ₄ Dried, concentrated in vacuo to give crude, which was purified by preparative TLC (PE/ea=2/1) to give 3- ((5-fluoropyridin-2-yl) methoxy) isonicotinic nitrile (480 mg, yield: 38%) as a yellow solid.

223-step 2

A mixture of 3- ((5-fluoropyridin-2-yl) methoxy) isonicotinic nitrile (480 mg,2.10 mmol) and Raney Ni (50 mg) in MeOH (20 mL) and AcOH (4 mL) was stirred at room temperature under a hydrogen atmosphere for 1h. The reaction mixture was filtered through celite and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM/MeOH/NH) ₄ Oh=10/1/0.1) to afford (3- ((5-fluoropyridin-2-yl) methoxy) pyridin-4-yl) methylamine (410 mg, yield: 84%) as a yellow solid.

223-step 3

A mixture of (3- ((5-fluoropyridin-2-yl) methoxy) pyridin-4-yl) methylamine (410 mg,1.76 mmol), 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4-hydroxy-6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (723 mg,1.76 mmol), pyBOP (1.1 g,2.1 mmol) and DIPEA (677 mg,5.25 mmol) in DMF (15 mL) was stirred at 30℃for 3H. After completion, the reaction was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under vacuum to obtainTo the crude product, which was purified by silica gel column chromatography (eluent: DCM/meoh=1/20) to give tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4- (((3- ((5-fluoropyridin-2-yl) methoxy) pyridin-4-yl) methyl) amino) -6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylate (330 mg, yield: 30%) as a yellow solid.

223-step 4

To a solution of tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4- (((3- ((5-fluoropyridin-2-yl) methoxy) pyridin-4-yl) methyl) amino) -6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylate (145 mg,0.23 mmol) in 1, 4-dioxane (5 mL) was added TFA (79 mg,0.69 mmol) and H ₂ O ₂ (30% H) ₂ O solution, 0.2mL,0.69 mmol). The resulting mixture was stirred at 80℃for 3h. The reaction mixture was concentrated to give the crude product, which was purified by preparative TLC (DCM/meoh=15/1) to give 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((5-fluoropyridin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c]Pyridin-4-one (29 mg, yield: 25.6%) was a yellow solid.

MS(ESI):C ₂₅ H ₂₁ ClFN ₅ O ₃ Calculated mass of (2): 493.13, m/z actual: 494.7[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO)δ11.87(s,1H),8.69(d,J＝2.8Hz,1H),8.42(s,1H),8.04(d,J＝5.1Hz,1H),7.87-7.82(m,1H),7.59(dd,J＝8.7,4.5Hz,1H),7.53(s,1H),7.33(d,J＝5.1Hz,1H),7.15(s,1H),6.68-6.65(m,2H),6.16(dd,J＝6.4,3.3Hz,1H),5.50(s,2H),3.86(s,3H),3.46-3.43(m,2H),2.95(t,J＝6.8Hz,2H)。

Example 224: (S) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (1- (pyridin-2-yl) ethoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (compound 532)

224-step 1

at-10deg.C, N ₂ To a stirred suspension of NaH (702 mg, 17.39 mmol) in anhydrous DMF (50 mL) was added (1S) -1- (pyridin-2-yl) ethanol (710 mg, 7.514 mmol) in DMF (5 mL). After stirring for 0.5h, 3-chloropyridine-4-carbonitrile (972 mg,7.012 mmol) in DMF (5 mL) was added to the solution at 0deg.C. The reaction mixture was stirred at 0℃for 1h. After completion, saturated NH was used ₄ The reaction mixture was quenched with Cl and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography on silica gel (PE/EA from 0 to 70%) to give (S) -3- (1- (pyridin-2-yl) ethoxy) isonicotinic nitrile (1 g, 63%) as a colorless oil.

MS(ESI):C ₁₃ H ₁₁ N ₃ The calculated mass of O: 225.1, m/z actual: 226.1[ M+H ]] ⁺ 。

224-step 2

At N ₂ Next, (S) -3- (1- (pyridin-2-yl) ethoxy) isonicotinic acid nitrile (0.97 g,4.306 mmol) in MeOH (50 mL) and NH ₃ .H ₂ Raney Ni (200 mg) was added to a stirred solution of O (5 mL). At H ₂ The reaction mixture was stirred at room temperature for 5h. After filtration, the filtrate was collected and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/MeOH from 0 to 10%) to give (S) - (3- (1- (pyridin-2-yl) ethoxy) pyridin-4-yl) methylamine (800 mg, 81%) as an orange-red oil.

MS(ESI):C ₁₃ H ₁₅ N ₃ The calculated mass of O: 229.1, m/z actual: 230.1[ M+H ]] ⁺ 。

224-step 3

To a stirred solution of (S) - (3- (1- (pyridin-2-yl) ethoxy) pyridin-4-yl) methylamine (500 mg,2.181 mmol) in DMF (40 mL) was added tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4-hydroxy-6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylate (900 mg,2.181 mmol), pyBOP (1.702 g,3.272 mmol), DIEA (846 mg,6.543 mmol). The reaction mixture was stirred at room temperature for 16h. After completion, the reaction mixture was quenched with water and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH from 0 to 10%) to give tert-butyl (S) -5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -6-oxo-4- (((3- (1- (pyridin-2-yl) ethoxy) pyridin-4-yl) methyl) amino) -3, 6-dihydropyridine-1 (2H) -carboxylate (1.3 g,80% pure) as a pale yellow oil.

MS(ESI):C ₃₁ H ₃₄ ClN ₅ O ₅ The calculated mass of S: 623.2, m/z actual: 624.2[ M+H ]] ⁺ 。

224-step 4

To a stirred solution of (S) -5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -6-oxo-4- (((3- (1- (pyridin-2-yl) ethoxy) pyridin-4-yl) methyl) amino) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (500 mg,0.8 mmol) in MeOH (15 mL) at 0deg.C was added H ₂ O ₂ (31%, 182mg,1.6 mmol), TFA (183 mg,1.6 mmol). The reaction mixture was then stirred at 80℃for 3h. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EA and the organic phase was washed with water, brine, over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by preparative HPLC and using the following conditions: welch 10u C18 250x21.2mm; mobile phase A: H ₂ O(0.1％NH ₃ ) ACN- -HPLC; the flow rate is 25mL/min; gradient 45% b to 55% b,9.5 min; 214nm; rt:8.28min to give (S) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (1- (pyridin-2-yl) ethoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3, 2-c)]Pyridin-4-one (46 mg, 12%) was a yellow solid.

MS(ESI):C ₂₆ H ₂₄ ClN ₅ O ₃ Calculated mass of (2): 489.2, m/z actual: 490.2[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO)δ12.20(s,1H),8.65(d,J＝4.3Hz,1H),8.38(s,1H),7.96(d,J＝5.0Hz,1H),7.85(t,J＝7.7,1.5Hz,1H),7.53–7.48(m,2H),7.39(dd,J＝7.0,5.3Hz,1H),7.27(d,J＝5.0Hz,1H),7.15(s,1H),6.68–6.63(m,2H),6.16(dd,J＝6.8,2.8Hz,1H),5.90(q,J＝6.3Hz,1H),3.87(s,3H),3.47–3.45(m,2H),3.02–2.93(m,2H),1.66(d,J＝6.3Hz,3H)。

Example 225: (R) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (1- (pyridin-2-yl) ethoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (compound 533)

225-step 1

At 0 ℃, N ₂ A solution of (1R) -1- (pyridin-2-yl) ethanol (770 mg,6.252 mmol) in anhydrous DMF (5 mL) was added to a mixture of NaH (618 mg,14.207 mmol) in anhydrous DMF (20 mL). After stirring for 0.5h, 3-chloropyridine-4-carbonitrile (787 mg,5.683 mmol) in anhydrous DMF (5 mL) was added to the mixture. The reaction mixture was stirred at 0℃for a further 1h. After completion, the reaction mixture was saturated with NH with ice ₄ The aqueous Cl solution was quenched and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography on silica gel (PE/EA from 0 to 65%) to give (R) -3- (1- (pyridin-2-yl) ethoxy) isonicotinic nitrile (1 g, 78%) as a colorless oil.

225-step 2

At N ₂ Next, (R) -3- (1- (pyridin-2-yl) ethoxy) isonicotinic acid nitrile (900 mg,3.996 mmol) in MeOH (50 mL) and NH ₃ .H ₂ Raney Ni (200 mg) was added to a stirred solution of O (5 mL). At H ₂ The reaction mixture was stirred at room temperature for 5h. After completion, the solvent was collected, depressurized and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH from 0 to 10%) to give (R) - (3- (1- (pyridin-2-yl) ethoxy) pyridin-4-yl) methylamine (760 mg, 82%) as a yellow oil.

225-step 3

To a stirred solution of (R) - (3- (1- (pyridin-2-yl) ethoxy) pyridin-4-yl) methylamine (500 mg,2.181 mmol) in DMF (40 mL) was added tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4-hydroxy-6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylate (900 mg,2.181 mmol), pyBOP (1.702 g,3.272 mmol), DIEA (846 mg,6.543 mmol). The reaction mixture was stirred at room temperature for 16h. After completion, the reaction mixture was quenched with water and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH from 0 to 10%) to give (R) -5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -6-oxo-4- (((3- (1- (pyridin-2-yl) ethoxy) pyridin-4-yl) methyl) amino) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (1.3 g,80% pure) as a deep yellow oil.

MS(ESI):C ₃₁ H ₃₄ ClN ₅ O ₅ Calculated mass of S623.2, m/z actual: 624.2[ M+H ]] ⁺ 。

225-step 4

To a stirred solution of (R) -5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -6-oxo-4- (((3- (1- (pyridin-2-yl) ethoxy) pyridin-4-yl) methyl) amino) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (500 mg,0.8 mmol) in MeOH (15 mL) at 0deg.C was added H ₂ O ₂ (31%, 182mg,1.6 mmol), TFA (183 mg,1.6 mmol). The reaction mixture was then stirred at 80℃for 3h. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EA and the organic phase was washed with water, brine, over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by preparative HPLC and using the following conditions: xbridge 5u C18 150x30mm; mobile phase A: H ₂ O (0.1% FA), mobile phase B ACN- -HPLC; the flow rate is 30mL/min; gradient 32% b to 45% b over 9 min; 214nm; rt:8min to give (R) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (1- (pyridin-2-yl) ethoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3, 2-c)]Pyridin-4-one (121 mg, 30%) was a yellow solid.

¹ H NMR(400MHz,DMSO)δ12.29(s,1H),8.66(d,J＝4.4Hz,1H),8.43(s,1H),8.02(d,J＝5.2Hz,1H),7.87(t,J＝7.7,1.6Hz,1H),7.63(s,1H),7.51(d,J＝7.9Hz,1H),7.40(dd,J＝6.9,5.1Hz,1H),7.33(d,J＝5.2Hz,1H),7.18(s,1H),6.72–6.65(m,2H),6.17(dd,J＝7.5,2.0Hz,1H),5.93(q,J＝6.3Hz,1H),3.88(s,3H),3.48(t,J＝6.1Hz,2H),3.00(dd,J＝6.8,4.8Hz,2H),1.68(d,J＝6.4Hz,3H)。

Example 226: (R) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (2- (pyridin-2-yl) propoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one/(S) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (2- (pyridin-2-yl) propoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 534/535)

226-step 1

A solution of methyl 2- (pyridin-2-yl) acetate (5 g,33.11 mmol) and t-Buona (3.34 g,34.77 mmol) in THF (175 mL) was stirred at 0deg.C under nitrogen for 30min. A solution of MeI (9.4 g,66.23 mmol) in THF (20 mL) was then added at 0deg.C and the reaction mixture stirred at room temperature for 1h. After completion, the mixture was treated with NH ₄ The aqueous saturated Cl (100 mL) was quenched and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (eluent: PE/etoac=2/1) to give methyl 2- (pyridin-2-yl) propionate (4.5 g, yield: 82%) as a yellow oil.

MS(ESI):C ₉ H ₁₁ NO ₂ Calculated mass of (2): 165.08, m/z actual: 166.2[ M+H ]] ⁺ 。

226-step 2

To a solution of methyl 2- (pyridin-2-yl) propionate (4.5 g,27.3 mmol) in THF (150 mL) at 0deg.C under nitrogen was added LiAlH dropwise ₄ (1M in THF, 35.4mL,35.4 mmol). The mixture was stirred at room temperature for 1h. After completion, the reaction mixture was taken up with Na ₂ SO ₄ ·10H ₂ O was quenched, filtered through celite and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (eluent: PE/etoac=2/1) to give 2- (pyridin-2-yl) propan-1-ol (2.8 g, yield: 75%) as a yellow oil.

MS(ESI):C ₈ H ₁₁ Calculated mass of NO: 137.08, m/z actual: 138.2[ M+H ]] ⁺ 。

226-step 3

To a solution of 2- (pyridin-2-yl) propan-1-ol (1.5 g,10.95 mmol) in DMF (75 mL) was added NaH (60% dispersion in mineral oil, 438mg,10.95 mmol) at 0deg.C and concentrated in N ₂ Stirred for 1h. Then at 0 ℃ N ₂ A solution of 3-chloroisonicotinic nitrile (1.51 g,10.95 mmol) in DMF (15 mL) was added thereto and stirred for 1h. After completion, use NH ₄ The reaction was quenched with saturated aqueous Cl (100 mL) and extracted with EtOAc (100 mL. Times.3). The combined organic layers were washed with brine (80 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (eluent: PE/etoac=2/1) to give 3- (2- (pyridin-2-yl) propoxy) isonicotinic nitrile (1.6 g, yield: 61%) as a yellow oil.

MS(ESI):C ₁₄ H ₁₃ N ₃ The calculated mass of O: 239.11, m/z actual: 240.1[ M+H ]] ⁺ 。

226-step 4

A mixture of 3- (2- (pyridin-2-yl) propoxy) isonicotinic nitrile (1.6 g,6.69 mmol) and Raney Ni (1.0 g) in MeOH (60 mL) and AcOH (15 mL) was stirred at room temperature under a hydrogen atmosphere for 2h. After completion, the mixture was filtered through celite and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (eluent: DCM/MeOH/NH) ₄ Oh=10/1/0.1) to afford (3- (2- (pyridin-2-yl) propoxy) pyridin-4-yl) methylamine (1.1 g, yield: 68%) as a yellow oil.

MS(ESI):C ₁₄ H ₁₇ N ₃ The calculated mass of O: 243.14, m/z actual: 244.2[ M+H ]] ⁺ 。

226-step 5

A solution of 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4-hydroxy-6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (678 mg,1.65 mmol), (3- (2- (pyridin-2-yl) propoxy) pyridin-4-yl) methylamine (400 mg,1.65 mmol), pyBOP (1.11 g,2.14 mmol) and DIPEA (1.07 g,8.23 mmol) in DMF (25 mL) was stirred at room temperature for 3H. After completion, the resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM/meoh=20/1) to give tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -6-oxo-4- (((3- (2- (pyridin-2-yl) propoxy) pyridin-4-yl) methyl) amino) -3, 6-dihydropyridine-1 (2H) -carboxylate (660 mg, yield: 63%) as a yellow solid.

MS(ESI):C ₃₂ H ₃₆ ClN ₅ O ₅ The calculated mass of S: 637.21, m/z actual: 638.2[ M+H ]] ⁺ 。

226-step 6

To a solution of tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -6-oxo-4- (((3- (2- (pyridin-2-yl) propoxy) pyridin-4-yl) methyl) amino) -3, 6-dihydropyridine-1 (2H) -carboxylate (350 mg 0.55 mmol) in 1, 4-dioxane (20 mL) was added H ₂ O ₂ (30% H) ₂ O solution, 0.5mL,1.65 mL). The reaction was stirred at 80℃for 1h. After completion, the reaction was concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (eluent: DCM/meoh=15/1) to give 3- ((3-chloro-2-methoxyphenyl) amino) -4-oxo-2- (3- (2- (pyridin-2-yl) propoxy) pyridin-4-yl) -1,4,6, 7-tetrahydro-5H-pyrrolo [3, 2-c)]Pyridine-5-carboxylic acid tert-butyl ester (155 mg, yield: 47%) as a yellow solid.

MS(ESI):C ₃₂ H ₃₄ ClN ₅ O ₅ Calculated mass of (2): 603.22, m/z actual: 604.2[ M+H ]] ⁺ 。

226-step 7

To a solution of tert-butyl 3- ((3-chloro-2-methoxyphenyl) amino) -4-oxo-2- (3- (2- (pyridin-2-yl) propoxy) pyridin-4-yl) -1,4,6, 7-tetrahydro-5H-pyrrolo [3,2-c ] pyridine-5-carboxylate (155 mg,0.26 mmol) in 1, 4-dioxane (10 mL) was added HCl (4M in 1, 4-dioxane, 2 mL). The resulting mixture was stirred at 0℃for 1h. The reaction mixture was concentrated to give the crude product, which was purified by preparative TLC (eluent: DCM/meoh=15/1) to give 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (2- (pyridin-2-yl) propoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (110 mg, yield: 84%) as a yellow solid.

MS(ESI):C ₂₇ H ₂₆ ClN ₅ O ₃ Calculated mass of (2): 503.17, m/z actual: 504.2[ M+H ]] ⁺ 。

226-step 83- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (2- (pyridin-2-yl) propoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (110 mg,0.22 mmol) was isolated by SFC (Daicel CHIRALPAK OD-H,20x250mm,5 μm 70/30CO2/MeOH [0.2% NH3 (7M in MeOH) ],50g/min,120 bar, 35 ℃) to give two enantiomers of (R) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (2- (pyridin-2-yl) propoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (33 mg, yield: 30%) as a white solid; and (S) -3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (2- (pyridin-2-yl) propoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (36 mg, yield: 33%) as a white solid.

P1:MS(ESI):C ₂₇ H ₂₆ ClN ₅ O ₃ Calculated mass of (2): 503.17, m/z actual: 504.2[ M+H ]] ⁺ 。

P1: ¹ H NMR(400MHz,DMSO)δ11.66(s,1H),8.56(d,J＝3.9Hz,1H),8.33(s,1H),7.97(d,J＝5.0Hz,1H),7.82–7.72(m,1H),7.48–7.39(m,2H),7.27(m,2H),7.13(s,1H),6.71–6.62(m,2H),6.04(m,1H),4.44–4.35(m,2H),3.88(s,3H),3.53(m,1H),3.43(m,2H),3.00–2.83(m,2H),1.40(d,J＝7.1Hz,3H)。

P2:MS(ESI):C ₂₇ H ₂₆ ClN ₅ O ₃ Calculated mass of (2): 503.17, m/z actual: 504.2[ M+H ]] ⁺ 。

P2: ¹ H H NMR(400MHz,DMSO)δ11.66(s,1H),8.56(d,J＝3.9Hz,1H),8.33(s,1H),7.97(d,J＝5.0Hz,1H),7.76(m,1H),7.48–7.37(m,2H),7.28(m,2H),7.13(s,1H),6.71–6.62(m,2H),6.04(m,1H),4.44–4.34(m,2H),3.88(s,3H),3.53(m,1H),3.44(m,2H),2.99–2.84(m,2H),1.40(d,J＝7.1Hz,3H)。

Example 227.3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (2-methyl-2- (pyridin-2-yl) propoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 536)

227-step 1

To a solution of 2-isopropylpyridine (9.5 g,0.0784 mol) in THF (100 mL) at 0deg.C was added n-BuLi (43.1 mL,0.0862mol,2M in hexane). The reaction mixture was stirred at room temperature for 0.5h, and paraformaldehyde (4.7 g,0.1568 mol) was added at-40 ℃. The reaction mixture was stirred at-40 ℃ for 0.5h and at room temperature for 1.5h. A 3N NaOH saturated aqueous solution was added. The mixture was extracted with EA (200 ml x 3). The organic layer was treated with anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash chromatography to give 2-methyl-2- (pyridin-2-yl) propan-1-ol (3 g, 24%) as a yellow solid.

MS(ESI):C ₉ H ₁₃ Calculated mass of NO: 151.10, m/z actual: 152.1[ M+H ]] ⁺ 。

227-step 2

To a solution of 2-methyl-2- (pyridin-2-yl) propan-1-ol (3 g,0.0198 mol) in DMF (40 mL) was added sodium hydride (0.95 g,0.0396 mol) at 0deg.C. The reaction was stirred at 0deg.C for 0.5h, and 3-chloropyridine-4-carbonitrile (2.74 g,0.0198 mol) was added at 0deg.C. The reaction was stirred at room temperature for 1h. The mixture was diluted with water and extracted with EA (100 ml x 3). The organic layer was treated with anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash chromatography to give a residue and it was purified by flash chromatography to give 3- (2-methyl-2- (pyridin-2-yl) propoxy) isonicotinic nitrile (4 g, 67%) as a yellow solid.

Calculated mass C of MS (ESI) ₁₅ H ₁₅ N ₃ O,253.12, m/z actual: 254.1[ M+H ]] ⁺ 。

227-step 3

At H ₂ Down to 3- [ 2-methyl-2- (pyridin-2-yl) propoxy]A solution of pyridine-4-carbonitrile (1 g,0.0039 mol) in MeOH (20 mL) was added Raney Ni (0.23 g,0.0039 mol). At 35 ℃ H ₂ The reaction mixture was stirred for 2.5h. The solution was filtered, the filtrate was collected and concentrated in vacuo to give the crude product. The residue was purified by flash chromatography to give a residue and it was purified by flash chromatography to give (3- (2-methyl-2- (pyridin-2-yl) propoxy) pyridin-4-yl) methylamine (0.9 g, 85%) as a yellow solid.

MS(ESI):C ₁₅ H ₁₉ N ₃ The calculated mass of O: 257.15, m/z actual: 258.1[ M+H ]] ⁺ 。

227-step 4

To {3- [ 2-methyl-2- (pyridin-2-yl) propoxy ]]Pyridin-4-yl } methylamine (900 mg,3.4974 mmol), {3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl)]A solution of tert-butyl 4-hydroxy-2-oxo-5, 6-dihydropyridin-1-yl } carboxylate (1516.27 mg,3.6722 mmol) in DMF (20 mL) was added N, N-diisopropylethylamine (1356.01 mg,10.4922 mmol) and PYBOP (2730.02 mg,5.2461 mmol). The reaction was stirred at room temperature for 4h. The mixture was diluted with water and extracted with EA (50 ml x 3). The organic layer was treated with anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash chromatography to give tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4- (((3- (2-methyl-2- (pyridin-2-yl) propoxy) pyridin-4-yl) methyl) amino) -6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylate (700 mg, 29%) as a yellow solid.

MS(ESI):C ₃₃ H ₃₈ ClN ₅ O ₅ The calculated mass of S: 651.23, m/z actual: 652.0/654.0[ M+H ]] ⁺ 。

227-step 5

At 0℃to {3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl } -]-4- [ ({ 3- [ 2-methyl-2- (pyridin-2-yl) propoxy)]Pyridin-4-yl } methyl) amino groups]-2-oxo-5, 6-dihydropyridin-1-yl } carboxylic acid tert-butyl esterA solution of butyl ester (300 mg,0.46 mmol) in MeOH (10 mL) was added trifluoroacetic acid (104.9 mg,0.92 mol) and hydrogen peroxide (31.29 mg,0.92 mol). The reaction was stirred at 80℃for 3h. Adding Na ₂ SO ₃ Saturated aqueous solution. The mixture was extracted with EA (30 ml x 3). The organic layer was treated with anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by preparative HPLC to give 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (2-methyl-2- (pyridin-2-yl) propoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3, 2-c)]Pyridin-4-one (54.7 mg, 23%) was a yellow solid.

MS(ESI):C ₂₈ H ₂₈ ClN ₅ O ₃ Calculated mass of (2): 517.19, m/z actual: 518.0[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO)δ11.85(s,1H),8.58(dd,J＝4.0,8.0Hz,1H),8.37(s,1H),8.04(d,J＝8.0Hz,1H),7.84-7.80(m,1H),7.57–7.55(m,2H),7.34(d,J＝8.0Hz,1H),7.31–7.28(m,1H),7.22(s,1H),6.72–6.66(m,2H),6.05(dd,J＝4.0,8.0Hz,1H),4.32(s,2H),3.88(s,3H),3.47-3.43(m,2H),2.91(t,J＝8.0Hz,2H),1.52(s,6H)。

Example 228:3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((6-methoxypyridin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (compound 537)

228-step 1

at-10deg.C, N ₂ To a stirred suspension of NaH (60%, 377mg,9.42 mmol) in DMF (50 mL) was added (6-methoxypyridin-2-yl) methanol (1.42 g,10.2 mmol) in DMF (5 mL). After stirring for 0.5h, 3-chloropyridine-4-carbonitrile (1.1 g,7.85 mmol) in DMF (5 mL) was added to the solution at-10deg.C. The reaction mixture was then stirred at-10℃for 1h. After completion, the reaction mixture was saturated with NH with ice ₄ The aqueous Cl solution was quenched and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was passed through a rapid reaction Silica gel column chromatography purification (EA/PE from 0 to 40%) afforded 3- ((6-methoxypyridin-2-yl) methoxy) isonicotinic acid nitrile (1.3 g, 68%) as a white solid.

MS(ESI):C ₁₃ H ₁₁ N ₃ O ₂ Calculated mass of (2): 241.1, m/z actual: 242.1[ M+H ]] ⁺ 。

228-step 2

At N ₂ Next, 3- [ (6-methoxypyridin-2-yl) methoxy group]Pyridine-4-carbonitrile (250 mg,1.036 mmol) in MeOH (25 mL) and NH ₃ .H ₂ Raney Ni (100 mg) was added to a stirred solution of O (2.5 mL). At H ₂ The reaction mixture was stirred at room temperature for 5h. After completion, the solvent was collected, depressurized and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/DCM from 0 to 10%) to give (3- ((6-methoxypyridin-2-yl) methoxy) pyridin-4-yl) methylamine (220 mg, 86%) as a white solid.

MS(ESI):C ₁₃ H ₁₅ N ₃ O ₂ Calculated mass of (2): 245.1, m/z actual: 246.1[ M+H ]] ⁺ 。

228-step 3

To a stirred solution of (3- ((6-methoxypyridin-2-yl) methoxy) pyridin-4-yl) methylamine (220 mg,0.897 mmol) in DMF (10 mL) was added 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4-hydroxy-6-oxo-3, 6-dihydropyridin-1 (2H) -carboxylic acid tert-butyl ester (431 mg,0.897 mmol), pyBOP (704 mg, 1.348 mmol), DIEA (348 mg,2.691 mmol). The reaction mixture was stirred at room temperature for 16h. After completion, the reaction mixture was quenched with water and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography (MeOH/DCM from 0 to 10%) to give tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4- (((3- ((6-methoxypyridin-2-yl) methoxy) pyridin-4-yl) methyl) amino) -6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylate (270 mg,80% pure) as a yellow oil.

MS(ESI):C ₃₁ H ₃₄ ClN ₅ O ₆ The calculated mass of S: 639.2, m/z actual: 640.2[ M+H ]] ⁺ 。

228-step 4

To a stirred solution of tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4- (((3- ((6-methoxypyridin-2-yl) methoxy) pyridin-4-yl) methyl) amino) -6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylate (220 mg,0.34 mmol) in MeOH (10 mL) at 0deg.C was added H ₂ O ₂ (31%, 78mg,0.688 mmol), TFA (79 mg,0.688 mmol). The reaction mixture was then stirred at 80℃for 3h. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EA and the organic phase was washed with water, brine, over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by preparative HPLC and using the following conditions: welch 10u C18 250x21.2mm; mobile phase A: H ₂ O (0.1% A), mobile phase B ACN- -HPLC; the flow rate is 30mL/min; gradient 32% b to 45% b over 9 min; 214nm; rt:8min to give 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((6-methoxypyridin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ]Pyridin-4-one (72 mg, 41%) was a yellow solid.

MS(ESI):C ₂₆ H ₂₄ ClN ₅ O ₄ Calculated mass of (2): 505.2, m/z actual: 506.2[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO)δ11.40(s,1H),8.38(s,1H),8.03(d,J＝5.0Hz,1H),7.73(t,J＝7.8Hz,1H),7.48(s,1H),7.31(d,J＝5.0Hz,1H),7.10(s,1H),7.01(d,J＝7.3Hz,1H),6.78(d,J＝8.3Hz,1H),6.66–6.60(m,2H),6.14(dd,J＝7.2,2.3Hz,1H),5.35(s,2H),3.82(d,J＝6.4Hz,6H),3.44–3.41(m,2H),2.87(t,J＝6.8Hz,2H)。

Example 229:2- [3- (benzyloxy) pyridin-4-yl ] -3- [ (3-fluoro-2-methylphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 538)

229-step 1

To 3-hydroxypyridine-4-carbonitrile (450 mg,3.75 mmol), pyridazin-3-ylmethanol (495mg, 4.49 mmol) and PPh at 0deg.C ₃ (1.20g,4.49 mmol) in DCM (20 mL) was added DIAD (909 mg,4.49 mmol) dropwise. The reaction mixture was stirred at 0℃for 1h. The mixture was concentrated to give a crude product. The crude product was purified by flash chromatography (PE/EA from 0 to 40%) to give the product 3- (pyridazin-3-ylmethoxy) pyridine-4-carbonitrile (260 mg,33% yield) as a yellow oil.

MS(ESI):C ₁₁ H ₈ N ₄ The calculated mass of O: 212.1, m/z actual: 213.1[ M+H ]] ⁺ 。

229-step 2

At N ₂ Next, 3- (pyridazin-3-ylmethoxy) pyridine-4-carbonitrile (260 mg,1.22 mmol) was reacted with NH ₃ A solution of MeOH (7M in methanol, 5 mL) and MeOH (20 mL) was added Raney Ni (260 mg). At H ₂ The reaction was stirred at 20℃for 16h. After completion, the solvent was collected and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/MeOH from 0 to 10%) to give [3- (pyridazin-3-ylmethoxy) pyridin-4-yl ]]Methylamine (250 mg,94% yield) as a yellow oil.

MS(ESI):C ₁₁ H ₁₂ N ₄ The calculated mass of O: 216.1, m/z actual: 217.1[ M+H ]] ⁺ 。

229-step 3

To [3- (pyridazin-3-ylmethoxy) pyridin-4-yl]Methylamine (250 mg,1.16 mmol), {3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl ]]A solution of tert-butyl 4-hydroxy-2-oxo-5, 6-dihydropyridin-1-yl } carboxylate (526 mg,1.27 mmol) and PYBOP (1.2 g,2.3 mmol) in DMA (10 mL) was added to DIPEA (750 mg,5.8 mmol). The reaction mixture was stirred at 20℃for 4h. After completion, the reaction mixture was quenched with water and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH from 0 to 10%) to give {3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl }]-4- { [ (3- { [6- (difluoromethyl) pyridin-2-yl)]Methoxy } pyridin-4-yl) methyl]Tert-butyl amino } -2-oxo-5, 6-dihydropyridin-1-yl } carboxylate (280 mg, 48%) as a yellow solid.

229-step 4

To {3- [ (3-chloro-2-methoxyphenyl) thio-amino })Formyl radicals]-2-oxo-4- ({ [3- (pyridazin-3-ylmethoxy) pyridin-4-yl)]A solution of tert-butyl methyl } amino) -5, 6-dihydropyridin-1-yl } carboxylate (160 mg,0.26 mmol) in 1, 4-dioxane (5.0 mL) was added TFA (60 mg,0.53 mmol) and H ₂ O ₂ (30%, 89mg,0.78 mmol). The reaction was stirred at 90℃for 1h. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EA and the organic phase was washed with water, brine, over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by preparative HPLC and using the following conditions: xbridge 5u C18 150x19mm; mobile phase A: H ₂ O (0.1% FA), mobile phase B ACN- -HPLC; the flow rate is 20mL/min; gradient 15% B to 45% B,8 min; 214nm; rt 5.7min to give 2- [3- (benzyloxy) pyridin-4-yl]-3- [ (3-fluoro-2-methylphenyl) amino group]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (43 mg, 29%) was a yellow solid.

MS(ESI):C ₂₄ H ₂₁ ClN ₆ O ₃ Calculated mass of (2): 476.2, m/z actual: 477.2[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO)δ12.27(s,1H),9.28(dd,J＝4.0,2.4Hz,1H),8.47(s,1H),8.05(d,J＝5.2Hz,1H),7.85–7.79(m,1H),7.53(s,1H),7.35(d,J＝4.8Hz,1H),7.15(s,1H),6.69(s,1H),6.68(d,J＝1.6Hz,1H),6.17(dd,J＝5.6,4.4Hz,1H),5.73(s,2H),3.87(s,3H),3.46-3.44(m,2H),2.98(t,J＝6.8Hz,2H)。

Example 230:3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((6- (difluoromethyl) pyridin-2-yl) methoxy) pyridin-4-yl) -6, 7-dihydro-1H-pyrrolo [3,2-c ] pyridin-4 (5H) -one (Compound 539)

230-step 1

To a solution of tert-butyl 2, 6-lutidine-2, 6-dicarboxylate (5.0 g,0.022 mol) in MeOH (50 mL) at 0deg.C was added sodium borohydride (3.3 g,0.088 mol) in portions. The reaction was stirred at 20℃for 16h. After completion, the reaction mixture was taken up in saturated Na ₂ CO ₃ (Water)Solution 10 mL) quench and concentrate the solvent to give a residue. DCM/MeOH (10/1, 200 mL) was then added and filtered. The filtrate is subjected to Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated to give pyridine-2, 6-diyl-dimethanol (3.0 g, 96%) as a white solid.

MS(ESI):C ₇ H ₉ NO ₂ Calculated mass of (2): 139.1, m/z actual: 140.2[ M+H ]] ⁺ 。

230-step 20 ℃ and N ₂ To a stirred suspension of NaH (1.0 g,60% in mineral oil, 0.025 mol)) in THF (25 mL) was added pyridine-2, 6-diyldimethanol (3.0 g,0.023 mol). After stirring for 0.5h, TBS-Cl (3.8 g,0.025 mol) in DMF (25 mL) was added to the suspension at 0deg.C. The reaction mixture was then stirred at 20℃for 6h. After completion, the reaction mixture was saturated with NH with ice ₄ The aqueous Cl solution was quenched and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography on silica gel (MeOH/DCM from 0 to 10%) to give (6- (((tert-butyldimethylsilyl) oxy) methyl) pyridin-2-yl) methanol (3.2 g, 53%) as a white solid.

MS(ESI):C ₁₃ H ₂₃ NO ₂ Calculated mass of Si: 253.2, m/z actual: 254.2[ M+H ]] ⁺ 。

230-step 3

To a solution of (6- (((tert-butyldimethylsilyl) oxy) methyl) pyridin-2-yl) methanol (3.2 g,0.0126 mol) in DCM (30 mL) was added Dess-Martin hyperiodide (2.9 g,0.0189 mol). The reaction was stirred at 20℃for 2h. After completion, the solvent was concentrated. The residue was purified by flash column chromatography on silica gel (PE/EA from 0 to 50%) to give 6- { [ (tert-butyldimethylsilyl) oxy ] methyl } pyridine-2-carbaldehyde (3.0 g, 94%) as a white oil.

MS(ESI):C ₁₃ H ₂₁ NO ₂ Calculated mass of Si: 251.1, m/z actual: 252.1[ M+H ]] ⁺ 。

230-step 4

At 0℃to 6- { [ (tert-butyldimethylsilyl) oxy]Methyl } pyridine-2-carbaldehyde (3.0 g,0.0119 mol) in DCM (30 mL)Et is added to the solution of (2) ₂ NSF ₃ (2.9 g,0.0178 mol). The reaction mixture was then stirred at 0℃for 6h. After completion, the reaction mixture was quenched with water, saturated NaHCO ₃ The aqueous solution was basified and extracted with DCM. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography on silica gel (PE/EA from 0 to 10%) to give 2- (((tert-butyldimethylsilyl) oxy) methyl) -6- (difluoromethyl) pyridine (1.5 g,60% pure) as a white oil.

MS(ESI):C ₁₃ H ₂₁ F ₂ Calculated mass of NOSi: 273.1, m/z actual: 274.2[ M+H ]] ⁺ 。

230-step 5

To a solution of 2- (((tert-butyldimethylsilyl) oxy) methyl) -6- (difluoromethyl) pyridine (1.5 g,0.0055 mol) in THF (15 mL) was added TBAF (1.58 g, 0.006mol). The reaction was stirred at 20℃for 2h. The solvent was concentrated. The crude product was purified by flash column chromatography on silica gel (DCM/MeOH from 0 to 10%) to give [6- (difluoromethyl) pyridin-2-yl ] methanol (0.6 g,32% two steps) as a white oil.

MS(ESI):C ₇ H ₇ F ₂ Calculated mass of NO: 159.1, m/z actual: 160.1[ M+H ] ] ⁺ 。

230-step 6

At 0 ℃, to [6- (difluoromethyl) pyridin-2-yl]Methanol (500 mg,3.14 mmol), 3-hydroxypyridine-4-carbonitrile (457 mg,3.77 mmol) and PPh ₃ A solution of (989 mg,3.77 mmol) in DCM (25 mL) was added dropwise DIAD (762 mg,3.77 mmol). The reaction mixture was stirred at 0℃for 1h. After completion, the solvent was collected, depressurized and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/EA from 0 to 20%) to give 3- { [6- (difluoromethyl) pyridin-2-yl]Methoxy } pyridine-4-carbonitrile (380 mg,46% yield) was a white solid.

MS(ESI):C ₁₃ H ₉ F ₂ N ₃ The calculated mass of O: 261.1, m/z actual: 262.2[ M+H ]] ⁺ 。

230-step 7

At N ₂ Next, 3- { [6- (difluoromethyl) pyridin-2-yl]Methoxy } pyridine-4-carbonitrile (380 mg,1.45 mmol) in NH ₃ A solution of-MeOH (7M, 5 mL) and MeOH (20 mL) was added Raney Ni (380 mg). At 20 ℃ H ₂ The reaction was stirred for 16h. After completion, the solvent was collected, depressurized and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH from 0 to 10%) to give (3- { [6- (difluoromethyl) pyridin-2-yl)]Methoxy } pyridin-4-yl) methylamine (360 mg,93% yield) as a white solid.

MS(ESI):C ₁₃ H ₁₃ F ₂ N ₃ The calculated mass of O: 265.1, m/z actual: 266.1[ M+H ]] ⁺ 。

230-step 8

To (3- { [6- (difluoromethyl) pyridin-2-yl ]Methoxy } pyridin-4-yl) methylamine (260 mg,0.98 mmol), {3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl]A solution of tert-butyl 4-hydroxy-2-oxo-5, 6-dihydropyridin-1-yl } carboxylate (227 mg,1.27 mmol) and PyBOP (2.0 g,3.92 mmol) in DMA (10 mL) was added to DIPEA (1000 mg,7.84 mmol). The reaction mixture was stirred at 20℃for 4h. After completion, the reaction mixture was quenched with water and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH from 0 to 10%) to give {3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl }]-4- { [ (3- { [6- (difluoromethyl) pyridin-2-yl)]Methoxy } pyridin-4-yl) methyl]Tert-butyl amino } -2-oxo-5, 6-dihydropyridin-1-yl } carboxylate (280 mg, 48%) as a yellow solid.

230-step 9

To {3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl })]-4- { [ (3- { [6- (difluoromethyl) pyridin-2-yl)]Methoxy } pyridin-4-yl) methyl]A solution of tert-butyl amino } -2-oxo-5, 6-dihydropyridin-1-yl } carboxylate (280 mg,0.42 mmol) in 1, 4-dioxane (5.0 mL) was added TFA (97 mg,0.85 mmol) and H ₂ O ₂ (30%, 144mg,1.27 mmol). The reaction was stirred at 90℃for 1h. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EA and the organic phase was washed with water, brine, over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. Residue removerPurification by preparative HPLC and use of the following conditions: xbridge 5u C18 150x19mm; mobile phase A: H ₂ O (0.1% FA), mobile phase B ACN- -HPLC; the flow rate is 20mL/min; gradient from 27% b to 37% b,8 min; 214nm; rt 5.63min to afford 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((6- (difluoromethyl) pyridin-2-yl) methoxy) pyridin-4-yl) -6, 7-dihydro-1H-pyrrolo [3,2-c]Pyridin-4 (5H) -one (28 mg, 13%) was a yellow solid.

MS(ESI):C ₂₆ H ₂₂ ClF ₂ N ₅ O ₃ Calculated mass of (2): 525.1, m/z actual: 526.1[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO)δ11.35(s,1H),8.37(s,1H),8.09–8.02(m,2H),7.68(d,J＝7.6Hz,1H),7.61(d,J＝8.0Hz,1H),7.51(s,1H),7.32(d,J＝4.8Hz,1H),7.13(s,0.25H),7.11(s,1H),7.00(s,0.5H),6.86(s,0.25H),6.67–6.61(m,2H),6.16(dd,J＝5.6,3.6Hz,1H),5.49(s,2H),3.80(s,3H),3.43(dt,J＝6.8,2.0Hz,2H),2.87(t,J＝6.8Hz,2H)。

Example 231:3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((3- (trifluoromethyl) pyridin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (compound 540)

231-step 1

To a solution of 3-hydroxyisonicotinic nitrile (416 mg,3.46 mmol), (3- (trifluoromethyl) pyridin-2-yl) methanol (614 mg,3.46 mmol) and triphenylphosphine (999 mg,3.81 mmol) in DCM (10 mL) was added DIAD (771 mg,3.81 mmol) dropwise at 0deg.C. The mixture was stirred at 25℃under nitrogen for 1 hour. After completion, the reaction mixture was saturated with NH with ice ₄ The aqueous Cl solution was quenched and extracted with DCM. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography on silica gel (EA/PE from 20% to 50%) to give 3- ((3- (trifluoromethyl) pyridin-2-yl) methoxy) isonicotinic nitrile (320 mg, 33%) as a white solid.

MS(ESI):C ₁₃ H ₈ F ₃ N ₃ The calculated mass of O: 279.1, m/z actual: 280.1[ M+H ]] ⁺ 。

231-step 2

At N ₂ Raney Ni (50 mg) and NH were added to a stirred solution of 3- ((3- (trifluoromethyl) pyridin-2-yl) methoxy) pyridine-4-carbonitrile (320 mg,1.15 mmol) in MeOH (10 mL) ₃ .H ₂ O (1 mL). Room temperature, H ₂ The reaction mixture was stirred for 16h. After completion, the solvent was collected and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/DCM from 0 to 10%) to give (3- ((3- (trifluoromethyl) pyridin-2-yl) methoxy) pyridin-4-yl) methylamine (230 mg, 70%) as a white solid.

MS(ESI):C ₁₃ H ₁₂ F ₃ N ₃ The calculated mass of O: 283.1, m/z actual: 284.1[ M+H ]] ⁺ 。

231-step 3

To a solution of (3- ((3- (trifluoromethyl) pyridin-2-yl) methoxy) pyridin-4-yl) methylamine (230 mg,0.81 mmol), (3- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4-hydroxy-2-oxo-5, 6-dihydropyridin-1-yl) carboxylic acid tert-butyl ester (403 mg,0.97 mmol), PYBOP (845 mg,1.62 mmol) in DMF (10 mL) was added N, N-diisopropylethylamine (105 mg,0.81 mmol). The reaction was stirred at 20℃under nitrogen for 2h. After completion, the reaction mixture was quenched with water and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH from 010%) to give tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -6-oxo-4- (((3- ((3- (trifluoromethyl) pyridin-2-yl) methoxy) pyridin-4-yl) methyl) amino) -3, 6-dihydropyridine-1 (2H) -carboxylate (220 mg, 39%) as a yellow oil.

MS(ESI):C ₃₁ H ₃₁ ClF ₃ N ₅ Calculated mass of O5S: 677.2, m/z actual: 678.2[ M+H ]] ⁺ 。

231-step 4

Stirring (3- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -2-oxo-4- (((3- ((3- (trifluoromethyl) pyridin-2-yl) methoxy) pyridine) at 90 DEG C-4-yl) methyl) amino) -5, 6-dihydropyridin-1-yl carboxylic acid tert-butyl ester (220 mg,0.32 mmol), hydrogen peroxide (30%, 73mg,2.14 mmol) and trifluoroacetic acid (148 mg,1.29 mmol) in dioxane (10 mL) for 1h. After completion, the reaction mixture was cooled to room temperature and taken up with Na ₂ SO ₃ Quenching with water solution. The mixture was extracted with EA and the organic phase was washed with water, brine, over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by preparative HPLC and using the following conditions: welch 5u C18 150x19mm; mobile phase A: H ₂ O (0.1% FA), mobile phase B ACN- -HPLC; the flow rate is 25mL/min; gradient 32% b to 42% b over 9 min; 214nm; rt:8min to give 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((3- (trifluoromethyl) pyridin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3, 2-c)]Pyridin-4-one (5.5 mg, 3%) was a yellow solid.

MS(ESI):C ₂₆ H ₂₁ ClF ₃ N ₅ O ₃ Calculated mass of (2): 543.1, m/z actual: 544.1[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ9.06(d,J＝4.8Hz,1H),8.60(s,1H),8.33(d,J＝7.6Hz,1H),8.10(d,J＝6.0Hz,1H),7.80–7.58(m,2H),6.82(dd,J＝8.0,1.2Hz,1H),6.72(t,J＝8.0Hz,1H),6.30(dd,J＝8.4,1.2Hz,1H),5.88(s,2H),4.02(s,3H),3.67(t,J＝7.2Hz,2H),3.20(t,J＝6.8Hz,2H)。

Example 232:3- ((3-chloro-2-methoxyphenyl) amino) -2- [3- (pyrazin-2-ylmethoxy) pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo (3, 2-c) pyridin-4-one (compound 541)

232-step 1

To a solution of 3-chloropyridine-4-carbonitrile (10.0 g,0.072 mol) in dry THF (30 mL) under nitrogen was added dropwise sodium methoxide (17.6 g,0.32 mol) in dry THF (30 mL). The reaction mixture was stirred at 80℃under nitrogen for 1h. After completion, the reaction mixture was quenched with aqueous citric acid and extracted with EA. The organic phase was washed with brine, passedAnhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated to give 3-methoxypyridine-4-carbonitrile (11.0 g, 97%) as a white solid. The crude product was used directly in the next step without further purification.

MS(ESI):C ₇ H ₆ N ₂ The calculated mass of O: 134.1, m/z actual: 135.1[ M+H ]] ⁺ 。

232-step 2

A round bottom flask containing 3-methoxypyridine-4-carbonitrile (6.0 g,0.0447 mol) and pyridine hydrochloride (18.1 g,0.16 mol) was placed in an oil bath and heated to 160℃under nitrogen for 5min. After completion, the reaction mixture was quenched with aqueous citric acid and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated to give 3-hydroxypyridine-4-carbonitrile (4.6 g, 81%) as a grey solid.

MS(ESI):C ₆ H ₄ N ₂ The calculated mass of O: 120.1, m/z actual: 121.1[ M+H ]] ⁺ 。

232-step 3

To 3-hydroxypyridine-4-carbonitrile (1.0 g,0.0082 mol), pyrazin-2-ylmethanol (1.0 g,0.0090 mol) and Ph at 0deg.C under nitrogen ₃ A solution of P (2.4 g,0.0090 mol) in DCM (20 mL) was added DIAD (1.82 g,0.0090 mol) dropwise. The mixture was stirred at 0℃under nitrogen for 1h. After completion, the mixture was washed with HCl (aqueous, 1.0M). NaHCO for aqueous phase ₃ The aqueous solution was neutralized and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The crude product was purified by flash chromatography (DCM/MeOH from 0 to 10%) to afford 3- (pyrazin-2-ylmethoxy) pyridine-4-carbonitrile (1.9 g, 81%) as a grey solid.

MS(ESI):C ₁₁ H ₈ N ₄ Calculated mass of O: 212.1, m/z actual: 213.1[ M+H ]] ⁺ 。

232-step 4

To a solution of 3- (pyrazin-2-ylmethoxy) pyridine-4-carbonitrile (1.0 g,0.0047 mol), ammonia (7.0M in MeOH, 15 mL) in MeOH (30 mL) was added Raney Ni (0.8 g). The mixture was stirred at room temperature under hydrogen for 16h. After completion, the solvent was collected, depressurized and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH from 0 to 10%) to give (3- (pyrazin-2-ylmethoxy) pyridin-4-yl) methylamine (0.9 g, 79%) as a yellow solid.

MS(ESI):C ₁₁ H ₁₂ N ₄ The calculated mass of O: 216.2, m/z actual: 217.2[ M+H ]] ⁺ 。

232-step 5

To 3- (pyrazin-2-ylmethoxy) pyridin-4-yl]A solution of tert-butyl methylamine (223 mg,1.03 mmol), (3- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4-hydroxy-2-oxo-5, 6-dihydropyridin-1-yl) carboxylate (640 mg, 1.540 mmol) and DIEA (1.07 mg,8.25 mmol) in DMA (5 mL) was added to PyBOP (2.15 g,4.12 mmol). The reaction mixture was stirred at room temperature under nitrogen for 16h. After completion, the reaction mixture was quenched with water and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH from 0 to 10%) to give tert-butyl (3- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -2-oxo-4- (((3- (pyrazin-2-ylmethoxy) pyridin-4-yl) methyl) amino) -5, 6-dihydropyridin-1-yl) carboxylate (950 mg, 45%) as a yellow oil.

MS(ESI):C ₂₉ H ₃₁ ClN ₆ O ₅ The calculated mass of S: 610.1, m/z actual: 511.1[ M-100+H] ⁺ 。

232-step 6

To a solution of tert-butyl (3- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -2-oxo-4- (((3- (pyrazin-2-ylmethoxy) pyridin-4-yl) methyl) amino) -5, 6-dihydropyridin-1-yl) carboxylate (650 mg,0.0016 mol) in 1, 4-dioxane (15 mL) was added dropwise H at room temperature under nitrogen atmosphere ₂ O ₂ (30%, 730mg,0.0064 mol) and trifluoroacetic acid (730 mg,0.0064 mol). The reaction mixture was stirred at 90℃under nitrogen for 1h. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EA and the organic phase was washed with water, brine, over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by preparative HPLC and using the following conditions:welch 10u C18 250x21.2mm; mobile phase a water (0.1% nh) ₃ ) ACN as mobile phase B; the flow rate is 25mL/min; gradient from 35% b to 45% b over 9 min; 214nm; rt:8min to give 3- ((3-chloro-2-methoxyphenyl) amino) -2- [3- (pyrazin-2-ylmethoxy) pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo (3, 2-c) pyridin-4-one (25 mg, 6%) as a white solid.

MS(ESI):C ₂₄ H ₂₁ ClN ₆ O ₃ 476.1, m/z actual: 477.1[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.70(s,1H),8.80(d,J＝1.2Hz,1H),8.74–8.73(m,1H),8.68(d,J＝2.4Hz,1H),8.46(s,1H),8.06(d,J＝4.8Hz,1H),7.51(s,1H),7.34(d,J＝5.2Hz,1H),7.14(s,1H),6.68–6.63(m,2H),6.16–6.14(m,1H),5.56(s,2H),3.84(s,3H),3.45–3.42(m,2H),2.91(t,J＝6.8Hz,2H).

Example 233.3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (2- (pyrazin-2-yl) ethoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (Compound 542)

233-step 10 ℃ to a solution of 3-hydroxyisonicotinic nitrile (0.8 g,6.66 mmol), 2- (pyrazin-2-yl) ethan-1-ol (0.8 g,6.66 mmol) and triphenylphosphine (1.9 g,7.33 mmol) in DCM (10 mL) was added dropwise DIAD (1.5 g,7.33 mmol). The mixture was stirred at 0℃under nitrogen for 2h. After completion, the reaction mixture was saturated with NH with ice ₄ The aqueous Cl solution was quenched and extracted with DCM. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography on silica gel (EA/PE from 20% to 50%) to give 3- (2- (pyrazin-2-yl) ethoxy) isonicotinic nitrile (1.1 g, 72%) as a white solid.

MS(ESI):C ₁₂ H ₁₀ N ₄ The calculated mass of O: 226.1, m/z actual: 227.1[ M+H ]] ⁺ 。

233-step 2

At N ₂ Down to 3- (2- (pyrazine)A stirred solution of 2-yl-ethoxy) isonicotinic nitrile (1.1 g,4.82 mmol) in MeOH (100 mL) was added Raney Ni (500 mg) and NH ₃ .H ₂ O (10 mL). At H ₂ The reaction mixture was stirred at room temperature for 16h. After completion, the solvent was collected, depressurized and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (MeOH/DCM from 0 to 10%) to give (3- (2- (pyrazin-2-yl) ethoxy) pyridin-4-yl) methylamine (850 mg, 76%) as a white solid.

MS(ESI):C ₁₄ H ₁₄ N ₄ The calculated mass of O: 230.1, m/z actual: 231.1[ M+H ]] ⁺ 。

233-step 3

A solution of (3- (2- (pyrazin-2-yl) ethoxy) pyridin-4-yl) methylamine (850 mg,3.69 mmol), (3- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4-hydroxy-2-oxo-5, 6-dihydropyridin-1-yl) carboxylic acid tert-butyl ester (1.8 g,4.43 mmol), PYBOP (3.8 g,7.38 mmol) and N, N-diisopropylethylamine (1.0 g,7.38 mmol) in DMF (15 mL) was stirred at 20℃for 3h. After completion, the reaction mixture was quenched with water and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH from 0 to 10%) to give tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -6-oxo-4- (((3- (2- (pyrazin-2-yl) ethoxy) pyridin-4-yl) methyl) amino) -3, 6-dihydropyridine-1 (2H) -carboxylate (1.1 g,48% pure) as a yellow solid.

MS(ESI):C ₃₀ H ₃₃ ClN ₆ O ₅ The calculated mass of S: 624.2, m/z actual: 625.2[ M+H ]] ⁺ 。

233-step 4

A solution of 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -6-oxo-4- (((3- (2- (pyrazin-2-yl) ethoxy) pyridin-4-yl) methyl) amino) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (800 mg,1.28 mmol), hydrogen peroxide (30%, 290mg,2.56 mmol) and trifluoroacetic acid (730 mg,6.4 mmol) in dioxane (30 mL) was stirred at 90℃for 1H. After completion, the reaction mixture was cooled to room temperature and taken up with Na ₂ SO ₃ Quenching with water solution. The mixture was extracted with EA and the organic phase was washed with water,Washing with brine, passing through anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was collected and concentrated. The residue was purified by preparative HPLC and using the following conditions: welch 5u C18 150x19mm; mobile phase A: H ₂ O (0.1% FA), mobile phase B ACN- -HPLC; the flow rate is 25mL/min; gradient 15% b to 35% b,9.5 min; 214nm; rt:8min to give 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- (2- (pyrazin-2-yl) ethoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3, 2-c)]Pyridin-4-one (21 mg, 3%) was a yellow solid.

MS(ESI):C ₂₅ H ₂₃ ClN ₆ O ₃ Calculated mass of (2): 490.2, m/z actual: 491.2[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO)δ11.33(s,1H),8.67(d,J＝1.2Hz,1H),8.60–8.59(m,1H),8.52(d,J＝2.4Hz,1H),8.38(s,1H),8.00(d,J＝4.8Hz,1H),7.46(s,1H),7.29(d,J＝4.8Hz,1H),7.13(s,1H),6.71–6.61(m,2H),6.04–6.01(m,1H),4.55(t,J＝6.0Hz,2H),3.87(s,3H),3.45–3.40(m,2H),3.38–3.35(m,2H),2.90(t,J＝6.8Hz,2H)。

Example 234:3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((6-vinylpyrazin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (compound 543)

234-step 1

A mixture of 3-hydroxyisonicotinic nitrile (1 g,8.3 mmol) and Pd/C (1 g) in MeOH (60 mL)/HCl (6 mL) was stirred at room temperature under a hydrogen atmosphere for 2h. After completion, the mixture was filtered and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH from 0 to 10%, 0.1% NH was added ₃ OH) was purified to give 4- (aminomethyl) pyridin-3-ol (800 mg, yield: 77.7%) as a yellow oil.

MS(ESI):C ₆ H ₈ N ₂ The calculated mass of O: 124.06, m/z actual: 125.2[ M+H ]] ⁺ 。

234-step 2

To a solution of 4- (aminomethyl) pyridin-3-ol (700 mg,5.6 mmol) in DCM (35 mL) at 0deg.C was added (Boc) ₂ O (1.8 g,8.4 mmol) and N at room temperature ₂ Stirring is carried out for 6h. After completion, use H ₂ The reaction was quenched with O (50 mL) and extracted with DCM (50 mL. Times.3). The combined organic layers were washed with brine (80 mL), and dried over Na ₂ SO ₄ Dried, concentrated in vacuo to give the crude product, which was purified by flash chromatography (PE/EtOAc from 0 to 60%) to give tert-butyl ((3- ((tert-butoxycarbonyl) oxy) pyridin-4-yl) methyl) carbamate (1.2 g, 66%) as a yellow oil.

MS(ESI):C ₁₆ H ₂₄ N ₂ O ₅ Calculated mass of (2): 324.17, m/z actual: 325.2[ M+H ]] ⁺ 。

234-step 3

At room temperature, N ₂ Tert-butyl ((3- ((tert-butoxycarbonyl) oxy) pyridin-4-yl) methyl) carbamate (1.2 g,3.7 mmol) and LiOH-H were stirred ₂ O (463 mg,11.1 mmol) in MeOH (15 mL)/THF (15 mL)/H ₂ The mixture in O (5 mL) was 2h. After completion, the mixture was filtered and washed with DCM (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH from 0 to 10%) to give tert-butyl ((3-hydroxypyridin-4-yl) methyl) carbamate (800 mg, yield: 96%) as a yellow oil.

MS(ESI):C ₁₁ H ₁₆ N ₂ O ₃ Calculated mass of (2): 224.12, m/z actual: 225.2[ M+H ]] ⁺ 。

234-step 4

To tert-butyl ((3-hydroxypyridin-4-yl) methyl) carbamate (600 mg,2.68 mmol), (6-bromopyrazin-2-yl) methanol (607 mg,3.2 mmol) and PPh at 0deg.C ₃ A stirred mixture of (840 mg,3.2 mmol) in THF (20 mL) was added DIAD (640 mg,3.2 mmol). At 0 ℃, N ₂ The reaction mixture was stirred for 1h. After completion, reaction H ₂ O (30 mL) was quenched and extracted with EtOAc (50 mL. Times.3). The combined organic layers were washed with brine (40 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give crude product which is purified by silica gel column chromatography (eluent: PE/EtOAc from 0 to 40%) to give ((3- ((6-bromopyrazin-2-yl) methoxy) pyridin-4-yl) methyl) Tert-butyl carbamate (120 mg, yield: 11%) as a yellow solid.

MS(ESI):C ₁₆ H ₁₉ BrN ₄ O ₃ Calculated mass of (2): 394.06, m/z actual: 395.2[ M+H ]] ⁺ 。

234-step 5

To a solution of tert-butyl ((3- ((6-bromopyrazin-2-yl) methoxy) pyridin-4-yl) methyl) carbamate (120 mg,0.3 mmol) in 1, 4-dioxane (5 mL) was added HCl (0.7 mL,2.8mmol,4M in 1, 4-dioxane) at 0deg.C. The resulting reaction mixture was stirred at 0℃for 1h. After completion, the reaction mixture was concentrated to give a residue, which was treated with NH ₃ (10 mL,7M MeOH solution) was neutralized and concentrated. The crude product was purified by preparative TLC (eluent: DCM/meoh=10/1) to give (3- ((6-bromopyrazin-2-yl) methoxy) pyridin-4-yl) methylamine (75 mg, yield: 85%) as a yellow solid.

MS(ESI):C ₁₁ H ₁₁ BrN ₄ The calculated mass of O: 294.01, m/z actual: 295.2[ M+H ]] ⁺ 。

234-step 6

A solution of (3- ((6-bromopyrazin-2-yl) methoxy) pyridin-4-yl) methylamine (75 mg,0.25 mmol), 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4-hydroxy-6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (80 mg,0.33 mmol), pyBOP (520 mg,0.48 mmol) and DIPEA (124 mg,0.96 mmol) in DMF (5 mL) was stirred at room temperature for 3H. After completion, the resulting mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH from 1 to 5%) to give tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -6-oxo-4- (((3- (2- (pyridin-2-yl) propoxy) pyridin-4-yl) methyl) amino) -3, 6-dihydropyridine-1 (2H) -carboxylate (115 mg, yield: 66%) as a yellow solid.

MS(ESI):C ₂₉ H ₃₀ BrClN ₆ O ₅ The calculated mass of S: 688.09, m/z actual: 689.1[ M+H ] ] ⁺ 。

234-step 7

To a solution of tert-butyl 4- (((3- ((6-bromopyrazin-2-yl) methoxy) pyridin-4-yl) methyl) amino) -5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylate (100 mg,0.14 mmol) in 1, 4-dioxane (5 mL) was added H ₂ O ₂ (74.8 mg,0.66mmol,30% H) ₂ O solution). The resulting mixture was stirred at 80℃for 3h. The reaction mixture was concentrated to give the crude product, which was purified by preparative TLC (DCM/meoh=15/1) to give 2- (3- ((6-bromopyrazin-2-yl) methoxy) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -4-oxo-1, 4,6, 7-tetrahydro-5H-pyrrolo [3,2-c ]]Pyridine-5-carboxylic acid tert-butyl ester (50 mg, yield: 54%) as a yellow solid.

MS(ESI):C ₂₉ H ₂₈ BrClN ₆ O ₅ Calculated mass of (2): 654.10, m/z actual: 657.0[ M+H ]] ⁺ 。

234-step 8

Stirring 2- (3- ((6-bromopyrazin-2-yl) methoxy) pyridin-4-yl) -3- ((3-chloro-2-methoxyphenyl) amino) -4-oxo-1, 4,6, 7-tetrahydro-5H-pyrrolo [3, 2-c) at 70 ℃]Pyridine-5-carboxylic acid tert-butyl ester (50 mg,0.076 mmol), 4, 5-tetramethyl-2-vinyl-1, 3, 2-dioxapentaborane (23.4 mg,0.152 mmol) and Pd (dppf) Cl ₂ (11.1 mg,0.015 mmol) and K ₂ CO ₃ (32.5 mg,0.228 mol) in 1, 4-dioxane/H ₂ A solution in O (5 mL/1 mL) for 1h. After completion, the resulting mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated to give the crude product, which was purified by preparative TLC (DCM/meoh=15/1) to provide 3- ((3-chloro-2-methoxyphenyl) amino) -4-oxo-2- (3- ((6-vinylpyr-azin-2-yl) methoxy) pyridin-4-yl) -1,4,6, 7-tetrahydro-5H-pyrrolo [3,2-c]Pyridine-5-carboxylic acid tert-butyl ester (35 mg, yield: 76%) as a yellow solid.

MS(ESI):C ₃₁ H ₃₁ ClN ₆ O ₅ Calculated mass of (2): 602.20, m/z actual: 603.3[ M+H ]] ⁺ 。

234-step 9

Stirring at room temperature 3- ((3)-chloro-2-methoxyphenyl) amino) -4-oxo-2- (3- ((6-vinylpyrazin-2-yl) methoxy) pyridin-4-yl) -1,4,6, 7-tetrahydro-5H-pyrrolo [3,2-c]Tert-butyl pyridine-5-carboxylate (15 mg,0.025 mmol), HCl (0.2 mL,0.8mmol,4M in 1, 4-dioxane) for 1h. The reaction mixture was concentrated to give the crude product, which was redissolved in MeOH (4 mL) and BuOK (2.8 mg,0.025 mmol) was then added thereto at-30℃for 1h. After completion, the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated to give the crude product, which was purified by preparative TLC (DCM/meoh=15/1) to provide 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((6-vinylpyr-azin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ]Pyridin-4-one (3.1 mg, yield: 60%) was a yellow solid.

MS(ESI):C ₂₆ H ₂₃ ClN ₆ O ₃ Calculated mass of (2): 502.15, m/z actual: 503.1[ M+H ]] ⁺ 。

¹ H NMR(400MHz,MeOD)δ8.64(s,1H),8.59(s,1H),8.39(s,1H),7.99(d,J＝5.2Hz,1H),7.45(d,J＝5.2Hz,1H),6.96–6.88(m,1H),6.65-6.63(m,1H),6.58(t,J＝8.1Hz,1H),6.41(dd,J＝17.5,1.1Hz,1H),6.17(dd,J＝8.1,1.5Hz,1H),5.67(dd,J＝10.9,1.1Hz,1H),5.49(s,2H),3.91(s,3H),3.57(t,J＝6.9Hz,2H),2.94(t,J＝6.9Hz,2H)。

Example 235:3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((6-methylpyrazin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-c ] pyridin-4-one (compound 549)

235-step 1

To a solution of 6-methylpyrazine-2-carboxylic acid (2 g,0.0145 mol) in MeOH (20 mL) was added thionyl chloride (3.45 g,0.029 mol) at 0deg.C. The reaction mixture was stirred at 80℃for 6h. Addition of NaHCO ₃ Saturated aqueous (100 mL) and extracted with EA (50 mL. Times.3). Anhydrous organic layerNa ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash chromatography to give methyl 6-methylpyrazine-2-carboxylate (1.5 g, 65%) as a yellow solid.

MS(ESI):C ₇ H ₈ N ₂ O ₂ Calculated mass of (2): 152.06, m/z actual: 153.1[ M+H ]] ⁺ 。

235-step 2

LiAlH was added to a solution of methyl 6-methylpyrazine-2-carboxylate (1.5 g,0.0099 mol) in THF (20 mL) at-70deg.C ₄ (0.41 g,0.0108 mol). The reaction mixture was stirred at-70℃for 1h. Adding Na ₂ SO ₄ ·10H ₂ O. The solution was filtered. The filtrate is subjected to anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash chromatography to give (6-methylpyrazin-2-yl) methanol (0.6 g, 46%) as a yellow solid.

MS(ESI):C ₆ H ₈ N ₂ The calculated mass of O: 124.6, m/z actual: 125.1[ M+H ]] ⁺ 。

235-step 3

To (6-methylpyrazin-2-yl) methanol (500 mg,4.0277 mmol), 3-hydroxypyridine-4-carbonitrile (507.95 mg,4.229 mmol) at 0deg.C under nitrogen, PPh ₃ A stirred solution of (1267.71 mg,4.8332 mmol) in THF (10 mL) was added DIAD (977.33 mg,4.8332 mmol). The reaction mixture was stirred at room temperature for 3h. The mixture was diluted with water and extracted with EA (50 ml x 3). The organic layer was treated with anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash chromatography to give the residue and it was purified by flash chromatography to give 3- ((6-methylpyrazin-2-yl) methoxy) isonicotinic nitrile (400 mg, 35%) as a yellow solid.

MS(ESI):C ₁₂ H ₁₀ N ₄ The calculated mass of O: 226.09, m/z actual: 227.0[ M+H ]] ⁺ 。

235-step 4

At H ₂ Down to 3- [ (6-methylpyrazin-2-yl) methoxy group]A solution of pyridine-4-carbonitrile (400 mg,1.7681 mmol) in MeOH (10 mL) was added Raney Ni (103.77 mg,1.7681 mmol). At H ₂ The reaction mixture was stirred at room temperature for 6h. The solution was filtered, the filtrate was collected and concentrated in vacuo to give the crude product. The residue was purified by flash chromatography to give the residue and it was purified by flash chromatography to give (3- ((6-methylpyrazin-2-yl) methoxy) pyridin-4-yl) methylamine (200 mg, 39%) as a yellow solid.

MS(ESI):C ₁₂ H ₁₄ N ₄ The calculated mass of O: 230.12, m/z actual: 231.1[ M+H ]] ⁺ 。

235-step 5

To {3- [ (6-methylpyrazin-2-yl) methoxy })]Pyridin-4-yl } methylamine (200 mg,0.8686 mmol), {3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl)]A solution of tert-butyl 4-hydroxy-2-oxo-5, 6-dihydropyridin-1-yl } carboxylate (359.51 mg,0.8686 mmol) in DMF (10 mL) was added N, N-diisopropylethylamine (336.77 mg,2.6058 mmol) and PYBOP (678.02 mg,1.3029 mmol). The reaction was stirred at room temperature for 3h. The mixture was diluted with water and extracted with EA (30 ml x 3). The organic layer was treated with anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash chromatography to give tert-butyl 5- ((3-chloro-2-methoxyphenyl) thiocarbamoyl) -4- (((3- ((6-methylpyrazin-2-yl) methoxy) pyridin-4-yl) methyl) amino) -6-oxo-3, 6-dihydropyridine-1 (2H) -carboxylate (260 mg, 42%) as a yellow solid.

MS(ESI):C ₃₀ H ₃₃ ClN ₆ O ₅ The calculated mass of S: 624.19, m/z actual: 625.0/627.0[ M+H ]] ⁺ 。

235-step 6

At 0℃to {3- [ (3-chloro-2-methoxyphenyl) thiocarbamoyl } -]-4- [ ({ 3- [ (6-methylpyrazin-2-yl) methoxy)]Pyridin-4-yl } methyl) amino groups]A solution of tert-butyl 2-oxo-5, 6-dihydropyridin-1-yl } carboxylate (260 mg,0.4152 mmol) in MeOH (10 mL) was added trifluoroacetic acid (94.68 mg,0.8304 mol) and hydrogen peroxide (28.25 mg,0.8304 mol). The reaction was stirred at 80℃for 3h. Adding saturated aqueous solution Na ₂ SO ₃ . The mixture was extracted with EA (30 ml x 3). The organic layer was treated with anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. The residue is prepared byHPLC purification to give 3- ((3-chloro-2-methoxyphenyl) amino) -2- (3- ((6-methylpyrazin-2-yl) methoxy) pyridin-4-yl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3, 2-c)]Pyridin-4-one (22.3 mg, 11%) was a yellow solid.

MS(ESI):C ₂₅ H ₂₃ ClN ₆ O ₃ Calculated mass of (2): 490.15, m/z actual: 491.1/493.1[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ11.38(s,1H),8.54(d,J＝4.0Hz,2H),8.44(s,1H),8.06(d,J＝4.0Hz,1H),7.50(s,1H),7.32(d,J＝8.0Hz,1H),7.12(s,1H),6.66–6.61(m,2H),6.14(dd,J＝4.0,8.0Hz,1H),5.46(s,2H),3.81(s,3H),3.45-3.41(m,2H),2.88(t,J＝8.0Hz,2H),2.54(s,3H)。

Example 236:2- (3- {2- [ (1S, 3R, 5S) -2- [ (2E) -4- (dimethylamino) but-2-enoyl ] -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 345)

236.1: synthesis of tert-butyl (1S, 3R, 5S) -3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylate

To 3- [ (3-fluoro-2-methoxyphenyl) amino group at room temperature under argon atmosphere]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (600 mg,1.25mmol,1.00 eq.), cuI (119 mg,0.62mmol,0.50 eq.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (255 mg,0.31mmol,0.25 eq.) in DMF (6 mL) was added dropwise (1S, 3R, 5S) -3-ethynyl-2-azabicyclo [ 3.1.0) ]Hexane-2-carboxylic acid tert-butyl ester (650 mg,3.13mmol,2.50 eq.) and DIEA (481 mg,3.76mmol,3 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The residue was purified by reverse phase flash chromatography using column, silica gel; mobile phase, meCN in water, gradient 10% to 50% within 10 min; a detector: UV 254nm. Concentrating the resulting mixture under reduced pressureAnd (3) an object. The residue was purified by column chromatography on silica gel eluting with DCM/MeOH (20:1) to provide (1S, 3R, 5S) -3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester (460 mg, 65.76%) as a yellow solid.

LC-MS:(M+H) ⁺ Actual: 558.20.

236.2: synthesis of 2- (3- {2- [ (1S, 3R, 5S) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

A stirred mixture of (1S, 3R, 5S) -3- [2- (4- {3- [ (3-fluoro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (100 mg,0.18mmol,1.00 eq.) in DCM (3 mL) was added TFA (1 mL) at room temperature under nitrogen. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- (3- {2- [ (1 s,3r,5 s) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (60 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 458.10

236.3: synthesis of 3- {2- [ (1S, 3R, 5S) -2- [ (2E) -4- (dimethylamino) but-2-enoyl ] -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- (3- {2- [ (1S, 3R, 5S) -2-azabicyclo [3.1.0] with DIEA]Hex-3-yl]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (60 mg,0.13mmol,1.00 g)Amount) of the solution in THF (3 mL) was basified to pH 8. (2E) -4- (dimethylamino) but-2-enoic acid (33 mg,0.26mmol,2.00 eq.) was added to the above mixture at 0deg.C under nitrogen followed by dropwise addition of T3P (83 mg,0.26mmol,2.00 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (80 mg) which was purified by preparative HPLC (column: xselect CSH F-phenyl OBD column, 19X 250mm,5 μm; mobile phase A: water (10 mmol/L NH4HCO 3), mobile phase B: ACN; flow rate: 25mL/min; gradient: 53% B to 83% B, over 7min, 83% B; wavelength: 254nm; RT1 (min): 6.53; running number: 0) to afford 2- (3- {2- [ (1S, 3R, 5S) -2- [ (2E) -4- (dimethylamino) but-2-enoyl) ]-2-azabicyclo [3.1.0]Hex-3-yl]Ethynyl } pyridin-4-yl) -3- [ (3-fluoro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (25.7 mg, 33.08%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 569.15

¹ H NMR (400 MHz, chloroform-d) delta 10.97 (s, 1H), 8.56 (s, 1H), 8.16 (d, j=5.6 hz, 1H), 7.70 (s, 1H), 7.50-7.44 (m, 1H), 7.03-6.92 (m, 1H), 6.74 (d, j=15.3 hz, 1H), 6.61-6.51 (m, 1H), 6.50-6.40 (m, 1H), 6.11-6.04 (m, 1H), 5.21 (s, 1H), 4.83-4.75 (m, 1H), 4.09 (d, j=1.3 hz, 3H), 3.65-3.57 (m, 3H), 3.32 (s, 2H), 3.24 (t, j=6.8 hz, 2H), 2.66-2.56 (m, 1H), 2.56-2.46 (m, 1H), 5.21 (s, 1H), 4.83-4.75 (m, 1H), 4.09 (d, j=1.3 hz, 3H), 3.65-3.57 (m, 1H), 3.32 (t, 1H).

Example 237: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1S, 3R, 5S) -2- [ (2E) -4- (dimethylamino) but-2-enoyl ] -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one (compound 466)

237.1: synthesis of tert-butyl (1S, 3R, 5S) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylate

To 3- [ (3-chloro-2-methoxyphenyl) amino group at room temperature under argon atmosphere ]-2- (3-iodopyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (20 mg,0.040mmol,1 eq.) and Pd (dppf) Cl2CH ₂ Cl ₂ (109.17 mg,0.134mmol,0.25 eq.) CuI (51.05 mg,0.268mmol,0.5 eq.) in DMF (2.5 mL) was added dropwise to a stirred mixture of (1S, 3R, 5S) -3-ethynyl-2-azabicyclo [ 3.1.0)]Hexane-2-carboxylic acid tert-butyl ester (16.76 mg,0.080mmol,2 eq.) and DIEA (207.85 mg,1.608mmol,3 eq.). The resulting mixture was stirred at 50℃under argon for 2h. The residue was purified by reverse phase flash chromatography using column, silica gel; mobile phase, meCN in water, gradient 10% to 50% within 10 min; a detector: UV 254nm. This gives (1S, 3R, 5S) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino)]-4-oxo-1H, 5H,6H, 7H-pyrrolo [3,2-c]Pyridin-2-yl pyridin-3-yl) ethynyl]-2-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester as yellow solid.

LC-MS:(M+H) ⁺ Actual: 574.10.

237.2: synthesis of 2- (3- {2- [ (1S, 3R, 5S) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

To a stirred mixture of (1 s,3r,5 s) -3- [2- (4- {3- [ (3-chloro-2-methoxyphenyl) amino ] -4-oxo-1 h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-2-yl } pyridin-3-yl) ethynyl ] -2-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (100 mg,0.14mmol,1.00 eq) in DCM (3 mL) was added TFA (1 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h and concentrated under reduced pressure to afford 2- (3- {2- [ (1 s,3r,5 s) -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino ] -1h,5h,6h,7 h-pyrrolo [3,2-c ] pyridin-4-one (80 mg, crude) as a red oil.

LC-MS:(M+H) ⁺ Actual: 474.00

237.3: synthesis of 3- [ (3-chloro-2-methoxyphenyl) amino ] -2- (3- {2- [ (1S, 3R, 5S) -2- [ (2E) -4- (dimethylamino) but-2-enoyl ] -2-azabicyclo [3.1.0] hex-3-yl ] ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c ] pyridin-4-one

2- (3- {2- [ (1S, 3R, 5S) -2-azabicyclo [3.1.0] with DIEA]Hex-3-yl]Ethynyl } pyridin-4-yl) -3- [ (3-chloro-2-methoxyphenyl) amino]-1H,5H,6H, 7H-pyrrolo [3,2-c]A solution of pyridin-4-one (80 mg,0.17mmol,1.00 eq.) in THF (3 mL) was basified to pH 8. (2E) -4- (dimethylamino) but-2-enoate hydrochloride (55 mg,0.34mmol,2.00 eq.) was added to the above mixture at 0deg.C under nitrogen followed by dropwise addition of T3P (322 mg,0.51mmol,3 eq., 50% in EA). The resulting mixture was stirred at room temperature under nitrogen for 1h. NaHCO at 0deg.C ₃ Saturated aqueous solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3X 10 mL) and dried over anhydrous Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product (140 mg) which was purified by preparative HPLC (column: XSelect CSH fluorophenyl, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH4HCO 3), mobile phase B: ACN; flow rate: 60mL/min; gradient: 44% B to 74% B, over 7 min; wavelength: 254nm; RT1 (min): 6.5; running number: 0) to provide 3- [ (3-chloro-2-methoxyphenyl) amino group ]-2- (3- {2- [ (1S, 3R, 5S) -2- [ (2E) -4- (dimethylamino) but-2-enoyl]-2-azabicyclo [3.1.0]Hex-3-yl]Ethynyl } pyridin-4-yl) -1H,5H,6H, 7H-pyrrolo [3,2-c]Pyridin-4-one (29.1 mg, 23.55%) was a yellow solid.

LC-MS:(M+H) ⁺ Actual: 585.05

¹ H NMR (300 MHz, chloroform-d) δ10.99 (s, 1H), 8.57 (s, 1H), 8.15 (d, j=5.6 Hz, 1H), 7.71 (s, 1H), 7.41 (d, j=5.5 Hz, 1H), 7.08-6.85 (m, 1H), 6.80-6.49 (m, 3H), 6.31-6.05 (m, 1H), 5.22 (s, 1H), 4.89-4.71 (m, 1H), 4.07 (s, 3H), 3.59 (d, j=7.0 Hz, 3H), 3.24 (t, j=6.7 Hz),4H),2.69–2.23(m,8H),2.06–1.93(m,1H),1.14–1.02(m,1H),0.69–0.60(m,1H)。

Biological activity

Example a: EGFR Activity

Cell lines were generated by transducing Ba/F3 cells with retroviruses containing the EGFR WT, EGFR exon 20NPG Ins D770_N771, EGFR exon 20ASV Ins V769_D770, EGFR exon 20SVD Ins D770_N771 or EGFR exon 20FQEA Ins A763_V764 gene and the puromycin selectable marker. Transduced cells were selected with puromycin for 7 days and then transferred to medium without interleukin 3 (IL 3). EGFR WT cells were maintained with supplemental EGF. Surviving cells were confirmed to express EGFR by Western blot and maintained as pools. The IC50 data are included in table 6.

Study design:

1. cell seeding

1.1 cells were collected from flasks into cell culture medium and the number of cells counted.

1.2 cells were diluted to the desired density with medium and 40 μl of cell suspension was added to each well of 384 well cell culture plates at a seeding density of 600 cells/well.

2 preparation and treatment of Compounds

2.1 test compounds were dissolved in DMSO stock solution up to 10mM. 45. Mu.L of stock was transferred to 384 well polypropylene plates (pp plates). 15 μl of compound was transferred to 30 μl DMSO using a TECAN (EVO 200) liquid handler, whereby a 3-fold, 10-point dilution was performed.

2.2 rotating plate at 1,000RPM for 1 minute at room temperature.

2.3 transfer 120nL of diluted compound from the compound source plate into the cell plate.

2.4 Compounds treatment plates were subjected to CTG assay as described in the "assay" section after 72 hours of compound treatment.

3. Detection of

3.1 the plates were removed from the incubator and equilibrated for 15 minutes at room temperature.

3.2 thawing CellTiter Glo reagent and equilibration to room temperature was performed prior to the experiment.

3.2 40. Mu.L CellTiter-Glo reagent was added to each well (1:1 ratio to medium). The plates were then left at room temperature for 30 minutes and then read on an EnVision.

4. Data analysis

4.1 the inhibitory activity was calculated according to the following formula:

% inhibition = 100x (LumHC-Lum sample)/(LumHC-LumLC)

Wherein HC is obtained only from cells treated with 0.1% dmso; LC was obtained only from the medium.

4.2.2 calculation of IC using Xlfit (v5.3.1.3), fitting equation 201 ₅₀ The equation 201 is:

y=bottom+ (top-bottom)/(1+10 ((log) ₅₀ -X) slope)

The IC50 data are included in table 4.

Example B: inhibitor Activity against EGFR phosphorylation (pEGFR)

EGFR mutant Ba/F3 cells were generated by transduction with retroviruses containing vectors expressing EGFR exon 20NPG Ins D770_N771, EGFR exon 20ASV Ins V769_D770 or EGFR exon 20SVD Ins D770_N771 genes and puromycin selection markers. Transduced cells were selected with puromycin for 7 days and then transferred to medium without interleukin 3 (IL 3). Surviving cells were confirmed to express EGFR by Western blot and maintained as pools. CUTO14 cells were obtained from Robert C.Doebelle doctor at the university of Colorado. The IC50 data are included in table 6.

Study design

1. Cell seeding

1.2 cells were diluted to the desired density with medium and 40. Mu.L of cell suspension was added to each well of 384 well cell culture plates at a seeding density of 50K cells/well (Ba/F3) or 12.5K cells/well (CUTO 14).

2 preparation and treatment of Compounds

2.2 rotating plate at 1,000RPM for 1 minute at room temperature.

2.3 transfer of 5nL of diluted compound from the compound source plate into the cell plate.

2.4 Compounds were treated for 2 hours and then pEGFR detection was performed on the compound treated plates by AlphaLISA (αLISA) as described in the "detection" section.

3. Detection by pEGFR AlphaLISA (Perkin-Elmer, perkin Elmer)

3.1 plates were removed from the incubator and equilibrated for 10 minutes at room temperature, and the medium was removed.

3.2 10. Mu.L of lysis buffer was added and the plate was shaken at 600rpm for 1hr.

3.3 preparation of receptor mixture before use and dispensing 5 μl of receptor mixture to all wells. Shake in the dark at 350rpm for 1hr.

3.4 donor mixtures were prepared under low light conditions prior to use. All wells were dispensed with 5 μl of donor mix. Mix well on shaker, seal and wrap with aluminum foil and incubate at room temperature in the dark for 1.5 hours.

Transfer 18.5 μl of the mixture to OptiPlate 384 and use Envision reading.

Table 6: IC50 data for EGFR activity and inhibitor activity for EGFR phosphorylation (pEGFR) ¹

/>

¹ "+". ++'s indication IC50<100nM；

"++" indicates 100nM < = IC50<1000nM; "+" indicates IC50> =1000 nM;

"NA" indicates that IC50 data for this compound was not obtained.

Sequence listing

<110> Scorpion therapy Co., ltd (Scorpion Therapeutics, inc.)

<120> pyrrolo [3,2-C ] pyridin-4-one derivatives for the treatment of cancer

<130> 50006-0049WO1

<150> 63/082,324

<151> 2020-09-23

<150> 63/092,970

<151> 2020-10-16

<160> 2

<170> PatentIn version 3.5

<210> 1

<211> 1210

<212> PRT

<213> Artificial work

<220>

<223> adult EGFR

<400> 1

Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala

1 5 10 15

Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln

20 25 30

Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe

35 40 45

Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn

50 55 60

Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys

65 70 75 80

Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val

85 90 95

Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr

100 105 110

Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn

115 120 125

Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu

130 135 140

His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu

145 150 155 160

Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met

165 170 175

Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro

180 185 190

Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln

195 200 205

Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg

210 215 220

Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys

225 230 235 240

Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp

245 250 255

Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro

260 265 270

Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly

275 280 285

Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His

290 295 300

Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu

305 310 315 320

Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val

325 330 335

Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn

340 345 350

Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp

355 360 365

Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr

370 375 380

Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu

385 390 395 400

Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp

405 410 415

Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln

420 425 430

His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu

435 440 445

Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser

450 455 460

Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu

465 470 475 480

Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu

485 490 495

Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro

500 505 510

Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn

515 520 525

Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly

530 535 540

Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro

545 550 555 560

Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro

565 570 575

Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val

580 585 590

Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp

595 600 605

Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys

610 615 620

Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly

625 630 635 640

Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu

645 650 655

Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg Arg Arg His

660 665 670

Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu Arg Glu Leu

675 680 685

Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln Ala Leu Leu

690 695 700

Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val Leu Gly Ser

705 710 715 720

Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro Glu Gly Glu

725 730 735

Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu Ala Thr Ser

740 745 750

Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val Met Ala Ser

755 760 765

Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys Leu Thr Ser

770 775 780

Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys Leu Leu Asp

785 790 795 800

Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr Leu Leu Asn

805 810 815

Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu Asp Arg Arg

820 825 830

Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys Thr Pro

835 840 845

Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu Leu Gly Ala

850 855 860

Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro Ile Lys Trp

865 870 875 880

Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His Gln Ser Asp

885 890 895

Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ser

900 905 910

Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser Ile Leu Glu

915 920 925

Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr

930 935 940

Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser Arg Pro Lys

945 950 955 960

Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg Asp Pro Gln

965 970 975

Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu Pro Ser Pro

980 985 990

Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu Asp Met Asp

995 1000 1005

Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln Gly Phe

1010 1015 1020

Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser Leu

1025 1030 1035

Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn

1040 1045 1050

Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg

1055 1060 1065

Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp

1070 1075 1080

Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro

1085 1090 1095

Lys Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln

1100 1105 1110

Pro Leu Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro

1115 1120 1125

His Ser Thr Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln

1130 1135 1140

Pro Thr Cys Val Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala

1145 1150 1155

Gln Lys Gly Ser His Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln

1160 1165 1170

Gln Asp Phe Phe Pro Lys Glu Ala Lys Pro Asn Gly Ile Phe Lys

1175 1180 1185

Gly Ser Thr Ala Glu Asn Ala Glu Tyr Leu Arg Val Ala Pro Gln

1190 1195 1200

Ser Ser Glu Phe Ile Gly Ala

1205 1210

<210> 2

<211> 1255

<212> PRT

<213> Artificial work

<220>

<223> adult HER2

<400> 2

Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu

1 5 10 15

Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys

20 25 30

Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His

35 40 45

Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr

50 55 60

Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val

65 70 75 80

Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu

85 90 95

Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr

100 105 110

Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro

115 120 125

Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser

130 135 140

Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln

145 150 155 160

Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn

165 170 175

Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys

180 185 190

His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser

195 200 205

Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys

210 215 220

Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys

225 230 235 240

Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu

245 250 255

His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val

260 265 270

Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg

275 280 285

Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu

290 295 300

Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln

305 310 315 320

Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys

325 330 335

Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu

340 345 350

Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys

355 360 365

Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp

370 375 380

Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe

385 390 395 400

Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro

405 410 415

Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg

420 425 430

Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu

435 440 445

Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly

450 455 460

Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val

465 470 475 480

Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr

485 490 495

Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His

500 505 510

Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys

515 520 525

Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys

530 535 540

Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys

545 550 555 560

Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys

565 570 575

Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp

580 585 590

Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu

595 600 605

Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln

610 615 620

Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys

625 630 635 640

Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser

645 650 655

Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly

660 665 670

Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg

675 680 685

Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly

690 695 700

Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu

705 710 715 720

Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys

725 730 735

Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile

740 745 750

Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu

755 760 765

Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg

770 775 780

Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu

785 790 795 800

Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg

805 810 815

Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly

820 825 830

Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala

835 840 845

Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe

850 855 860

Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp

865 870 875 880

Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg

885 890 895

Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val

900 905 910

Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala

915 920 925

Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro

930 935 940

Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met

945 950 955 960

Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe

965 970 975

Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu

980 985 990

Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu

995 1000 1005

Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr

1010 1015 1020

Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly

1025 1030 1035

Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg

1040 1045 1050

Ser Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu

1055 1060 1065

Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser

1070 1075 1080

Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu

1085 1090 1095

Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser

1100 1105 1110

Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val

1115 1120 1125

Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro

1130 1135 1140

Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro

1145 1150 1155

Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu

1160 1165 1170

Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly

1175 1180 1185

Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala

1190 1195 1200

Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp

1205 1210 1215

Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro

1220 1225 1230

Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr

1235 1240 1245

Leu Gly Leu Asp Val Pro Val

1250 1255

Claims

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R ⁵ selected from the group consisting of:

optionally by 1-4R ^c Substituted C _6-10 An aryl group;

·C _3-10 cycloalkyl or C _3-10 Cycloalkenyl groups, each optionally substituted with 1-4 substituents, each independently selected from: oxo and R ^c ；

·Wherein ring D is a heterocyclylene or heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^X 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O andS(O) _0-2 and wherein the heterocyclylene or heterocyclylene is optionally substituted with 1-4 substituents, each substituent independently selected from the group consisting of: oxo and-R ^c ；

·-S(O) _0-2 (C _1-6 Alkyl) optionally substituted with 1-6R ^a Substitution;

·-R ^W

·-R ^g2 -R ^W or-R ^g2 -R ^Y ；

·-L ⁵ -R ^g2 -R ^W or-L ⁵ -R ^g2 -R ^Y ；

R ⁶ Selected from the group consisting of:

·H；

halogen;

·-OH；

·-NR ^e R ^f ；

·-R ^g ；

·-R ^w

·-L ⁶ -R ^g ；

·-R ^g2 -R ^W or-R ^g2 -R ^Y ；

L ⁵ and L ⁶ independently-O-, -S (O) _0-2 -NH or-N (R) ^d )-；

R ^W is-L ^W -W，

W is C _2-6 Alkenyl groups; c (C) _2-6 Alkynyl; or C _3-10 Cumulatively dienyl, each of which is optionally substituted with 1-3R ^a Substituted and also optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W Thereby providing an alpha, beta-unsaturated system; and is also provided with

R ^Y selected from the group consisting of: -R ^g And- (L) ^g ) _g -R ^g ；

R ^1c 、R ^2a 、R ^2b 、R ^3a And R is ^3b Each independently selected from the group consisting of: h is formed; halogen; -OH; -C (O) OH or-C (O) NH ₂ ；-CN；-R ^b ；-L ^b -R ^b ；-C _1-6 Alkoxy or-C _1-6 Thioalkoxy groups, each of which is optionally substituted with 1-6R ^a ；-NR ^e R ^f ；R ^g And- (L) ^g ) _g -R ^g Substitution; provided that R ^1c Not halogen, -CN or-C (O) OH; or alternatively

Ring A is R ^g ；

R ⁴ Selected from the group consisting of: h and R ^d ；

Each R ⁷ R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the n is 0, 1, 2 or 3;

l of each occurrence ^b Independently C (=o); c (=o) O; s (O) _1-2 ；C(＝O)NH*；C(＝O)NR ^d *；S(O) _1-2 NH; or S (O) _1-2 N(R ^d ) Wherein asterisks represent the linkage to R ^b Is a point of (2);

R of each occurrence ^d Independently selected from the group consisting of: c (C) _1-6 Alkyl, optionally substituted with 1-3 independently selected R ^a Substitution; -C (O) (C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR’R”；-S(O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; and C _1-4 An alkoxy group;

r of each occurrence ^e And R is ^f Independently selected from the group consisting of: h is formed; optionally by 1-3C _1-3 Alkyl substituted C _3-5 Cycloalkyl; heterocyclyl comprising 3 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 Optionally substituted with 1-4 substituents independently selected from oxo and R ^c The method comprises the steps of carrying out a first treatment on the surface of the C optionally substituted with 1-3 substituents _1-6 Alkyl, each of said substituents being independently selected from NR 'R', -OH, C _1-6 Alkoxy, C _1-6 Haloalkoxy and halogen; -C (O) (C _1-4 An alkyl group); -C (O) O (C) _1-4 An alkyl group); -CONR' R "; s (O) _1-2 NR’R”；-S(O) _1-2 (C _1-4 An alkyl group); -OH; and C _1-4 An alkoxy group;

r of each occurrence ^g Independently selected from the group consisting of:

optionally by 1-4R ^c Substituted C _6-10 An aryl group;

l of each occurrence ^g Independently selected from the group consisting of: -O-, -NH-, -NR ^d 、-S(O) _0-2 C (O), and optionallyGround cover 1-3R ^a Substituted C _1-3 An alkylene group;

each g is independently 1, 2 or 3;

each R ^g2 Is divalent R ^g A group; and is also provided with

provided that when R ^2a 、R ^2b 、R ^3a And R is ^3b Each is H; r is R ^1c Is H or methyl; ring a is phenyl optionally substituted with 1-2F; x is X ¹ is-O-L ¹ -R ⁵ The method comprises the steps of carrying out a first treatment on the surface of the and-L ¹ Is CH ₂ When, then:

2. The compound of claim 1, wherein X ¹ is-O-L ¹ -R ⁵ 。

3. The compound of claim 1 or 2, wherein R ⁵ Is a heteroaryl group comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

4. A compound according to any one of claims 1 to 3 wherein R ⁵ Is a monocyclic heteroaryl group comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroaryl group is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

5. The compound of any one of claims 1-4, wherein R ⁵ Is a monocyclic heteroaryl group comprising 5 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroaryl group is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

6. The compound of any one of claims 1-5, wherein R ⁵ Selected from the group consisting of: furyl, thienyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, each of which is optionally substituted with 1-2R ^cA Substituted, and the ring nitrogen is optionally substituted by R ^d Substitution, wherein each R ^cA R is independently selected ^c 。

7. The compound of any one of claims 1-6, wherein R ⁵ Selected from the group consisting of: each of which is optionally substituted with 1-2R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

8. The compound of any one of claims 1-4, wherein R ⁵ Is a monocyclic heteroaryl group comprising 6 ring atoms, wherein 1 to 4 ring atoms are ring nitrogen atoms, and wherein the heteroaryl group is optionally substituted with 1 to 4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

9. The compound of any one of claims 1-4 or 8, wherein R ⁵ Selected from the group consisting of: pyridyl, pyridonyl, pyrimidinyl, pyrazinyl and pyridazinyl, each of which is optionally substituted with 1-3R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

10. The compound of any one of claims 1-4 or 8-9, wherein R ⁵ Selected from the group consisting of: for example->For exampleEach of which is optionally R ^cA Further substitution, wherein each R ^cA R is independently selected ^c 。

11. The compound of any one of claims 1-4 or 8-9, wherein R ⁵ Selected from the group consisting of:for example->Each of which is optionally R ^cA Further substitution, wherein each R ^cA R is independently selected ^c 。

12. A compound according to any one of claims 1 to 3 wherein R ⁵ Is a bicyclic heteroaryl group comprising 8 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

13. The compound of any one of claims 1-3 or 12, wherein R ⁵ Is a bicyclic heteroaryl group containing 8 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

14. The compound of any one of claims 1-3 or 12-13, wherein R ⁵ Selected from the group consisting of:each of which is optionally substituted with 1-2R ^cA Further substitution, wherein each R ^cA R is independently selected ^c 。

15. The compound of any one of claims 1-2 or 12-13, wherein R ⁵ Selected from the group consisting of: each of which is optionally substituted with 1-2R ^cA Further substitution, wherein each R ^cA R is independently selected ^c 。

16. The compound of any one of claims 1-3 or 12, wherein R ⁵ Is a bicyclic heteroaryl group containing 9 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

17. The compound of any one of claims 1-3, 12 or 16, wherein R ⁵ Is imidazopyrazineA pyridyl, pyrazolopyridyl or benzotriazole group, each of which is optionally substituted with 1-2R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

18. The compound of any one of claims 1-3, 12 or 16-17, wherein R ⁵ Is that Each of which is optionally substituted with 1-2R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

19. A compound according to any one of claims 1 to 3 wherein R ⁵ Is a bicyclic ten membered heteroaryl wherein 1-4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

20. The compound of any one of claims 3-19, wherein each R ^cA Independently selected from the group consisting of: halogen; cyano group; -OH; optionally R is selected from 1 to 6 independently ^a Substituted C _1-6 An alkyl group; c (C) _1-4 Alkoxy, optionally C _1-4 Alkoxy or C _1-4 Haloalkoxy substitution; c (C) _1-4 Haloalkoxy groups; and-C (=o) NR' R ".

21. The compound of any one of claims 3-20, wherein one occurrence of R ^cA Is an independently selected halogen, such as-F or-Cl.

22. The compound of any one of claims 3-21, wherein one occurrence of R ^cA Is cyano.

23. The compound of any one of claims 3-22, wherein one occurrence of R ^cA Is optionally selected from 1 to 6R ^a Substituted C _1-6 An alkyl group.

24. The compound of any one of claims 3-23, wherein one occurrence of R ^cA Is C _1-6 Alkyl radicals, e.g. C _1-3 An alkyl group.

25. The compound of any one of claims 3-23, wherein one occurrence of R ^cA is-OH or-NR ^e R ^f Substituted C _1-6 Alkyl radicals, e.g. by-OH or NH ₂ Substituted C _1-3 An alkyl group.

26. The compound of any one of claims 3-25, wherein one occurrence of R ^cA Is C _1-4 Alkoxy, optionally C _1-4 Alkoxy or C _1-4 Haloalkoxy substitution, e.g. R in one occurrence ^cA Is C _1-4 Alkoxy, such as methoxy or ethoxy.

27. The compound of any one of claims 3-26, wherein one occurrence of R ^cA is-C (=O) NR' R ", e.g. C (=O) NH ₂ 。

28. The compound of claim 1 or 2, wherein R ⁵ Is thatRing D is a heterocyclylene or heterocyclylene group comprising 3-10 ring atoms, wherein 0-2 ring atoms (except bonded to R ^X 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene or heterocyclylene group is optionally substituted with 1 to 4 substituents, each substituentIndependently selected from oxo and-R ^c 。

29. The compound of any one of claims 1-2 or 28, wherein R ⁵ Is thatWhich is optionally substituted with 1-2R ^c Substitution, wherein x1 and x2 are each independently 0, 1 or 2.

30. The compound of claim 29, wherein x1=0 and x2=0.

31. The compound of claim 29, wherein x1=0 and x2=1.

32. The compound of claim 29, wherein x1=0 and x2=2.

33. The compound of any one of claims 1-2 or 28-29, wherein R ⁵ Selected from the group consisting of:for exampleFor example->And->For example

34. The compound of any one of claims 28-33, wherein R ^X Is C (=O) (C _1-4 Alkyl) or S (O) ₂ (C _1-4 Alkyl).

35. The compound of any one of claims 28-34, wherein R ^X Is C (=O) (C _1-4 Alkyl), for example C (=o) Me or C (=o) Et.

36. The compound of any one of claims 28-34, wherein R ^X Is S (O) ₂ (C _1-4 Alkyl), e.g. S (O) ₂ Me。

37. The compound of claim 1 or 2, wherein R ⁵ is-R ^g2 -R ^W 。

38. The compound of any one of claims 1-2 or 37, wherein R ⁵ is-R ^g2 -R ^W The method comprises the steps of carrying out a first treatment on the surface of the and-R ^g2 -R ^W In the presence of-R ^g2 Is a heterocyclylene or heterocyclylene group comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene or heterocyclylene is optionally substituted with 1-4 substituents independently selected from oxo and R ^c 。

39. The compound of any one of claims 1-2 or 37-38, wherein-R ⁵ Is thatWherein ring D is a heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^W 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from the group consisting of: oxo and-R ^c 。

40. The method of claim 1-2 or 37-39, wherein–R ⁵ Is thatWhich is optionally substituted with 1-2R ^c Substitution, wherein x1 and x2 are each independently 0, 1 or 2.

41. The compound of claim 40, wherein x1=0 and x2=0.

42. The compound of claim 40, wherein x1=0 and x2=1; or x1=0 and x2=2.

43. The compound of any one of claims 1-2 or 37-42, wherein R ⁵ Selected from the group consisting of:for example For example-> For example For example->For example

44. The compound of any one of claims 1 or 2, wherein R ⁵ Is R ^W 。

45. The compound of any one of claims 37-44, wherein R ^W is-L ^W -W; and L is ^W Is C (=O) NHC (=O) or NHS (O) _1-2 * Wherein the asterisks represent the points of attachment to W.

46. The compound of any one of claims 37-45, wherein W is C _2-6 Alkenyl or C _2-6 Alkynyl, optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W 。

47. The compound of claims 37-46, wherein W is C _2-4 Alkenyl or C _2-4 Alkynyl, optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W 。

48. The compound of claims 37-47, wherein W is ch=ch ₂ 、CH＝CHCH ₂ NMe ₂ Or (b)

49. The compound of claims 37-48, wherein-L ^W -W is-C (=o) ch=ch ₂ 、–C(＝O)CH＝CHCH ₂ NMe ₂ Or (b)

50. Such as weightThe compound of claim 1 or 2, wherein R ⁵ is-R ^g2 -R ^Y 。

51. The compound of any one of claims 1-2 or 50, wherein R ⁵ is-R ^g2 -R ^Y wherein-R is ^g2 -R ^Y In the presence of-R ^g2 Is a heterocyclylene or heterocyclylene group comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene or heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from oxo and R ^c 。

52. The compound of any one of claims 1-2 or 50-51, wherein-R ⁵ Is thatWherein ring D is a heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^Y 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from oxo and-R ^c 。

53. The compound of any one of claims 1-2 or 50-52, wherein-R ⁵ Is thatWhich is optionally substituted with 1-2R ^c Substitution, wherein x1 and x2 are each independently 0, 1 or 2.

54. The compound of claim 53, wherein x1=0 and x2=0.

55. The compound of claim 53, wherein x1=0 and x2=1.

56. The compound of claim 53, wherein x1=0 and x2=2.

57. The compound of any one of claims 1-2 or 50-53, wherein R ⁵ Selected from the group consisting of:for example For example->And->For example

58. The compound of any one of claims 1-2 or 50, wherein R ⁵ is-R ^g2 -R ^Y The method comprises the steps of carrying out a first treatment on the surface of the and-R ^g2 -R ^Y In the presence of-R ^g2 Is a monocyclic heteroarylene group comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroarylene group is optionally substituted with 1-3R ^c And (3) substitution.

59. The compound of any one of claims 1-2, 50 or 58, wherein R ⁵ is-R ^g2 -R ^Y The method comprises the steps of carrying out a first treatment on the surface of the and-R ^g2 -R ^Y In the presence of-R ^g2 Is a monocyclic heteroarylene group comprising 5 ring atoms, which isWherein 1-4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroarylene group is optionally substituted with 1-2R ^c And (3) substitution.

60. The compound of any one of claims 1-2, 50, or 58-59, wherein R ⁵ Selected from the group consisting of:

61. the compound of any one of claims 50-60, wherein-R ^Y is-R ^g 。

62. The compound of any one of claims 50-61, wherein-R ^Y Selected from the group consisting of:

optionally by 1-4R ^c Substituted C _6-10 Aryl groups.

63. The compound of any one of claims 50-62, wherein-R ^Y Is optionally substituted with 1 to 4R ^c Substituted C _6-10 Aryl groups.

64. The compound of any one of claims 50-63, wherein-R ^Y Is phenyl, optionally substituted with 1-3R ^c And (3) substitution.

65. The compound of any one of claims 50-62, wherein-R ^Y Is a heteroaryl group comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

66. The compound of any one of claims 50-62 or 65, wherein-R ^Y Is a monocyclic heteroaryl group comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

67. The compound of any one of claims 50-62 or 65-66, wherein-R ^Y Selected from the group consisting of: pyridinyl and pyrazolyl, each of which is optionally substituted with 1-2R ^c And (3) substitution.

68. The compound of claim 1 or 2, wherein R ⁵ Is C _3-10 Cycloalkyl or C _3-10 Cycloalkenyl groups, each optionally substituted with 1-4 substituents, each independently selected from: oxo and R ^c 。

69. The compound of any one of claims 1-2 or 68, wherein R ⁵ Is C substituted by 1-4 substituents _3-10 Cycloalkyl groups, each of said substituents being independently selected from: oxo and R ^c 。

70. The compound of any one of claims 1-2 or 68-69, wherein R ⁵ Is quilt C _1-4 Alkoxy or C _1-4 Haloalkoxy-substituted C _3-6 Cycloalkyl; and R is ⁵ Further optionally substituted with 1-2 substituents, each substituent independently selected from: oxo and R ^c 。

71. The compound of any one of claims 1-2 or 68-70, wherein R ⁵ Is quilt C _1-4 Alkoxy or C _1-4 Haloalkoxy-substituted cyclopropyl; for example:for example->

72. The compound of claim 1 or 2, wherein R ⁵ is-S (O) _0-2 (C _1-6 Alkyl) optionally substituted with 1-6R ^a And (3) substitution.

73. The compound of any one of claims 1-2 or 72, wherein R ⁵ is-S (O) ₂ (C _1-6 Alkyl) optionally substituted with 1-6R ^a And (3) substitution.

74. The compound of any one of claims 1-2 or 72-73, wherein R ⁵ is-S (O) ₂ (C _1-6 Alkyl), e.g. -S (O) ₂ (C _1-3 Alkyl).

75. The compound of claim 1 or 2, wherein R ⁵ Selected from-L ⁵ -R ^g 、-L ⁵ -R ^g2 -R ^Y and-L ⁵ -R ^g2 -R ^W 。

76. The compound of any one of claims 1-2 or 75, wherein R ⁵ is-L ⁵ -R ^g 。

77. The compound of any one of claims 1-2 or 75-76, wherein R ⁵ is-O-R ^g 。

78. The compound of any one of claims 1-2 or 75-77, wherein R ⁵ is-O-R ^g The method comprises the steps of carrying out a first treatment on the surface of the and-O-R ^g R present in (a) ^g Is C _3-10 Cycloalkyl or C _3-10 Cycloalkenyl groups, each optionally substituted with 1-4 substituents, each independently selected from: oxo and R ^c 。

79. The compound of any one of claims 1-2 or 75-78, wherein R ⁵ is-O- (C) _3-6 Cycloalkyl), wherein C _3-6 Cycloalkyl is optionally substituted with 1-3R ^c And (3) substitution.

80. The compound of any one of claims 1-2 or 75-79, wherein R ⁵ Is that

81. The compound of any one of claims 1-80, wherein L ¹ Is optionally substituted with 1 to 6R ^a Substituted C _1-10 An alkylene group.

82. The compound of any one of claims 1-81, wherein L ¹ Is optionally substituted with 1 to 6R ^a Substituted C _1-6 An alkylene group.

83. The compound of any one of claims 1-82, wherein L ¹ Is optionally substituted with 1 to 6R ^a Substituted C _1-4 An alkylene group.

84. The compound of any one of claims 1-83, wherein L ¹ Is C _1-4 An alkylene group.

85. The compound of any one of claims 1-84, wherein L ¹ is-CH ₂ -or-CH ₂ CH ₂ -。

86. The compound of any one of claims 1-84, wherein L ¹ Is thatWherein asterisks represent the linkage to R ^W Is a point of (2).

87. The compound of any one of claims 1-80, wherein L ¹ Is a key.

88. The compound of claim 1, wherein X ¹ Is that

89. The compound of claim 1 or 88, wherein R ⁶ Is R ^g 。

90. The compound of any one of claims 1 or 88-89, wherein R ⁶ Is a heterocyclic or heterocycloalkenyl group comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl or heterocyclenyl is optionally substituted with 1-4 substituents independently selected from oxo and R ^c 。

91. The compound of any one of claims 1 or 88-90, wherein R ⁶ Is a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from oxo and R ^c For example: wherein R is ⁶ Is a heterocyclic group containing 4 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-2 substituents independently selected from the group consisting of: oxo and R ^c 。

92. The compound of any one of claims 1 or 88-91, wherein R ⁶ Selected from the group consisting of: pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, each of which isOptionally substituted with 1-2 substituents independently selected from oxo and R ^c Wherein the ring nitrogen of pyrrolidinyl or piperidinyl is optionally substituted with R ^d Substitution, e.g. where R ⁶ Is that(e.g.)>)、/> />

93. The compound of any one of claims 1 or 88-89, wherein R ⁶ Is a heteroaryl group comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c Substitution; for example:

wherein R is ⁶ Is a heteroaryl group comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c Substitution, for example: wherein R is ⁶ Is that

94. The compound of claim 1 or 88, wherein R ⁶ Is that ^– R ^g2 -R ^W or-R ^g2 -R ^Y 。

95. The compound of any one of claims 1, 88, or 94, wherein R ⁶ Is that ^– R ^g2 -R ^W 。

96. The compound of any one of claims 1, 88, or 94-95, wherein-R ⁶ Is thatWherein ring D is a heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^W 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from the group consisting of: oxo and-R ^c The method comprises the steps of carrying out a first treatment on the surface of the Optionally, wherein-R ⁶ Is a monocyclic heterocyclylene ring comprising 3 to 10 ring atoms as defined above, wherein the nitrogen atom is bonded to R ^W (e.g.)>For example For example->) The method comprises the steps of carrying out a first treatment on the surface of the Optionally, wherein-R ⁶ Is a bicyclic heterocyclylene ring comprising 3 to 10 ring atoms as defined above, wherein the nitrogen atom is bonded to R ^W (e.g.For example-> For example-> For example->)。

97. The compound of any one of claims 1, 88, or 94-96, wherein-R ⁶ Is thatWhich is optionally substituted with 1-2R ^c Substitution, wherein x1 and x2 are each independently 0, 1 or 2./>

98. The method of claim 97, wherein x1=0 and x2=0; or x1=0 and x2=1; or x1=0 and x2=2.

99. The compound of any one of claims 1, 88, or 94-98, wherein R ⁶ Selected from the group consisting of:for exampleFor example-> For exampleFor example->For example

100. The compound of any one of claims 1, 88, 94-95, wherein R ⁶ Is covered by R ^W Substituted C ₃ -C ₆ Cycloalkyl (e.g., cyclobutyl); or by R ^W Substituted oxetanyl; or by R ^W Substituted tetrahydrofuranyl.

101. The compound of any one of claims 1 or 88, wherein R ⁶ is-R ^W 。

102. The compound of any one of claims 94-101, wherein-R ^W is-L ^W -W; and L is ^W Is C (=O) NHC (=O) and NR ^d C (=o) (e.g., NMeC (=o)) or NHS (O) _1-2 * Wherein the asterisks represent the points of attachment to W.

103. The compound of any one of claims 94-102 wherein W is C _2-6 Alkenyl or C _2-6 Optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W 。

104. The compound of any one of claims 94-103 wherein W is C _2-4 Alkenyl (e.g., ch=ch ₂ ) Or C _2-4 Alkynyl groups (e.g.,) Optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W 。

105. The compound of any one of claims 94-104, wherein-L ^W -W is-C (=o) ch=ch ₂ ；–C(＝O)NHCH＝CH ₂ ；C(＝O)CH＝CHCH ₂ NR ^e R ^f (e.g., C (=o) ch=chch ₂ N(HMe)、C(＝O)CH＝CHCH ₂ NMe ₂ 、 ) The method comprises the steps of carrying out a first treatment on the surface of the Or->

106. The compound of claim 1 or 88, wherein R ⁶ is-C _1-6 Alkoxy or-S (O) _0-2 (C _1-6 Alkyl) each optionally substituted with 1-6R ^a And (3) substitution.

107. The compound of any one of claims 1, 88, or 106, wherein R ⁶ is-C _1-6 Alkoxy radicals, e.g. -C _1-3 Alkoxy groups such as methoxy.

108. The compound of any one of claims 1 or 88-107, wherein L ² Is a key.

109. The compound of any one of claims 1 or 88-107, wherein L ² Is C _1-10 Alkylene, optionally substituted with 1-6R ^a Substitution, wherein R ^a is-NR ^e R ^f (e.g., NMe) ₂ ) Halogen (e.g., fluorine), alkoxy (e.g., methoxy).

110. Any one of claims 1, 88-107 or 109The compound of item, wherein L ² Is optionally substituted with 1 to 6R ^a Substituted C _1-6 Alkylene group, wherein R is ^a is-NR ^e R ^f (e.g., NMe) ₂ ) Halogen (e.g., fluorine), alkoxy (e.g., methoxy).

111. The compound of any one of claims 1, 88-107, or 109-110, wherein L ² Is optionally substituted with 1 to 6R ^a Substituted branching C _3-6 Alkylene group, wherein R is ^a is-NR ^e R ^f (e.g., NMe) ₂ ) Halogen (e.g., fluorine), alkoxy (e.g., methoxy).

112. The method of claim 1, 88-107, or 109-111, wherein L ² Is that(e.g.)> )、/>(e.g.)>)、/>(e.g.)>)、/>(e.g.)>)、/>(e.g.)>) Or->(e.g., )。

113. The compound of any one of claims 1-112, wherein n is 0.

114. The compound of any one of claims 1-112, wherein n is 1 or 2.

115. The compound of any one of claims 1-112 or 114, wherein n is 1.

116. The compound of any one of claims 1-112 or 114-115, whereinPart is

117. The compound of any one of claims 1-112 or 114-116, wherein one occurrence of R ⁷ Is NR ^e R ^f For example: NH (NH) ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ 。

118. The compound of any one of claims 1-112 or 114-117, wherein one occurrence of R ⁷ Is NH ₂ Or NH (C) _1-3 Alkyl), e.g., where R is present at one time ⁷ Is NH ₂ 。

119. The compound of any one of claims 1-112, whereinPart is->And R is ⁷ Is NR ^e R ^f 。

120. The compound of claim 119, wherein R ⁷ Is NH ₂ Or NH (C) _1-3 Alkyl), e.g., wherein R ⁷ Is NH ₂ 。

121. The compound of any one of claims 1-120, wherein R ^1c Is H.

122. The compound of any one of claims 1-121, wherein R ^2a And R is ^2b Is H.

123. The compound of any one of claims 1-121, wherein R ^2a And R is ^2b 1-2 of (a) are substituents other than H.

124. The compound of claim 123, wherein R ^2a And R is ^2b One of them is C _1-3 Alkyl, optionally substituted with 1-3R ^a Substitution, e.g. C _1-3 An alkyl group; and R is ^2a And R is ^2b The other of (2) is H.

125. As in claims 1-124The compound of any one of claims, wherein R ^3a And R is ^3b Is H.

126. The compound of any one of claims 1-124, wherein R ^3a And R is ^3b 1-2 of (a) are substituents other than H.

127. The compound of claim 126, wherein R ^3a And R is ^3b One of them is C _1-3 Alkyl, optionally substituted with 1-3R ^a Substituted, e.g. C optionally substituted by 1-3-F _1-3 An alkyl group; and R is ^2a And R is ^2b The other of (2) is H.

128. The compound of any one of claims 1-124, wherein R ^3a And R is ^3b Together with the ring atoms of the ring B to which they are each attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms;

129. The compound of any one of claims 1-124 or 128, wherein R ^3a And R is ^3b Together with the ring atoms of ring B to which they are each attached, form a fused saturated ring of 4 to 8 ring atoms;

Wherein the fused saturated ring of 4 to 8 ring atoms is optionally substituted with 1 to 4 substituents independently selected from oxo, R ^c And R is ^W 。

130. The compound of any one of claims 1-124 or 128-129, wherein R ^3a And R is ^3b Together with the ring atoms of the ring B to which they are each attached formWhich is optionally substituted with 1-2 substituents independently selected from oxo and R ^c And the following steps:

p1 and p2 are independently 0, 1 or 2;

R ^Q is H, R ^d C (=O) -W or S (O) ₂ W is a metal; and is also provided with

cc represents a bond to C (R ^2a R ^2b ) Is a point of (2).

131. The compound of any one of claims 1-124 or 128-130, wherein R ^3a And R is ^3b Together with the ring atoms of the ring B to which they are each attached formWherein R is ^Q Is H, R ^d C (=O) -W or S (O) ₂ W is a metal; and cc represents a bond to C (R ^2a R ^2b ) Is a point of (2).

132. The compound of any one of claims 1-124 or 128-130, wherein R ^3a And R is ^3b Together with the ring atoms of ring B to which they are each attached, form a fused ring selected from the group consisting of: For example->For example->For example->(e.g.)>)；/>For example-> For example-> For exampleAnd->For example->(e.g.)>) Wherein R is ^Q Is H, R ^d C (=O) -W or S (O) ₂ W is a metal; and cc represents a bond to C (R ^2a R ^2b ) Is a point of (2).

133. The compound of any one of claims 130-132, wherein R ^Q Is H.

134. As claimed in130-132, wherein R ^Q Is R ^d 。

135. The compound of any one of claims 130-132 or 134, wherein R ^Q Is C _1-6 Alkyl, optionally substituted with 1-3 independently selected R ^a And (3) substitution.

136. The compound of any one of claims 130-132, wherein R ^Q Is C (=O) -W or S (O) ₂ W。

137. The compound of any one of claims 130-132 or 136, wherein W is C _2-4 Alkenyl groups.

138. The compound of any one of claims 130-132 or 136-137, wherein R ^Q Is C (=O) -CH ₂ ＝CH ₂ 。

139. The compound of any one of claims 1-138, wherein ring a isWherein each R is ^cB R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And m is 0, 1, 2, 3 or 4.

140. The compound of claim 139, wherein m is 1, 2, or 3.

141. The compound of claim 139 or 140, wherein m is 1 or 2, e.g., 2.

142. The compound of any one of claims 1-141, wherein ring a is (e.g.)>) Wherein each R is ^cB R is independently selected ^c 。

143. The compound of any one of claims 139-142, wherein each R ^cB Independently selected from the group consisting of: halogen, such as-Cl and-F; -CN; c (C) _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy groups; c (C) _1-3 An alkyl group; and C substituted with 1-6 independently selected halogens _1-3 An alkyl group.

144. The compound of any one of claims 1-143, wherein ring a isWherein R is ^cB1 Is R ^c The method comprises the steps of carrying out a first treatment on the surface of the And R is ^cB2 Is H or R ^c 。

145. The compound of claim 144, wherein R ^cB1 Halogen, for example-F or-Cl, for example-F.

146. The compound of claim 144 or 145, wherein R ^cB2 Is C _1-4 Alkoxy or C _1-4 Haloalkoxy radicals, e.g. C _1-4 Alkoxy groups such as methoxy.

147. The compound of any one of claims 1-146, wherein ring a is

148. The compound of any one of claims 1-138, wherein ring a is a heteroaryl comprising 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom independently selected from N, N (H), N (R ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c Substitution, for example:

wherein ring A is a bicyclic heteroaryl group comprising 9-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c Substitution, for example:

wherein ring a is selected from the group consisting of:for example-> For example->For example-> For example->Each of which is further optionally R ^c And (3) substitution.

149. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-a)

Or a pharmaceutically acceptable salt thereof,

wherein ring D1 is selected from the group consisting of:

wherein each R is ^cA R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

150. The compound of claim 149, wherein ring D1 is a monocyclic heteroaryl comprising 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R ^d ) O and S, and wherein the heteroaryl group is optionally substituted with 1-4R ^cA And (3) substitution.

151. The compound of claim 149 or 150, wherein ring D1 is selected from the group consisting of: each of which is optionally substituted with 1-2R ^cA And (3) substitution.

152. The compound of claim 149, wherein ring D1 is a ring comprising 6 ring atomsMonocyclic heteroaryl, wherein 1-4 ring atoms are ring nitrogen atoms, and wherein heteroaryl is optionally substituted with 1-4R ^cA And (3) substitution.

153. The compound of claim 149 or 152, wherein ring D1 is selected from the group consisting of: for example->For exampleFor exampleEach of which is optionally R ^cA Further substitution.

154. The compound of claim 149, wherein ring D1 is-R ^g2 -R ^Y The method comprises the steps of carrying out a first treatment on the surface of the and-R ^g2 -R ^Y In the presence of-R ^g2 Is a monocyclic heteroarylene group comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroarylene group is optionally substituted with 1-3R ^cA And (3) substitution.

155. The compound of claim 149 or 154, wherein ring D1 is-R ^g2 -R ^Y The method comprises the steps of carrying out a first treatment on the surface of the and-R ^g2 -R ^Y In the presence of-R ^g2 Is a monocyclic heteroarylene group comprising 5 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom is independently selected from N, N (H), N (R) ^d ) O and S, and wherein the heteroarylene group is optionally substituted with 1-2R ^cA And (3) substitution.

156. The compound of any one of claims 149-155, wherein R ^Y Selected from the group consisting of:

optionally by 1-3R ^c A substituted phenyl group; and

157. The compound of any one of claims 149-156, wherein n is 0.

158. The compound of any of claims 149-156, wherein n is 1 or 2, e.g., n is 1.

159. The compound of any one of claims 149-156 or 158, whereinIs->

160. The compound of any one of claims 149-156 or 158-159, wherein R ⁷ Is NR ^e R ^f For example NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

161. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-b)

Or a pharmaceutically acceptable salt thereof,

162. The compound of claim 161, wherein ring D2 is heteroaryl comprising 8 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom independently selected from N, N (H), N (R ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

163. The compound of claim 161 or 162, wherein ring D2 is selected from the group consisting of: each of which is optionally substituted with 1-2R ^cA Further substitution, wherein each R ^cA R is independently selected ^c 。/>

164. The compound of claim 161 or 162, wherein ring D2 is selected from the group consisting of: each of which is optionally substituted with 1-2R ^cA Further substitution, wherein each R ^cA R is independently selected ^c 。

165. The compound of claim 161, wherein ring D2 is a bicyclic heteroaryl comprising 9 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom independently selected from N, N (H), N (R ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

166. The compound of claim 161 or 165, wherein ring D2 is imidazopyridinyl, pyrazolopyridinyl, or benzotriazole, each optionally substituted with 1-2R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

167. The compound of any one of claims 161 or 165-166, wherein ring D2 isEach of which is optionally substituted with 1-2R ^cA Substitution, wherein each R ^cA R is independently selected ^c 。

168. The compound of any one of claims 161-167, wherein n is 0.

169. The compound of any of claims 161-167, wherein n is 1 or 2, e.g., n is 1.

170. The compound of any one of claims 161-167 or 169, whereinIs->

171. The compound of any one of claims 161-167 or 169-170, wherein R ⁷ Is NR ^e R ^f For example NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

172. The compound of any one of claims 149-171, wherein each R ^cA Independently selected from the group consisting of: halogen; cyano group; -OH; optionally R is selected from 1 to 6 independently ^a Substituted C _1-6 An alkyl group; optionally by C _1-4 Alkoxy or C _1-4 Haloalkoxy-substituted C _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy groups; and-C (=o) NR' R ".

173. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-c)

Or a pharmaceutically acceptable salt thereof,

wherein ring D is a heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^Z 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from oxo and-R ^c ；

174. The compound of claim 173, wherein R ^Z Is R ^X 。

175. The compound of claim 173 or 174, wherein R ^Z Is C (=O) (C _1-4 Alkyl).

176. The compound of claim 173 or 174, wherein R ^Z Is S (O) ₂ (C _1-4 Alkyl).

177. The compound of claim 173, wherein R ^Z Is R ^Y 。

178. The compound of claim 173 or 177, wherein R ^Z Is R ^g 。

179. The compound of any one of claims 173 or 177-178, wherein R ^Z Selected from the group consisting of:

phenyl, optionally substituted with 1-3R ^c Substitution; and

180. The compound of any one of claims 173-179, wherein n is 0.

181. The compound of any one of claims 173-179, wherein n is 1 or 2, e.g., wherein n is 1.

182. The compound of any one of claims 173-179 or 181, whereinIs that/>

183. The compound of any one of claims 173-179 or 181-182, wherein R ⁷ Is NR ^e R ^f For example NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

184. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (I-d)

Or a pharmaceutically acceptable salt thereof,

wherein ring D is a heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^W 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from the group consisting of: oxo and-R ^c The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

185. The compound of claim 184, wherein R ^W is-L ^W -W; and L is ^W Is C (=o).

186. The compound of claim 184 or 185, wherein W is C _2-6 Alkenyl or C _2-6 Alkynyl, optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W 。

187. The compound of any one of claims 184-186, wherein W is ch=ch ₂ 、CH＝CHCH ₂ NMe ₂ Or (b)

188. The compound of any one of claims 184-187, wherein n is 0.

189. The compound of any one of claims 184-187, wherein n is 1 or 2, e.g., wherein n is 1.

190. The compound of any one of claims 184-187 or 189 whereinIs that

191. The compound of any one of claims 184-187 or 189-190 wherein R ⁷ Is NR ^e R ^f For example NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

192. The compound of any one of claims 173-191, wherein ring D isWhich is optionally substituted with 1-2R ^c Substitution, wherein x1 and x2 are each independently 0, 1 or 2.

193. The compound of claim 192, wherein x1 is 0.

194. The compound of any one of claims 173-193, wherein ring D is selected from the group consisting of:for example For example-> For example-> For example->For example->

195. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-e):

or a pharmaceutically acceptable salt thereof,

L ¹ Is optionally covered by1-6R ^a Substituted C _1-10 An alkylene group.

196. The compound of claim 195, wherein R ^5A is-L ⁵ -R ^g 。

197. The compound of claim 195 or 196, wherein R ^5A is-O-R ^g 。

198. The compound of any one of claims 195-197, wherein R ^5A is-O-R ^g The method comprises the steps of carrying out a first treatment on the surface of the and-O-R ^g R present in (a) ^g Is C _3-10 Cycloalkyl or C _3-10 Cycloalkenyl groups, each optionally substituted with 1-4 substituents, each independently selected from: oxo and R ^c 。

199. The compound of any one of claims 195-198, wherein R ^5A is-O- (C) _3-6 Cycloalkyl), wherein C _3-6 Cycloalkyl is optionally substituted with 1-3R ^c Substitution, e.g. where R ⁵ Is that

200. The compound of claim 195, wherein R ^5A is-S (O) _0-2 (C _1-6 Alkyl) optionally substituted with 1-6R ^a And (3) substitution.

201. The compound of claim 195 or 200, wherein R ^5A is-S (O) ₂ (C _1-6 Alkyl) optionally substituted with 1-6R ^a And (3) substitution.

202. The compound of any one of claims 195 or 200-201, wherein R ^5A is-S (O) ₂ (C _1-3 Alkyl), e.g. -S (O) ₂ Me。

203. The compound of any one of claims 195-202, wherein n is 0.

204. The compound of any one of claims 195-202, wherein n is 1 or 2, e.g., wherein n is 1.

205. The compound of any one of claims 195-202 or 204, wherein Is->

206. The compound of any one of claims 195-202 or 204-205, wherein R ⁷ Is NR ^e R ^f For example NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

207. The compound of any one of claims 149-206, wherein L ¹ Is optionally substituted with 1 to 6R ^a Substituted C _1-3 An alkylene group.

208. The compound of any one of claims 149-207, wherein L ¹ Is C _1-3 An alkylene group.

209. The compound of any one of claims 149-208, wherein L ¹ is-CH ₂ -。

210. The compound of any one of claims 149-208, wherein L ¹ is-CH ₂ CH ₂ -。

211. The any one of claims 149-194Wherein L is ¹ Is a key.

212. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-f):

or a pharmaceutically acceptable salt thereof,

wherein ring D3 is C substituted with 1-4 substituents _3-10 Cycloalkyl, each substituent is independently selected from: oxo and R ^c 。

213. The compound of claim 212, wherein ring D3 is C _1-4 Alkoxy or C _1-4 Haloalkoxy-substituted C _3-6 Cycloalkyl; and R is ⁵ Further optionally substituted with 1-2 substituents, each substituent independently selected from: oxo and R ^c 。

214. The compound of claim 212 or 213, wherein R ⁵ Is quilt C _1-4 Alkoxy or C _1-4 Haloalkoxy-substituted cyclopropyl; for example:for example->

215. The compound of any one of claims 212-214, wherein n is 0.

216. The compound of any of claims 212-214, wherein n is 1 or 2, e.g., wherein n is 1.

217. The method of any one of claims 212-214 or 216A compound whereinIs->

218. The compound of any one of claims 212-214 or 216-217, wherein R ⁷ Is NR ^e R ^f For example NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

219. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-g):

or a pharmaceutically acceptable salt thereof,

220. The compound of claim 219, wherein R ^6A Is optionally substituted with 1 to 6R ^a substituted-C _1-6 An alkoxy group.

221. The compound of claim 219 or 220 wherein R ^6A is-C _1-3 An alkoxy group.

222. The compound of claim 219, wherein R ^6A Is NR ^e R ^f 。

223. The compound of claim 219, wherein R ^6A Is H, halogen or-OH.

224. The compound of any one of claims 219-223, wherein L ² Is branched C _3-6 An alkylene group.

225. The compound of any one of claims 219-224, wherein L ² Is that

226. The compound of any one of claims 219-223, wherein L ² Is C _1-3 Alkylene radicals, e.g. -CH ₂ -。

227. The compound of any one of claims 219-226, wherein n is 0.

228. The compound of any one of claims 219-226, wherein n is 1 or 2, e.g., wherein n is 1.

229. The compound of any one of claims 219-226 or 228, whereinIs that

230. The compound of any one of claims 219-226 or 228-229, wherein R ⁷ Is NR ^e R ^f For example NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

231. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-h):

or a pharmaceutically acceptable salt thereof,

wherein ring D4 is R ^g 。

232. The compound of claim 231, wherein ring D4 is selected from the group consisting of:

heterocyclyl or heterocycloalkenyl comprising 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl or heterocyclenyl is optionally substituted with 1-4 substituents independently selected from oxo and R ^c 。

233. The compound of claim 231 or 232, wherein ring D4 is a heterocyclyl comprising 4-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from oxo and R ^c 。

234. The compound of any one of claims 231-233, wherein ring D4 is selected from the group consisting of: pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, each of which is optionally substituted with 1-2 substituents independently selected from oxo and R ^c Wherein the ring nitrogen of pyrrolidinyl or piperidinyl is optionally substituted with R ^d Substitution, for example, wherein ring D4 is:(e.g.)>)、/>

235. The compound of claim 231, wherein ring D4 is heteroaryl comprising 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom independently selected from N, N (H), N (R ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c Substitution, for example: wherein R is ⁶ Is that

236. The compound of any one of claims 231-235, wherein n is 0.

237. The compound of any one of claims 231-235, wherein n is 1 or 2, e.g., wherein n is 1.

238. The compound of any one of claims 231-235 or 237, whereinIs that

239. The method of claim 231-235 or 237-238The compound of any one of claims, wherein R ⁷ Is NR ^e R ^f For example NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

240. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-I)

Or a pharmaceutically acceptable salt thereof,

wherein ring D is a heterocyclylene group comprising 3 to 10 ring atoms, wherein 0 to 2 ring atoms (except bonded to R ^W 0-2 ring atoms other than the ring nitrogen atom) are heteroatoms, each independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclylene is optionally substituted with 1-3 substituents, each substituent independently selected from the group consisting of: oxo and-R ^c 。

241. The compound of claim 240, wherein R ^W is-L ^W -W; and L is ^W Is C (=o).

242. The compound of claim 240 or 241, wherein W is C _2-6 Alkenyl or C _2-6 Alkynyl, optionally substituted with 1-3R ^a Substituted, and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W 。

243. The compound of any one of claims 240-242, wherein W is ch=ch ₂ 、CH＝CHCH ₂ NMe ₂ Or (b)

244. The compound of any one of claims 240-243, wherein ring D isWhich is optionally substituted with 1-2R ^c Substitution, wherein x1 and x2 are each independently 0, 1 or 2.

245. The compound of claim 244, wherein x1 is 0.

246. The compound of any one of claims 240-245, wherein ring D is selected from the group consisting of:for example For example-> For example-> For example->And->For example->

247. The compound of any one of claims 240-246, wherein n is 0.

248. The compound of any of claims 240-246, wherein n is 1 or 2, e.g., wherein n is 1.

249. The compound of any one of claims 240-246 or 248, whereinIs that

250. The compound of any one of claims 240-246 or 248 wherein R ⁷ Is NR ^e R ^f For example NH ₂ 、NH(C _1-3 Alkyl) or N (C) _1-3 Alkyl group ₂ For example, wherein R ⁷ Is NH ₂ 。

251. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-j):

or a pharmaceutically acceptable salt thereof,

252. The compound of claim 251, wherein R ^W is-L ^W -W; and L is ^W Is C (=O), NHC (=O) or NHS (O) _1-2 * Wherein the asterisks represent the points of attachment to W.

253. The compound of claim 251 or 252, wherein W is C _2-6 Alkenyl or C _2-6 Alkynyl, optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W 。

254. The compound of any one of claims 251-253, wherein W can be ch=ch ₂ 、CH＝CHCH ₂ NMe ₂ Or (b)

255. The compound of any one of claims 251-254, wherein-L ^W -W is-C (=o) ch=ch ₂ 、–NHSO ₂ CH＝CH ₂ 、–C(＝O)CH＝CHCH ₂ NMe ₂ Or (b)

256. The compound of any one of claims 251-255, wherein L ² Is optionally substituted with 1 to 6R ^a Substituted C _1-3 Alkylene group, wherein R is ^a is-NR ^e R ^f (e.g., NMe) ₂ ) Halogen (e.g., fluorine) or alkoxy (e.g., methoxy).

257. The compound of any one of claims 251-256, wherein L ² Is that(e.g.,)、/>(e.g.)>)、/>(e.g.)> )、(e.g.)>)、/>(e.g.)>) Or->(e.g.)>)。

258. The compound of any one of claims 251-257, wherein n is 0.

259. The compound of any one of claims 251-257, wherein n is 1 or 2, e.g., wherein n is 1.

260. The compound of any one of claims 251-258, whereinIs that

261. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-k):

or a pharmaceutically acceptable salt thereof,

wherein ring D5 is R ^g2 。

262. The compound of claim 261, wherein ring D5 is selected from the group consisting of:

263. The compound of claim 261 or 262, wherein ring D5 is a heterocyclylene comprising 4-6 ring atomsWherein 1-3 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from oxo and R ^c 。

264. The compound of claim 261 or 262, wherein ring D5 is C ₃ -C ₆ Cycloalkylene (e.g., cyclobutylene), oxetylene, or tetrahydrofuranylene.

265. The compound of any one of claims 261-264, wherein R ^W is-L ^W -W; and L is ^W Is C (=O) or NHC (=O), NR ^d C(＝O)*、NHS(O) _1-2 * Wherein the asterisks represent the points of attachment to W.

266. The compound of any one of claims 261 to 265, wherein W is C _2-6 Alkenyl or C _2-6 Alkynyl, optionally substituted with 1-3R ^a Substituted and further optionally substituted with R ^g Substitution, where W passes through sp ² Or sp hybridized carbon atom to L ^W 。

267. The compound of any one of claims 261-266, wherein W is ch=ch ₂ 、CH＝CHCH ₂ NMe ₂ Or (b)

268. The compound of any one of claims 261-267, wherein-L ^W -W is-C (=o) ch=ch ₂ 、–C(＝O)CH＝CHCH ₂ NMe ₂ Or (b)

269. The compound of any one of claims 184-187, wherein n is 0.

270. The compound of any one of claims 184-187 or 189 whereinIs->

271. The compound of any one of claims 149-270, wherein R ^1c Is H.

272. The compound of any one of claims 149-271, wherein R ^2a And R is ^2b Is H.

273. The compound of any one of claims 149-272, wherein R ^3a And R is ^3b Is H.

274. The compound of any one of claims 149-272, wherein R ^3a And R is ^3b Together with the ring atoms of ring B to which they are each attached, form a fused saturated ring of 4 to 8 ring atoms;

275. The compound of any one of claims 149-272 or 274, wherein R ^3a And R is ^3b Together with the ring atoms of the ring B to which they are each attached form:which is optionally substituted with 1-2 substituents independently selected from oxo and R ^c And the following steps:

p1 and p2 are independently 0, 1 or 2;

R ^Q is H, R ^d C (=O) -W or S (O) ₂ W is a metal; and is also provided with

cc represents a bond to C (R ^2a R ^2b ) Is a point of (2).

276. The compound of any one of claims 149-272 or 274-275, wherein R ^3a And R is ^3b Together with the ring atoms of the ring B to which they are each attached formWherein R is ^Q Is H, R ^d C (=O) -W or S (O) ₂ W is a metal; and cc represents a bond to C (R ^2a R ^2b ) Is a point of (2).

277. The compound of any one of claims 149-272 or 274-275, wherein R ^3a And R is ^3b Together with the ring atoms of ring B to which they are each attached, form a fused ring selected from the group consisting of: For exampleFor example->For example->(e.g.)>)；/>For example-> For example-> For exampleFor example->(e.g.)>) Wherein R is ^Q Is H, R ^d C (=O) -W or S (O) ₂ W is a metal; and cc represents a bond to C (R ^2a R ^2b ) Is a point of (2).

278. The compound of any one of claims 275-277, wherein R ^Q Is H.

279. The compound of any one of claims 275-277, wherein R ^Q Is C _1-6 Alkyl, optionally substituted with 1-3 independently selected R ^a And (3) substitution.

280. The compound of any one of claims 275-277, wherein R ^Q Is C (=O) -W or S (O) ₂ W, optionally, wherein W is C _2-4 Alkenyl groups.

281. The compound of any one of claims 275-277 or 280, wherein R ^Q Is C (=O) -CH ₂ ＝CH ₂ 。

282. The compound of any one of claims 149-281, wherein ring a isWherein each R is ^cB R is independently selected ^c The method comprises the steps of carrying out a first treatment on the surface of the And m is 1, 2 or 3.

283. The compound of claim 282, wherein m is 1 or 2, such as 2.

284. The compound of any one of claims 149-283, wherein ring a is (e.g.)>) Wherein each R is ^cB Independently selected from the group consisting of: halogen, such as-Cl and-F; -CN; c (C) _1-4 An alkoxy group; c (C) _1-4 Haloalkoxy groups; c (C) _1-3 An alkyl group; and C substituted with 1-6 independently selected halogens _1-3 An alkyl group.

285. The compound of any one of claims 149-284, wherein ring a isWherein R is ^cB1 Is R ^c The method comprises the steps of carrying out a first treatment on the surface of the And R is ^cB2 Is H or R ^c 。

286. The assembly of claim 285Wherein R is a compound of formula (I) ^cB1 Halogen, for example-F or-Cl, for example-F.

287. The compound of claim 285 or 286, wherein R ^cB2 Is C _1-4 Alkoxy or C _1-4 Haloalkoxy radicals, e.g. C _1-4 Alkoxy groups such as methoxy.

288. The compound of any one of claims 149-287, wherein ring a is

289. The compound of any one of claims 149-281, wherein ring a is a heteroaryl comprising 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R) ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

290. The compound of any of claims 149-281 or 289, wherein ring a is a bicyclic heteroaryl comprising 9-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each heteroatom being independently selected from N, N (H), N (R ^d ) O and S (O) _0-2 And wherein heteroaryl is optionally substituted with 1-4R ^c And (3) substitution.

291. The compound of any one of claims 149-281 or 289-290, wherein ring a is selected from the group consisting of: For example->For example-> For example->And->For example->Each of which is further optionally R ^c And (3) substitution.

292. The compound of any one of claims 1-291, wherein R ⁴ Is H.

293. The compound of claim 1, wherein the compound is selected from the compounds in table C1 or a pharmaceutically acceptable salt thereof.

294. A pharmaceutical composition comprising a compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

295. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 294.

296. A method of treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 294.

297. A method of treating an EGFR-related cancer in a subject, the method comprising: administering to a subject identified or diagnosed as having EGFR-related cancer a therapeutically effective amount of a compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 294.

298. A method of treating an EGFR-related cancer in a subject, the method comprising:

(a) Determining that the cancer of the subject is an EGFR-associated cancer; and

(b) Administering to a subject a therapeutically effective amount of a compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 294.

299. A method of treating a subject, the method comprising: administering to a subject a therapeutically effective amount of a compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 294, a clinical record of which indicates that the subject has abnormal expression or activity or level of EGFR gene, EGFR kinase, or any one thereof.

300. The method of any one of claims 296 and 298, wherein determining that the cancer of the subject is an EGFR-associated cancer comprises: assays are performed in samples from subjects to detect dysregulation of expression or activity or level of the EGFR gene, EGFR kinase protein, or any of them.

301. The method of claim 300, further comprising obtaining a sample from the subject.

302. The method of claim 301, wherein the sample is a biopsy sample.

303. The method of any one of claims 300-302, wherein the assay is selected from the group consisting of: sequencing, immunohistochemistry, enzyme-linked immunosorbent assay and Fluorescence In Situ Hybridization (FISH).

304. The method of claim 303, wherein FISH is a split FISH assay.

305. The method of claim 303, wherein sequencing is pyrosequencing or next generation sequencing.

306. The method of any one of claims 296, 299, and 300, wherein dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase protein, or any thereof, is one or more point mutations in the EGFR gene.

307. The method of claim 306, wherein one or more point mutations in the EGFR gene result in translation of the EGFR protein with one or more amino acid substitutions at the one or more amino acid positions exemplified in table 1a and table 1 b.

308. The method of claim 307, wherein the one or more point mutations are selected from the mutations in table 1a and table 1b (e.g., L858R, G719S, G719C, G A, L861Q, a deletion in exon 19, and/or an insertion in exon 20).

309. The method of claim 307, wherein the one or more point mutations is an EGFR inhibitor resistance mutation (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A).

310. The method of claim 307, wherein the one or more point mutations in the EGFR gene comprises a deletion in exon 19 of the human EGFR gene.

311. The method of claim 307, wherein the one or more mutations is an EGFR insertion in exon 20 of the human EGFR gene.

312. The method of claim 311, wherein the insertion in exon 20 of the human EGFR gene is selected from the group consisting of: v769_d770insX, d770_n771insX, n771_p772insx, p772_h773insX and h773_v774insX.

313. The method of claim 311 or 312, wherein the insertion in exon 20 of the human EGFR gene is selected from the group consisting of: y772_a775dup, a775_g776insvma, G776delinsVC, G776delinsVV, v777_g778insGSP, and p780_y781insGSP.

314. The method of any one of claims 297, 298, and 300-313, wherein the EGFR-related cancer is selected from the group consisting of: oral cancer, oropharyngeal cancer, nasopharyngeal cancer, respiratory cancer, genitourinary system cancer, gastrointestinal carcinoid, central or peripheral nervous system tissue cancer, endocrine or neuroendocrine cancer, hematopoietic cancer, glioma, sarcoma, carcinoma, lymphoma, melanoma, fibroma, meningioma, brain cancer, oropharyngeal cancer, nasopharyngeal cancer, renal cancer, cholangiocarcinoma, pheochromocytoma, li Famei-nii tumor, thyroid cancer, parathyroid cancer, pituitary tumor, adrenal tumor, osteosarcoma, breast cancer, lung cancer, head and neck cancer, prostate cancer, esophageal cancer, tracheal cancer, liver cancer, bladder cancer, stomach cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer, and skin cancer.

315. The method of any one of claims 297, 298, and 300-314, wherein the EGFR-related cancer is selected from the group consisting of: lung cancer, pancreatic cancer, head and neck cancer, melanoma, colon cancer, renal cancer, leukemia, glioblastoma, or breast cancer.

316. The method of claim 314 or 315, wherein lung cancer is non-small cell lung cancer.

317. The method of any one of claims 295-316, wherein is a HER 2-related cancer.

318. The method of claim 317, wherein the HER 2-related cancer is associated with dysregulation of expression or activity or level of HER2 gene, HER2 kinase, or any of them.

319. The method of any one of claims 317 and 318, wherein determining that the cancer of the subject is HER 2-related cancer comprises: assays are performed in samples from subjects to detect dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them.

320. The method of claim 319, further comprising obtaining a sample from the subject.

321. The method of claim 320, wherein the sample is a biopsy sample.

322. The method of any one of claims 319-321, wherein the assay is selected from the group consisting of: sequencing, immunohistochemistry, enzyme-linked immunosorbent assay and Fluorescence In Situ Hybridization (FISH).

323. The method of claim 322, wherein sequencing is pyrosequencing or next generation sequencing.

324. The method of any one of claims 318-323, wherein dysregulation of expression or activity or level of the HER2 gene, HER2 kinase protein, or any of them is one or more point mutations in the HER2 gene.

325. The method of claim 324, wherein one or more point mutations in the HER2 gene result in translation of the HER2 protein with one or more amino acid substitutions at one or more of the amino acid positions listed below as exemplified in table 3.

326. The method of claim 325, wherein the one or more point mutations are selected from the group consisting of the mutations of table 3 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L and V842I).

327. The method of any one of claims 295-326, wherein cancer is selected from the group consisting of: non-small cell lung cancer, pancreatic cancer and colorectal cancer.

328. The method of any one of claims 295-327, further comprising administering to the subject an additional therapy or therapeutic agent.

329. The method of claim 328, wherein the additional therapy or therapeutic agent is selected from the group consisting of: radiotherapy, cytotoxic chemotherapeutic agents, kinase targeted therapeutic agents, apoptosis modulators, signal transduction inhibitors, immune targeted therapies and angiogenesis targeted therapies.

330. The method of claim 329, wherein the additional therapeutic agent is selected from one or more kinase-targeted therapeutic agents.

331. The method of claim 330, wherein the additional therapeutic agent is a tyrosine kinase inhibitor.

332. The method of claim 331, wherein the additional therapeutic agent is a second EGFR inhibitor.

333. The method of claim 328, wherein the additional therapeutic agent is selected from the group consisting of: oritinib, gefitinib, erlotinib, afatinib, lapatinib, lenatinib, AZD-9291, CL-387785, CO-1686, WZ4002, and combinations thereof.

334. The method of claim 328, wherein the additional therapeutic agent is a second compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 294.

335. The method of claim 328 or 329, wherein the additional therapeutic agent is a HER2 inhibitor.

336. The method of claim 335, wherein the HER2 inhibitor is selected from trastuzumab, pertuzumab, enmtutrastuzumab, lapatinib, KU004, lenatinib, dactyltinib, afatinib, liroteinib, erlotinib, pyrroltinib, wave Ji Tini, CP-724714, cudc-101, saproteinib (AZD 8931), tamspiramycin (17-AAG), IPI-504, pf299, perlitinib, S-222611, and AEE-788.

337. The method of any one of claims 328-336, wherein the compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 274, and the additional therapeutic agent are administered simultaneously as separate doses.

338. The method of any one of claims 328-336, wherein the compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 274, and the additional therapeutic agent are administered sequentially in any order as separate doses.

339. A method of treating a subject having cancer, wherein the method comprises:

(a) Administering one or more doses of a first EGFR inhibitor to the subject over a period of time;

(c) If the subject is determined to have at least one EGFR inhibitor resistance mutation in the cancer cells and the resistance mutation is such that the cancer cells or tumor have increased resistance to treatment with the first EGFR inhibitor of step (a), administering to the subject the compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with another anticancer agent; or alternatively

(d) If the subject is not determined to have at least one EGFR inhibitor resistance mutation in the cancer cells and the resistance mutation results in an increase in the resistance of the cancer cells or tumor to treatment with the first EGFR inhibitor of step (a), then an additional dose of the first EGFR inhibitor of step (a) is administered to the subject.

340. The method of claim 339, wherein the anti-cancer agent in step (c) is a second EGFR inhibitor, immunotherapy, HER2 inhibitor, or a combination thereof.

341. The method of claim 339, wherein the anti-cancer agent in step (c) is the first EGFR inhibitor administered in step (a).

342. The method of claim 339, wherein the subject is administered an additional dose of the first EGFR inhibitor of step (a), and the method further comprises (e) administering another anti-cancer agent to the subject.

343. The method of claim 342, wherein the anti-cancer agent of step (e) is a second EGFR inhibitor, immunotherapy, or combination thereof.

344. The method of claim 342, wherein the anti-cancer agent of step (e) is the compound of any one of claims 1-313, or a pharmaceutically acceptable salt thereof.

345. The method of any one of claims 339-344, wherein the EGFR inhibitor resistance mutation is a substitution at amino acid position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A).

346. A method of treating an EGFR-related cancer in a subject, the method comprising: the compound of any one of claims 1-313, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 294, administered to a subject identified or diagnosed as having an EGFR-related cancer and having one or more EGFR inhibitor resistance mutations.

347. A method of treating an EGFR-related cancer in a subject, the method comprising:

(a) Determining that the cancer of the subject has one or more EGFR inhibitor resistance mutations; and

(b) Administering to the subject a therapeutically effective amount of a compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 294.

348. A method of treating a subject having cancer, wherein the method comprises:

(b) If the subject is determined to have at least one EGFR inhibitor resistance mutation in the cancer cells and the resistance mutation is such that the cancer cells or tumor have increased resistance to the first EGFR inhibitor treatment previously administered to the subject, then administering to the subject the compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with another anticancer agent; or alternatively

(c) If the subject is not determined to have at least one EGFR inhibitor resistance mutation in the cancer cells and the resistance mutation results in an increase in the resistance of the cancer cells or tumor to treatment with the first EGFR inhibitor previously administered to the subject, then an additional dose of the first EGFR modulator is administered to the subject.

349. The method of claim 348, wherein the anti-cancer agent in step (b) is a second EGFR inhibitor, immunotherapy, HER2 inhibitor, or a combination thereof.

350. The method of claim 348, wherein the anti-cancer agent in step (b) is a first EGFR inhibitor previously administered to the subject.

351. The method of claim 348, wherein the subject is administered an additional dose of a first EGFR inhibitor that is the first EGFR inhibitor previously administered to the subject, and the method further comprises (d) administering another anti-cancer agent to the subject.

352. The method of claim 351, wherein the anti-cancer agent of step (d) is a second EGFR inhibitor, immunotherapy, or combination thereof.

353. The method of claim 351, wherein the anti-cancer agent of step (d) is the compound of any one of claims 1 to 293, or a pharmaceutically acceptable salt thereof.

354. The method of claim 353, wherein the second EGFR inhibitor is selected from the group consisting of: oritinib, gefitinib, erlotinib, afatinib, lapatinib, lenatinib, AZD-9291, CL-387785, CO-1686, WZ4002, and combinations thereof.

355. The method of any one of claims 346-354, wherein said cancer is selected from the group consisting of: non-small cell lung cancer, pancreatic cancer and colorectal cancer.

356. The method of any one of claims 346-355, wherein the cancer is associated with dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any one thereof.

357. The method of claim 356, wherein the dysregulation of expression or activity or level of HER2 gene, HER2 kinase protein, or any thereof is one or more point mutations in the HER2 gene.

358. The method of claim 357, wherein one or more point mutations in the HER2 gene result in translation of the HER2 protein with one or more amino acid substitutions at one or more of the amino acid positions set forth below as exemplified in table 3.

359. The method of claim 358, wherein the one or more point mutations are selected from the group consisting of the mutations of table 3 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L and V842I).

360. A method for modulating EGFR in mammalian cells, the method comprising: contacting a mammalian cell with an effective amount of a compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof.

361. The method of claim 360, wherein contacting occurs in vivo.

362. The method of claim 360, wherein contacting occurs in vitro.

363. The method of any one of claims 360-362, wherein the mammalian cell is a mammalian cancer cell.

364. The method of claim 363, wherein the mammalian cancer cell is a mammalian EGFR-associated cancer cell.

365. The method of any one of claims 360-363, wherein the cell has dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase protein, or any of them.

366. The method of claim 365, wherein dysregulation of expression or activity or level of an EGFR gene, an EGFR kinase protein, or any thereof is one or more point mutations in the EGFR gene.

367. The method of claim 366, wherein one or more point mutations in an EGFR gene result in translation of an EGFR protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in table 1a and table 1 b.

368. The method of claim 366, wherein the one or more point mutations are selected from the group consisting of mutations in table 1a and table 1b (e.g., L858R, G719S, G719C, G A, L861Q, a deletion in exon 19, and/or an insertion in exon 20).

369. The method of claim 366, wherein the one or more point mutations is an EGFR inhibitor resistance mutation (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A).

370. The method of claim 366, wherein the one or more point mutations in an EGFR gene comprise a deletion in exon 19 of the human EGFR gene.

371. The method of claim 366, wherein the one or more point mutations is an EGFR insertion in exon 20 of the human EGFR gene.

372. The method of claim 371, wherein the insertion in exon 20 of the human EGFR gene is selected from the group consisting of: A767_V769insX, V769_D770insX, D770_N771insX, N771_P772insX, P772_H2773 insX and H2773_V774 insX.

373. The method of claim 372, wherein the insertion in exon 20 of the human EGFR gene is selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H2773 dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H2773 insDNP, P772_H2773 insPNP, H2773_V 774insNPH, H2773_V 774insPH, H2773_V 774insAH, and P772_H2773 insIndH.

374. A method of treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with dysregulation of expression or activity or level of the HER2 gene, HER2 kinase, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 294.

375. A method of treating HER 2-related cancer in a subject, the method comprising: administering to a subject identified or diagnosed as having HER 2-related cancer a therapeutically effective amount of the compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 294.

376. A method of treating HER 2-related cancer in a subject, the method comprising:

(a) Determining that the cancer of the subject is HER 2-related cancer; and

377. A method of treating a subject, the method comprising: administering to a subject a therapeutically effective amount of the compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 294, a clinical record of which indicates that the subject has abnormal expression or activity or level of HER2 gene, HER2 kinase, or any one thereof.

378. The method of any one of claims 374 and 376, wherein the step of determining that the cancer of the subject is HER 2-related cancer comprises: assays are performed in samples from subjects to detect dysregulation of expression or activity or level of the HER2 gene, HER2 kinase protein, or any of them.

379. The method of claim 378, further comprising obtaining a sample from the subject.

380. The method of claim 379, wherein the sample is a biopsy sample.

381. The method of any one of claims 374-380, wherein the assay is selected from the group consisting of: sequencing, immunohistochemistry, enzyme-linked immunosorbent assay and Fluorescence In Situ Hybridization (FISH).

382. The method of claim 381, wherein FISH is an isolated FISH assay.

383. The method of claim 381, wherein sequencing is pyrosequencing or next generation sequencing.

384. The method of any one of claims 374, 377, and 378, wherein dysregulation of expression or activity or level of HER2 gene, HER2 kinase protein, or any thereof, is one or more point mutations in the HER2 gene.

385. The method of claim 384, wherein one or more point mutations in the HER2 gene result in translation of the HER2 protein with one or more amino acid substitutions at one or more of the amino acid positions listed below as exemplified in table 3.

386. The method of claim 384, wherein the one or more point mutations are selected from the group consisting of the mutations of table 3 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L and V842I).

387. The method of any one of claims 373, 376 and 377, wherein the dysregulation of expression or activity or level of the HER2 gene, HER2 kinase protein, or any thereof, is an insertion in exon 20 of the human HER2 gene.

388. The method of claim 387, wherein the insertion in exon 20 of the human HER2 gene is a deletion of an amino acid position selected from the group consisting of 774, 775, 776, 777, 778, and 780.

389. The method of claim 388, wherein the insertion in exon 20 of the human HER2 gene is selected from the group consisting of: m774AYVM, M774del insWLV, A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V777insV, V777_G778insCG, G778_S779insCPG and P780_Y781insGSP.

390. The method of any one of claims 375, 376 and 378, wherein HER 2-related cancer is selected from the group consisting of: colon cancer, lung cancer or breast cancer.

391. The method of claim 390, wherein the lung cancer is non-small cell lung cancer.

392. The method of any one of claims 377-391, further comprising administering to the subject an additional therapeutic or therapeutic agent.

393. The method of claim 392, wherein the additional therapy or therapeutic agent is selected from the group consisting of: radiotherapy, cytotoxic chemotherapeutic agents, kinase targeted therapies, apoptosis modulators, signal transduction inhibitors, immune targeted therapies, and angiogenesis targeted therapies.

394. The method of claim 392, wherein the additional therapeutic agent is a second compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 274.

395. The method of claim 392, wherein the additional therapeutic agent is selected from one or more kinase-targeted therapeutic agents.

396. The method of claim 392, wherein the additional therapeutic agent is a tyrosine kinase inhibitor.

397. The method of claim 392, wherein the additional therapeutic agent is an EGFR inhibitor.

398. The method of claim 392, wherein the additional therapeutic agent is selected from the group consisting of: oritinib, gefitinib, erlotinib, afatinib, lapatinib, lenatinib, AZD-9291, CL-387785, CO-1686, WZ4002, and combinations thereof.

399. The method of claim 392, wherein the additional therapeutic agent is a HER2 inhibitor.

400. The method of claim 399, wherein said HER2 inhibitor is selected from trastuzumab, pertuzumab, enmtutrastuzumab, lapatinib, KU004, lenatinib, dactyltinib, afatinib, liroteinib, erlotinib, pyrroltinib, wave Ji Tini, CP-724714, cudc-101, saproteinib (AZD 8931), tamspiramycin (17-AAG), IPI-504, pf299, perlitinib, S-222611 and AEE-788.

401. The method of any one of claims 395-400, wherein the compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 274, and the additional therapeutic agent are administered simultaneously as separate doses.

402. The method of any one of claims 395-400, wherein the compound of any one of claims 1-293, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 274, and the additional therapeutic agent are administered sequentially in any order as separate doses.